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Author Correction: Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis. Nature communications Liu, Q., Zaba, L. C., Satpathy, A. T., Longmire, M., Zhang, W., Li, K., Granja, J., Guo, C., Lin, J., Li, R., Tolentino, K., Kania, G., Distler, O., Fiorentino, D., Chung, L., Qu, K., Chang, H. Y. 2020; 11 (1): 6416
View details for DOI 10.1038/s41467-020-20411-w

View details for PubMedID 33318485
Changes in mental health symptoms from pre-COVID-19 to COVID-19 among participants with systemic sclerosis from four countries: A Scleroderma Patient-centered Intervention Network (SPIN) Cohort study JOURNAL OF PSYCHOSOMATIC RESEARCH Thombs, B. D., Kwakkenbos, L., Henry, R. S., Carrier, M., Patten, S., Harb, S., Bourgeault, A., Tao, L., Bartlett, S. J., Mouthon, L., Varga, J., Benedetti, A., Fortune, C., Gietzen, A., Guillot, G., Lewis, N., Richard, M., Sauve, M., Welling, J., Fligelstone, K., Gottesman, K., Leite, C., Perez, E., Baron, M., Malcarne, V., Mayes, M. D., Nielson, W. R., Riggs, R., Assassi, S., Ells, C., van den Ende, C., Frech, T., Harel, D., Hinchcliff, M., Hudson, M., Johnson, S. R., Larche, M., Nguyen, C., Pope, J., Rannou, F., Reyna, T., Schouffoer, A. A., Suarez-Almazor, M. E., Agard, C., Albert, A., Bernstein, E. J., Berthier, S., Bissonnette, L., Bruns, A., Carreira, P., Chaigne, B., Chung, L., Correia, C., Denton, C., Domsic, R., Dunne, J., Dunogue, B., Farge-Bancel, D., Fortin, P. R., Gordon, J., Granel-Rey, B., Hatron, P., Herrick, A. L., Hoa, S., Jones, N., Fernandes, A. B., Kafaja, S., Khalidi, N., Launay, D., Manning, J., Marie, I., Martin, M., Mekinian, A., Melchor, S., Nikpour, M., Olagne, L., Proudman, S., Regent, A., Riviere, S., Robinson, D., Rodriguez, E., Roux, S., Sobanski, V., Steen, V., Sutton, E., Thorne, C., Wilcox, P., Ayala, M., Carboni-Jimenez, A., Gagarine, M., Nordlund, J., Ostbo, N., Rice, D. B., Turner, K. A., Culos-Reed, N., Dyas, L., El-Baalbaki, G., Hebblethwaite, S., Bustamante, L., Duchek, D., Ellis, K. 2020; 139: 110262
Abstract

No studies have reported mental health symptom comparisons prior to and during COVID-19 in vulnerable medical populations.To compare anxiety and depression symptoms among people with a pre-existing medical condition and factors associated with changes.Pre-COVID-19 Scleroderma Patient-centered Intervention Network Cohort data were linked to COVID-19 data from April 2020. Multiple linear and logistic regression were used to assess factors associated with continuous change and�?�1 minimal clinically important difference (MCID) change for anxiety (PROMIS Anxiety 4a v1.0; MCID�=�4.0) and depression (Patient Health Questionnaire-8; MCID�=�3.0) symptoms, controlling for pre-COVID-19 levels.Mean anxiety symptoms increased 4.9 points (95% confidence interval [CI] 4.0 to 5.7). Depression symptom change was negligible (0.3 points; 95% CI -0.7 to 0.2). Compared to France (N�=�159), adjusted anxiety symptom change scores were significantly higher in the United Kingdom (N�=�50; 3.3 points, 95% CI 0.9 to 5.6), United States (N�=�128; 2.5 points, 95% CI 0.7 to 4.2), and Canada (N�=�98; 1.9 points, 95% CI 0.1 to 3.8). Odds of ?1 MCID increase were 2.6 for the United Kingdom (95% CI 1.2 to 5.7) but not significant for the United States (1.6, 95% CI 0.9 to 2.9) or Canada (1.4, 95% CI 0.7 to 2.5). Older age and adequate financial resources were associated with less continuous anxiety increase. Employment and shorter time since diagnosis were associated with lower odds of a�?�1 MCID increase.Anxiety symptoms, but not depression symptoms, increased dramatically during COVID-19 among people with a pre-existing medical condition.

View details for DOI 10.1016/j.jpsychores.2020.110262

View details for Web of Science ID 000598116400009

View details for PubMedID 33070043

View details for PubMedCentralID PMC7532799
Safety and efficacy of abatacept in early diffuse cutaneous systemic sclerosis (ASSET): open-label extension of a phase 2, double-blind randomised trial LANCET RHEUMATOLOGY Chung, L., Spino, C., McLain, R., Johnson, S. R., Denton, C. P., Molitor, J. A., Steen, V. D., Lafyatis, R., Simms, R. W., Kafaja, S., Frech, T. M., Hsu, V., Domsic, R. T., Pope, J. E., Gordon, J. K., Mayes, M. D., Sandorfi, N., Hant, F. N., Bernstein, E. J., Chatterjee, S., Castelino, F. V., Ajam, A., Allanore, Y., Matucci-Cerinic, M., Whitfield, M. L., Distler, O., Singer, O., Young, A., Nagaraja, V., Fox, D. A., Furst, D. E., Khanna, D. 2020; 2 (12): E743?E753
View details for DOI 10.1016/S2665-9913(20)30237-X

View details for Web of Science ID 000595474100011
Efficacy and safety of nintedanib in Asian patients with systemic sclerosis-associated interstitial lung disease: Subgroup analysis of the SENSCIS trial. Respiratory investigation Azuma, A., Chung, L., Behera, D., Chung, M., Kondoh, Y., Ogura, T., Okamoto, M., Swarnakar, R., Zeng, X., Zou, H., Meng, X., Gahlemann, M., Alves, M., Kuwana, M., SENSCIS trial investigators 2020
Abstract

BACKGROUND AND OBJECTIVE: In the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks by 44% in comparison with placebo, with manageable adverse events in most patients. We analyzed the efficacy and safety of nintedanib in patients of Asian race.METHODS: Patients with SSc-ILD were randomized to receive nintedanib or placebo. The outcomes over 52 weeks were analyzed in Asian versus non-Asian patients.RESULTS: Of the 288 patients in each treatment group, 62 (21.5%) in the nintedanib group and 81 (28.1%) in the placebo group were Asian; 90.2% of the Asian patients were enrolled in Asian countries. In the placebo group, the rate of FVC decline over 52 weeks was consistent between Asian and non-Asian patients (-99.9 and -90.6mL/year, respectively). The effect of nintedanib on reducing the rate of FVC decline over 52 weeks was consistent between Asian (difference, 44.3mL/year [95% CI: -32.8, 121.4]) and non-Asian patients (difference, 39.0mL/year [95% CI: -5.1, 83.1]) (treatment-by-time-by-subgroup interaction, p=0.91). Diarrhea was the most frequent adverse event and was reported in similar proportions of Asian and non-Asian patients in the nintedanib group (80.6% and 74.3%, respectively) and placebo group (28.4% and 32.9%, respectively).CONCLUSIONS: In patients with SSc-ILD, nintedanib had a consistent benefit on slowing the progression of SSc-ILD in Asian and non-Asian patients, with a similar adverse event profile.TRIAL REGISTRATION: ClinicalTrials.gov NCT02597933.

View details for DOI 10.1016/j.resinv.2020.10.005

View details for PubMedID 33223487
Response to Mittal and Sharma Letter to the Editor. Arthritis & rheumatology (Hoboken, N.J.) Spiera, R., Chung, L., Frech, T., Domsic, R., Hsu, V., Furst, D., Simms, R., Mayes, M., Martyanov, V., Whitfield, M., Dgetluck, N., Dinh, Q., White, B. 2020
Abstract

On behalf of the authors, we appreciate the interest from Mittal and Sharma in the Phase 2 study results of lenabasum for the treatment of diffuse cutaneous systemic sclerosis (dcSSc) [1]. The small sample size and specified set of efficacy analyses done in this study preclude separate subset analyses of the course of interstitial lung disease, pulmonary artery hypertension, gastrointestinal involvement, or all efficacy analyses by disease duration or background immunosuppressant use, over 16 weeks.

View details for DOI 10.1002/art.41579

View details for PubMedID 33164325
Considerations for a combined index for limited cutaneous systemic sclerosis to support drug development and improve outcomes JOURNAL OF SCLERODERMA AND RELATED DISORDERS Lescoat, A., Murphy, S. L., Roofeh, D., Pauling, J. D., Hughes, M., Sandler, R., Zimmermann, F., Wessel, R., Townsend, W., Chung, L., Denton, C. P., Merkel, P. A., Steen, V., Allanore, Y., Del Galdo, F., Godard, D., Cella, D., Farrington, S., Buch, M. H., Khanna, D. 2020
View details for DOI 10.1177/2397198320961967

View details for Web of Science ID 000575848200001
Clinical Outcomes Among Participants with Diffuse Systemic Sclerosis Contracting COVID-19 During Clinical Studies of Lenabasum: A Case Series Domsic, R., Chung, L., Molitor, J., Spiera, R., Bloom, B., White, B., Dinh, Q. WILEY. 2020
View details for Web of Science ID 000587568504134
Prevalence of a Diagnosis of Osteopenia/Osteoporosis Amongst Patients with Systemic Sclerosis and Identification of Associated Clinical Factors Wang, G., Mar, D., Wu, J., Simard, J., Popat, R., Chung, L. WILEY. 2020
View details for Web of Science ID 000587568500395
Chest CT Ordering Practices at Expert Scleroderma Centers in the United States Bernstein, E., VanBuren, J., Assassi, S., Castelino, F., Chung, L., Correia, C., Evnin, L., Frech, T., Startup, E., Gordon, J., Hant, F., Hummers, L., Sandorfi, N., Shah, A., Shanmugam, V., Steen, V., Khanna, D. WILEY. 2020
View details for Web of Science ID 000587568500399
Intergenic HLA Variants in African American Patients with Systemic Sclerosis Regulate Expression of HLA-DRB1 Kaundal, U., Hartman, J., Borden, C., Wang, J., Shah, A., Mayes, M., Doumatey, A., Bentley, A., Shriner, D., Domsic, R., Medsger, T., Ramos, P., Silver, R., Steen, V., Varga, J., Hsu, V., Saketkoo, L., Schiopu, E., Khanna, D., Gordon, J., Criswell, L., Gladue, H., Derk, C., Bernstein, E., Bridges, S., Shanmugam, V., Kolstad, K., Chung, L., Kafaja, S., Jan, R., Trojanowski, M., Goldberg, A., Korman, B., Hinchcliff, M., Chandrasekharappa, S., Gadina, M., Randazzo, D., Dell'Orso, S., Adeyemo, A., Rotimi, C., Remmers, E., Wigley, F., Casellas, R., Kastner, D., Boin, F., Gourh, P. WILEY. 2020
View details for Web of Science ID 000587568505029
Baseline Characteristics of Systemic Sclerosis (SSc) Patients with Restrictive Lung Disease in a Multi-Center United States Based Longitudinal Registry Castelino, F., VanBuren, J., Startup, E., Assassi, S., Bernstein, E., Chung, L., Correia, C., Evnin, L., Frech, T., Gordon, J., Hant, F., Hummers, L., Khanna, D., Sandorfi, N., Shah, A., Shanmugam, V., Steen, V. WILEY. 2020
View details for Web of Science ID 000587568500391
A Pilot Study to Evaluate the Safety and Efficacy of Treprostinil in the Treatment of Calcinosis in Patients with Systemic Sclerosis Chung, M., Valenzuela Vergara, A., Catanese, B., Li, S., Stevens, K., Chung, L. WILEY. 2020
View details for Web of Science ID 000587568500386
Increased Rates of Obstetric Complications Prior to Systemic Sclerosis Diagnosis Chung, M., Kolstad, K., Dontsi, M., Manwani, P., Zhao, H., Postlethwaite, D., Kesh, S., Simard, J., Chung, L. WILEY. 2020
View details for Web of Science ID 000587568500383
African Ancestry-Specific Variants Regulate TGFB3 Expression in Systemic Sclerosis Hartman, J., Conte, A., Borden, C., Kaundal, U., Zhao, Y., Safran, S., Shah, A., Mayes, M., Doumatey, A., Bentley, A., Shriner, D., Domsic, R., Medsger, T., Ramos, P., Silver, R., Steen, V., Varga, J., Hsu, V., Saketkoo, L., Schiopu, E., Khanna, D., Gordon, J., Criswell, L., Gladue, H., Derk, C., Bernstein, E., Bridges, S., Shanmugam, V., Kolstad, K., Chung, L., Kafaja, S., Jan, R., Trojanowski, M., Goldberg, A., Korman, B., Hinchcliff, M., Chandrasekharappa, S., Dell'orso, S., Adeyemo, A., Rotimi, C., Remmers, E., Wigley, F., Kastner, D., Boin, F., Casellas, R., Gourh, P. WILEY. 2020
View details for Web of Science ID 000587568500396
CD47 prevents the elimination of diseased fibroblasts in scleroderma. JCI insight Lerbs, T., Cui, L., King, M. E., Chai, T., Muscat, C., Chung, L., Brown, R., Rieger, K., Shibata, T., Wernig, G. 2020; 5 (16)
Abstract

Scleroderma is a devastating fibrotic autoimmune disease. Current treatments are partly effective in preventing disease progression but do not remove fibrotic tissue. Here, we evaluated whether scleroderma fibroblasts take advantage of the "don't-eat-me-signal" CD47 and whether blocking CD47 enables the body's immune system to get rid of diseased fibroblasts. To test this approach, we used a Jun-inducible scleroderma model. We first demonstrated in patient samples that scleroderma upregulated transcription factor JUN and increased promoter accessibilities of both JUN and CD47. Next, we established our scleroderma model, demonstrating that Jun mediated skin fibrosis through the hedgehog-dependent expansion of CD26+Sca1- fibroblasts in mice. In a niche-independent adaptive transfer model, JUN steered graft survival and conferred increased self-renewal to fibroblasts. In vivo, JUN enhanced the expression of CD47, and inhibiting CD47 eliminated an ectopic fibroblast graft and increased in vitro phagocytosis. In the syngeneic mouse, depleting macrophages ameliorated skin fibrosis. Therapeutically, combined CD47 and IL-6 blockade reversed skin fibrosis in mice and led to the rapid elimination of ectopically transplanted scleroderma cells. Altogether, our study demonstrates the efficiency of combining different immunotherapies in treating scleroderma and provides a rationale for combining CD47 and IL-6 inhibition in clinical trials.

View details for DOI 10.1172/jci.insight.140458

View details for PubMedID 32814713
Protocol for a partially nested randomised controlled trial to evaluate the effectiveness of the scleroderma patient-centered intervention network COVID-19 home-isolation activities together (SPIN-CHAT) program to reduce anxiety among at-risk scleroderma patients. Journal of psychosomatic research Fortune, C., Gietzen, A., Guillot, G., Lewis, N., Nielsen, K., Richard, M., Sauve, M., Welling, J., SPIN Investigators, Baron, M., Furst, D. E., Gottesman, K., Malcarne, V., Mayes, M. D., Mouthon, L., Nielson, W. R., Riggs, R., Wigley, F., Assassi, S., Boutron, I., Ells, C., van den Ende, C., Fligelstone, K., Frech, T., Godard, D., Harel, D., Hinchcliff, M., Hudson, M., Johnson, S. R., Larche, M., Leite, C., Nguyen, C., Pope, J., Portales, A., Rannou, F., Reyna, T. S., Schouffoer, A. A., Suarez-Almazor, M. E., Agard, C., Albert, A., Andre, M., Arsenault, G., Benzidia, I., Bernstein, E. J., Berthier, S., Bissonnette, L., Boire, G., Bruns, A., Carreira, P., Casadevall, M., Chaigne, B., Chung, L., Cohen, P., Correia, C., Dagenais, P., Denton, C., Domsic, R., Dubois, S., Dunne, J. V., Dunogue, B., Fare, R., Farge-Bancel, D., Fortin, P. R., Gill, A., Gordon, J., Granel-Rey, B., Gyger, G., Hachulla, E., Hatron, P., Herrick, A. L., Hij, A., Hoa, S., Ikic, A., Jones, N., Fernandes, A. J., Kafaja, S., Khalidi, N., Lambert, M., Launay, D., Liang, P., Maillard, H., Maltez, N., Manning, J., Marie, I., Martin, M., Martin, T., Masetto, A., Maurier, F., Mekinian, A., Melchor, S., Nikpour, M., Olagne, L., Poindron, V., Proudman, S., Regent, A., Riviere, S., Robinson, D., Rodriguez, E., Roux, S., Smets, P., Smith, D., Sobanski, V., Spiera, R., Steen, V., Stevens, W., Sutton, E., Terrier, B., Thorne, C., Varga, J., Wilcox, P., Ayala, M. C., Ostbo, N., Thombs, B. D., Kwakkenbos, L., Carrier, M., Bourgeault, A., Tao, L., Harb, S., Gagarine, M., Rice, D., Bustamante, L., Ellis, K., Duchek, D., Wu, Y., Bhandari, P. M., Neupane, D., Carboni-Jimenez, A., Henry, R. S., Krishnan, A., Sun, Y., Levis, B., He, C., Turner, K. A., Benedetti, A., Culos-Reed, N., El-Baalbaki, G., Hebblethwaite, S., Bartlett, S. J., Dyas, L., Patten, S., Varga, J., Scleroderma Patient-centered Intervention Network (SPIN), COVID-19 Patient Advisory Team 2020: 110132
Abstract

Objective: Contagious disease outbreaks and related restrictions can lead to negative psychological outcomes, particularly in vulnerable populations at risk due to pre-existing medical conditions. No randomised controlled trials (RCTs) have tested interventions to reduce mental health consequences of contagious disease outbreaks. The primary objective of the Scleroderma Patient-centered Intervention Network COVID-19 Home-isolation Activities Together (SPIN-CHAT) Trial is to evaluate the effect of a videoconference-based program on symptoms of anxiety. Secondary objectives include evaluating effects on symptoms of depression, stress, loneliness, boredom, physical activity, and social interaction.Methods: The SPIN-CHAT Trial is a pragmatic RCT that will be conducted using the SPIN-COVID-19 Cohort, a sub-cohort of the SPIN Cohort. Eligible participants will be SPIN-COVID-19 Cohort participants without a positive COVID-19 test, with at least mild anxiety (PROMIS Anxiety 4a v1.0 T-score???55), not working from home, and not receiving current counselling or psychotherapy. We will randomly assign 162 participants to intervention groups of 7 to 10 participants each or waitlist control. We will use a partially nested RCT design to reflect dependence between individuals in training groups but not in the waitlist control. The SPIN-CHAT Program includes activity engagement, education on strategies to support mental health, and mutual participant support. Intervention participants will receive the 4-week (3 sessions per week) SPIN-CHAT Program via videoconference. The primary outcome is PROMIS Anxiety 4a score immediately post-intervention.Ethics and dissemination: The SPIN-CHAT Trial will test whether a brief videoconference-based intervention will improve mental health outcomes among at-risk individuals during contagious disease outbreak.

View details for DOI 10.1016/j.jpsychores.2020.110132

View details for PubMedID 32419703
A Novel Utility to Correct for Plate/Batch/Lot and Nonspecific Binding Artifacts in Luminex Data. Journal of immunology (Baltimore, Md. : 1950) Maecker, H. T., Rosenberg-Hasson, Y., Kolstad, K. D., Steen, V. D., Chung, L. S. 2020
Abstract

Cytokines and other secreted soluble proteins are routinely assayed as fluorescence intensities on the Luminex (Luminex, Austin, TX) platform. As with any immunoassay, a portion of the measured Ab binding can be nonspecific. Use of spiked-in microbead controls (e.g., AssayChex Process, Control Panel; Radix Biosolutions, Georgetown, TX) can determine the level of nonspecific binding on a per specimen basis. A statistical approach for correction of this assay's nonspecific binding artifact was first described in earlier work. The current paper describes a novel utility written in the R language (https://www.r-project.org), that refines correction for nonspecific binding in three important ways: 1) via local polynomial regression, the utility allows for curvature in relationships between soluble protein median fluorescence intensities and nonspecific binding median fluorescence intensities; 2) to stabilize correction, the fit of the nonlinear regression function is obtained via repeated cross-validation; and 3) the utility addresses possible bias due to technical error in measured nonspecific binding. The utility first logarithm transforms and then removes plate/batch/lot artifacts from median fluorescence intensities prior to correction for nonspecific binding, even when plates/batches/lots are unbalanced with respect to experimental factors of interest. Continuous (e.g., age) and categorical (e.g., diagnosis) covariates are accommodated in plate/batch/lot artifact correction. We present application of the utility to a panel of 62 cytokines in a sample of human patients diagnosed with systemic sclerosis and to an experiment that examined multiple lots of a human 51-cytokine panel. The R script for our new utility is publicly available for download from the web.

View details for DOI 10.4049/jimmunol.2000017

View details for PubMedID 32376648
Digital ulcers: should debridement be a standard of care in systemic sclerosis? LANCET RHEUMATOLOGY Hughes, M., Alcacer-Pitarch, B., Allanore, Y., Baron, M., Boin, F., Bruni, C., Chung, L., Del Galdo, F., Denton, C. P., Matucci-Cerinic, M. 2020; 2 (5): E302?E307
View details for DOI 10.1016/S2665-9913(19)30164-X

View details for Web of Science ID 000547843800016
Safety and efficacy of lenabasum in a phase 2 randomized, placebo-controlled trial in adults with systemic sclerosis. Arthritis & rheumatology (Hoboken, N.J.) Spiera, R., Hummers, L., Chung, L., Frech, T. M., Domsic, R., Hsu, V., Furst, D. E., Gordon, J., Mayes, M., Simms, R., Lafyatis, R., Martyanov, V., Wood, T., Whitfield, M. L., Constantine, S., Lee, E., Dgetluck, N., White, B. 2020
Abstract

OBJECTIVE: Assess safety and efficacy of lenabasum in diffuse cutaneous systemic sclerosis (dcSSc).METHODS: A double-blind, randomized, placebo-controlled Phase 2 study was conducted at nine SSc clinics in the USA. Adults with dcSSc ? 6 years duration on stable standard-of-care treatment received lenabasum (N = 27) or placebo (N = 15). Lenabasum doses were 5 mg once daily (QD), 20 mg QD, or 20 mg twice daily (BID) for 4 weeks, then 20 mg BID for 8 weeks. Safety and efficacy assessments were done at weeks 4, 8, 12, and 16.RESULTS: Adverse events occurred in 63% of the lenabasum group and 60% of the placebo group, with no serious adverse events related to lenabasum. Lenabasum treatment compared to placebo was associated with greater improvement in American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score and other efficacy outcomes that assessed overall disease, skin involvement, and patient-reported function. CRISS score increased in the lenabasum group during the study, reaching 0.33 versus 0.00 in the placebo group at Week 16 (p = 0.07, 2-sided mixed model repeated measures). Gene expression in inflammation and fibrosis pathways was reduced and inflammation and fibrosis improved by histological evaluation of skin biopsies from the lenabasum group compared to the placebo group (all p ? 0.05).CONCLUSION: Despite a short trial duration in a small number of patients, lenabasum improved efficacy outcomes and underlying disease pathology with a favorable safety profile in this Phase 2 study in dcSSc.

View details for DOI 10.1002/art.41294

View details for PubMedID 32336038
Calcinosis biomarkers in and Juvenile Dermatomyositis. Autoimmunity reviews Chung, M. P., Richardson, C., Kirakossian, D., Orandi, A. B., Saketkoo, L. A., Rider, L. G., Schiffenbauer, A., von Muhlen, C. A., Chung, L., International Myositis Assessment, Clinical Studies Group (IMACS) Calcinosis Scientific Interest Group 2020: 102533
Abstract

Dermatomyositis (DM) is a rare idiopathic inflammatory myopathy characterized by muscle weakness and cutaneous manifestations in adults and children. Calcinosis, a complication of DM, is the abnormal deposition of insoluble calcium salts in tissues, including skin, subcutaneous tissue, tendons, fascia, and muscle. Calcinosis is more commonly seen in juvenile DM (JDM), but also develops in adult DM. Although the mechanism of calcinosis remains unclear, several pathogenic hypotheses have been proposed, including intracellular accumulation of calcium secondary to an alteration of the cellular membrane by trauma and inflammation, local vascular ischemia, dysregulation of mechanisms controlling the deposition and solubility of calcium and phosphate, and mitochondrial damage of muscle cells. Identifying calcinosis biomarkers is important for early disease detection and risk assessment, and may lead to novel therapeutic targets for the prevention and treatment of DM-associated calcinosis. In this review, we summarize myositis autoantibodies associated with calcinosis in DM, histopathology and chemical composition of calcinosis, genetic and inflammatory markers that have been studied in adult DM and JDM-associated calcinosis, as well as potential novel biomarkers.

View details for DOI 10.1016/j.autrev.2020.102533

View details for PubMedID 32234404
Increased Mortality in Asians With Systemic Sclerosis in Northern California. ACR open rheumatology Chung, M. P., Dontsi, M., Postlethwaite, D., Kesh, S., Simard, J. F., Fiorentino, D., Zaba, L. C., Chung, L. 2020
Abstract

OBJECTIVE: The objective of this study is to evaluate racial/ethnic differences in disease manifestations and survival in a US cohort of patients with systemic sclerosis (SSc), with a focus on Asian patients.METHODS: A retrospective cohort study was conducted among Kaiser Permanente Northern California adults with an incident SSc diagnosis by a rheumatologist from 2007 to 2016, confirmed by a chart review to fulfill 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria. Self-reported race/ethnicity was categorized as non-Hispanic white, Asian, Hispanic, and black. Disease manifestations and survival were compared, using white patients as the reference.RESULTS: A total of 609 patients with incident SSc were identified: 89% were women, and 81% had limited cutaneous SSc, with a mean age at diagnosis of 55.4 � 14.8 years. The racial/ethnic distribution was 51% non-Hispanic white (n = 310), 25% Hispanic (n = 154), 16% Asian (n = 96), and 8% black (n = 49). Compared with white patients, black patients had a greater prevalence of diffuse disease (14.5% vs. 44.9%; P < 0.001), and Asians had higher rates of anti-U1-RNP antibodies (32.1% vs. 11.9%; P = 0.005). Nine-year overall survival rates following SSc diagnosis were lower in Asian (52.3%), black (52.2%), and Hispanic patients (68.2%) compared with white patients (75.8%). Pulmonary hypertension and infections were the leading causes of death in Asian patients. Asian race was associated with higher mortality on univariable (hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.08-2.99]; P = 0.020) and multivariable analyses (HR 1.80 [95% CI 0.99-3.16]; P = 0.047) when adjusting for age, sex, body mass index, cutaneous subtype, smoking status, interstitial lung disease, pulmonary hypertension, renal crisis, and malabsorption syndrome.CONCLUSION: Asian patients with SSc in this US cohort had increased mortality compared with white patients. These patients warrant close monitoring for disease progression.

View details for DOI 10.1002/acr2.11126

View details for PubMedID 32198914
Drugs in phase I and phase II clinical trials for systemic sclerosis. Expert opinion on investigational drugs Chung, M. P., Chung, L. 2020
Abstract

INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune connective tissue disease that is characterized by excessive collagen deposition, vascular dysfunction, and fibrosis of cutaneous and visceral organs. Current therapeutic options are limited and provide only modest benefit.Areas covered: This review summarizes investigational agents in recent Phase I and II clinical trials evaluated for the treatment of SSc with a focus on skin in patients with early diffuse disease and interstitial lung disease. We performed a search on Pubmed and https://clinicaltrials.gov with keywords systemic sclerosis, Phase I clinical trial, and Phase II clinical trial to identify relevant studies from 2015-2019.Expert opinion: Therapeutic interventions in SSc should be guided by the level of disease activity and degree of organ involvement. While most novel agents have failed to meet the primary endpoints of reducing skin thickening as measured by the modified Rodnan skin score, some have shown promise in improving the Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis (CRISS), reducing lung function decline, or improving patient reported outcomes. However, most of the current evidence is based on small or open-label clinical trials. Well-designed, large, randomized, Phase III clinical trials are necessary to define the roles of investigational agents in treating SSc.

View details for DOI 10.1080/13543784.2020.1743973

View details for PubMedID 32178544
Developing classification criteria for skin-predominant dermatomyositis: the Delphi process BRITISH JOURNAL OF DERMATOLOGY Concha, J. S., Pena, S., Gaffney, R. G., Patel, B., Tarazi, M., Kushner, C. J., Merola, J. F., Fiorentino, D., Dutz, J. P., Goodfield, M., Nyberg, F., Volc-Platzer, B., Fujimoto, M., Ang, C. C., Werth, V. P., Skin Myositis Delphi Grp 2020; 182 (2): 410?17
View details for DOI 10.1111/bjd.18096

View details for Web of Science ID 000511207000040
Increased Rates of Obstetric Complications Prior to Systemic Sclerosis Diagnosis. Arthritis care & research Chung, M. P., Kolstad, K. D., Dontsi, M., Postlethwaite, D., Manwani, P., Zhao, H., Kesh, S., Simard, J. F., Chung, L. 2020
Abstract

To investigate whether obstetric complications prior to systemic sclerosis (SSc) diagnosis are more common compared to the general obstetric population.A case-control study was performed at Kaiser Permanente Northern California to compare prior obstetric complications in adult women who later developed SSc (cases) with women from the general obstetric population who did not develop SSc (controls; matched 10:1 by age and year of delivery) from 2007-2016. Exposures included past hypertensive disorders of pregnancy (preeclampsia, eclampsia, gestational hypertension), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), maternal infections, neonatal intensive care unit (NICU) admission, and preterm birth. Fischer's exact tests were used to compare categorical variables. Conditional logistic regression models estimated the odds ratio (OR) and corresponding 95% confidence intervals for the outcome SSc.Seventeen SSc cases and 170 non-SSc controls were identified, with median maternal age at delivery 34 years (range 23-46 years) and median time from delivery to SSc diagnosis 2 years (range 0.2-7.3 years). SSc cases were more likely to be Hispanic and Black. Prior obstetric complications appeared higher in women with an eventual SSc diagnosis compared to controls (70.6% vs. 50%), including hypertensive disorders (17.7% vs. 9.4%), PROM (11.8% vs. 4.1%), IUGR (5.9% vs 1.8%), maternal infection (29.4% vs. 14.1%), NICU admissions (23.5% vs. 7.7%), and preterm delivery (29.4% vs. 21.8%). Cases had a higher odds of delivering infants requiring NICU admission (OR=4.7, 95% CI 1.2-18.8).Women who eventually develop SSc had trends towards more complicated pregnancy histories before overt diagnosis.

View details for DOI 10.1002/acr.24533

View details for PubMedID 33290624
Raynaud phenomenon and digital ulcers in systemic sclerosis. Nature reviews. Rheumatology Hughes, M., Allanore, Y., Chung, L., Pauling, J. D., Denton, C. P., Matucci-Cerinic, M. 2020
Abstract

Raynaud phenomenon is a symptom complex caused by impaired digital perfusion and can occur as a primary phenomenon or secondary to a wide range of underlying causes. Raynaud phenomenon occurs in virtually all patients with systemic sclerosis (SSc) and is often the earliest clinical manifestation to occur. Careful assessment is required in patients with Raynaud phenomenon to avoid missing secondary causes such as SSc. Digital ulcers are a painful and disabling visible manifestation of digital vascular injury in patients with SSc. Progress has been made in the classification and assessment of digital ulcers and in understanding ulcer pathogenesis, and there are a wide range of treatments available to both prevent and heal digital ulcers, some of which are also used in Raynaud phenomenon management. In this Review, the assessment of patients with Raynaud phenomenon is discussed, including 'red flags' that are suggestive of SSc. The pathogenesis, classification and assessment of SSc-associated digital ulcers are also covered, alongside an overview of management approaches for SSc-associated Raynaud phenomenon and digital ulcers. Finally, unmet needs are discussed and the concept of a unified vascular phenotype in which therapies that affect the vasculature to support disease modification strategies is introduced.

View details for DOI 10.1038/s41584-020-0386-4

View details for PubMedID 32099191
A Mortality Risk Score Model for Clinically Amyopathic Dermatomyositis-Associated Interstitial Lung Disease: Will It Have the Necessary "FLAIR" to Improve Clinical Outcomes? Chest Baker, M. C., Chung, L., Fiorentino, D. F. 2020; 158 (4): 1307?9
View details for DOI 10.1016/j.chest.2020.06.001

View details for PubMedID 33036075
Calcinosis is associated with ischemic manifestations and increased disability in patients with systemic sclerosis. Seminars in arthritis and rheumatism Valenzuela, A., Baron, M., Rodriguez-Reyna, T. S., Proudman, S., Khanna, D., Young, A., Hinchcliff, M., Steen, V., Gordon, J., Hsu, V., Castelino, F. V., Schoenfeld, S., Li, S., Wu, J. Y., Fiorentino, D., Chung, L. 2020; 50 (5): 891?96
Abstract

Calcinosis is a debilitating complication of systemic sclerosis (SSc) with no effective treatments. We sought to identify clinical correlations and to characterize complications and disability associated with calcinosis in a multi-center, international cohort of SSc patients.We established a cohort of 568 consecutive SSc patients who fulfill 2013 revised ACR/EULAR criteria at 10 centers within North America, Australia, and Mexico. Calcinosis was defined as subcutaneous calcium deposition by imaging and/or physical examination, or a clear history of extruded calcium. All patients completed the Scleroderma Health Assessment Questionnaire Disability Index and Cochin Hand Functional Scale.215 (38%) patients had calcinosis. In multivariable analysis, disease duration (OR=1.24, p�=�0.029), digital ischemia (OR=1.8, p�=�0.002) and Acro-osteolysis (OR=2.97, p�=�0.008) were significantly associated with calcinosis. In the subset of patients with bone densitometry (n�=�68), patients with calcinosis had significantly lower median T-scores than patients without (-2.2�vs. -1.7, p�=�0.004). The most common location of calcinosis lesions was the hands (70%), particularly the thumbs (19%) with decreasing frequency moving to the fifth fingers (8%). The most common complications were tenderness (29% of patients) and spontaneous extrusion of calcinosis through the skin (20%), while infection was rare (2%). Disability and hand function were worse in patients with calcinosis, particularly if locations in addition to the fingers/thumbs were involved.We confirmed a strong association between calcinosis and digital ischemia. Calcinosis in SSc patients most commonly affects the hands and is associated with a high burden of disability and hand dysfunction.

View details for DOI 10.1016/j.semarthrit.2020.06.007

View details for PubMedID 32898758
Development and Assessment of a Novel Lung Ultrasound Interpretation Criteria for the Detection of Interstitial Lung Disease in Systemic Sclerosis. Arthritis care & research Fairchild, R., Chung, M., Yang, D., Sharpless, L., Li, S., Chung, L. 2020
Abstract

Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc), and ILD screening, characterization, and monitoring are important for therapeutic decision-making and prognostication. Lung ultrasonography (LUS) is a potential alternative imaging modality for ILD detection. In this study, we develop and test a novel LUS examination technique and interpretation criteria for detecting SSc-ILD.LUS acquisition was performed by collecting short ultrasound movies at 14 lung positions. LUS interpretation criteria for SSc-ILD detection focused on visualized pleural changes. To assess the performance of our methodology for SSc-ILD detection, we prospectively enrolled SSc patients with high resolution computed tomography (HRCT) imaging within 3 months of LUS. LUS exams were scored independently by two blinded readers (one ultrasonographer and one non-ultrasonographer). The sensitivity and specificity for SSc-ILD detection was assessed and agreement was measured with Cohen's Kappa statistic.To test the performance of our LUS acquisition technique and interpretation criteria, 20 SSc patients were evaluated by LUS (278 lung zones) and HRCT. HRCT confirmed ILD in 9 patients (45%). LUS was positive for SSc-ILD in 11 patients (55%) with a sensitivity of 100% and specificity of 82% versus HRCT, with perfect agreement between the two readers (?=1). Analysis by individual lung zones found excellent agreement between readers with 93.8% concordance and ?=0.82.We developed a novel LUS examination technique and interpretation criteria that are highly sensitive and specific for SSc-ILD detection in an SSc cohort, affording perfect agreement between ultrasonographer and non-ultrasonographer readers.

View details for DOI 10.1002/acr.24338

View details for PubMedID 32475026
Ultrasound Detection of Calcinosis and Association with Ulnar Artery Occlusion in Patients with Systemic Sclerosis. Arthritis care & research Fairchild, R., Chung, M., Sharpless, L., Li, S., Chung, L. 2020
Abstract

To investigate the ability of ultrasound (US) compared to radiographs in detecting calcinosis in hands/wrists of systemic sclerosis (SSc) patients, and assess US markers of pathologic perfusion.SSc patients were evaluated for�calcinosis�in the hands/wrists by X-ray and US. Presence or absence of calcinosis was recorded by patient, hand, and anatomical zone; sensitivity and specificity for calcinosis detection by US versus X-ray was determined. Bilateral US vascular measurements of ulnar artery occlusion (UAO) and finger pulp blood flow (FPBF) were obtained. For each hand, associations between markers of pathologic blood flow (UAO, FPBF, and a composite severity score of UAO and FPBF) and presence of calcinosis were assessed using generalized estimating equations.Of 43 SSc patients (19 diffuse, 24 limited), 39.5% had calcinosis on X-ray compared to 30.2% on US. Sensitivity and specificity for US was 61% and 95% by zone, 78% and 98% by hand, and 76% and 100% by patient, respectively. UAO was seen in 30% and 28% of left and right hands, respectively; FPBF was absent in ?1 digit of the left and right hands in 49% and 44%, respectively. UAO was associated with X-ray identified calcinosis by hand (OR 8.08, 95% CI 2.45-26.60, p<0.001), whereas FPBF and the composite severity score were not significant. UAO was associated with calcinosis even in the absence of digital ulcers (OR 33.00, 95% CI 3.39-321.09, p=0.003).US was sensitive and highly specific in detecting calcinosis in SSc. UAO was strongly associated with X-ray identified calcinosis.

View details for DOI 10.1002/acr.24327

View details for PubMedID 32475057
The Scleroderma Patient-Centered Intervention Network Self-Management Program: Protocol for a Randomized Feasibility Trial. JMIR research protocols Carrier, M. E., Kwakkenbos, L., Nielson, W. R., Fedoruk, C., Nielsen, K., Milette, K., Pope, J., Frech, T., Gholizadeh, S., Hummers, L., Johnson, S. R., Piotrowski, P., Jewett, L., Gordon, J., Chung, L., Bilsker, D., Turner, K. A., Cumin, J., Welling, J., Fortune, C., Leite, C., Gottesman, K., Sauve, M., Rodr�guez-Reyna, T. S., Hudson, M., Larche, M., van Breda, W., Suarez-Almazor, M. E., Bartlett, S. J., Malcarne, V. L., Mayes, M. D., Boutron, I., Mouthon, L., Wigley, F., Thombs, B. D. 2020; 9 (4): e16799
Abstract

Systemic sclerosis (SSc), or scleroderma, is a rare disease that often results in significant disruptions to activities of daily living and can negatively affect physical and psychological well-being. Because there is no known cure, SSc treatment focuses on reducing symptoms and disability and improving health-related quality of life (HRQoL). Self-management programs are known to increase self-efficacy for disease management in many chronic diseases. The Scleroderma Patient-centered Intervention Network (SPIN) developed a Web-based self-management program (SPIN self-management; SPIN-SELF) to increase self-efficacy for disease management and to improve HRQoL for patients with SSc.The proposed study aims to assess the feasibility of conducting a full-scale randomized controlled trial (RCT) of the SPIN-SELF program by evaluating the trial implementation processes, required resources and management, scientific aspects, and participant acceptability and usage of the SPIN-SELF program.The SPIN-SELF feasibility trial will be conducted via the SPIN Cohort. The SPIN Cohort was developed as a framework for embedded pragmatic trials using the cohort multiple RCT design. In total, 40 English-speaking SPIN Cohort participants with low disease management self-efficacy (Self-Efficacy for Managing Chronic Disease Scale score ?7), who have indicated interest in using a Web-based self-management program, will be randomized with a 3:2 ratio into the SPIN-SELF program or usual care for 3 months. Feasibility outcomes include trial implementation processes, required resources and management, scientific aspects, and patient acceptability and usage of the SPIN-SELF program.Enrollment of the 40 participants occurred between July 5, 2019, and July 27, 2019. By November 25, 2019, data collection of trial outcomes was completed. Data analysis is underway, and results are expected to be published in 2020.The SPIN-SELF program is a self-help tool that may improve disease-management self-efficacy and improve HRQoL in patients with SSc. The SPIN-SELF feasibility trial will ensure that trial methodology is robust, feasible, and consistent with trial participant expectations. The results will guide adjustments that need to be implemented before undertaking a full-scale RCT of the SPIN-SELF program.DERR1-10.2196/16799.

View details for DOI 10.2196/16799

View details for PubMedID 32329747
Gastric antral vascular ectasia in systemic sclerosis: Association with anti-RNA polymerase III and negative anti-nuclear antibodies. Seminars in arthritis and rheumatism Serling-Boyd, N., Chung, M. P., Li, S., Becker, L., Fernandez-Becker, N., Clarke, J., Fiorentino, D., Chung, L. 2020; 50 (5): 938?42
Abstract

Gastric antral vascular ectasia (GAVE) is a vascular manifestation of systemic sclerosis (SSc) that can lead to iron deficiency anemia or acute gastrointestinal (GI) bleeding. We aimed to identify clinical features associated with GAVE.We performed a cohort study of SSc patients who were seen at Stanford between 2004 and 2018 and had undergone esophagogastroduodenoscopy (EGD). We compared the clinical features of those with and without GAVE, and multivariable logistic regression was performed to identify clinical correlates with GAVE.A total of 225 patients with SSc who underwent EGD were included in this study and 19 (8.4%) had GAVE. Those with GAVE were more likely to have scleroderma renal crisis (SRC) (21% vs 3%; p < 0.01), positive anti-RNA polymerase III antibody (71% vs 19%; p < 0.01), nucleolar pattern of anti-nuclear antibody (ANA) (33% vs 11%; p=0.04), and negative ANA (<1:80 by immunofluorescence) (33% vs 11%; p=0.02). On multivariate analysis with multiple imputation, anti-RNA polymerase III positivity (OR 4.57; 95% CI (1.57 - 13.23), p < 0.01) and ANA negativity (OR 3.75; 95% CI (1.21 - 11.62), p=0.02) remained significantly associated with GAVE.Positive anti-RNA polymerase III antibody and ANA negativity were significantly associated with GAVE. Further studies are necessary to determine whether patients with these autoantibody profiles should undergo screening endoscopies for GAVE.

View details for DOI 10.1016/j.semarthrit.2020.06.016

View details for PubMedID 32906028
Does hand involvement in systemic sclerosis limit completion of patient-reported outcome measures? Clinical rheumatology Frech, T. M., VanBuren, J. M., Startup, E., Assassi, S., Bernstein, E. J., Castelino, F. V., Chung, L., Correia, C., Gordon, J. K., Hant, F. N., Hummers, L., Khanna, D., Sandorfi, N., Shah, A. A., Shanmugam, V. K., Steen, V., Evnin, L. 2020
Abstract

The objective of this analysis is to examine whether the severity of systemic sclerosis (SSc)-hand involvement influences patient-reported outcome measure (PROM) completion rate in a US cohort of early disease. Participants included SSc patients with less than 5 years disease duration consented and enrolled in the Collaborative, National, Quality, and Efficacy Registry (CONQUER) between June 2018 and December 2019. Participants' socio-demographics, hand clinical features (severe modified Rodnan skin score, presence of small joint contractures, acro-osteolysis, calcinosis, and digital ulcers), and completion rates of seven PROMs including a Resource Use Questionnaire were analyzed. Cohort characteristics and baseline PROM completion were evaluated. Multivariable logistic regression assessed the relationship between hand limitations and PROM incompletion at several time points using generalized estimating equations. At the time of data lock, 339 CONQUER subjects had a total of 600 visits available for analysis. Calcinosis (odds ratio [OR] 6.35, confidence interval [CI] 2.41-16.73 and acro-osteolysis OR 3.88 (1.57-9.55) were significantly associated with incomplete PROM. The Resource Use Questionnaire was the PROM most commonly not completed. Increasing age was correlated with resource use questionnaire incompletion rate. Acro-osteolysis and calcinosis were associated with lower PROM completion rates in a US SSc cohort, independent of the length of the questionnaires or the modality of administration (electronic or paper). Resource Use Questionnaires are important for understanding the economic impact and burden of chronic disease; however, in this study, it had lower completion rates than PROMs devoted to clinical variables. Key points ?Multiple strategies are needed to ensure optimal completion of PROM in longitudinal cohort studies. Even if patients request electronic surveys, we have found it is important to follow up incomplete surveys with paper forms provided at the time of a clinical visit. ?The Resource Utilization Questionnaire was lengthy and prone to non-completion in the younger population. ?Acro-osteolysis and calcinosis were associated with reduced PROM completion rates.

View details for DOI 10.1007/s10067-020-05467-9

View details for PubMedID 33094395
Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis. Nature communications Liu, Q., Zaba, L., Satpathy, A. T., Longmire, M., Zhang, W., Li, K., Granja, J., Guo, C., Lin, J., Li, R., Tolentino, K., Kania, G., Distler, O., Fiorentino, D., Chung, L., Qu, K., Chang, H. Y. 2020; 11 (1): 5843
Abstract

Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory elements of eight types of primary cells in normal skin from healthy controls, as well as clinically affected and unaffected skin from SSc patients. We find that accessible DNA elements in skin-resident dendritic cells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) and predict the degrees of skin fibrosis in patients. DCs also have the greatest disease-associated changes in chromatin accessibility and the strongest alteration of cell-cell interactions in SSc lesions. Lastly, data from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned skin. Thus, the DCs epigenome links inherited susceptibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogenesis.

View details for DOI 10.1038/s41467-020-19702-z

View details for PubMedID 33203843
Rituximab Versus Mycophenolate in the Treatment of Recalcitrant Connective Tissue Disease-Associated Interstitial Lung Disease. ACR open rheumatology Zhu, L., Chung, M. P., Gagne, L., Guo, H. H., Guenther, Z., Li, S., Jacobs, S., Morisset, J., Mooney, J. J., Raj, R., Chung, L. 2020
Abstract

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in connective tissue diseases (CTDs). We aimed to assess the effect of rituximab � mycophenolate mofetil (MMF) compared with MMF on pulmonary function and prednisone dosage in patients with CTD-related ILD (CTD-ILD).This retrospective study included 83 patients from Stanford and Centre Hospitalier de l'Universite de Montreal. Fifteen patients received rituximab � MMF (rituximab group), and 68 patients received MMF only (control group).Median ILD duration at the start of treatment was longer in the rituximab group at 47 months (range: 4-170) versus 6.5 months (range: 0-164) in controls. Forced vital capacity (FVC) decreased by 3.0% (range: 11%-21%) after treatment in the rituximab group, whereas it increased by 2.0% (range: 14%-25%) in the control group (p = 0.025). Diffusing capacity of carbon monoxide (DLCO) decreased by 3.0% (range: 10%-12%) after treatment in the rituximab group, whereas it increased by 4.5% (range: 30%-36%) in the control group (p = 0.046). Mixed model analysis controlling for ILD duration, baseline DLCO, systemic sclerosis, pulmonary hypertension, and prednisone use showed no significant difference in FVC or DLCO between groups at 6 months or 1 year. The average daily prednisone dose score decreased after treatment in the rituximab group, whereas it remained unchanged in the control group (p = 0.017).Rituximab � MMF did not significantly change pulmonary function compared with MMF alone, but it did result in a relative decrease in average daily prednisone dose in a population with recalcitrant CTD-ILD.

View details for DOI 10.1002/acr2.11210

View details for PubMedID 33274857
Upper Extremity Angiographic Patterns in Systemic Sclerosis: Implications for Surgical Treatment JOURNAL OF HAND SURGERY-AMERICAN VOLUME Leyden, J., Burn, M. B., Wong, V., Leon, D., Kaizawa, Y., Chung, L., Chang, J. 2019; 44 (11)
View details for DOI 10.1016/j.jhsa.2019.01.004

View details for Web of Science ID 000493892500013
Prevalence and Clinical Associations of Degos Lesions in Systemic Sclerosis Song, P., Chung, M., Li, S., Fiorentino, D., Chung, L. WILEY. 2019
View details for Web of Science ID 000507466904361
Change in Calcinosis over 1 Year Using the SCTC Radiologic Scoring System for Calcinosis of the Hands in Patients with Systemic Sclerosis Valenzuela, A., Chung, M., Rodriguez-Reyna, T. S., Proudman, S., Baron, M., Castelino, F., Hsu, V., Li, S., Fiorentino, D., Stevens, K., Chung, L. WILEY. 2019
View details for Web of Science ID 000507466902497
Ancestry-Specific Classical HLA Alleles Define Phenotypic Subsets in the African American Scleroderma Population Gourh, P., Safran, S., Boyden, S., Shah, A., Mayes, M., Doumatey, A., Bentley, A., Shriner, D., Domsic, R., Medsger, T., Ramos, P., Silver, R., Steen, V., Varga, J., Hsu, V., Saketkoo, L., Schiopu, E., Khanna, D., Gordon, J., Kron, B., Criswell, L., Gladue, H., Derk, C., Bernstein, E., Bridges, S., Shanmugam, V., Kolstad, K., Chung, L., Kafaja, S., Jan, R., Trojanowski, M., Goldberg, A., Korman, B., Steinbach, P., Chandrasekharappa, S., Mullikin, J., Adeyemo, A., Rotimi, C., Wigley, F., Kastner, D., Boin, F., Remmers, E., Alexander, T. WILEY. 2019
View details for Web of Science ID 000507466905146
Ultrasound Evaluation of the Hands in Patients with Systemic Sclerosis: Osteophytosis Is a Major Contributor to Tender Joints Fairchild, R., Chung, M., Sharpless, L., Li, S., Hong, J., Sheth, K., Chung, L. WILEY. 2019
View details for Web of Science ID 000507466901134
Ultrasound Detection of Calcinosis and Correlation with Ulnar Artery Occlusion in Patients with Systemic Sclerosis Fairchild, R., Chung, M., Sharpless, L., Li, S., Chung, L. WILEY. 2019
View details for Web of Science ID 000507466904371
Subsets in Systemic Sclerosis-ILD: Working Towards Consensus-Based Definitions Roofeh, D., Brown, K., Tashkin, D., Assassi, S., Barratt, S., Bernstein, E., Bhatt, N., Chung, L., Collard, H., Conway, R., Dellaripa, P., Denton, C., Distler, O., Domsic, R., Doyle, T. J., Garcha, P., Gupta, N., Hoffmann-Vold, A., Hsu, V., Ingegnoli, F., Johannson, K., Kahaleh, B., Kawano-Dourado, L., Kazerooni, E., Khanna, S., Korsten, P., Lin, C. F., Maher, T., Mathai, S., Martinez, F., Matteson, E., Nagaraja, V., Oddis, C., Ovalles-Bonilla, J., Pauling, J., Raghu, G., Rodriguez-Pinto, I., Rosas, I., Seibold, J., Steen, V., Strand, V., Volkmann, E., Vummidi, D., Walsh, S., Zoz, D., Wells, A., Khanna, D. WILEY. 2019
View details for Web of Science ID 000507466904372
Development and Preliminary Validation of a Novel Lung Ultrasound Interpretation Criteria for the Detection of Interstitial Lung Disease in Patients with Systemic Sclerosis Fairchild, R., Yang, D., Chung, M., Sharpless, L., Li, S., Chung, L. WILEY. 2019
View details for Web of Science ID 000507466904514
The Collaborative National Quality and Efficacy Registry for Scleroderma: Data Completion Outcomes from a Multicenter United States Cohort Using Guideline-Based Registry Practices Shanmugam, V., Frech, T., Steen, V., Hummers, L., Shah, A., Bernstein, E., Khanna, D., Gordon, J., Castelino, F., Chung, L., Hant, F., Startup, E., VanBuren, J., Evnin, L., Assassi, S. WILEY. 2019
View details for Web of Science ID 000507466902503
Aggregation of Functional Variants in NOTCH4 Gene Increases SSc Risk Gourh, P., Safran, S., Alexander, T., Boyden, S., Shah, A., Mayes, M., Doumatey, A., Bentley, A., Shriner, D., Domsic, R., Medsger, T., Ramos, P., Silver, R., Steen, V., Varga, J., Hsu, V., Saketkoo, L., Schiopu, E., Khanna, D., Gordon, J., Kron, B., Criswell, L., Gladue, H., Derk, C., Bernstein, E., Bridges, S., Shanmugam, V., Kolstad, K., Chung, L., Kafaja, S., Jan, R., Trojanowski, M., Goldberg, A., Korman, B., Steinbach, P., Chandrasekharappa, S., Mullikin, J., Adeyemo, A., Rotimi, C., Wigley, F., Kastner, D., Boin, F., Remmers, E. WILEY. 2019
View details for Web of Science ID 000507466903302
Safety and Efficacy of B-cell Depletion with Rituximab for the Treatment of Systemic Sclerosis-associated Pulmonary Arterial Hypertension in a Multi-center NIH Clinical Trial Nicolls, M., Badesch, D., Chung, L., Domsic, R., Medsger, T., Pinckney, A., Keyes-Elstein, L., D'Aveta, C., Spychala, M., White, R., Hassoun, P., Torres, F., Molitor, J., Khanna, D., Maeker, H., Welch, B., Goldmuntz, E., Zamanian, R., ASC01 Investigators WILEY. 2019
View details for Web of Science ID 000507466901290
Cytokine Signatures Differentiate Systemic Sclerosis Patients at High versus Low Risk for Pulmonary Arterial Hypertension Kolstad, K., Khatri, A., Donato, M., Chang, S., Li, S., Steen, V., Utz, P., Khatri, P., Chung, L. WILEY. 2019
View details for Web of Science ID 000507466901493
Preterm birth phenotypes in women with autoimmune rheumatic diseases: A population based cohort study. BJOG : an international journal of obstetrics and gynaecology Kolstad, K. D., Mayo, J. A., Chung, L., Chaichian, Y., Kelly, V. M., Druzin, M., Stevenson, D. K., Shaw, G. M., Simard, J. F. 2019
Abstract

OBJECTIVE: To investigate preterm birth (PTB) phenotypes in women with different autoimmune rheumatic diseases in a large population-based cohort.DESIGN: Retrospective cohort study.SETTING: California, USA.POPULATION: All live singleton births in California between 2007 and 2011 were analyzed. Patients with autoimmune disease at delivery were identified by ICD-9 codes for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), polymyositis/dermatomyositis (DM/PM), and juvenile idiopathic arthritis (JIA).METHODS: Maternally linked hospital and birth certificate records of 2,481,516 deliveries were assessed (SLE n=2,272, RA n=1,501, SSc n=88, JIA n=187, DM/PM n=38). Multivariable Poisson regression models estimated risk ratios (RRs) for different PTB phenotypes (relative to term deliveries) for each autoimmune disease compared to the general obstetric population adjusting for maternal age, race/ethnicity, body mass index, smoking, education, payer, parity, and prenatal care.MAIN OUTCOME MEASURES: PTB was assessed overall (20-36 weeks) and by subphenotype: pre-term premature rupture of membranes (PPROM), spontaneous, or medically indicated PTB. Risk of PTB overall and each phenotype was partitioned by gestational age: early (20-31 weeks) and late (32-36 weeks).RESULTS: Risks for PTB were elevated for each autoimmune disease evaluated: SLE (RR 3.27 95%CI 3.01-3.56), RA (RR 2.04 95%CI 1.79-2.33), SSc (RR 3.74 95%CI 2.51-5.58), JIA (RR 2.23 95%CI 1.54-3.23), and DM/PM (RR 5.26 95%CI 3.12-8.89). These elevated risks were observed for the majority of PTB phenotypes as well.CONCLUSIONS: Women with systemic autoimmune diseases appear to have an elevated risk of various PTB phenotypes. Therefore, preconception counseling and close monitoring during pregnancy is crucial.

View details for DOI 10.1111/1471-0528.15970

View details for PubMedID 31571337
Late Breaking Abstract - Safety and efficacy of B-cell depletion with rituximab for the treatment of systemic sclerosis-associated pulmonary arterial hypertension Zamanian, R., Badesch, D., Chung, L., Domsic, R., Medsger, T., Pinckney, A., Keyes-Elstein, L., D'Aveta, C., Spychala, M., White, J., Hassoun, P., Torres, F., Molitor, J., Khanna, D., Maeker, H., Welch, B., Goldmuntz, E., Nicolls, M., Asco1 Investigators EUROPEAN RESPIRATORY SOC JOURNALS LTD. 2019
View details for DOI 10.1183/13993003.congress-2019.RCT1884

View details for Web of Science ID 000507372408095
Microvascular hand surgery for digital ischemia in scleroderma JOURNAL OF SCLERODERMA AND RELATED DISORDERS Satteson, E. S., Chung, M. P., Chung, L. S., Chang, J. 2019
View details for DOI 10.1177/2397198319863565

View details for Web of Science ID 000479419000001
Abatacept in Early Diffuse Cutaneous Systemic Sclerosis - Results of a Phase 2 Investigator-Initiated, Multicenter, Double-Blind Randomized Placebo-Controlled Trial. Arthritis & rheumatology (Hoboken, N.J.) Khanna, D., Spino, C., Johnson, S., Chung, L., Whitfield, M., Denton, C. P., Berrocal, V., Franks, J., Mehta, B., Molitor, J., Steen, V. D., Lafyatis, R., Simms, R. W., Gill, A., Kafaja, S., Frech, T. M., Hsu, V., Domsic, R. T., Pope, J. E., Gordon, J. K., Mayes, M. D., Schiopu, E., Young, A., Sandorfi, N., Park, J., Hant, F. N., Bernstein, E. J., Chatterjee, S., Castelino, F. V., Ajam, A., Wang, Y., Wood, T., Allanore, Y., Matucci-Cerinic, M., Distler, O., Singer, O., Bush, E., Fox, D., Furst, D. E. 2019
Abstract

OBJECTIVES: T cells play a key role in the pathogenesis of early systemic sclerosis. This study assessed the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc).METHODS: A 12-month, randomized, double-blind, placebo-controlled trial with participants randomized in a 1:1 ratio to either abatacept 125 mg subcutaneous or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at six months for worsening disease. The co-primary end points were change in modified Rodnan skin score (mRSS) and safety over 12 months. Treatment differences in longitudinal outcomes were assessed using linear mixed models, with outcomes censored after initiation of escape therapy. Baseline skin tissue was classified into intrinsic gene expression subsets.RESULTS: Among 88 participants, the adjusted mean change in mRSS at 12 months was -6.24 units in the abatacept and -4.49 units in the placebo, with adjusted mean treatment difference of -1.75 units (p=0.28). Two secondary outcome measures (HAQ-DI and a composite measure) were clinically and statistically significant favoring abatacept. A larger proportion of placebo subjects required escape therapy relative to abatacept (36% vs. 16%). Decline in mRSS over 12 months was clinically and significantly higher in abatacept vs. placebo for the Inflammatory (p<0.001) and Normal-like skin gene expression subsets (p=0.03). 35 participants in the abatacept versus 40 in the placebo had adverse events (AEs), including two and one deaths, respectively.CONCLUSIONS: In this Phase 2 trial, abatacept was well tolerated, but change in mRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed some evidence in favor of abatacept. These data should be confirmed in a Phase 3 trial. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/art.41055

View details for PubMedID 31342624
ABATACEPT IN EARLY DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS- RESULTS OF A PHASE 2 INVESTIGATOR-INITIATED, MULTICENTER, DOUBLE-BLIND RANDOMIZED PLACEBO-CONTROLLED TRIAL Khanna, D., Spino, C., Bush, E., Johnson, S., Chung, L., Denton, C., Molitor, J., Steen, V., Lafyatis, R., Simms, R., Kafaja, S., Frech, T., Hsu, V., Domsic, R., Pope, J., Gordon, J., Mayes, M., Schiopu, E., Young, A., Sandorfi, N., Park, J., Hant, F., Bernstein, E., Chatterjee, S., Castelino, F., AliAjam, Allanore, Y., Matucci-Cerinic, M., Distler, O., Gewurz-Singer, O., Fox, D., Furst, D. BMJ PUBLISHING GROUP. 2019: 106?7
View details for DOI 10.1136/annrheumdis-2019-eular.1719

View details for Web of Science ID 000472207100282
Development and validation of the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI): a novel instrument to quantify organ damage in systemic sclerosis ANNALS OF THE RHEUMATIC DISEASES Ferdowsi, N., Huq, M., Stevens, W., Hudson, M., Wang, M., Tay, T., Burchell, J. L., Mancuso, S., Rabusa, C., Sundararajan, V., Prior, D., Proudman, S. M., Baron, M., Nikpour, M., Frech, T., Hudson, M., Proudman, S., Stevens, W., Tay, T., Chatterjee, S., Chung, L., Gordon, J. K., Haemel, A., Johnson, S. R., Khanna, D., Medsger, T. A., Merkel, P., Pauling, J., Pope, J. E., Rodriguez-Reyna, T., Saketkoo, L., Seibold, J. R., Shah, A., Steen, V., Strickland, G., Ngian, G., Nikpour, M., Proudman, S., Rischmueller, M., Roddy, J., Sahhar, J., Stevens, W., Strickland, G., Walker, J., Youssef, P., Pope, J., Baron, M., Markland, J., Robinson, D., Jones, N., Khalidi, N., Docherty, P., Kaminska, E., Masetto, A., Sutton, E., Mathieu, J., Hudson, M., Ligier, S., Grodzicky, T., LeClercq, S., Thorne, C., Gyger, G., Smith, D., Fortin, P. R., Larche, M., Abu-Hakima, M., Rodriguez-Reyna, T. S., Cabral, A. R., Fritzler, M., Scleroderma Clinical Trials, Australian Scleroderma Interest, Canadian Scleroderma Res Grp 2019; 78 (6): 807?16
Abstract

We sought to develop the first Damage Index (DI) in systemic sclerosis (SSc).The conceptual definition of 'damage' in SSc was determined through consensus by a working group of the Scleroderma Clinical Trials Consortium (SCTC). Systematic literature review and consultation with patient partners and non-rheumatologist experts produced a list of potential items for inclusion in the DI. These steps were used to reduce the items: (1) Expert members of the SCTC (n=331) were invited to rate the appropriateness of each item for inclusion, using a web-based survey. Items with >60% consensus were retained; (2) Using a prospectively acquired Australian cohort data set of 1568 patients, the univariable relationships between the remaining items and the endpoints of mortality and morbidity (Physical Component Summary score of the Short Form 36) were analysed, and items with p<0.10 were retained; (3) using multivariable regression analysis, coefficients were used to determine a weighted score for each item. The DI was externally validated in a Canadian cohort.Ninety-three (28.1%) complete survey responses were analysed; 58 of 83 items were retained. The univariable relationships with death and/or morbidity endpoints were statistically significant for 22 items, with one additional item forced into the multivariable model by experts due to clinical importance, to create a 23-item weighted SCTC DI (SCTC-DI). The SCTC-DI was predictive of morbidity and mortality in the external cohort.Through the combined use of consensus and data-driven methods, a 23-item SCTC-DI was developed and retrospectively validated.

View details for DOI 10.1136/annrheumdis-2018-214764

View details for Web of Science ID 000471072800030

View details for PubMedID 30928903
Shortening patient-reported outcome measures through optimal test assembly: application to the Social Appearance Anxiety Scale in the Scleroderma Patient-centered Intervention Network Cohort BMJ OPEN Harel, D., Mills, S. D., Kwakkenbos, L., Carrier, M., Nielsen, K., Portales, A., Bartlett, S. J., Malcarne, V. L., Thombs, B. D., Baron, M., Furst, D. E., Gottesman, K., Mayes, M. D., Mouthon, L., Nielson, W. R., Riggs, R., Sauve, M., Wigley, F., Assassi, S., Boutron, I., Maia, A., El-Baalbaki, G., Ells, C., van den Ende, C., Fligelstone, K., Fortune, C., Frech, T., Godard, D., Hudson, M., Impens, A., Jang, Y., Johnson, S. R., Kennedy, A., Korner, A., Larche, M., Leite, C., Marra, C., Pope, J., Rodriguez Reyna, T., Schouffoer, A. A., Steele, R. J., Suarez-Almazor, M. E., Welling, J., Wong-Rieger, D., Agard, C., Albert, A., Andre, M., Arsenault, G., Benmostefa, N., Benzidia, I., Berthier, S., Bissonnette, L., Boire, G., Bruns, A., Carreira, P., Casadevall, M., Chaigne, B., Chung, L., Cohen, P., Dagenais, P., Denton, C., Domsic, R., Dubois, S., Dunne, J. V., Dunogue, B., Esquinca, A., Fare, R., Farge-Bancel, D., Fortin, P. R., Gill, A., Gordon, J., Granel-Rey, B., Grange, C., Gyger, G., Hachulla, E., Hatron, P., Herrick, A. L., Hij, A., Hinchcliff, M., Ikic, A., Jones, N., Fernandes, A. B., Kafaja, S., Khalidi, N., Korman, B., Launay, D., Liang, P., London, J., Luna, D., Maillard, H., Manning, J., Martin, M., Martin, T., Masetto, A., Maurier, F., Mekinian, A., Melchor, S., Nikpour, M., Paule, R., Proudman, S., Regent, A., Riviere, S., Robinson, D., Rodriguez, E., Roux, S., Smets, P., Smith, D., Sobanski, V., Spiera, R., Steen, V., Stevens, W., Sutton, E., Terrier, B., Thorne, C., Varga, J., Wilcox, P., Wilson, M., Cumin, J., Fox, R. S., Gholizadeh, S., Jewett, L. R., Levis, B., Pepin, M. R., Turner, K. A., Lambert, M., SPIN Investigators 2019; 9 (2): e024010
Abstract

The Social Appearance Anxiety Scale (SAAS) is a 16-item measure that assesses social anxiety in situations where appearance is evaluated. The objective was to use optimal test assembly (OTA) methods to develop and validate a short-form SAAS based on objective and reproducible criteria.This study was a cross-sectional analysis of baseline data from adults enrolled in the Scleroderma Patient-centered Intervention Network (SPIN) Cohort.Adults in the SPIN Cohort in the present study were enrolled at 28 centres in Canada, the USA and the UK.The SAAS was administered to 926 adults with scleroderma.The SAAS, Brief Fear of Negative Evaluation II (BFNE II), Brief Satisfaction with Appearance Scale (Brief-SWAP), Patient Health Questionnaire-8 (PHQ8) and Social Interaction Anxiety Scale-6 (SIAS-6) were collected, as well as demographic characteristics.OTA methods identified a maximally informative shortened version for each possible form length between 1 and 15 items. The final shortened version was selected based on prespecified criteria for reliability, concurrent validity and statistically equivalent convergent validity with the BFNE II scale. A five-item short version was selected (SAAS-5). The SAAS-5 had a Cronbach's ? of 0.95 and had high concurrent validity with the full-length form (r=0.97). The correlation of the SAAS-5 with the BFNE II was 0.66, which was statistically equivalent to that of the full-length form. Furthermore, the correlation of the SAAS-5 with the two subscales of the Brief-SWAP, and the SIAS-6, were statistically equivalent to that of the full-length form.OTA was an efficient method for shortening the full-length SAAS to create the SAAS-5.

View details for DOI 10.1136/bmjopen-2018-024010

View details for Web of Science ID 000471124600104

View details for PubMedID 30798308

View details for PubMedCentralID PMC6398718
SAFETY AND EFFICACY OF LENABASUM IN AN OPEN-LABEL EXTENSION OF A PHASE 2 STUDY IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS SUBJECTS (DCSSC) Spiera, R., Hummers, L., Chung, L., Frech, T., Domsic, R., Hsu, V., Furst, D., Gordon, J., Mayes, M., Simms, R., Lee, E., Constantine, S., Dgetluck, N., White, B. BMJ PUBLISHING GROUP. 2019: 245
View details for DOI 10.1136/annrheumdis-2019-eular.3390

View details for Web of Science ID 000472207100538
Upper Extremity Angiographic Patterns in Systemic Sclerosis: Implications for Surgical Treatment. The Journal of hand surgery Leyden, J., Burn, M. B., Wong, V., Leon, D. S., Kaizawa, Y., Chung, L., Chang, J. 2019
Abstract

PURPOSE: Conventional angiography is often used in the preoperative work-up of hand surgery patients with systemic sclerosis. The goal of this study was to propose a classification system based on the pattern of arterial involvement in a series of upper extremity angiograms. The authors hypothesized that this classification system would demonstrate high inter- and intrarater reliability.METHODS: A retrospective review of 110 upper extremity angiograms in patients with systemic sclerosis (obtained between 1996 and 2017) was performed. Images were classified into 4 types based on the patency of the radial and ulnar arteries at the wrist, and into 3 subtypes based on the patency of the superficial and deep palmar arches. Classification reliability was compared with Fleiss' Kappa (for inter-rater) and Cohen's (for intrarater) coefficient between 4 fellowship-trained hand surgeons and a hand fellow.RESULTS: The inter-rater reliability between all 5 observers using types alone was 0.83 (0.80-0.85), whereas the inter-rater reliability using subtypes was 0.64 (confidence interval [CI] 95%, 0.62-0.65). The intrarater reliability using types alone ranged from 0.80 to 0.95, whereas intrarater reliabilities using subtypes were 0.81 (CI 95%, 0.72-0.90), 0.78 (CI 95%, 0.69-0.87), 0.87 (CI 95%, 0.80-0.95), 0.64 (CI 95%, 0.53-0.75), and 0.92 (CI 95%, 0.86-0.98) for the 4 attendings and a hand fellow, respectively. Fifty-seven percent of angiograms were interpreted as having loss of ulnar artery patency at the wrist (type 2) with 77% having additional loss of superficial palmar arch patency (type 2A).CONCLUSIONS: This large series of angiograms in patients with systemic sclerosis demonstrates a classification system for conventional angiography that shows high inter-rater and intrarater reliability using type alone. When subtypes were used, the inter-rater and intrarater reliabilities decreased to moderate and moderate-to-high, respectively.CLINICAL RELEVANCE: This study represents the first step in establishing a classification system that, by grouping patients with similar angiogram findings, may allow for targeted research into risk stratification, monitoring, and treatment in systemic sclerosis.

View details for PubMedID 30797658
Risk Factors for Mortality and Cardiopulmonary Hospitalization in Systemic Sclerosis Patients At Risk for Pulmonary Hypertension, in the PHAROS Registry JOURNAL OF RHEUMATOLOGY Hsu, V. M., Chung, L., Hummers, L. K., Shah, A., Simms, R., Bolster, M., Hant, F. N., Silver, R. M., Fischer, A., Hinchcliff, M. E., Varga, J., Goldberg, A. Z., Derk, C. T., Schiopu, E., Khanna, D., Shapiro, L. S., Domsic, R. T., Medsger, T., Mayes, M. D., Furst, D., Csuka, M., Molitor, J. A., Saketkoo, L., Salazar, C. R., Steen, V. D. 2019; 46 (2): 176?83
View details for DOI 10.3899/jrheum.180018

View details for Web of Science ID 000457479200010
An interim report of the Scleroderma Clinical Trials Consortium working groups JOURNAL OF SCLERODERMA AND RELATED DISORDERS Baron, M., Kahaleh, B., Bernstein, E. J., Chung, L., Clements, P. J., Denton, C., Domsic, R. T., Ferdowsi, N., Foeldvari, I., Frech, T., Gordon, J. K., Hudson, M., Johnson, S. R., Khanna, D., McMahan, Z., Merkel, P. A., Narain, S., Nikpour, M., Pauling, J. D., Ross, L., Vergara, A., Vacca, A. 2019; 4 (1): 17?27
View details for DOI 10.1177/2397198318783926

View details for Web of Science ID 000457768700004
Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma: outcomes from a multicenter US-based systemic sclerosis registry. Clinical rheumatology Shanmugam, V. K., Frech, T. M., Steen, V. D., Hummers, L. K., Shah, A. A., Bernstein, E. J., Khanna, D., Gordon, J. K., Castelino, F. V., Chung, L., Hant, F. N., Startup, E., VanBuren, J. M., Evnin, L. B., Assassi, S. 2019
Abstract

The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5�years of first non-Raynaud's symptom. The data collection methodology incorporates successful models from other SSc registries. The cohort is designed to provide linked bio-specimen and clinical outcomes data on a longitudinal cohort of SSc patients for validation of hypothesis-driven research and to provide a platform for studying patient-reported outcomes in scleroderma. The CONQUER registry was developed using the guidelines of the International Society for Biological Repositories, and was an iterative process between physicians with an expertise in SSc, patient stakeholders, and information technology experts. Enrollment commenced in June 2018. During the first 6�months of the CONQUER Scleroderma study, 151 SSc patients with less than 5�years of disease duration (from first non-Raynaud's symptom) have been recruited. The mean age is 51?�?14�years, 83% are female, and 60% of patients have diffuse disease. Survey completion rates are above 88% for all patient-reported outcome surveys. Bio-specimen collection rates are over 97%, and disease severity score completion rates are over 98%. Pulmonary function test data is available on 91% of patients, and echocardiography is available 80%. The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. KEY POINTS : ? The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5�years of first non-Raynaud's symptom. ? The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. ? CONQUER is innovative in its design in that it is focused on prospective collection of paired clinical and patient outcome data with bio-specimens.

View details for DOI 10.1007/s10067-019-04792-y

View details for PubMedID 31667644
An Interim Report of the Scleroderma Clinical Trials Consortium Working Groups. Journal of scleroderma and related disorders Baron, M., Kahaleh, B., Bernstein, E. J., Chung, L., Clements, P. J., Denton, C., Domsic, R. T., Ferdowsi, N., Foeldvari, I., Frech, T., Gordon, J. K., Hudson, M., Johnson, S. R., Khanna, D., McMahan, Z., Merkel, P. A., Narain, S., Nikpour, M., Pauling, J. D., Ross, L., Valenzuela Vergara, A. M., Vacca, A. 2019; 4 (1): 17?27
Abstract

The Scleroderma Clinical Trials Consortium (SCTC) represents many of the clinical researchers in the world who are interested in improving the efficiency of clinical trials in Systemic Sclerosis (SSc). The SCTC has established 11 working groups (WGs) to develop and validate better ways of measuring and recording multiple aspects of this heterogeneous disease. These include groups working on arthritis, disease damage, disease activity, cardiac disease, juvenile SSc, the gastrointestinal tract, vascular component, calcinosis, scleroderma renal crisis, interstitial lung disease, and skin measurement. Members of the SCTC may join any one or more of these groups. Some of the WGs have only recently started their work, some are nearing completion of their mandated tasks and others are in the midst of their projects. All these projects, which are described in this paper, will help to improve clinical trials and observational studies by improving or developing better, more sensitive ways of measuring various aspects of the disease. As Lord Kelvin stated, "To measure is to know. If you cannot measure it you cannot improve it." The SCTC is dedicated to improving the lives of patients with SSc and it is our hope that the contributions of the WGs will be one important step in this process.

View details for PubMedID 30906878
Developing classification criteria for skin-predominant dermatomyositis: the Delphi process. The British journal of dermatology Concha, J. S., Pena, S., Gaffney, R. G., Patel, B., Tarazi, M., Kushner, C. J., Merola, J. F., Fiorentino, D., Dutz, J. P., Goodfield, M., Nyberg, F., Volc-Platzer, B., Fujimoto, M., Ang, C. C., Werth, V. P. 2019
Abstract

The European League Against Rheumatism / American College of Rheumatology (EULAR / ACR) classification criteria for inflammatory myopathies are able to classify patients with skin-predominant dermatomyositis (DM). However, approximately 25% of patients with skin-predominant DM do not meet 2 out of the 3 hallmark skin signs and fail to meet the criteria.We aim to develop a set of skin-focused classification criteria that will distinguish cutaneous DM from mimickers and allow a more inclusive definition of skin-predominant disease.An extensive literature review was done to generate items for the Delphi. Items were grouped into categories of distribution, morphology, symptoms, antibodies, histology, and contextual factors. Using REDCap? , participants rated these items in terms of appropriateness and distinguishing ability from mimickers. The relevance score ranged from 1 to 100, and the median score determined a rank-ordered list. A pre-specified median score cut-off was decided by the steering committee and the participants. There was a pre-Delphi and two rounds of actual Delphi.There were 50 participating dermatologists and rheumatologists from North America, South America, Europe, and Asia. After a cutoff score of 70 during the first round, 37 out of the initial 54 items were retained and carried over to the next round. The cutoff was raised to 80 during round two, and a list of 25 items was generated.This project is a key step in the development of prospectively validated classification criteria that will create a more inclusive population of DM patients for clinical research. This article is protected by copyright. All rights reserved.

View details for PubMedID 31049930
HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry. Proceedings of the National Academy of Sciences of the United States of America Gourh, P., Safran, S. A., Alexander, T., Boyden, S. E., Morgan, N. D., Shah, A. A., Mayes, M. D., Doumatey, A., Bentley, A. R., Shriner, D., Domsic, R. T., Medsger, T. A., Ramos, P. S., Silver, R. M., Steen, V. D., Varga, J., Hsu, V., Saketkoo, L. A., Schiopu, E., Khanna, D., Gordon, J. K., Kron, B., Criswell, L. A., Gladue, H., Derk, C. T., Bernstein, E. J., Bridges, S. L., Shanmugam, V. K., Kolstad, K. D., Chung, L., Kafaja, S., Jan, R., Trojanowski, M., Goldberg, A., Korman, B. D., Steinbach, P. J., Chandrasekharappa, S. C., Mullikin, J. C., Adeyemo, A., Rotimi, C., Wigley, F. M., Kastner, D. L., Boin, F., Remmers, E. F. 2019
Abstract

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 � 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA ?/? allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

View details for DOI 10.1073/pnas.1906593116

View details for PubMedID 31871193
Calcinosis in scleroderma CURRENT OPINION IN RHEUMATOLOGY Valenzuela, A., Song, P., Chung, L. 2018; 30 (6): 554?61
View details for DOI 10.1097/BOR.0000000000000539

View details for Web of Science ID 000457625900004
Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans ARTHRITIS & RHEUMATOLOGY Gourh, P., Remmers, E. F., Boyden, S. E., Alexander, T., Morgan, N. D., Shah, A. A., Mayes, M. D., Doumatey, A., Bentley, A. R., Shriner, D., Domsic, R. T., Medsger, T. A., Steen, V. D., Ramos, P. S., Silver, R. M., Korman, B., Varga, J., Schiopu, E., Khanna, D., Hsu, V., Gordon, J. K., Saketkoo, L., Gladue, H., Kron, B., Criswell, L. A., Derk, C. T., Bridges, S., Shanmugam, V. K., Kolstad, K. D., Chung, L., Jan, R., Bernstein, E. J., Goldberg, A., Trojanowski, M., Kafaja, S., Maksimowicz-McKinnon, K. M., Mullikin, J. C., Adeyemo, A., Rotimi, C., Boin, F., Kastner, D. L., Wigley, F. M. 2018; 70 (10): 1654?60
Abstract

Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients.SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls.Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 � 10-4 ).In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility.

View details for PubMedID 29732714

View details for PubMedCentralID PMC6160338
Risk Factors for Mortality and Cardiopulmonary Hospitalization in Systemic Sclerosis Patients At Risk for Pulmonary Hypertension, in the PHAROS Registry. The Journal of rheumatology Hsu, V. M., Chung, L., Hummers, L. K., Shah, A., Simms, R., Bolster, M., Hant, F. N., Silver, R. M., Fischer, A., Hinchcliff, M. E., Varga, J., Goldberg, A. Z., Derk, C. T., Schiopu, E., Khanna, D., Shapiro, L. S., Domsic, R. T., Medsger, T., Mayes, M. D., Furst, D., Csuka, M. E., Molitor, J. A., Saketkoo, L. A., Salazar, C. R., Steen, V. D. 2018
Abstract

OBJECTIVE: We sought to identify predictors of mortality and cardiopulmonary hospitalizations in patients at risk for pulmonary hypertension (PH) and enrolled in PHAROS, a prospective cohort study to investigate the natural history of PH in systemic sclerosis (SSc).METHODS: The at-risk population for PH was defined by the following entry criteria: echocardiogram systolic pulmonary arterial pressure > 40 mmHg, or DLCO < 55% predicted or ratio of % forced vital capacity/%DLCO > 1.6, measured by pulmonary function testing. Baseline clinical measures were evaluated as predictors of hospitalization and death between 2005 and 2014. Cox proportional hazards models were censored at date of PH onset or latest study visit and adjusted for age, sex, race, and disease duration.RESULTS: Of the 236 at-risk subjects who were followed for a median of 4 years (range 0.4-8.5 yrs), 35 developed PH after entering PHAROS (reclassified as PH group). In the at-risk group, higher mortality was strongly associated with male sex, low %DLCO, exercise oxygen desaturation, anemia, abnormal dyspnea scores, and baseline pericardial effusion. Risks for cardiopulmonary hospitalization were associated with increased dyspnea and pericardial effusions, although PH patients with DLCO < 50% had the highest risk of cardiopulmonary hospitalizations.CONCLUSION: Risk factors for poor outcome in patients with SSc who are at risk for PH were similar to others with SSc-PH and SSc-pulmonary arterial hypertension, including male sex, DLCO < 50%, exercise oxygen desaturation, and pericardial effusions. This group should undergo right heart catheterization and receive appropriate intervention if PH is confirmed.

View details for PubMedID 30275260
Long-Term Outcomes in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension From the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry (PHAROS) CHEST Kolstad, K. D., Li, S., Steen, V., Chung, L., PHAROS Investigators 2018; 154 (4): 862?71
View details for DOI 10.1016/j.chest.2018.05.002

View details for Web of Science ID 000446060400026
Increased Mortality in Black and Asian Patients with Systemic Sclerosis in Northern California Chung, M., Dontsi, M., Postlethwaite, D., Kesh, S., Zaba, L., Chung, L. WILEY. 2018
View details for Web of Science ID 000447268905018
Strong HLA and Novel Non-HLA Associations Identified By Auto-Antibody Subset Analysis of African Americans with Scleroderma from the Genome Research in African American Scleroderma Patients Cohort Gourh, P., Remmers, E. F., Alexander, T., Boyden, S., Morgan, N. D., Shah, A. A., Mayes, M. D., Doumatey, A., Bentley, A., Shriner, D., Domsic, R. T., Medsger, T. A., Steen, V. D., Ramos, P. S., Silver, R., Korman, B. D., Varga, J., Schiopu, E., Khanna, D., Hsu, V., Gordon, J. K., Saketkoo, L., Gladue, H., Kron, B., Criswell, L. A., Derk, C. T., Bridges, S., Shanmugam, V., Kolstad, K. D., Chung, L., Jan, R., Bernstein, E. J., Goldberg, A., Trojanowski, M., Kafaja, S., Maksimowicz-McKinnon, K., Chandrasekharappa, S. C., Adeyemo, A., Rotimi, C., Wigley, F. M., Boin, F., Kastner, D. L. WILEY. 2018
View details for Web of Science ID 000447268902221
Abatacept Vs. Placebo in Early Diffuse Cutaneous Systemic Sclerosis-Results of a Phase 2 Investigator Initiated, Double- Blind, Placebo-Controlled, Multicenter, Randomized Controlled Trial Study Khanna, D., Spino, C., Bush, E., Johnson, S., Chung, L., Molitor, J., Steen, V. D., Lafyatis, R., Simms, R. W., Denton, C. P., Kafaja, S., Frech, T. M., Hsu, V., Domsic, R. T., Pope, J. E., Gordon, J. K., Mayes, M. D., Schiopu, E., Young, A., Sandorfi, N., Park, J., Hant, F. N., Bernstein, E. J., Chatterjee, S., Castelino, F. V., Ajam, A., Allanore, Y., Matucci-Cerinic, M., Distler, O., Singer, O., Zhong, H., Fox, D., Furst, D. E. WILEY. 2018
View details for Web of Science ID 000447268902001
Identification of Risk Factors for Gastric Antral Vascular Ectasia (GAVE) Among Systemic Sclerosis Patients Serling-Boyd, N., Li, S., Fiorentino, D., Becker, L., Fernandez-Becker, N., Clarke, J., Chung, L. WILEY. 2018
View details for Web of Science ID 000447268901344
Multi-Organ RNA-Sequencing of Patients with Systemic Sclerosis (SSc) Finds That Intrinsic Subsets Are Conserved across Organ Systems Mehta, B. K., Franks, J., Wang, Y., Cai, G., Toledo, D. M., Wood, T. A., Archambault, K. A., Kosarek, N., Kolstad, K. D., Stark, M., Valenzuela, A., Fiorentino, D., Fernandez-Becker, N., Becker, L., Nguyen, L., Clarke, J., Boin, F., Wolters, P., Chung, L., Whitfield, M. L. WILEY. 2018
View details for Web of Science ID 000447268902203
The Scleroderma Patient-Centered Intervention Network Cohort: baseline clinical features and comparison with other large scleroderma cohorts RHEUMATOLOGY Dougherty, D. H., Kwakkenbos, L., Carrier, M., Salazar, G., Assassi, S., Baron, M., Bartlett, S. J., Furst, D. E., Gottesman, K., van den Hoogen, F., Malcarne, V. L., Mouthon, L., Nielson, W. R., Poiraudeau, S., Sauve, M., Boire, G., Bruns, A., Chung, L., Denton, C., Dunne, J. V., Fortin, P., Frech, T., Gill, A., Gordon, J., Herrick, A. L., Hinchcliff, M., Hudson, M., Johnson, S. R., Jones, N., Kafaja, S., Larche, M., Manning, J., Pope, J., Spiera, R., Steen, V., Sutton, E., Thorne, C., Wilcox, P., Thombs, B. D., Mayes, M. D., SPIN Investigators 2018; 57 (9): 1623?31
Abstract

The Scleroderma Patient-centered Intervention Network (SPIN) Cohort is a web-based cohort designed to collect patient-reported outcomes at regular intervals as a framework for conducting trials of psychosocial, educational, self-management and rehabilitation interventions for patients with SSc. The aim of this study was to present baseline demographic, medical and patient-reported outcome data of the SPIN Cohort and to compare it with other large SSc cohorts.Descriptive statistics were used to summarize SPIN Cohort characteristics; these were compared with published data of the European Scleroderma Trials and Research (EUSTAR) and Canadian Scleroderma Research Group (CSRG) cohorts.Demographic, organ involvement and antibody profile data for SPIN (N = 1125) were generally comparable with that of the EUSTAR (N = 7319) and CSRG (N = 1390) cohorts. There was a high proportion of women and White patients in all cohorts, though relative proportions differed. Scl70 antibody frequency was highest in EUSTAR, somewhat lower in SPIN, and lowest in CSRG, consistent with the higher proportion of interstitial lung disease among dcSSc patients in SPIN compared with in CSRG (48.5 vs 40.3%). RNA polymerase III antibody frequency was highest in SPIN and remarkably lower in EUSTAR (21.1 vs 2.4%), in line with the higher prevalence of SSc renal crisis (4.5 vs 2.1%) in SPIN.Although there are some differences, the SPIN Cohort is broadly comparable with other large prevalent SSc cohorts, increasing confidence that insights gained from the SPIN Cohort should be generalizable, although it should be noted that all three cohorts include primarily White participants.

View details for PubMedID 29868924
HLA Contributions to Risk and Protection for Anti-Centromere Autoantibody-Positive Scleroderma Remmers, E. F., Alexander, T., Morgan, N. D., Shah, A. A., Mayes, M. D., Adeyemo, A., Doumatey, A., Bentley, A., Shriner, D., Chandrasekharappa, S. C., Carns, M. A., Chung, L., Criswell, L. A., Derk, C. T., Domsic, R. T., Gladue, H., Goldberg, A., Gordon, J. K., Hsu, V., Jan, R., Khanna, D., Medsger, T. A., Ramos, P. S., Trojanowski, M. A., Saketkoo, L., Schiopu, E., Shanmugam, V., Korman, B. D., Kron, B., Louis Bridges, S., Kolstad, K. D., Bernstein, E. J., Kafaja, S., Maksimowicz-McKinnon, K., Silver, R., Steen, V. D., Varga, J., Rotimi, C., Boin, F., Wigley, F. M., Kastner, D. L., Gourh, P. WILEY. 2018
View details for Web of Science ID 000447268903165
Safety and Efficacy of Lenabasum in an Open-Label Extension of a Phase 2 Study in Diffuse Cutaneous Systemic Sclerosis Subjects Spiera, R. F., Hummers, L. K., Chung, L., Frech, T. M., Domsic, R. T., Hsu, V., Furst, D. E., Gordon, J. K., Mayes, M. D., Simms, R. W., Lee, E., Constantine, S., White, B. WILEY. 2018
View details for Web of Science ID 000447268902814
Rituximab Versus Mycophenolate Mofetil in Interstitial Lung Disease Secondary to Connective Tissue Disease Zhu, L., Li, S., Gagne, L., Jacobs, S., Morisset, J., Mooney, J., Raj, R., Chung, L. WILEY. 2018
View details for Web of Science ID 000447268902402
Calcinosis in scleroderma. Current opinion in rheumatology Valenzuela, A., Song, P., Chung, L. 2018
Abstract

PURPOSE OF REVIEW: To provide an update on the available literature regarding the epidemiology, pathophysiology, diagnosis, and treatment of calcinosis cutis in patients with systemic sclerosis (SSc).RECENT FINDINGS: We identified observational studies that describe the frequency of calcinosis in SSc and associated clinical features; molecular studies exploring potential pathogenic mechanisms; and case reports and case series describing new diagnostic approaches and treatments.SUMMARY: Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It represents a major clinical problem in patients with SSc affecting at least one quarter of patients. It is associated with longer disease duration, digital ulcers, acro-osteolysis, positive anticentromere antibody, and positive anti-PM/Scl antibody. Although pathogenesis is unknown, there is evidence supporting local trauma, chronic inflammation, vascular hypoxia, and dysregulation of bone matrix proteins as potential mechanisms. Diagnosis can be made clinically or with plain radiography. Several pharmacologic therapies have been tried for calcinosis with variable and modest results, but surgical excision of calcium deposits remains the mainstay of treatment.

View details for PubMedID 30124603
Non-invasive right ventricular load adaptability indices in patients with scleroderma-associated pulmonary arterial hypertension PULMONARY CIRCULATION French, S., Amsallem, M., Ouazani, N., Li, S., Kudelko, K., Zamanian, R. T., Haddad, F., Chung, L. 2018; 8 (3)
View details for DOI 10.1177/2045894018788268

View details for Web of Science ID 000439609900001
Clinical significance of autoantibodies in dermatomyositis and systemic sclerosis CLINICS IN DERMATOLOGY Tartar, D. M., Chung, L., Fiorentino, D. F. 2018; 36 (4): 508?24
Abstract

Autoimmune connective tissue diseases, including dermatomyositis and systemic sclerosis, have a heterogeneous clinical presentation and prognosis; moreover, their clinical features are often incomplete and overlap with other rheumatic disorders, which can make diagnosis and prognostic stratification challenging. Specific autoantibodies have been associated with certain clinical findings as well as prognostic implications, and many new associations have been made over the last decade. Although patient populations manifest considerable heterogeneity, autoantibodies can be used to help predict clinical features, prognosis, and response to therapy. In this review, the clinical and prognostic implications associated with disease-specific autoantibodies in dermatomyositis and scleroderma are summarized with an emphasis on how the clinician can use this information for patient care.

View details for PubMedID 30047434
Pregnancy outcomes in adult patients with dermatomyositis and polymyositis SEMINARS IN ARTHRITIS AND RHEUMATISM Kolstad, K. D., Fiorentino, D., Li, S., Chakravarty, E. F., Chung, L. 2018; 47 (6): 865?69
View details for DOI 10.1016/j.semarthrit.2017.11.005

View details for Web of Science ID 000434493800012
Long-term Outcomes in Systemic Sclerosis Associated Pulmonary Arterial Hypertension from the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry (PHAROS). Chest Kolstad, K. D., Li, S., Steen, V., Chung, L., PHAROS investigators 2018
Abstract

BACKGROUND: Pulmonary arterial hypertension (PAH) is a leading cause of death in patients with systemic sclerosis (SSc). The purpose of this study was to assess long-term outcomes in patients with SSc-PAH.METHODS: Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma is a prospective registry of SSc patients at high risk for or with incident pulmonary hypertension based on right heart catheterization (RHC). Incident World Health Organization Group I PAH patients were analyzed. Kaplan-Meier survival curves were generated for the overall cohort and those who died of PAH. Multivariate cox regression models identified predictors of mortality.RESULTS: Survival in 160 incident SSc-PAH patients at 1, 3, 5, and 8-years was 95%, 75%, 63%, and 49%, respectively. PAH accounted for 52% of all deaths. When restricted to deaths due to PAH, respective survival rates were 97%, 83%, 76%, and 76%, with 93% of PAH-related deaths occurring within 4 years of diagnosis. Male sex (HR 3.11 95%CI 1.38-6.98), diffuse disease (HR 2.12 95%CI 1.13-3.93), systolic pulmonary artery pressure (PAP) on echocardiogram (HR 1.06 95%CI 1.01-1.11), mean PAP on RHC (HR 1.03 95%CI 1001-1.07), six-minute walk distance (HR 0.92 95%CI 0.86-0.99), and diffusing capacity for carbon monoxide (HR 0.65 95% CI 0.46-0.92) significantly impacted survival on multivariate analysis.CONCLUSION: Overall survival in PHAROS was higher than other SSc-PAH cohorts. PAH accounted for more than half of deaths and primarily within the first few years after PAH diagnosis. Optimization of treatment for those at greatest risk of early PAH-related death is crucial.

View details for PubMedID 29777655
Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study ANNALS OF THE RHEUMATIC DISEASES Herrick, A. L., Peytrignet, S., Lunt, M., Pan, X., Hesselstrand, R., Mouthon, L., Silman, A. J., Dinsdale, G., Brown, E., Czirjak, L., Distler, J. W., Distler, O., Fligelstone, K., Gregory, W. J., Ochiel, R., Vonk, M. C., Ancuta, C., Ong, V. H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, O., Jobanputra, P., Jordan, A. C., Stevens, W., Moinzadeh, P., Hall, F. C., Agard, C., Anderson, M. E., Diot, E., Madhok, R., Akil, M., Buch, M. H., Chung, L., Damjanov, N. S., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A. J., McHugh, N., Mueller-Ladner, U., Riemekasten, G., Becker, M., Roddy, J., Carreira, P. E., Fauchais, A., Hachulla, E., Hamilton, J., Inanc, M., McLaren, J. S., van Laar, J. M., Pathare, S., Proudman, S. M., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D. J., Grange, C., Trad, G., Denton, C. P. 2018; 77 (4): 563?70
Abstract

Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs).The modified Rodnan skin score (mRSS) was recorded every 3?months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (�3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV).66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%.Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years.NCT02339441.

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Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study RHEUMATOLOGY Peytrignet, S., Denton, C. P., Lunt, M., Hesselstrand, R., Mouthon, L., Silman, A., Pan, X., Brown, E., Czirjak, L., Distler, J. W., Distler, O., Fligelstone, K., Gregory, W. J., Ochiel, R., Vonk, M., Ancuta, C., Ong, V. H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, O., Jordan, A. C., Stevens, W., Moinzadeh, P., Hall, F. C., Agard, C., Anderson, M. E., Diot, E., Madhok, R., Akil, M., Buch, M. H., Chung, L., Damjanov, N., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A. J., McHugh, N., Muller-Ladner, U., Riemekasten, G., Becker, M., Roddy, J., Carreira, P. E., Fauchais, A., Hachulla, E., Hamilton, J., Inanc, M., McLaren, J. S., van Laar, J. M., Pathare, S., Proudman, S., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D. J., Grange, C., Trad, G., Herrick, A. L. 2018; 57 (2): 370?81
Abstract

Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features.Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined.The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (? = 0.34, P < 0.0001 and ? = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (? = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (? = 0.40, P < 0.0001), decreasing hand function (? = 0.57, P < 0.0001) and increasing fatigue (? = -0.53, P < 0.0001).The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.

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An Update on Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: a Review of the Current Literature CURRENT RHEUMATOLOGY REPORTS Sundaram, S. M., Chung, L. 2018; 20 (2): 10
Abstract

This review will summarize the most current literature on the clinical impact, epidemiology, risk factors, screening recommendations, predictors of outcomes, and treatment options in patients with pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc).PAH continues to be a major cause of morbidity and mortality in SSc. Many risk factors and predictors of outcomes have been identified in patients with SSc including clinical, hemodynamic, and laboratory parameters. Screening for PAH in SSc patients is important and screening algorithms have been developed. Despite many available treatment options for PAH, prognosis remains poor. Awareness of risk factors, early detection, and up-front combination treatment are important considerations in SSc-PAH and may lead to improved outcomes. Further research to develop better biomarkers and therapies is needed to continue to improve survival and outcomes in patients with SSc-PAH.

View details for PubMedID 29488016
Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate) ANNALS OF THE RHEUMATIC DISEASES Khanna, D., Denton, C. P., Lin, C. F., van Laar, J. M., Frech, T. M., Anderson, M. E., Baron, M., Chung, L., Fierlbeck, G., Lakshminarayanan, S., Allanore, Y., Pope, J. E., Riemekasten, G., Steen, V., Mueller-Ladner, U., Spotswood, H., Burke, L., Siegel, J., Jahreis, A., Furst, D. E. 2018; 77 (2): 212?20
Abstract

Assess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study.Patients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162?mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96.Overall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95%?CI)) change from baseline in mRSS was -3.1 (6.3 (-5.4 to -0.9)) for placebo and -5.6 (9.1 (-8.9 to-2.4)) for tocilizumab at week 48 and -9.4 (5.6 (-8.9 to -2.4)) for placebo-tocilizumab and -9.1 (8.7 (-12.5 to -5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95%?CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95%?CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10%?absolute decline in %pFVC. Serious infection rates/100 patient-years (95%?CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period.Skin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab.NCT01532869; Results.

View details for PubMedID 29066464

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Evidence supports blind screening for internal malignancy in dermatomyositis Data from 2 large US dermatology cohorts MEDICINE Leatham, H., Schadt, C., Chisolm, S., Fretwell, D., Chung, L., Callen, J. P., Fiorentino, D. 2018; 97 (2): e9639
Abstract

The association between dermatomyositis and internal malignancy is well established, but there is little consensus about the methods of cancer screening that should be utilized.We wished to analyze the prevalence and yield of selected cancer screening modalities in patients with dermatomyositis.We performed a retrospective analysis of 2 large US dermatomyositis cohorts comprising 400 patients.We measured the frequency of selected screening tests used to search for malignancy. Patients with a biopsy-confirmed malignancy were identified. Prespecified clinical and laboratory factors were tested for association with malignancy. For each malignancy we identified the screening test(s) that led to diagnosis and classified these tests as either blind (not guided by suspicious sign/symptom) or triggered (by a suspicious sign or symptom).Forty-eight patients (12.0% of total cohort) with 53 cancers were identified with dermatomyositis-associated malignancy. Twenty-one of these 53 cancers (40%) were diagnosed within 1 year of dermatomyositis symptom onset. In multivariate analysis, older age (P?=?.0005) was the only significant risk factor for internal malignancy. There was no significant difference in cancer incidence between classic and clinically amyopathic patients. Twenty-seven patients (6.8% of the total cohort) harbored an undiagnosed malignancy at the time of dermatomyositis diagnosis. The majority (59%) of these cancers were asymptomatic and computed tomography (CT) scans were the most common studies to reveal a cancer.This is the largest US cohort studied to examine malignancy prevalence and screening practices in dermatomyositis patients. Our results demonstrate that, while undiagnosed malignancy is present in <10% of US patients at the time of dermatomyositis onset, it is often not associated with a suspicious sign or symptom. Our data suggest that effective malignancy screening of dermatomyositis patients often requires evaluation beyond a history, physical examination, and "age-appropriate" cancer screening-these data may help to inform future guidelines for malignancy screening in this population.

View details for PubMedID 29480875
Patient acceptable symptom state in scleroderma: results from the tocilizumab compared with placebo trial in active diffuse cutaneous systemic sclerosis RHEUMATOLOGY Arnold, M. B., Khanna, D., Denton, C. P., van Laar, J. M., Frech, T. M., Anderson, M. E., Baron, M., Chung, L., Fierlbeck, G., Lakshminarayanan, S., Allanore, Y., Riemekasten, G., Steen, V., Mueller-Ladner, U., Spotswood, H., Burke, L., Siegel, J., Jahreis, A., Furst, D. E., Pope, J. E. 2018; 57 (1): 152?57
Abstract

Patient acceptable symptom state (PASS) as an absolute state of well-being has shown promise as an outcome measure in many rheumatologic conditions. We aimed to assess whether PASS may be effective in active diffuse cutaneous SSc differentiating active from placebo.Data from the phase 2 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (faSScinate) trial were used, which compared tocilizumab (TCZ) vs placebo over 48 weeks followed by an open-label TCZ period to 96 weeks. Three different types of PASS questions were evaluated at weeks 8, 24, 48 and 96, including if a current state would be acceptable over time as a yes vs no response and Likert scales about how acceptable a current state is if remaining over time. Additional outcomes assessed included modified Rodnan skin score, HAQ disability index (HAQ-DI), physician and patient global assessments on a visual analogue scale, CRP and ESR.The placebo group consisted of 44 patients and the TCZ group had 43 patients. At baseline, 33% achieved a PASS for all three PASS questions, with the proportion increasing to 69, 71 and 78%, respectively, at 96 weeks. Changes in PASS scores showed a moderately negative correlation with HAQ-DI and patient and physician global assessments visual analogue scales, which indicates expected improvements as PASS improved. The PASS question, 'Considering all of the ways your scleroderma has affected you, how acceptable would you rate your level of symptoms?' showed significant correlations with patient-reported outcomes and differentiating placebo vs TCZ at 48 weeks (P = 0.023).PASS may be used as a patient-centred outcome in SSc, especially as a 7-point Likert scale. Further validation is required to determine the utility as an outcome measure in trials and clinical practice.

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EXPRESS: Non-invasive Right Ventricular Load Adaptability Indices in Patients with Scleroderma-Associated Pulmonary Arterial Hypertension. Pulmonary circulation French, S., Amsallem, M., Ouazani, N., Li, S., Kudelko, K., Zamanian, R., Haddad, F., Chung, L. 2018: 2045894018788268
View details for PubMedID 29938590
Factors Associated With Clinical Remission of Skin Disease in Dermatomyositis JAMA DERMATOLOGY Wolstencroft, P. W., Chung, L., Li, S., Casciola-Rosen, L., Fiorentino, D. F. 2018; 154 (1): 44?51
Abstract

Cutaneous disease represents a significant burden for patients with dermatomyositis. However, quantitative estimates of the probability of skin disease remission and clinical factors associated with skin outcomes are lacking.To characterize cutaneous disease course in adult patients with dermatomyositis.Prospective cohort study conducted at a dermatology clinic at a tertiary academic referral center. All adult patients with dermatomyositis (age?>18 years) seen between May 15, 2007, and October 28, 2016, were eligible. Patients were included in the current analysis if they had a baseline Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score of 12 or higher, and 2 or more CDASI scores separated by 3 months or more within their first 3 years of follow-up.The percentage of patients who achieved clinical remission of their cutaneous disease as measured by the CDASI over a 3-year follow-up.A total of 74 patients met our inclusion criteria (mean [SD] age at initial CDASI scoring, 54 [13] years; 58 women [78%]), and 28 (38%) achieved clinical remission during our 3-year follow-up period. Increased age (odds ratio [OR], 1.07; 95% CI, 1.02-1.12; P?=?.01), a dermatomyositis-associated malignancy (OR, 14.46; 95% CI, 2.18-96.07; P?=?.01), and treatment with mycophenolate mofetil (OR, 6.00; 95% CI, 1.66-21.78; P?=?.01) were significantly associated with clinical remission of skin disease in multivariable analysis. Patients with anti-melanoma differentiation-associated protein 5 antibodies had a significantly lower probability of meeting outcome criteria in our time-to-event analysis. Baseline cutaneous disease activity, disease duration at baseline, and disease duration before first systemic therapy were not significantly associated with clinical remission of skin disease.Clinical remission was relatively uncommon in our population despite aggressive systemic therapy, and patients with anti-melanoma differentiation-associated protein 5 antibodies were even less likely to enter clinical remission during a 3-year follow-up period. Although mycophenolate mofetil compared favorably with other treatment options, our data provide evidence that a substantial population of patients with dermatomyositis have skin disease that is not adequately managed with standard-of-care therapies.

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Clinical and serological features of systemic sclerosis in a multicenter African American cohort: Analysis of the genome research in African American scleroderma patients clinical database MEDICINE Morgan, N. D., Shah, A. A., Mayes, M. D., Domsic, R. T., Medsger, T. A., Steen, V. D., Varga, J., Carns, M., Ramos, P. S., Silver, R. M., Schiopu, E., Khanna, D., Hsu, V., Gordon, J. K., Gladue, H., Saketkoo, L. A., Criswell, L. A., Derk, C. T., Trojanowski, M. A., Shanmugam, V. K., Chung, L., Valenzuela, A., Jan, R., Goldberg, A., Remmers, E. F., Kastner, D. L., Wigley, F. M., Gourh, P., Boin, F. 2017; 96 (51): e8980
Abstract

Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1?�?13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ?50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry.

View details for PubMedID 29390428

View details for PubMedCentralID PMC5758130
Pregnancy outcomes in adult patients with dermatomyositis and polymyositis. Seminars in arthritis and rheumatism Kolstad, K. D., Fiorentino, D., Li, S., Chakravarty, E. F., Chung, L. 2017
Abstract

OBJECTIVE: The idiopathic inflammatory myopathies dermatomyositis (DM) and polymyositis (PM) are autoimmune diseases that can affect females of childbearing potential. We assessed pregnancy outcomes in DM and PM patients compared with the general obstetric population.METHODS: The Nationwide Inpatient Sample (NIS) (1993-2007) was used to identify delivery-associated hospitalizations in women with DM or PM (DM/PM, n = 853). Controls were from the general obstetric population delivery-associated hospitalizations matched to each case by year of delivery. Pregnancy outcomes included hospital length of stay (LOS), hypertensive disorders (HTN), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), and cesarean delivery. Multivariate regression analyses were performed using maternal age, race/ethnicity, and diabetes mellitus as covariates.RESULTS: On multivariate analysis, patients with DM/PM had longer LOS compared to controls (p < 0.001). DM/PM was associated with an increased risk of hypertensive disorders compared to controls (OR = 2.90, 95% CI: 2.00-4.22). There were no differences in rates of PROM, IUGR, or cesarean section in patients with DM/PM compared with controls. Independent of a DM/PM diagnosis, African-American race, older age, and diagnosis of diabetes increased the hospital LOS (p < 0.001). African-American race and diabetes increased the risk of hypertensive disorders (OR = 1.38, 95% CI: 1.19-1.60; OR = 2.94, 95% CI: 2.04-4.23, respectively) compared to controls.CONCLUSION: These data suggest that patients with inflammatory myopathies are at increased risk of hypertensive disorders of pregnancy and longer length of hospitalization. Vigilant monitoring of blood pressure is advisable in pregnant patients with DM or PM.

View details for PubMedID 29217291
2016 ACR-EULAR adult dermatomyositis and polymyositis and juvenile dermatomyositis response criteria-methodological aspects RHEUMATOLOGY Rider, L. G., Ruperto, N., Pistorio, A., Erman, B., Bayat, N., Lachenbruch, P. A., Rockette, H., Feldman, B. M., Huber, A. M., Hansen, P., Oddis, C. V., Lundberg, I. E., Amato, A. A., Chinoy, H., Cooper, R. G., Chung, L., Danko, K., Fiorentino, D., Garcia-De la Torre, I., Reed, A. M., Song, Y., Cimaz, R., Cuttica, R. J., Pilkington, C. A., Martini, A., van der Net, J., Maillard, S., Miller, F. W., Vencovsky, J., Aggarwal, R., Int Myositis Assessment Clinical, Paediat Rheumatology Int Trials 2017; 56 (11): 1884?93
Abstract

The objective was to describe the methodology used to develop new response criteria for adult DM/PM and JDM.Patient profiles from prospective natural history data and clinical trials were rated by myositis specialists to develop consensus gold-standard ratings of minimal, moderate and major improvement. Experts completed a survey regarding clinically meaningful improvement in the core set measures (CSM) and a conjoint-analysis survey (using 1000Minds software) to derive relative weights of CSM and candidate definitions. Six types of candidate definitions for response criteria were derived using survey results, logistic regression, conjoint analysis, application of conjoint-analysis weights to CSM and published definitions. Sensitivity, specificity and area under the curve were defined for candidate criteria using consensus patient profile data, and selected definitions were validated using clinical trial data.Myositis specialists defined the degree of clinically meaningful improvement in CSM for minimal, moderate and major improvement. The conjoint-analysis survey established the relative weights of CSM, with muscle strength and Physician Global Activity as most important. Many candidate definitions showed excellent sensitivity, specificity and area under the curve in the consensus profiles. Trial validation showed that a number of candidate criteria differentiated between treatment groups. Top candidate criteria definitions were presented at the consensus conference.Consensus methodology, with definitions tested on patient profiles and validated using clinical trials, led to 18 definitions for adult PM/DM and 14 for JDM as excellent candidates for consideration in the final consensus on new response criteria for myositis.

View details for PubMedID 28977549

View details for PubMedCentralID PMC5850656
Preterm Birth Phenotypes in Women with Autoimmune Diseases Kolstad, K. D., Mayo, J. A., Chung, L., Chaichian, Y., Kelly, V. M., Druzin, M., Stevenson, D. K., Shaw, G. M., Simard, J. F. WILEY. 2017
View details for Web of Science ID 000411824102207
Transcriptome Sequencing Reveals Genetic Polymorphisms Associated with Ssc Gene Expression Subtypes Cai, G., Mehta, B. K., Huang, M., Franks, J., Wood, T. A., Kolstad, K. D., Stark, M., Valenzuela, A., Fiorentino, D., Simms, R. W., Orzechowski, N., Chung, L., Whitfield, M. L. WILEY. 2017
View details for Web of Science ID 000411824101058
Safety and Efficacy of Anabasum (JBT-101) in Diffuse Cutaneous Systemic Sclerosis (dcSSc) Subjects Treated in an Open-Label Extension of Trial JBT101-SSc-001 Spiera, R. F., Hummers, L. K., Chung, L., Frech, T. M., Domsic, R. T., Hsu, V., Furst, D. E., Gordon, J. K., Mayes, M. D., Simms, R. W., Constantine, S., White, B. WILEY. 2017
View details for Web of Science ID 000411824101008
HLA Type Imputation in the Genome Research in African American Scleroderma Patients (GRASP) Cohort Reveals Strong Associations of African Ancestry MHC Class II Types with Scleroderma and Lack of Class I HLA Type Associations Remmers, E. F., Gourh, P., Boyden, S., Morgan, N. D., Shah, A. A., Adeyemo, A., Bentley, A., Carns, M. A., Chandrasekharappa, S. C., Chung, L., Criswell, L. A., Derk, C. T., Domsic, R. T., Doumatey, A., Gladue, H., Goldberg, A., Gordon, J. K., Hsu, V. M., Jan, R., Khanna, D., Mayes, M. D., Medsger, T. A., Ramos, P. S., Trojanowski, M. A., Saketkoo, L. A., Schiopu, E., Shanmugam, V. K., Shriner, D., Silver, R. M., Steen, V. D., Valenzuela, A., Varga, J., Rotimi, C., Wigley, F. M., Boin, F., Kastner, D. L. WILEY. 2017
View details for Web of Science ID 000411824101202
A Phase 2 Study of Safety and Efficacy of Anabasum (JBT-101), a Cannabinoid Receptor Type 2 Agonist, in Diffuse Cutaneous Systemic Sclerosis Spiera, R. F., Hummers, L. K., Chung, L., Frech, T. M., Domsic, R. T., Hsu, V., Furst, D. E., Gordon, J. K., Mayes, M. D., Simms, R. W., Constantine, S., White, B. WILEY. 2017
View details for Web of Science ID 000411824106388
Factors Associated with Clinical Remission of Skin Disease in Dermatomyositis Wolstencroft, P., Chung, L., Li, S., Casciola-Rosen, L., Fiorentino, D. WILEY. 2017
View details for Web of Science ID 000411824104386
Multi-Organ RNA-Sequencing of Patients with Systemic Sclerosis (SSc) Finds That Intrinsic Subsets Are Conserved across Organ Systems Mehta, B. K., Franks, J., Cai, G., Toledo, D., Wood, T. A., Archambault, K. A., Kosarek, N., Kolstad, K., Stark, M., Valenzuela, A., Fiorentino, D., Fernandez-Becker, N., Becker, L., Nguyen, L., Clarke, J., Boin, F., Wolters, P., Chung, L., Whitfield, M. L. WILEY. 2017
View details for Web of Science ID 000411824106435
Transforming Growth Factor Beta 3 (TGFB3) - a Novel Systemic Sclerosis Susceptibility Locus Involved in Fibrosis and Th17 Cell Development Identified By Genome-Wide Association Study in African Americans from the Genome Research in African American Scleroderma Patients Consortium Gourh, P., Remmers, E. F., Satpathy, A., Boyden, S., Morgan, N. D., Shah, A. A., Adeyemo, A., Bentley, A., Carns, M. A., Chandrasekharappa, S. C., Chung, L., Criswell, L. A., Derk, C. T., Domsic, R. T., Doumatey, A., Gladue, H., Goldberg, A., Gordon, J. K., Hsu, V., Jan, R., Khanna, D., Mayes, M. D., Medsger, T. A., Mumbach, M., Ramos, P. S., Trojanowski, M., Saketkoo, L., Schiopu, E., Shanmugam, V. K., Shriner, D., Silver, R. M., Steen, V. D., Valenzuela, A., Varga, J., Chang, H., Rotimi, C., Wigley, F. M., Boin, F., Kastner, D. L. WILEY. 2017
View details for Web of Science ID 000411824106434
Clinical and Serological Features of Systemic Sclerosis in a Multicenter African American Cohort: Analysis of the Genome Research in African American Scleroderma Patients Clinical Database Morgan, N. D., Shah, A. A., Mayes, M. D., Domsic, R. T., Medsger, T. A., Steen, V. D., Varga, J., Carns, M. A., Ramos, P. S., Silver, R. M., Schiopu, E., Khanna, D., Hsu, V., Gordon, J. K., Gladue, H., Saketkoo, L. A., Criswell, L. A., Derk, C. T., Trojanowski, M. A., Shanmugam, V. K., Chung, L., Valenzuela, A., Jan, R., Goldberg, A., Remmers, E. F., Kastner, D. L., Wigley, F. M., Gourh, P., Boin, F. WILEY. 2017
View details for Web of Science ID 000411824101229
Identification of Biomarkers Predictive of Pulmonary Arterial Hypertension in Systemic Sclerosis Kolstad, K. D., Holmes, T., Rosenberg-Hasson, Y., Sweatt, A., Zamanian, R. T., Li, S., Steen, V. D., Utz, P. J., Chung, L. WILEY. 2017
View details for Web of Science ID 000411824101041
Differential expression of hepatocyte growth factor in patients with systemic sclerosis-associated pulmonary arterial hypertension JOURNAL OF SCLERODERMA AND RELATED DISORDERS Sung, Y. K., Zamanian, R. T., Wagner, C. A., Robinson, W., Steen, V., Chung, L. 2017; 2 (3): 225?30
View details for DOI 10.5301/jsrd.5000245

View details for Web of Science ID 000412826600013
Patient Centered Approach to Disease Modification in Scleroderma: Results from the faSScinate Trial of Tocilizumab Compared to Placebo in Active Diffuse Cutaneous Systemic Sclerosis Arnold, M., Khanna, D., Denton, C., Lin, C., van Laar, J., Frech, T., Anderson, M., Baron, M., Chung, L., Fierlbeck, G., Allanore, Y., Riemekasten, G., Steen, V., Mueller-Ladner, U., Spotswood, H., Burke, L., Siegel, J., Jahreis, A., Furst, D., Pope, J. J RHEUMATOL PUBL CO. 2017: 881
View details for Web of Science ID 000404641800094
2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative ARTHRITIS & RHEUMATOLOGY Aggarwal, R., Rider, L. G., Ruperto, N., Bayat, N., Erman, B., Feldman, B. M., Oddis, C. V., Amato, A. A., Chinoy, H., Cooper, R. G., Dastmalchi, M., Fiorentino, D., Isenberg, D., Katz, J. D., Mammen, A., de Visser, M., Ytterberg, S. R., Lundberg, I. E., Chung, L., Danko, K., Garcia-De La Torre, I., Song, Y. W., Villa, L., Rinaldi, M., Rockette, H., Lachenbruch, P. A., Miller, F. W., Vencovsky, J. 2017; 69 (5): 898-910
Abstract

To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM).Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus.Consensus was reached for a conjoint analysis-based continuous model using absolute percent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ?20, ?40, and ?60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (P?
View details for DOI 10.1002/art.40064

View details for Web of Science ID 000400068300004

View details for PubMedID 28382787
2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative ANNALS OF THE RHEUMATIC DISEASES Aggarwal, R., Rider, L. G., Ruperto, N., Bayat, N., Erman, B., Feldman, B. M., Oddis, C. V., Amato, A. A., Chinoy, H., Cooper, R. G., Dastmalchi, M., Fiorentino, D., Isenberg, D., Katz, J. D., Mammen, A., de Visser, M., Ytterberg, S. R., Lundberg, I. E., Chung, L., Danko, K., Garcia-De La Torre, I., Song, Y. W., Villa, L., Rinaldi, M., Rockette, H., Lachenbruch, P. A., Miller, F. W., Vencovsky, J. 2017; 76 (5)
Abstract

To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ?20, ?40, and ?60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p<0.001). The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

View details for DOI 10.1136/annrheumdis-2017-211400

View details for Web of Science ID 000398387200006

View details for PubMedID 28385805
Proteomic Analysis of Sera from Individuals with Diffuse Cutaneous Systemic Sclerosis Reveals a Multianalyte Signature Associated with Clinical Improvement during Imatinib Mesylate Treatment JOURNAL OF RHEUMATOLOGY Haddon, D. J., Wand, H. E., Jarrell, J. A., Spiera, R. F., Utz, P. J., Gordon, J. K., Chung, L. S. 2017; 44 (5): 631-638
Abstract

Imatinib has been investigated for the treatment of systemic sclerosis (SSc) because of its ability to inhibit the platelet-derived growth factor receptor and transforming growth factor-? signaling pathways, which have been implicated in SSc pathogenesis. In a 12-month open-label clinical trial assessing the safety and efficacy of imatinib in the treatment of diffuse cutaneous SSc (dcSSc), significant improvements in skin thickening were observed. Here, we report our analysis of sera collected during the clinical trial.We measured the levels of 46 cytokines, chemokines, and growth factors in the sera of individuals with dcSSc using Luminex and ELISA. Autoantigen microarrays were used to measure immunoglobulin G reactivity to 28 autoantigens. Elastic net regularization was used to identify a signature that was predictive of clinical improvement (reduction in the modified Rodnan skin score ? 5) during treatment with imatinib. The signature was also tested using sera from a clinical trial of nilotinib, a tyrosine kinase inhibitor that is structurally related to imatinib, in dcSSc.The elastic net algorithm identified a signature, based on levels of CD40 ligand, chemokine (C-X-C motif) ligand 4 (CXCL4), and anti-PM/Scl-100, that was significantly higher in individuals who experienced clinical improvement than in those who did not (p = 0.0011). The signature was validated using samples from a clinical trial of nilotinib.Identification of patients with SSc with the greatest probability of benefit from treatment with imatinib has the potential to guide individualized treatment. Validation of the signature will require testing in randomized, placebo-controlled studies. Clinicaltrials.gov NCT00555581 and NCT01166139.

View details for DOI 10.3899/jrheum.160833

View details for Web of Science ID 000401094300016

View details for PubMedID 28298564
Insights into CCL21's roles in immunosurveillance and immunotherapy for gliomas JOURNAL OF NEUROIMMUNOLOGY Nguyen, T., Lagman, C., Chung, L. K., Chen, C. H., Poon, J., Ong, V., Voth, B. L., Yang, I. 2017; 305: 29-34
Abstract

Chemokine (C-C) motif ligand 21 (CCL21) is involved in immunosurveillance and has recently garnered the attention of neuro-oncologists and neuroscientists. CCL21 contains an extended C-terminus, which increases binding to lymphatic glycosaminoglycans and provides a mechanism for cell trafficking by forming a stationary chemokine concentration gradient that allows cell migration via haptotaxis. CCL21 is expressed by endothelial cells of the blood-brain barrier in physiologic and pathologic conditions. CCL21 has also been implicated in leukocyte extravasation into the central nervous system. In this review, we summarize the role of CCL21 in immunosurveillance and explore its potential as an immunotherapeutic agent for the treatment of gliomas.

View details for DOI 10.1016/j.jneuroim.2017.01.010

View details for Web of Science ID 000397694200006

View details for PubMedID 28284342
Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS). Annals of the rheumatic diseases Herrick, A. L., Pan, X., Peytrignet, S., Lunt, M., Hesselstrand, R., Mouthon, L., Silman, A., Brown, E., Czirj�k, L., Distler, J. H., Distler, O., Fligelstone, K., Gregory, W. J., Ochiel, R., Vonk, M., Ancuta, C., Ong, V. H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, �., Jordan, A. C., Jobanputra, P., Stevens, W., Moinzadeh, P., Hall, F. C., Agard, C., Anderson, M. E., Diot, E., Madhok, R., Akil, M., Buch, M. H., Chung, L., Damjanov, N., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A. J., McHugh, N., M�ller-Ladner, U., Riemekasten, G., Becker, M., Roddy, J., Carreira, P. E., Fauchais, A. L., Hachulla, E., Hamilton, J., Inan�, M., McLaren, J. S., van Laar, J. M., Pathare, S., Proudman, S., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D. J., Grange, C., Trad, G., Denton, C. P. 2017
Abstract

The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches.This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24?months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival.Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24?months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12?months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24?months.These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12?months and that better treatments are needed.NCT02339441.

View details for DOI 10.1136/annrheumdis-2016-210503

View details for PubMedID 28188239
The cutaneous and systemic findings associated with nuclear matrix protein-2 antibodies in adult dermatomyositis patients. Arthritis care & research Rogers, A., Chung, L., Li, S., Casciola-Rosen, L., Fiorentino, D. F. 2017
Abstract

To characterize the cutaneous and systemic clinical phenotype of dermatomyositis patients with anti-NXP-2 antibodies.We conducted a retrospective cohort analysis of 178 dermatomyositis patients seen at the Stanford University Clinic. Electronic chart review employing a keyword search strategy was performed to collect clinical and laboratory data. Anti-NXP-2 antibodies were assayed by immunoprecipitation using NXP-2 produced by in vitro transcription/translation.Antibodies to NXP-2 were detected in 20 (11%) of the 178 patients. Anti-NXP-2 antibodies were associated with male gender (50% vs. 25%, p=0.02), dysphagia (74% vs. 39%, p=0.006), myalgia (89% vs. 52%, p=0.002), peripheral edema (35% vs. 11%, p=0.016), and calcinosis (37% vs. 11%, p=0.007). These patients were less likely to be clinically amyopathic (5% vs 23%, p=0.08). Five of the 20 patients with NXP-2 antibodies (25%) had an associated internal malignancy. No other cutaneous characteristics were associated with anti-NXP-2 antibodies except a decreased frequency of Gottron's sign (44% vs. 75%, p=0.012) and the fact that these patients were more likely to have mild skin disease.Dermatomyositis patients with anti-NXP2 antibodies have a distinct and often severe systemic phenotype that includes myalgia, peripheral edema and significant dysphagia despite having milder inflammatory skin disease. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/acr.23210

View details for PubMedID 28129490
Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations HUMAN MOLECULAR GENETICS Seow, W. J., Matsuo, K., Hsiung, C. A., Shiraishi, K., Song, M., Kim, H. N., Wong, M. P., Hong, Y., Hosgood, H. D., Wang, Z., Chang, I., Wang, J., Chatterjee, N., Tucker, M., Wei, H., Mitsudomi, T., Zheng, W., Kim, J. H., Zhou, B., Caporaso, N. E., Albanes, D., Shin, M., Chung, L. P., An, S., Wang, P., Zheng, H., Yatabe, Y., Zhang, X., Kim, Y. T., Shu, X., Kim, Y., Bassig, B. A., Chang, J., Ho, J. C., Ji, B., Kubo, M., Daigo, Y., Ito, H., Momozawa, Y., Ashikawa, K., Kamatani, Y., Honda, T., Sakamoto, H., Kunitoh, H., Tsuta, K., Watanabe, S., Nokihara, H., Miyagi, Y., Nakayama, H., Matsumoto, S., Tsuboi, M., Goto, K., Yin, Z., Shi, J., Takahashi, A., Goto, A., Minamiya, Y., Shimizu, K., Tanaka, K., Wu, T., Wei, F., Wong, J. Y., Matsuda, F., Su, J., Kim, Y. H., Oh, I., Song, F., Lee, V. H., Su, W., Chen, Y., Chang, G., Chen, K., Huang, M., Yang, P., Lin, H., Xiang, Y., Seow, A., Park, J. Y., Kweon, S., Chen, C., Li, H., Gao, Y., Wu, C., Qian, B., Lu, D., Liu, J., Jeon, H., Hsiao, C., Sung, J. S., Tsai, Y., Jung, Y. J., Guo, H., Hu, Z., Wang, W., Chung, C. C., Lawrence, C., Burdett, L., Yeager, M., Jacobs, K. B., Hutchinson, A., Berndt, S. I., He, X., Wu, W., Wang, J., Li, Y., Choi, J. E., Park, K. H., Sung, S. W., Liu, L., Kang, C. H., Hu, L., Chen, C., Yang, T., Xu, J., Guan, P., Tan, W., Wang, C., Sihoe, A. D., Chen, Y., Choi, Y. Y., Hung, J., Kim, J. S., Yoon, H., Cai, Q., Lin, C., Park, I. K., Xu, P., Dong, J., Kim, C., He, Q., Perng, R., Chen, C., Vermeulen, R., Wu, J., Lim, W., Chen, K., Chan, J. K., Chu, M., Li, Y., Li, J., Chen, H., Yu, C., Jin, L., Lo, Y., Chen, Y., Fraumeni, J. F., Liu, J., Yamaji, T., Yang, Y., Hicks, B., Wyatt, K., Li, S. A., Dai, J., Ma, H., Jin, G., Song, B., Wang, Z., Cheng, S., Li, X., Ren, Y., Cui, P., Iwasaki, M., Shimazu, T., Tsugane, S., Zhu, J., Jiang, G., Fei, K., Wu, G., Chien, L., Chen, H., Su, Y., Tsai, F., Chen, Y., Yu, J., Stevens, V. L., Laird-Offringa, I. A., Marconett, C. N., Lin, D., Chen, K., Wu, Y., Landi, M. T., Shen, H., Rothman, N., Kohno, T., Chanock, S. J., Lan, Q. 2017; 26 (2): 454-465
Abstract

To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P?
View details for DOI 10.1093/hmg/ddw414

View details for Web of Science ID 000397066400018

View details for PubMedCentralID PMC5856088
beta-Catenin overexpression causes an increase in inflammatory cytokines and NF-kappa B activation in cardiomyocytes CELLULAR AND MOLECULAR BIOLOGY Lin, J. C., Chang, R., Chen, Y., Yang, J., Baskaran, R., Chung, L., Chen, R., Day, C. H., Padma, V. V., Huang, C. 2017; 63 (1): 17-22
View details for DOI 10.14715/cmb/2017.63.1.4

View details for Web of Science ID 000397291600004
Validation of the Body Concealment Scale for Scleroderma (BCSS): Replication in the Scleroderma Patient-centered Intervention Network (SPIN) Cohort. Body image Jewett, L. R., Kwakkenbos, L., Carrier, M. E., Malcarne, V. L., Harcourt, D., Rumsey, N., Mayes, M. D., Assassi, S., K�rner, A., Fox, R. S., Gholizadeh, S., Mills, S. D., Fortune, C., Thombs, B. D. 2017; 20: 99?106
Abstract

Body concealment is an important component of appearance distress for individuals with disfiguring conditions, including scleroderma. The objective was to replicate the validation study of the Body Concealment Scale for Scleroderma (BCSS) among 897 scleroderma patients. The factor structure of the BCSS was evaluated using confirmatory factor analysis and the Multiple-Indicator Multiple-Cause model examined differential item functioning of SWAP items for sex and age. Internal consistency reliability was assessed via Cronbach's alpha. Construct validity was assessed by comparing the BCSS with a measure of body image distress and measures of mental health and pain intensity. Results replicated the original validation study, where a bifactor model provided the best fit. The BCSS demonstrated strong internal consistency reliability and construct validity. Findings further support the BCSS as a valid measure of body concealment in scleroderma and provide new evidence that scores can be compared and combined across sexes and ages.

View details for DOI 10.1016/j.bodyim.2016.11.007

View details for PubMedID 28068643
Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Chung, L., Fairchild, R. M., Furst, D. E., Li, S., Alkassab, F., Bolster, M. B., Csuka, M. E., Derk, C. T., Domsic, R. T., Fischer, A., Frech, T. M., Gomberg-Maitland, M., Gordon, J. K., Hinchcliff, M., Hsu, V., Hummers, L. K., Khanna, D., Medsger, T. A., Molitor, J. A., Preston, I. R., Schiopu, E., Shapiro, L., Hant, F., Silver, R., Simms, R., Varga, J., Steen, V. D., Zamanian, R. T. 2017; 35 (4): S106?S113
View details for Web of Science ID 000418419000015
Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severity. JCI insight Lofgren, S., Hinchcliff, M., Carns, M., Wood, T., Aren, K., Arroyo, E., Cheung, P., Kuo, A., Valenzuela, A., Haemel, A., Wolters, P. J., Gordon, J., Spiera, R., Assassi, S., Boin, F., Chung, L., Fiorentino, D., Utz, P. J., Whitfield, M. L., Khatri, P. 2016; 1 (21)
Abstract

Systemic sclerosis (SSc) is a rare autoimmune disease with the highest case-fatality rate of all connective tissue diseases. Current efforts to determine patient response to a given treatment using the modified Rodnan skin score (mRSS) are complicated by interclinician variability, confounding, and the time required between sequential mRSS measurements to observe meaningful change. There is an unmet critical need for an objective metric of SSc disease severity. Here, we performed an integrated, multicohort analysis of SSc transcriptome data across 7 datasets from 6 centers composed of 515 samples. Using 158 skin samples from SSc patients and healthy controls recruited at 2 centers as a discovery cohort, we identified a 415-gene expression signature specific for SSc, and validated its ability to distinguish SSc patients from healthy controls in an additional 357 skin samples from 5 independent cohorts. Next, we defined the SSc skin severity score (4S). In every SSc cohort of skin biopsy samples analyzed in our study, 4S correlated significantly with mRSS, allowing objective quantification of SSc disease severity. Using transcriptome data from the largest longitudinal trial of SSc patients to date, we showed that 4S allowed us to objectively monitor individual SSc patients over time, as (a) the change in 4S of a patient is significantly correlated with change in the mRSS, and (b) the change in 4S at 12 months of treatment could predict the change in mRSS at 24 months. Our results suggest that 4S could be used to distinguish treatment responders from nonresponders prior to mRSS change. Our results demonstrate the potential clinical utility of a novel robust molecular signature and a computational approach to SSc disease severity quantification.

View details for DOI 10.1172/jci.insight.89073

View details for PubMedID 28018971

View details for PubMedCentralID PMC5161207
Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells ONCOTARGET Li, Q., Yin, L., Jones, L. W., Chu, G. C., Wu, J. B., Huang, J., Li, Q., You, S., Kim, J., Lu, Y., Mrdenovic, S., Wang, R., Freeman, M. R., Garraway, I., Lewis, M. S., Chung, L. W., Zhau, H. E. 2016; 7 (51): 84645-84657
Abstract

Lethal progression of prostate cancer metastasis can be improved by developing animal models that recapitulate the clinical conditions. We report here that cytokeratin 13 (KRT13), an intermediate filament protein, plays a directive role in prostate cancer bone, brain, and soft tissue metastases. KRT13 expression was elevated in bone, brain, and soft tissue metastatic prostate cancer cell lines and in primary and metastatic clinical prostate, lung, and breast cancer specimens. When KRT13 expression was determined at a single cell level in primary tumor tissues of 44 prostate cancer cases, KRT13 level predicted bone metastasis and the overall survival of prostate cancer patients. Genetically enforced KRT13 expression in human prostate cancer cell lines drove metastases toward mouse bone, brain and soft tissues through a RANKL-independent mechanism, as KRT13 altered the expression of genes associated with EMT, stemness, neuroendocrine/neuromimicry, osteomimicry, development, and extracellular matrices, but not receptor activator NF-?B ligand (RANKL) signaling networks in prostate cancer cells. Our results suggest new inhibitors targeting RANKL-independent pathways should be developed for the treatment of prostate cancer bone and soft tissue metastases.

View details for DOI 10.18632/oncotarget.13175

View details for Web of Science ID 000391353200069

View details for PubMedID 27835867
Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A Scleroderma Clinical Trials Consortium study SEMINARS IN ARTHRITIS AND RHEUMATISM Valenzuela, A., Baron, M., Herrick, A. L., Proudman, S., Stevens, W., Rodriguez-Reyna, T. S., Vacca, A., Medsger, T. A., Hinchcliff, M., Hsu, V., Wu, J. Y., Fiorentino, D., Chung, L. 2016; 46 (3): 344-349
Abstract

We sought to identify the clinical factors associated with calcinosis in an international multicenter collaborative effort with the Scleroderma Clinical Trials Consortium (SCTC).This is a retrospective cohort study of 5218 patients with systemic sclerosis (SSc). Logistic regression was used to obtain odds ratios (OR) relating calcinosis to various clinical features in multivariate analyses.A total of 1290 patients (24.7%) had calcinosis. In univariate analyses, patients with calcinosis were older than patients without calcinosis, more likely to be female, and had longer disease duration from the first non-Raynaud phenomenon symptom. Patients with calcinosis were more likely to have digital ulcers, telangiectasias, acro-osteolysis, cardiac disease, pulmonary hypertension, gastrointestinal involvement, arthritis, and osteoporosis, but less likely to have muscle disease. Anti-Scl-70, RNA-polymerase-III, and U1-RNP autoantibodies were significantly less common in patients with calcinosis, while anticentromere (ACA), anti-PM/Scl, and anticardiolipin antibodies were more frequent. In multivariate analysis, the strongest associations with calcinosis were digital ulcers (OR = 3.9; 95% CI: 2.7-5.5; p < 0.0001) and osteoporosis (OR = 4.2; 95% CI: 2.3-7.9; p < 0.0001).One quarter of patients with SSc have calcinosis at some time during their illness. Our data confirm a strong association of calcinosis with digital ulcers, and support a novel association with osteoporosis.

View details for DOI 10.1016/j.semarthrit.2016.05.008

View details for Web of Science ID 000390979200012

View details for PubMedID 27371996
Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry. Clinical and experimental rheumatology Chung, L., Fairchild, R. M., Furst, D. E., Li, S., Alkassab, F., Bolster, M. B., Csuka, M. E., Derk, C. T., Domsic, R. T., Fischer, A., Frech, T., Gomberg-Maitland, M., Gordon, J. K., Hinchcliff, M., Hsu, V., Hummers, L. K., Khanna, D., Medsger, T. A., Molitor, J. A., Preston, I. R., Schiopu, E., Shapiro, L., Hant, F., Silver, R., Simms, R., Varga, J., Steen, V. D., Zamanian, R. T. 2016: -?
Abstract

To assess the utility of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) in detecting and monitoring pulmonary hypertension (PH) in systemic sclerosis (SSc).PHAROS is a multicenter prospective cohort of SSc patients at high risk for developing pulmonary arterial hypertension (SSc-AR-PAH) or with a definitive diagnosis of SSc-PH. We evaluated 1) the sensitivity and specificity of BNP?64 and NT-proBNP?210 pg/mL for the detection of SSc-PAH and/ or SSc-PH in the SSc-AR-PAH population; 2) baseline and longitudinal BNP and NT-proBNP levels as predictors of progression to SSc-PAH and/or SSc-PH; 3) baseline BNP?180, NT-proBNP?553 pg/mL, and longitudinal changes in BNP and NT-proBNP as predictors of mortality in SSc-PH diagnosed patients.172 SSc-PH and 157 SSc-AR- PAH patients had natriuretic peptide levels available. Median BNP and NT-proBNP were significantly higher in the SSc-PH versus SSc-AR-PAH group. The sensitivity and specificity for SSc-PAH detection using baseline BNP?64 pg/mL was 71% and 59%; and for NT-proBNP?210 pg/mL, 73% and 78%. NT-proBNP showed stronger correlations with haemodynamic indicators of right ventricular dysfunction than BNP. Baseline creatinine, RVSP > 40 mmHg, and FVC%:DLco% ratio ?1.8 were associated with progression from SSc-AR-PAH to SSc-PH but no association with individual or combined baseline BNP and NT-proBNP levels was observed. Baseline and follow-up BNP or NT-proBNP levels were not predictive of death, however, a composite BNP/NT-proBNP group predicted mortality (HR 3.81 (2.08-6.99), p<.0001).NT-proBNP may be more useful than BNP in the detection and monitoring of PAH in SSc patients, but additional studies are necessary.

View details for PubMedID 27908301
Multi-Organ RNA-Sequencing of Systemic Sclerosis (SSc) Patients Shows Reproducible Gene Expression Profiles Across Organ Systems Mehta, B. K., Johnson, M. E., Archambault, K. A., Wood, T. A., Valenzuela, A., Crawford, A., Fiorentino, D., Fernandez-Becker, N., Becker, L., Nguyen, L., Boin, F., Wolters, P., Chung, L., Whitfield, M. WILEY. 2016
View details for Web of Science ID 000417143401207
Predictors of Long-Term Outcomes in Systemic Sclerosis Associated Pulmonary Arterial Hypertension from the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry Kolstad, K., Li, S., Steen, V. D., Chung, L. WILEY. 2016
View details for Web of Science ID 000417143405369
Comprehensive Characterization of Calcinosis in a Multicenter International Cohort of Patients with Systemic Sclerosis Valenzuela, A., Gordon, J. K., Sofia Rodriguez-Reyna, T., Proudman, S., Baron, M., Hinchcliff, M., Khanna, D., Young, A., Castelino, F. V., Schoenfeld, S. R., Steen, V. D., Fiorentino, D., Chung, L. WILEY. 2016
View details for Web of Science ID 000417143401240
Right Ventricular Load-Adaptability and Response to Therapy in Scleroderma Versus Idiopathic Pulmonary Arterial Hypertension French, S., Ouazani, N., Amsallem, M., Li, S., Zamanian, R. T., Chung, L., Haddad, F. WILEY. 2016
View details for Web of Science ID 000417143403065
Dermatomyositis and Pregnancy: Assessment of Disease Activity and Pregnancy Outcomes Complicated By Maternal Dermatomyositis Miller, G., Moore, E., Valenzuela, A., Chung, L., Werth, V. P. WILEY. 2016
View details for Web of Science ID 000417143404074
Immunosignature Technology Differentiates Patients with Systemic Sclerosis and Internal Organ Involvement Chung, L., Fiorentino, D., Gerwien, R., Jia, K., Legutki, J., Vergara, A., Zhu, L., Tarasow, T. M., Sykes, K. WILEY. 2016
View details for Web of Science ID 000417143403071
Combined cell surface carbonic anhydrase 9 and CD147 antigens enable high-efficiency capture of circulating tumor cells in clear cell renal cell carcinoma patients ONCOTARGET Liu, S., Tian, Z., Zhang, L., Hou, S., Hu, S., Wu, J., Jing, Y., Sun, H., Yu, F., Zhao, L., Wang, R., Tseng, H., Zhau, H. E., Chung, L. W., Wu, K., Wang, H., Wu, J. B., Nie, Y., Shao, C. 2016; 7 (37): 59877-59891
Abstract

Circulating tumor cells (CTCs) have emerged as promising tools for noninvasive cancer detection and prognosis. Most conventional approaches for capturing CTCs use an EpCAM-based enrichment strategy, which does not work well in cancers that show low or no expression of EpCAM, such as renal cell carcinoma (RCC). In this study, we developed a new set of cell surface markers including CA9 and CD147 as alternative CTC-capture antigens specifically designed for RCC patients. We showed that the expression of both CA9 and CD147 was prevalent in a RCC patient cohort (n=70) by immunohistochemical analysis, with both molecules in combination covering 97.1% of cases. The NanoVelcro platform combined with CA9-/CD147-capture antibodies demonstrated significantly higher efficiency for capturing both CTC-mimicking renal cancer cells and RCC CTCs in peripheral blood, compared to the conventional EpCAM-based method. Using immunofluorescence cytological validation at the single-cell level, we were able to identify bona fide CTCs in RCC patient blood following the well-accepted criteria in our CTC-capture system. We further demonstrated a significant association of CTC numbers as well as the CTC expression status of Vimentin, a mesenchymal marker, with disease progression, including pathologic features and clinical staging. These results provide new insights into developing novel, effective targets/approaches for capturing CTCs, making CTCs a valuable tool for improved cancer detection, prognosis and treatment in RCC.

View details for DOI 10.18632/oncotarget.10979

View details for Web of Science ID 000387153900087

View details for PubMedID 27494883
An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial. journal of rheumatology Khanna, D., Albera, C., Fischer, A., Khalidi, N., Raghu, G., Chung, L., Chen, D., Schiopu, E., Tagliaferri, M., Seibold, J. R., Gorina, E. 2016; 43 (9): 1672-1679
Abstract

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) shares a number of clinical features and pathogenic mechanisms with idiopathic pulmonary fibrosis (IPF). This study was designed to evaluate the tolerability of the IPF treatment pirfenidone in SSc-ILD. The known gastrointestinal, skin, and liver adverse events (AE) of pirfenidone are of importance given the involvement of these organs in SSc.All patients received pirfenidone and were randomized 1:1 to either a 2- or 4-week titration starting at 801 mg/day and finishing at a maintenance dose of 2403 mg/day. Patients received pirfenidone for 16 weeks in total. Assessments included treatment-emergent AE (TEAE) and exploratory disease outcomes.Sixty-three patients were randomized; 96.8% experienced a TEAE and more patients reported TEAE during the titration versus the maintenance period. The most commonly reported TEAE were consistent with those observed for pirfenidone in IPF (nausea, headache, fatigue) and were similar regardless of titration schedule. More patients discontinued treatment because of TEAE in the 2- versus 4-week titration group (5 vs 1, respectively); all discontinuation events occurred > 3 weeks after reaching the full dose of pirfenidone. Mycophenolate mofetil (MMF), taken by 63.5% of patients in addition to pirfenidone, did not appear to affect tolerability. Exploratory disease outcomes remained largely unchanged.Pirfenidone showed an acceptable tolerability profile in SSc-ILD, although a longer titration may be associated with better tolerability. Tolerability was not affected by concomitant MMF. The present findings support further investigation of pirfenidone in future clinical trials in patients with SSc-ILD.ClinicalTrials.gov; www.clinicaltrials.gov NCT01933334.

View details for DOI 10.3899/jrheum.151322

View details for PubMedID 27370878
Secondhand Smoke Exposure Enhances Cardiac Fibrosis Effects on the Aging Rat Hearts ACTA CARDIOLOGICA SINICA Wu, J., Chang-Lee, S. N., Day, C. H., Ho, T., Viswanadha, V. P., Chung, L., Hwang, J., Jong, G., Kuo, W., Huang, C. 2016; 32 (5): 594-603
Abstract

Examining aging rats exposed to secondhand smoke (SHS) engenders changes in left ventricular remodeling due to age- or disease-dependent alterations.Rats were placed in whole-body exposure chambers and exposed to 10 cigarettes. Filtered air was introduced into the chamber at a low rate. Rats were exposed to SHS for 30 min, twice a day, 5 days per week for 1 month. After 4 weeks SHS exposure, rats were sacrificed for morphological study with trichome staining and left ventricular remodeling related protein analysis using western blot.Characteristic fibrotic morphology in the left ventricle increased significantly with aging and exposure to SHS. Exposure to SHS elevated TGF?1/p-Smad2/3/CTGF and MMP2/MMP9 protein expression levels (p < 0.05). No significant differences in FGF-2 and UPA protein expression were noted as a result of SHS exposure. However, TIMP-1, TIMP-2, TIMP-3 and TIMP-4 protein expression were suppressed by SHS exposure. We also observed increased TGF?1/p-Smad2/3/CTGF (p < 0.01), FGF-2/UPA (p < 0.05) and decreased TIMPs protein expression levels. Corresponding MMP2 and MMP9 upregulation occurred with aging and exposure to SHS. TGF?1/p-Smad2/3/CTGF and FGF-2/UPA protein expression from SHS exposure were higher than that from aging. In contrast, MMP2 and MMP9 were increased in aging rats compared with SHS exposed rats (p < 0.05); however, TIMP-1 (p < 0.01), TIMP-2 (p < 0.01) and TIMP-3 (p < 0.05) were decreased. TIMP-4 protein expression levels were decreased compared with SHS exposed rats (p < 0.01).Aging and SHS exposure in rats will produce elevated fibrosis. Exposure to SHS will accelerate aging and left ventricular fibrosis.

View details for DOI 10.6515/ACS20150824C

View details for Web of Science ID 000384516400010

View details for PubMedID 27713609
Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial LANCET Khanna, D., Denton, C. P., Jahreis, A., van Laar, J. M., Frech, T. M., Anderson, M. E., Baron, M., Chung, L., Fierlbeck, G., Lakshminarayanan, S., Allanore, Y., Pope, J. E., Riemekasten, G., Steen, V., Mueller-Ladner, U., Lafyatis, R., Stifano, G., Spotswood, H., Chen-Harris, H., Dziadek, S., Morimoto, A., Sornasse, T., Siegel, J., Furst, D. E. 2016; 387 (10038): 2630-2640
Abstract

Systemic sclerosis is a rare disabling autoimmune disease with few treatment options. The efficacy and safety of tocilizumab, an interleukin 6 receptor-? inhibitor, was assessed in the faSScinate phase 2 trial in patients with systemic sclerosis.We did this double-blind, placebo-controlled study at 35 hospitals in Canada, France, Germany, the UK, and the USA. We enrolled adults with progressive systemic sclerosis of 5 or fewer years' duration from first non-Raynaud's sign or symptom. Patients were randomly assigned (1:1) to weekly subcutaneous tocilizumab 162 mg or placebo. The primary endpoint was the difference in mean change from baseline in modified Rodnan skin score at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT01532869.We enrolled 87 patients: 43 assigned to tocilizumab and 44 assigned to placebo. The least squares mean change in modified Rodnan skin score at 24 weeks was -3�92 in the tocilizumab group and -1�22 in the placebo group (difference -2�70, 95% CI -5�85 to 0�45; p=0�0915). The least squares mean change at 48 weeks was -6�33 in the tocilizumab group and -2�77 in the placebo group (treatment difference -3�55, 95% CI -7�23 to 0�12; p=0�0579). In one of several exploratory analyses, fewer patients in the tocilizumab group than in the placebo group had a decline in percent predicted forced vital capacity at 48 weeks (p=0�0373). However, we detected no significant difference in disability, fatigue, itching, or patient or clinician global disease severity. 42 (98%) of 43 patients in the tocilizumab group versus 40 (91%) of 44 in the placebo group had adverse events. 14 (33%) versus 15 (34%) had serious adverse events. Serious infections were more common in the tocilizumab group (seven [16%] of 43 patients) than in the placebo group (two [5%] of 44). One patient died in relation to tocilizumab treatment.Tocilizumab was not associated with a significant reduction in skin thickening. However, the difference was greater in the tocilizumab group than in the placebo group and we found some evidence of less decline in forced vital capacity. The efficacy and safety of tocilizumab should be investigated in a phase 3 trial before definitive conclusions can be made about its risks and benefits.F Hoffmann-La Roche, Genentech.

View details for DOI 10.1016/S0140-6736(16)00232-4

View details for Web of Science ID 000378390500031

View details for PubMedID 27156934
Characterization of patients with clinical overlap of morphea and systemic sclerosis: A case series JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Chen, J. K., Chung, L., Fiorentino, D. F. 2016; 74 (6): 1272?74
View details for PubMedID 27185438
Intestinal pseudo-obstruction in patients with systemic sclerosis: an analysis of the Nationwide Inpatient Sample. Rheumatology Valenzuela, A., Li, S., Becker, L., Fernandez-Becker, N., Khanna, D., Nguyen, L., Chung, L. 2016; 55 (4): 654-658
Abstract

Intestinal pseudo-obstruction is a rare gastrointestinal complication in patients with SSc without large studies examining its prevalence or outcomes. We aimed to compare outcomes in SSc patients with intestinal pseudo-obstruction to patients with intestinal pseudo-obstruction secondary to other causes, and SSc patients without intestinal pseudo-obstruction.This is a case-control study using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample for the period 2002-2011. We included patients with the previously validated International Classification of Diseases-Clinical Modification-9 code 710.1 for SSc in combination with codes for intestinal pseudo-obstruction, and determined length of hospitalization and the risks for surgical procedures, use of total parenteral nutrition (TPN) and in-hospital mortality.A total of 193 610 SSc hospitalizations occurred in the USA between 2002 and 2011, of which 5.4% (n = 10 386) were associated with a concurrent intestinal pseudo-obstruction diagnosis (cases). In-hospital mortality was 7.3%. In multivariate analyses, cases were more likely to die during the inpatient stay and to receive TPN than patients with idiopathic intestinal pseudo-obstruction (control group 1), patients with intestinal pseudo-obstruction and diabetes (control group 2), and SSc patients without intestinal pseudo-obstruction (control group 3). Cases had longer in-hospital stay than control groups 2 and 3, and were less likely to undergo surgical procedures than control groups 1 and 2.Intestinal pseudo-obstruction is a rare cause of hospitalization in patients with SSc, but is associated with high in-hospital mortality in comparison with other SSc patients and those with intestinal pseudo-obstruction secondary to other causes.

View details for DOI 10.1093/rheumatology/kev393

View details for PubMedID 26615031
SREBP-2 promotes stem cell-like properties and metastasis by transcriptional activation of c-Myc in prostate cancer ONCOTARGET Li, X., Wu, J. B., Li, Q., Shigemura, K., Chung, L. W., Huang, W. 2016; 7 (11): 12869-12884
Abstract

Sterol regulatory element-binding protein-2 (SREBP-2) transcription factor mainly controls cholesterol biosynthesis and homeostasis in normal cells. The role of SREBP-2 in lethal prostate cancer (PCa) progression remains to be elucidated. Here, we showed that expression of SREBP-2 was elevated in advanced pathologic grade and metastatic PCa and significantly associated with poor clinical outcomes. Biofunctional analyses demonstrated that SREBP-2 induced PCa cell proliferation, invasion and migration. Furthermore, overexpression of SREBP-2 increased the PCa stem cell population, prostasphere-forming ability and tumor-initiating capability, whereas genetic silencing of SREBP-2 inhibited PCa cell growth, stemness, and xenograft tumor growth and metastasis. Clinical and mechanistic data showed that SREBP-2 was positively correlated with c-Myc and induced c-Myc activation by directly interacting with an SREBP-2-binding element in the 5'-flanking c-Myc promoter region to drive stemness and metastasis. Collectively, these clinical and experimental results reveal a novel role of SREBP-2 in the induction of a stem cell-like phenotype and PCa metastasis, which sheds light on translational potential by targeting SREBP-2 as a promising therapeutic approach in PCa.

View details for Web of Science ID 000375679600084

View details for PubMedID 26883200
Corticosteroids in Myositis and Scleroderma. Rheumatic diseases clinics of North America Postolova, A., Chen, J. K., Chung, L. 2016; 42 (1): 103-118
Abstract

Idiopathic inflammatory myopathies (IIMs) involve inflammation of the muscles and are classified by the patterns of presentation and immunohistopathologic features on skin and muscle biopsy into 4 categories: dermatomyositis, polymyositis, inclusion body myositis, and immune-mediated necrotizing myopathy. Systemic corticosteroid (CS) treatment is the standard of care for IIM with muscle and organ involvement. The extracutaneous features of systemic sclerosis are frequently treated with CS; however, high doses have been associated with scleroderma renal crisis in high-risk patients. Although CS can be effective first-line agents, their significant side effect profile encourages concomitant treatment with other immunosuppressive medications to enable timely tapering.

View details for DOI 10.1016/j.rdc.2015.08.011

View details for PubMedID 26611554
Corticosteroids in Myositis and Scleroderma. Rheumatic diseases clinics of North America Postolova, A., Chen, J. K., Chung, L. 2016; 42 (1): 103-118
Abstract

Idiopathic inflammatory myopathies (IIMs) involve inflammation of the muscles and are classified by the patterns of presentation and immunohistopathologic features on skin and muscle biopsy into 4 categories: dermatomyositis, polymyositis, inclusion body myositis, and immune-mediated necrotizing myopathy. Systemic corticosteroid (CS) treatment is the standard of care for IIM with muscle and organ involvement. The extracutaneous features of systemic sclerosis are frequently treated with CS; however, high doses have been associated with scleroderma renal crisis in high-risk patients. Although CS can be effective first-line agents, their significant side effect profile encourages concomitant treatment with other immunosuppressive medications to enable timely tapering.

View details for DOI 10.1016/j.rdc.2015.08.011

View details for PubMedID 26611554
Digital Sympathectomy in Patients With Scleroderma: An Overview of the Practice and Referral Patterns and Perceptions of Rheumatologists. Annals of plastic surgery Chiou, G., Crowe, C., Suarez, P., Chung, L., Curtin, C., Chang, J. 2015; 75 (6): 637-643
Abstract

Periarterial sympathectomy is a treatment option for patients with systemic sclerosis (SSc) suffering from digital vasculopathy. Despite potential benefits of ulcer healing, pain improvement, and amputation prevention, this operation appears to be infrequently performed. The aims of our study are as follows: (1) to assess national digital sympathectomy rates in patients with SSc and (2) to improve our understanding of referring physicians' perceptions of operative management and access to hand surgeons. Our hypothesis is that rheumatologists' practices largely influence their referral patterns for digital sympathectomy.To determine the rates and demographics of hospitalized patients with SSc who had undergone digital sympathectomy, we queried the Nationwide Inpatient Sample from 2006 to 2010. Additionally, we mailed a self-administered survey to a national sample of 500 board-certified rheumatologists to elicit their practice patterns and perceptions of digital sympathectomy. Using logistic regression, we analyzed potential predictor variables associated with rheumatologists performing the following: (1) routinely counseling patients about digital sympathectomy and (2) expressing the desire to refer these patients for operative evaluation.Of 348,539 hospitalizations associated with a diagnosis of SSc, only 0.2% were for digital sympathectomy. Our questionnaire revealed that only 50% of rheumatologists routinely counseled, whereas 67% expressed the desire to refer. Factors associated with increased rheumatologists' interest in surgical management for patients with SSc included positive perception of the operation's efficacy, comfort with postoperative management, and interdisciplinary relationship with a hand surgeon.Critical components to increasing appropriate utilization of digital sympathectomy include enhancing rheumatologists' understanding of the operation, comfort with postoperative management, and promoting strong, interdisciplinary relationships with hand surgeons. Increasing education and awareness, as well as establishing a solid referral network of hand surgeons may thereby improve patient access to digital sympathectomy.

View details for DOI 10.1097/SAP.0000000000000614

View details for PubMedID 26418780
Anti-cancer efficacy of SREBP inhibitor, alone or in combination with docetaxel, in prostate cancer harboring p53 mutations ONCOTARGET Li, X., Wu, J. B., Chung, L. W., Huang, W. 2015; 6 (38): 41018-41032
Abstract

Mutant p53 proteins (mutant p53s) have oncogenic gain-of-function properties correlated with tumor grade, castration resistance, and prostate cancer (PCa) tumor recurrence. Docetaxel is a standard first-line treatment for metastatic castration-resistant PCa (mCRPC) after the failure of hormone therapy. However, most mCRPC patients who receive docetaxel experience only transient benefits and rapidly develop incurable drug resistance, which is closely correlated with the p53 mutation status. Mutant p53s were recently reported to regulate the metabolic pathways via sterol regulatory element-binding proteins (SREBPs). Therefore, targeting the SREBP metabolic pathways with docetaxel as a combination therapy may offer a potential strategy to improve anti-tumor efficacy and delay cellular drug resistance in mCRPC harboring mutant p53s. Our previous data showed that fatostatin, a new SREBP inhibitor, inhibited cell proliferation and induced apoptosis in androgen receptor (AR)-positive PCa cell lines and xenograft mouse models. In this study, we demonstrated that mutant p53s activate the SREBP-mediated metabolic pathways in metastatic AR-negative PCa cells carrying mutant p53s. By blocking the SREBP pathways, fatostatin inhibited cell growth and induced apoptosis in metastatic AR-negative PCa cells harboring mutant p53s. Furthermore, the combination of fatostatin and docetaxel resulted in greater proliferation inhibition and apoptosis induction compared with single agent treatment in PCa cells in vitro and in vivo, especially those with mutant p53s. These data suggest for the first time that fatostatin alone or in combination with docetaxel could be exploited as a novel and promising therapy for metastatic PCa harboring p53 mutations.

View details for Web of Science ID 000366115500048

View details for PubMedID 26512780
Survival in systemic sclerosis-pulmonary arterial hypertension by serum autoantibody status in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) Registry SEMINARS IN ARTHRITIS AND RHEUMATISM Hinchcliff, M., Khanna, S., Hsu, V. M., Lee, J., Almagor, O., Chang, R. W., Steen, V., Chung, L. 2015; 45 (3): 309-314
Abstract

To determine the association between serum autoantibodies and survival in patients with incident systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) Registry.Patients with definite PAH diagnosed by right heart catheterization within 6 months of registry enrollment were studied. Serum autoantibodies were assayed at each participating institution's clinical laboratory. Mortality data were collected from electronic medical records and/or the Social Security Death Index. Kaplan-Meier survival estimates were reported for five autoantibody groups (anticentromere/AC, nucleolar ANA/NUC, anti-topoisomerase/Scl-70, overlapping or non-specific autoantibodies/other, and a combined group with similar survival consisting of RNA polymerase III, U1RNP, and autoantibody-negative patients). Cox proportional hazards models permitted examination of the association between autoantibody groups and overall survival, controlling for age, sex, race, and SSc disease duration.In all, 162 subjects had PAH, and serum autoantibody and survival information; 60 (37%) had AC, 39 (24%) NUC, 11 (7%) Scl-70, 28 (17%) had other, 9 (6%) RNA pol, 8 (5%) U1RNP autoantibodies, and 7 (4%) had negative antibodies; 32 (20%) subjects died over a median follow-up time of 2.1 years (range: 0.01-6.8); 1- and 3-year survival estimates were, respectively, 94% and 78% for AC, 94% and 72% for NUC, 89% and 63% for Scl-70, 92% and 79% for the other group, and 100% and 93% for the combined group. Unadjusted and adjusted hazard ratios revealed no statistically significant association between risk of death and autoantibodies.Anticentromere and NUC autoantibodies are prevalent in SSc-PAH patients. An association between serum autoantibodies and survival in patients with SSc-PAH was not identified in the PHAROS cohort.

View details for DOI 10.1016/j.semarthrit.2015.06.011

View details for PubMedID 26210782
Leukotriene B-4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension HYPERTENSION Qian, J., Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Shuffle, E. M., Tu, A. B., Valenzuela, A., Jiang, S., Zamanian, R. T., Fiorentino, D. F., Voelkel, N. F., Peters-Golden, M., Stenmark, K. R., Chung, L., Rabinovitch, M., Nicolls, M. R. 2015; 66 (6): 1227-1239
Abstract

A recent study demonstrated a significant role for leukotriene B4 (LTB4) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB4 enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein-coupled receptor, BLT1. LTB4 activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB4 further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts.

View details for DOI 10.1161/HYPERTENSIONAHA.115.06370

View details for PubMedID 26558820
Calcinosis: pathophysiology and management. Current opinion in rheumatology Valenzuela, A., Chung, L. 2015; 27 (6): 542-548
Abstract

This article reviews the most updated literature regarding the epidemiology, pathophysiology, diagnosis, and treatment of calcinosis cutis in patients with systemic sclerosis (SSc).Our review identified observational studies that describe the frequency of calcinosis in SSc and associated clinical features, genetic studies in animal models of heritable disorders leading to calcium deposition, and case series and case reports describing new diagnostic approaches and therapeutic interventions.Calcinosis cutis is the deposition of calcium in the skin and subcutaneous tissues. It affects almost one quarter of patients with SSc, and is associated with longer disease duration, digital ulcers, acroosteolysis, positive anticentromere antibody, and positive anti-PM/Scl antibody. Local trauma, chronic inflammation, and vascular hypoxia have been proposed as potential pathomechanisms. The development of mouse models that mimic heritable ectopic mineralization disorders are contributing to the understanding of the process of calcification. Diagnosis can be made clinically or with plain radiography. Experimental diagnostic studies include ultrasonography, multidetector computed tomography, and dual-energy computed tomography. Several pharmacologic therapies have been tried for calcinosis with variable results, but surgical excision of calcium deposits remains the mainstay of treatment.

View details for DOI 10.1097/BOR.0000000000000220

View details for PubMedID 26352733
Validation of the Cutaneous Dermatomyositis Disease Area and Severity Index: characterizing disease severity and assessing responsiveness to clinical change BRITISH JOURNAL OF DERMATOLOGY Anyanwu, C. O., Fiorentino, D. F., Chung, L., Dzuong, C., Wang, Y., Okawa, J., Carr, K., PROPERT, K. J., Werth, V. P. 2015; 173 (4): 969-974
Abstract

The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) was developed for use in clinical trials and longitudinal patient assessment.To characterize disease severity using the CDASI and assess the responsiveness of this instrument to clinically meaningful changes in disease activity.Patients with cutaneous dermatomyositis at the University of Pennsylvania (UPenn, n�=�93) and Stanford University (Stanford, n�=�106) were prospectively evaluated using the CDASI, physician global assessment (PGA) Likert scales and a visual analogue scale (VAS). Data was analysed using logistic regression models and receiver operating characteristic curves to select cut-offs.Baseline CDASI activity scores for the patients evaluated at UPenn ranged from 0 to 47 (median 17), and baseline PGA VAS scores ranged from 0 to 9�6 (median 1�1). At UPenn a CDASI activity score of 19 differentiated mild from moderate and severe disease. At Stanford baseline CDASI scores ranged from 0 to 48 (median 21), baseline PGA VAS scores ranged from 0 to 9�7 (median 4�2) and CDASI activity scores of 14 or less characterized mild disease. When a 2-cm change in the PGA VAS was regarded as a clinically significant improvement, a 4-point (UPenn) or 5-point (Stanford) change in CDASI reflected a minimal clinically significant response.The CDASI is a valid and responsive measure that can be used to characterize cutaneous dermatomyositis severity and detect improvement in disease activity. Variations in cut-offs may be due to differences in disease severity between the two populations or inter-rater variations in the use of the external gold measures.

View details for DOI 10.1111/bjd.13915

View details for Web of Science ID 000363896800020

View details for PubMedID 25994337

View details for PubMedCentralID PMC4878996
Activity of Type I and Type II Interferons in Dermatomyositis Skin Is Correlated with Characteristic Pathologic Features Leatham, H. W., Rieger, K., Chung, L., Li, S., Higgs, B. W., Yao, Y., Sarin, K., Fiorentino, D. WILEY-BLACKWELL. 2015
View details for Web of Science ID 000370860202208
Calcinosis Is Associated with Digital Ulcers and Osteoporosis in Patients with Systemic Sclerosis Valenzuela, A., Baron, M., Herrick, A. L., Proudman, S., Stevens, W., Sofia Rodriguez-Reyna, T., Vacca, A., Medsger, T. A., Hinchcliff, M., Hsu, V., Fiorentino, D., Chung, L., Canadian Scleroderma Res Grp WILEY-BLACKWELL. 2015
View details for Web of Science ID 000370860202096
Dermatomyositis Associated with Anti-Melanoma Differentiation-Associated Gene 5 Antibodies: A Longitudinal Analysis Lewis, M., Li, S., Chung, L., Fiorentino, D. WILEY-BLACKWELL. 2015
View details for Web of Science ID 000370860203770
There Is a Need for New Systemic Sclerosis Subset Criteria: A Content Analytic Approach Johnson, S., Soowamber, M., Fransen, J., Khanna, D., van den Hoogen, F. J., Baron, M., Cerinic, M., Denton, C. P., Medsger, T. A., Carreira, P. E., Riemekasten, G., Distler, J. W., Gabrielli, A., Steen, V. D., Chung, L., Silver, R., Varga, J., Mueller-Ladner, U., Vonk, M. C., Walker, U. A., Wollheim, F., Herrick, A. L., Furst, D. E., Czirjak, L., Kowal-Bielecka, O., Del Galdo, F., Cutolo, M., Hunzelmann, N., Murray, C., Foeldvari, I., Mouthon, L., Damjanov, N., Kahaleh, B., Frech, T. M., Assassi, S., Saketkoo, L., Pope, J. E. WILEY-BLACKWELL. 2015
View details for Web of Science ID 000370860203294
Safety and Tolerability of Pirfenidone in Patients with Systemic Sclerosis Interstitial Lung Disease Khanna, D., Albera, C., Fischer, A., Seibold, J. R., Khalidi, N. A., Raghu, G., Chung, L., Schiopu, E., Chen, D., Gorina, E. WILEY-BLACKWELL. 2015
View details for Web of Science ID 000370860204683
Near-infrared fluorescence heptamethine carbocyanine dyes mediate imaging and targeted drug delivery for human brain tumor BIOMATERIALS Wu, J. B., Shi, C., Chu, G. C., Xu, Q., Zhang, Y., Li, Q., Yu, J. S., Zhau, H. E., Chung, L. W. 2015; 67: 1-10
Abstract

Brain tumors and brain metastases are among the deadliest malignancies of all human cancers, largely due to the cellular blood-brain and blood-tumor barriers that limit the delivery of imaging and therapeutic agents from the systemic circulation to tumors. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. Here we identified and synthesized a group of near-infrared fluorescence (NIRF) heptamethine carbocyanine dyes and derivative NIRF dye-drug conjugates for effective imaging and therapeutic targeting of brain tumors of either primary or metastatic origin in mice, which is mechanistically mediated by tumor hypoxia and organic anion-transporting polypeptide genes. We also demonstrate that these dyes, when conjugated to chemotherapeutic agents such as gemcitabine, significantly restricted the growth of both intracranial glioma xenografts and prostate tumor brain metastases and prolonged survival in mice. These results show promise in the application of NIRF dyes as novel theranostic agents for the detection and treatment of brain tumors.

View details for DOI 10.1016/j.biomaterials.2015.07.028

View details for Web of Science ID 000361078600001

View details for PubMedID 26197410
Myopathy associated with SSc a joint EUSTAR-SCTC sub-cohort initiative Maurer, B., Jaeger, V., Chung, L., Hsu, V., Walker, U., Distler, O., EUSTAR-SCTC E M H SWISS MEDICAL PUBLISHERS LTD. 2015: 8S
View details for Web of Science ID 000447700900020
Surgical treatment of systemic sclerosis-is it justified to offer peripheral sympathectomy earlier in the disease process? Microsurgery Momeni, A., Sorice, S. C., Valenzuela, A., Fiorentino, D. F., Chung, L., Chang, J. 2015; 35 (6): 441-446
Abstract

Systemic sclerosis (SSc) is a rare connective tissue disease associated with significant digital vasculopathy. Peripheral sympathectomy is frequently offered late in the disease process after severe digital ischemia has already occurred with patients being symptomatic for numerous years. The purpose of the present study was to analyze the results of peripheral sympathectomy in patients with a confirmed diagnosis of SSc.A retrospective analysis of 17 patients (26 hands) who underwent peripheral sympathectomy between January 2003 and September 2013 was performed. Data regarding patient demographics, clinical features, and postoperative outcomes were retrieved. Of note, preoperative pain was present in all patients with a mean duration of 9.6 years prior to peripheral sympathectomy.Pain improvement/resolution was seen in 24 hands (92.3%). Digital ulcers healed in all patients with only two patients (two hands; 7.7%) requiring surgical intervention for ulcer recurrence 6 months and 4.5 years later. Minor complications were seen in seven hands (26.9%); including infection, wound opening, and stitch abscess, but none required surgical intervention. Seven of eight patients queried would have preferred surgical treatment at an earlier point in the disease process.Peripheral sympathectomy is a well-tolerated procedure in patients with SSc and is associated with predictable pain relief and ulcer healing in the majority of patients. In light of these findings it seems prudent to offer surgical treatment not as a last resort but rather earlier in the disease process to decrease the duration that patients suffer pain. � 2015 Wiley Periodicals, Inc. Microsurgery, 2015.

View details for DOI 10.1002/micr.22379

View details for PubMedID 25585522
Safety and tolerability of pirfenidone (PFD) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD)-The LOTUSS study Khanna, D., Albera, C., Fischer, A., Seibold, J., Raghu, G., Khalidi, N., Chung, L., Schiopu, E., Chen, D., Gorina, E. EUROPEAN RESPIRATORY SOC JOURNALS LTD. 2015
View details for DOI 10.1183/13993003.congress-2015.OA4489

View details for Web of Science ID 000451979400370
Monitoring and Diagnostic Approaches for Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis. Rheumatic diseases clinics of North America Valenzuela, A., Nandagopal, S., Steen, V. D., Chung, L. 2015; 41 (3): 489-506
Abstract

Pulmonary arterial hypertension (PAH) is one of the leading causes of death in patients with systemic sclerosis (SSc). Given the high prevalence and poor survival of SSc-PAH, and that aggressive management of mild disease may be associated with better outcomes, screening is critical. Right heart catheterization (RHC) is the gold standard for the definitive diagnosis of PAH, and should be performed in those patients in whom this diagnosis is suspected. Once a diagnosis of PAH is confirmed by RHC, treatment with PAH-specific therapies should be initiated as soon as possible.

View details for DOI 10.1016/j.rdc.2015.04.009

View details for PubMedID 26210131
Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis ARTHRITIS RESEARCH & THERAPY Chakravarty, E. F., Martyanov, V., Fiorentino, D., Wood, T. A., Haddon, D. J., Jarrell, J. A., Utz, P. J., Genovese, M. C., Whitfield, M. L., Chung, L. 2015; 17
Abstract

Systemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic.Adult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ?30% post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment.Ten subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud's symptom was significantly longer (8.8 � 3.8 years vs. 2.4 � 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71%) randomized to abatacept and one out of three patients (33%) randomized to placebo experienced ?30% improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (-8.6 � 7.5, p = 0.0625) while those in the placebo group did not (-2.3 � 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (-13.5 � 3.1 vs. -4.5 � 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks.Clinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin.ClinicalTrials.gov NCT00442611. Registered 1 March 2007.

View details for DOI 10.1186/s13075-015-0669-3

View details for Web of Science ID 000357069900001

View details for PubMedID 26071192

View details for PubMedCentralID PMC4487200
Cutaneous ulceration in dermatomyositis: association with anti-melanoma differentiation-associated gene 5 antibodies and interstitial lung disease. Arthritis care & research Narang, N. S., Casciola-Rosen, L., Li, S., Chung, L., Fiorentino, D. F. 2015; 67 (5): 667-672
Abstract

To identify clinical and serologic correlates of cutaneous ulcers in dermatomyositis (DM).We retrospectively examined a cohort of 152 DM patients. We compared the features of patients with ulcers to those without ulcers using chi-square or Fisher's exact tests and used univariate and multivariate logistic regression models to assess the association between ulcers and clinical features such as malignancy, interstitial lung disease (ILD), and amyopathic disease.Forty-three patients (28%) had cutaneous ulcers. Nearly half the patients had ulcers present in more than 1 location: 24 (56%) had ulcers over the extensor surfaces of joints, 18 (42%) at the digital pulp or periungual areas, and 25 (58%) had ulcers located elsewhere. In univariate analysis ulcers were associated with Asian race, but not with other clinical and demographic features, including malignancy or ILD. In multivariate analysis ulcers were significantly associated with anti-melanoma differentiation gene 5 (anti-MDA5) antibodies (odds ratio 10.14, 95% confidence interval 1.95-52.78; P?=?0.0059) and this was greatest for ulcers located at the digital pulp. In patients with cutaneous ulcers, ILD risk was specifically increased only in patients with anti-MDA5-positive antibodies.We confirmed the strong association between anti-MDA5 antibodies and cutaneous ulcers, with the novel finding that the association of cutaneous ulcers with ILD depends upon the presence of anti-MDA5 antibodies. DM patients who display this cutaneous phenotype should undergo appropriate evaluation for ILD.

View details for DOI 10.1002/acr.22498

View details for PubMedID 25331610

View details for PubMedCentralID PMC4404195
Connective tissue disease-associated pulmonary arterial hypertension. Rheumatic diseases clinics of North America Sung, Y. K., Chung, L. 2015; 41 (2): 295-313
Abstract

Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling of pulmonary arterioles that leads to increased pulmonary vascular resistance, right heart failure, and death. It is associated with connective tissue diseases, including systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. PAH is characterized by dyspnea on exertion and fatigue. Syncopal events suggest severe disease. Patients may present with signs of right heart failure. One- and 3-year survival rates are approximately 81% and 52%, respectively. Given the high prevalence and mortality, algorithms for screening are currently under investigation and will hopefully lead to earlier diagnosis and improved survival.

View details for DOI 10.1016/j.rdc.2015.01.003

View details for PubMedID 25836644
Validation of the ICD-9-CM code for systemic sclerosis using updated ACR/EULAR classification criteria SCANDINAVIAN JOURNAL OF RHEUMATOLOGY VALENZUELA, A., Yaqub, A., Fiorentino, D., Krishnan, E., Chung, L. 2015; 44 (3): 253-255
View details for DOI 10.3109/03009742.2015.1008038

View details for Web of Science ID 000354392800013

View details for PubMedID 25744697
Connective Tissue Disease-Associated Pulmonary Arterial Hypertension RHEUMATIC DISEASE CLINICS OF NORTH AMERICA Sung, Y. K., Chung, L. 2015; 41 (2): 295-?
Abstract

Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling of pulmonary arterioles that leads to increased pulmonary vascular resistance, right heart failure, and death. It is associated with connective tissue diseases, including systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. PAH is characterized by dyspnea on exertion and fatigue. Syncopal events suggest severe disease. Patients may present with signs of right heart failure. One- and 3-year survival rates are approximately 81% and 52%, respectively. Given the high prevalence and mortality, algorithms for screening are currently under investigation and will hopefully lead to earlier diagnosis and improved survival.

View details for DOI 10.1016/j.rdc.2015.01.003

View details for Web of Science ID 000353435900011
Distinctive cutaneous and systemic features associated with antitranscriptional intermediary factor-1? antibodies in adults with dermatomyositis. Journal of the American Academy of Dermatology Fiorentino, D. F., Kuo, K., Chung, L., Zaba, L., Li, S., Casciola-Rosen, L. 2015; 72 (3): 449-455
Abstract

Antibodies against transcriptional intermediary factor (TIF)-1? are associated with malignancy in dermatomyositis (DM). Identification of clinical findings associated with anti-TIF-1? antibodies in DM is a high priority for both patient diagnosis and risk assessment.We sought to define the clinical phenotype of patients with anti-TIF-1? DM.Using a novel, sensitive, and specific assay for anti-TIF-1? antibodies, we retrospectively tested plasma from 134 adult patients with DM and examined associations between anti-TIF-1? antibodies and particular clinical and laboratory features.In all, 55 (41%) patients had autoantibodies to TIF-1?. Anti-TIF-1? positive patients were less likely to have systemic features including interstitial lung disease, Raynaud phenomenon, and arthritis/arthralgia. Patients with TIF-1? autoantibodies had more extensive skin involvement, and some patients manifested characteristic findings including palmar hyperkeratotic papules, psoriasis-like lesions and a novel finding of hypopigmented and telangiectatic ("red on white") patches.This was a retrospective study from a single tertiary referral center.TIF-1? is the most commonly targeted DM-specific autoantigen in adults in a large US cohort. Although these patients tend to have less systemic involvement, their skin disease is often extensive and characteristic. Recognition of cutaneous findings in anti-TIF-1? positive patients may allow more accurate and timely diagnosis and effective treatment of patients with DM.

View details for DOI 10.1016/j.jaad.2014.12.009

View details for PubMedID 25595720
Validation of a Novel Radiographic Scoring System for Calcinosis Affecting the Hands of Patients With Systemic Sclerosis ARTHRITIS CARE & RESEARCH Chung, L., Valenzuela, A., Fiorentino, D., Stevens, K., Li, S., Harris, J., Hutchinson, C., Assassi, S., Beretta, L., Lakshminarayanan, S., Rodriguez-Reyna, T. S., Denton, C. P., Taillefer, R. G., Herrick, A. L., Baron, M. 2015; 67 (3): 425-430
Abstract

Objective: There are currently no validated outcome measures to assess calcinosis severity in systemic sclerosis (SSc). We sought to develop and validate a novel radiographic scoring system for calcinosis affecting the hands of SSc patients for potential use in future clinical trials. Methods: Following a 1-hour teleconference training session, 12 investigators (8 rheumatologists, 1 dermatologist, 3 radiologists) scored 12 hand radiographs in random order using two scoring systems (termed "simple" and "complex"), and re-scored 2 randomly assigned radiographs after a minimum of 24 hours. Inter-rater and intra-rater reliability were assessed using a weighted kappa coefficient for the simple system, and intraclass correlation coefficient (ICC) for the complex system (ICC < 0.4 poor, 0.4-0.7 moderate, > 0.7 excellent). Results: Mean time to complete the complex scoring system was significantly longer than the simple scoring system (4.0 vs. 0.4 minutes, p<.0001). Overall inter-rater reliability for the simple scoring system was poor (kappa=0.39, 95% CI 0.1-0.52), but improved if dichotomized as mild/moderate vs. severe (kappa=0.51, 95% CI 0.26-0.7). Inter-rater reliability was excellent for the complex scoring system (ICC=0.89, 95% CI 0.86-0.92). Intra-rater reliability was moderate for the simple scoring system (kappa=0.67, 95% CI 0.37-0.96), but almost perfect for the complex scoring system (ICC=0.93, 95%CI 0.89-0.97). Conclusion: We developed a novel radiographic scoring system that accounts for the area coverage, density, and anatomic location of calcinosis affecting the hands in patients with SSc. This scoring system is feasible with excellent reliability and should undergo further validation testing for use in clinical trials. � 2014 American College of Rheumatology.

View details for DOI 10.1002/acr.22434

View details for PubMedID 25155948
Monoamine Oxidase A Inhibitor-Near-Infrared Dye Conjugate Reduces Prostate Tumor Growth JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wu, J. B., Lin, T., Gallagher, J. D., Kushal, S., Chung, L. W., Zhau, H. E., Oenyuk, B. Z., Shih, J. C. 2015; 137 (6): 2366-2374
Abstract

Development of anti-cancer agents with high tumor-targeting specificity and efficacy is critical for modern multidisciplinary cancer research. Monoamine oxidase A (MAOA), a mitochondria-bound enzyme, degrades monoamine neurotransmitters and dietary monoamines. Recent evidence suggests a correlation between increased MAOA expression and prostate cancer (PCa) progression with poor outcomes for patients. MAOA induces epithelial-mesenchymal transition (EMT) and augments hypoxic effects by producing excess reactive oxygen species. Thus, development of MAOA inhibitors which selectively target tumors becomes an important goal in cancer pharmacology. Here we describe the design, synthesis, and in vitro and in vivo evaluation of NMI, a conjugate that combines a near-infrared dye for tumor targeting with the moiety derived from the MAOA inhibitor clorgyline. NMI inhibits MAOA with low micromolar IC50, suppresses PCa cell proliferation and colony formation, and reduces migration and invasion. In mouse PCa xenografts, NMI targets tumors with no detectable accumulation in normal tissues, providing effective reduction of the tumor burden. Analysis of tumor specimens shows reduction in Ki-67(+) and CD31(+) cells, suggesting a decrease of cell proliferation and angiogenesis and an increase in M30(+) cells, indicating increased apoptosis. Gene expression profiles of tumors treated with NMI demonstrate reduced expression of oncogenes FOS, JUN, NFKB, and MYC and cell cycle regulators CCND1, CCNE1, and CDK4/6, along with increases in the levels of tumor suppressor gene TP53, cell cycle inhibitors CDKN1A and CDKN2A, and MAOA-downstream genes that promote EMT, tumor hypoxia, cancer cell migration, and invasion. These data suggest that NMI exerts its effect through tumor-targeted delivery of a MAOA-inactivating group, making NMI a valuable anti-tumor agent.

View details for DOI 10.1021/ja512613j

View details for Web of Science ID 000349807000039

View details for PubMedID 25585152
Management of digital ischemia Raynaud's Phenomenon: A Guide to Pathogenesis and Treatment Chung, L., Valenzuela, A., Adeduntan, R. Heidelberg, Dordrecht, London, Springer. 2015; 1: 339?360
Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis. Arthritis research & therapy Chakravarty, E. F., Martyanov, V., Fiorentino, D., Wood, T. A., Haddon, D. J., Jarrell, J. A., Utz, P. J., Genovese, M. C., Whitfield, M. L., Chung, L. 2015; 17: 159-?
Abstract

Systemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic.Adult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ?30% post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment.Ten subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud's symptom was significantly longer (8.8 � 3.8 years vs. 2.4 � 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71%) randomized to abatacept and one out of three patients (33%) randomized to placebo experienced ?30% improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (-8.6 � 7.5, p = 0.0625) while those in the placebo group did not (-2.3 � 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (-13.5 � 3.1 vs. -4.5 � 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks.Clinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin.ClinicalTrials.gov NCT00442611. Registered 1 March 2007.

View details for DOI 10.1186/s13075-015-0669-3

View details for PubMedID 26071192

View details for PubMedCentralID PMC4487200
Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry. Chest Chung, L., Farber, H. W., Benza, R., Miller, D. P., Parsons, L., Hassoun, P. M., McGoon, M., Nicolls, M. R., Zamanian, R. T. 2014; 146 (6): 1494-1504
Abstract

Background:Patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-APAH) experience higher mortality rates than patients with idiopathic disease and those with other connective tissue diseases (CTD-APAH). We sought to identify unique predictors of mortality associated with SSc-APAH in the CTD-APAH population. Methods:The Registry to Evaluate Early and Long-Term PAH Management (REVEAL) is a multicenter, prospective US-based registry of patients with previously and newly diagnosed (enrollment within 90 days of diagnostic right heart catheterization) PAH. Cox regression models evaluated all previously identified candidate predictors of mortality in the overall REVEAL population to identify significant predictors of mortality in the SSc-APAH (n=500) versus non-SSc-CTD-APAH (n=304) populations. Results:Three-year survival in the previously diagnosed and newly diagnosed SSc-APAH group was 61.4�2.7% and 51.2�4.0%, respectively, compared with 80.9�2.7% and 76.4�4.6%, respectively, in the non-SSc-CTD-APAH group (P<.001). In multivariate analyses, males aged >60 years, systolic blood pressure (SBP) ?110 mmHg, 6-minute walk distance (6MWD) <165 m, mean right atrial pressure (mRAP) >20 mmHg within 1 year, and pulmonary vascular resistance (PVR) >32 WU remained unique predictors of mortality in the SSc-APAH group; 6MWD ?440 m was protective in the non-SSc-CTD-APAH group, but not the SSc-APAH group. Conclusions:Patients with SSc-APAH have higher mortality rates than non-SSc-CTD-APAH patients. Identifying SSc-APAH patients who are at particularly high risk of death, including elderly males and patients with low baseline SBP or 6MWD, or markedly elevated mRAP or PVR, will enable clinicians to identify patients who may benefit from closer monitoring and more aggressive treatment. Registered at:www.clinicaltrials.gov #NCT00370214.Patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-APAH) experience higher mortality rates than patients with idiopathic disease and those with other connective tissue diseases (CTD-APAH). We sought to identify unique predictors of mortality associated with SSc-APAH in the CTD-APAH population.The Registry to Evaluate Early and Long-Term PAH Management (REVEAL) is a multicenter, prospective US-based registry of patients with previously and newly diagnosed (enrollment within 90 days of diagnostic right heart catheterization) PAH. Cox regression models evaluated all previously identified candidate predictors of mortality in the overall REVEAL population to identify significant predictors of mortality in the SSc-APAH (n=500) versus non-SSc-CTD-APAH (n=304) populations.Three-year survival in the previously diagnosed and newly diagnosed SSc-APAH group was 61.4�2.7% and 51.2�4.0%, respectively, compared with 80.9�2.7% and 76.4�4.6%, respectively, in the non-SSc-CTD-APAH group (P<.001). In multivariate analyses, males aged >60 years, systolic blood pressure (SBP) ?110 mmHg, 6-minute walk distance (6MWD) <165 m, mean right atrial pressure (mRAP) >20 mmHg within 1 year, and pulmonary vascular resistance (PVR) >32 WU remained unique predictors of mortality in the SSc-APAH group; 6MWD ?440 m was protective in the non-SSc-CTD-APAH group, but not the SSc-APAH group.Patients with SSc-APAH have higher mortality rates than non-SSc-CTD-APAH patients. Identifying SSc-APAH patients who are at particularly high risk of death, including elderly males and patients with low baseline SBP or 6MWD, or markedly elevated mRAP or PVR, will enable clinicians to identify patients who may benefit from closer monitoring and more aggressive treatment.www.clinicaltrials.gov #NCT00370214.

View details for DOI 10.1378/chest.13-3014

View details for PubMedID 24992469
Pulmonary hypertension and interstitial lung disease within PHAROS: impact of extent of fibrosis and pulmonary physiology on cardiac haemodynamic parameters CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Fischer, A., Swigris, J. J., Bolster, M. B., Chung, L., Csuka, M. E., Domsic, R. T., Frech, T., Hinchcliff, M., Hsu, V., Hummers, L. K., Gomberg-Maitland, M., Mathai, S. C., Simms, R., Steen, V. D. 2014; 32 (6): S109-S114
View details for Web of Science ID 000344721500018
Pulmonary hypertension and interstitial lung disease within PHAROS: impact of extent of fibrosis and pulmonary physiology on cardiac haemodynamic parameters. Clinical and experimental rheumatology Fischer, A., Swigris, J. J., Bolster, M. B., Chung, L., Csuka, M. E., Domsic, R., Frech, T., Hinchcliff, M., Hsu, V., Hummers, L. K., Gomberg-Maitland, M., Mathai, S. C., Simms, R., Steen, V. D. 2014; 32 (6): S-109 14
Abstract

We sought to examine the relationship between measures of ILD severity and PH in patients with SSc.We identified 55 subjects from 12 PHAROS sites with RHC-proven PH and HRCT evidence of ILD. Subjects with PH due to left heart disease were excluded. Baseline HRCT scans were scored by a standardised system that graded severity of ILD. Summary statistics were generated for baseline characteristics. Spearman correlation and linear regression were used to examine relationships between ILD and PH severity variables.The majority of subjects were white women; nearly half had limited cutaneous SSc. Most subjects were New York Heart Association functional class II or III. Pulmonary function testing revealed moderate restriction (mean FVC 64.3 � 17.2% predicted) with severe reduction in diffusing capacity (mean DLco 34.2 � 13.3% predicted). RHC demonstrated mild to moderate PH (mean PAP 35 � 9 mmHg, mean PVR 5.1 � 3.7 WU). There was no correlation between severity of ILD (by either HRCT or PFT) and cardiac haemodynamic parameters of PH.No association between severity of ILD and cardiac haemodynamic profiles were identified in this cohort. We believe this underscores the complex nature of PH and ILD in individuals with SSc. We do suspect that some individuals with SSc-ILD will also have concomitant pulmonary vascular disease but simple assessments to grade severity of ILD - by PFT or HRCT estimates of ILD extent - are likely not enough to reliably distinguish between PAH versus PH-ILD. Further research into how to distinguish and manage these subsets is warranted.

View details for PubMedID 25372796
Heptamethine carbocyanine dye-mediated near-infrared imaging of canine and human cancers through the HIF-1 alpha/OATPs signaling axis ONCOTARGET Shi, C., Wu, J. B., Chu, G. C., Li, Q., Wang, R., Zhang, C., Zhang, Y., Kim, H. L., Wang, J., Zhau, H. E., Pan, D., Chung, L. W. 2014; 5 (20): 10114-10126
Abstract

Near-infrared (NIR) fluorescence imaging agents are promising tools for noninvasive cancer imaging. This study explored the specific uptake and retention of a NIR heptamethine carbocyanine MHI-148 dye by canine cancer cells and tissues and human prostate cancer (PCa) specimens and also the dye uptake mechanisms. The accumulation of MHI-148 was detected specifically in canine cancer cells and tissues and freshly harvested human PCa tissues xenografted in mice by NIR fluorescence microscopy and whole-body NIR optical imaging. Specific dye uptake in canine spontaneous tumors was further confirmed by PET imaging. Higher hypoxia-inducible factor-1? (HIF-1?) and organic anion-transporting polypeptide (OATP) protein and mRNA expression was demonstrated by multiplex quantum dots labeling and qPCR in tumors over that of normal tissues. Treating cancer cells with HIF-1? stabilizers activated HIF-1? downstream target genes, induced OATP superfamily gene expression and enhanced cellular uptake and retention of NIR dyes. Moreover, silencing HIF-1? by siRNA significantly decreased OATP mRNA expression and blocked NIR dye uptake in cancer cells. Together, these results demonstrated the preferential uptake of NIR dyes by canine and human cancer cells and tissues via the HIF-1?/OATPs signaling axis, which provides insights into future application of these dyes for cancer detection and treatment.

View details for Web of Science ID 000348036500046

View details for PubMedID 25361418
Muscle Disease in Systemic Sclerosis Is Associated with an Increased Risk for Cardiac Involvement Hong, J., Valenzuela, A., Fiorentino, D., Chung, L. WILEY-BLACKWELL. 2014: S314?S315
View details for Web of Science ID 000344384901265
Luminex and Autoantigen Microarray Analysis of Sera from Patients with Diffuse Cutaneous Systemic Sclerosis Reveals Changes Associated with Imatinib Mesylate Treatment. Haddon, D., Wand, H., Utz, P. J., Spiera, R. F., Gordon, J. K., Chung, L. WILEY-BLACKWELL. 2014: S388
View details for Web of Science ID 000344384901422
Intestinal Pseudo-Obstruction in Patients with Systemic Sclerosis: An Analysis of the Nationwide Inpatient Sample. Valenzuela, A., Li, S., Becker, L., Fernandez-Becker, N., Khanna, D., Linda Nguyen, Chung, L. WILEY-BLACKWELL. 2014: S1310
View details for Web of Science ID 000344384906230
Survival in Systemic Sclerosis-Pulmonary Arterial Hypertension By Serum Autoantibody Status Hinchcliff, M., Khanna, S., Lee, J., Almagor, O., Chang, R. W., Steen, V. D., Chung, L. WILEY-BLACKWELL. 2014: S1180
View details for Web of Science ID 000344384905375
Connective tissue disease-associated pulmonary arterial hypertension: "Beijing style" EUROPEAN RESPIRATORY JOURNAL Chung, L., Kawut, S. M. 2014; 44 (4): 839?41
View details for PubMedID 25271223
Lower Socioeconomic Status, Male Gender and Diffuse Scleroderma Are Associated with Worse Survival in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Cohort Gordon, J. K., Zhang, W., Chung, L., Ma, Y., Steen, V. D., PHAROS Investigators WILEY-BLACKWELL. 2014: S321?S322
View details for Web of Science ID 000344384901278
Near-infrared fluorescence imaging of cancer mediated by tumor hypoxia and HIFI alpha/OATPs signaling axis BIOMATERIALS Wu, J. B., Shao, C., Li, X., Shi, C., Li, Q., Hu, P., Chen, Y., Dou, X., Sahu, D., Li, W., Harada, H., Zhang, Y., Wang, R., Zhau, H. E., Chung, L. W. 2014; 35 (28): 8175-8185
Abstract

Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the mechanistic properties of a specific group of NIR heptamethine carbocyanines including MHI-148 dye we identified and synthesized, and demonstrated these dyes to achieve cancer-specific imaging and targeting via a hypoxia-mediated mechanism. We found that cancer cells and tumor xenografts exhibited hypoxia-dependent MHI-148 dye uptake in�vitro and in�vivo, which was directly mediated by hypoxia-inducible factor 1? (HIF1?). Microarray analysis and dye uptake assay further revealed a group of hypoxia-inducible organic anion-transporting polypeptides (OATPs) responsible for dye uptake, and the correlation between OATPs and HIF1? was manifested in progressive clinical cancer specimens. Finally, we demonstrated increased uptake of MHI-148 dye in situ in perfused clinical tumor samples with activated HIF1?/OATPs signaling. Our results establish these NIRF dyes as potential tumor hypoxia-dependent cancer-targeting agents and provide a mechanistic rationale for continued development of NIRF imaging agents for improved cancer detection, prognosis and therapy.

View details for DOI 10.1016/j.biomaterials.2014.05.073

View details for Web of Science ID 000339774700012

View details for PubMedID 24957295
Effect of the endothelin type A-selective endothelin receptor antagonist ambrisentan on digital ulcers in patients with systemic sclerosis: Results of a prospective pilot study. Journal of the American Academy of Dermatology Chung, L., Ball, K., Yaqub, A., Lingala, B., Fiorentino, D. 2014; 71 (2): 400-401
View details for DOI 10.1016/j.jaad.2014.04.028

View details for PubMedID 25037794
Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults CHEST Guideline and Expert Panel Report CHEST Taichman, D. B., Ornelas, J., Chung, L., Klinger, J. R., Lewis, S., Mandel, J., Palevsky, H. I., Rich, S., Sood, N., Rosenzweig, E. B., Trow, T. K., Yung, R., Elliott, C. G., Badesch, D. B. 2014; 146 (2): 449-475
Abstract

Choices of pharmacologic therapies for pulmonary arterial hypertension (PAH) are ideally guided by high-level evidence. The objective of this guideline is to provide clinicians advice regarding pharmacologic therapy for adult patients with PAH as informed by available evidence.This guideline was based on systematic reviews of English language evidence published between 1990 and November 2013, identified using the MEDLINE and Cochrane Library databases. The strength of available evidence was graded using the Grades of Recommendations, Assessment, Development, and Evaluation methodology. Guideline recommendations, or consensus statements when available evidence was insufficient to support recommendations, were developed using a modified Delphi technique to achieve consensus.Available evidence is limited in its ability to support high-level recommendations. Therefore, we drafted consensus statements to address many clinical questions regarding pharmacotherapy for patients with PAH. A total of 79 recommendations or consensus statements were adopted and graded.Clinical decisions regarding pharmacotherapy for PAH should be guided by high-level recommendations when sufficient evidence is available. Absent higher level evidence, consensus statements based upon available information must be used. Further studies are needed to address the gaps in available knowledge regarding optimal pharmacotherapy for PAH.

View details for DOI 10.1378/chest.14-0793

View details for Web of Science ID 000340482400052

View details for PubMedID 24937180

View details for PubMedCentralID PMC4137591
Development of pulmonary hypertension in a high-risk population with systemic sclerosis in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) cohort study. Seminars in arthritis and rheumatism Hsu, V. M., Chung, L., Hummers, L. K., Wigley, F., Simms, R., Bolster, M., Silver, R., Fischer, A., Hinchcliff, M. E., Varga, J., Goldberg, A. Z., Derk, C. T., Schiopu, E., Khanna, D., Shapiro, L. S., Domsic, R. T., Medsger, T., Mayes, M. D., Furst, D., Csuka, M. E., Molitor, J. A., Alkassab, F., Steen, V. D. 2014; 44 (1): 55-62
Abstract

PHAROS registry is a prospective longitudinal cohort study to understand the natural history of pulmonary hypertension (PH) in systemic sclerosis (SSc)."At-risk" pulmonary arterial hypertension (PAH) is defined by these entry criteria: echocardiogram (echo) systolic pulmonary arterial pressure (sPAP) >40mmHg, diffusion lung capacity of carbon monoxide (DLco) <55% predicted, or ratio of percentage forced vital capacity (FVC)/percentage DLco >1.6, as measured by pulmonary function testing (PFT). Patients were followed up annually and right heart catheterization (RHC) performed if PH was suspected. We used descriptive statistics and Kaplan-Meier estimate of time to PH diagnosis.A total of 251 "at-risk" subjects were enrolled between 2005 and 2012 and followed up for mean of 2.5 � 1.2 years. The mean age at entry was 56.7 � 11.0 and disease duration was 9.9 � 8.7 years. Overall, 82 patients had RHC, and 35 were confirmed to have new PH. There were no differences in age, gender, SSc subtypes, antibodies, and disease duration between the "at-risk" and new PH groups. Using Kaplan-Meier survival, the time to PH was 10% at 2 years, 13% at 3 years, and 25% at 5 years. Most new PH patients at entry met the PFT criteria (76%), had significantly higher sPAP (p = 0.013), had shorter 6-min walk distance, and had exercise-induced hypoxia (p = 0.003) than "at-risk" PAH group.A low DLco, high FVC/DLco, exercise-induced hypoxia and entry echo sPAP > 40 were strongly associated with future PH, though RHC was necessary to confirm PH. This ongoing prospective study confirms that these high-risk factors do predict future PH.

View details for DOI 10.1016/j.semarthrit.2014.03.002

View details for PubMedID 24709277
Identification of clinical features and autoantibodies associated with calcinosis in dermatomyositis. JAMA dermatology Valenzuela, A., Chung, L., Casciola-Rosen, L., Fiorentino, D. 2014; 150 (7): 724-729
Abstract

Prior studies have estimated that up to 20% of adults with dermatomyositis (DM) have calcinosis, which can lead to significant morbidity. Identification of risk factors may provide a better understanding of the pathogenesis and ultimately therapy for this difficult clinical problem. Risk factors for calcinosis in adults with DM have not been extensively studied.To determine the prevalence of calcinosis and to identify associated clinical features in a cohort of extensively phenotyped adults with DM.A cross-sectional study of 126 patients diagnosed as having DM from January 1, 2006, through January 1, 2013, was performed. Patients were adults (?18 years of age) attending the Stanford University Medical Center clinic.Calcinosis, defined as the presence of calcium deposition in the skin and subcutaneous tissues on physical examination.Fourteen patients (11.1%) had calcinosis, with the extremities most commonly involved. Patients with vs those without calcinosis had a longer disease duration (median, 6.9 years; range, 2.4-18.1; vs median, 3.9 years; range, 0.2-19.2 years; P?=?.003) and more fingertip ulcers (50.0% vs 9.3%, P?
View details for DOI 10.1001/jamadermatol.2013.10416

View details for PubMedID 24869801
Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis JOURNAL OF CLINICAL INVESTIGATION Wu, J. B., Shao, C., Li, X., Li, Q., Hu, P., Shi, C., Li, Y., Chen, Y., Yin, F., Liao, C., Stiles, B. L., Zhau, H. E., Shih, J. C., Chung, L. W. 2014; 124 (7): 2891-2908
Abstract

Tumors from patients with high-grade aggressive prostate cancer (PCa) exhibit increased expression of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines. Despite the association between MAOA and aggressive PCa, it is unclear how MAOA promotes PCa progression. Here, we found that MAOA functions to induce epithelial-to-mesenchymal transition (EMT) and stabilize the transcription factor HIF1?, which mediates hypoxia through an elevation of ROS, thus enhancing growth, invasiveness, and metastasis of PCa cells. Knockdown and overexpression of MAOA in human PCa cell lines indicated that MAOA induces EMT through activation of VEGF and its coreceptor neuropilin-1. MAOA-dependent activation of neuropilin-1 promoted AKT/FOXO1/TWIST1 signaling, allowing FOXO1 binding at the TWIST1 promoter. Importantly, the MAOA-dependent HIF1?/VEGF-A/FOXO1/TWIST1 pathway was activated in high-grade PCa specimens, and knockdown of MAOA reduced or even eliminated prostate tumor growth and metastasis in PCa xenograft mouse models. Pharmacological inhibition of MAOA activity also reduced PCa xenograft growth in mice. Moreover, high MAOA expression in PCa tissues correlated with worse clinical outcomes in PCa patients. These findings collectively characterize the contribution of MAOA in PCa pathogenesis and suggest that MAOA has potential as a therapeutic target in PCa.

View details for DOI 10.1172/JCI070982

View details for Web of Science ID 000338688400017

View details for PubMedID 24865426
Cardiac arrhythmias and conduction defects in systemic sclerosis. Rheumatology Vacca, A., Meune, C., Gordon, J., Chung, L., Proudman, S., Assassi, S., Nikpour, M., Rodriguez-Reyna, T. S., Khanna, D., Lafyatis, R., Matucci-Cerinic, M., Distler, O., Allanore, Y. 2014; 53 (7): 1172-1177
Abstract

Signs and symptoms of arrhythmias or conduction defects are frequently reported in patients with SSc. These rhythm disorders may have several origins (i.e., related to primary heart involvement, pericardial disease, valvular regurgitation or pulmonary arterial hypertension) and may negatively affect the overall prognosis of these patients. It is therefore important to identify patients at high risk for cardiac arrhythmias with a complete cardiological evaluation and to identify the underlying heart disease, including SSc-related myocardial involvement. In addition, some therapeutic options in SSc patients may differ from those recommended in other populations.

View details for DOI 10.1093/rheumatology/ket377

View details for PubMedID 24241036
Cardiac arrhythmias and conduction defects in systemic sclerosis RHEUMATOLOGY Vacca, A., Meune, C., Gordon, J., Chung, L., Proudman, S., Assassi, S., Nikpour, M., Rodriguez-Reyna, T. S., Khanna, D., Lafyatis, R., Matucci-Cerinic, M., Distler, O., Allanore, Y. 2014; 53 (7): 1172-1177
Abstract

Signs and symptoms of arrhythmias or conduction defects are frequently reported in patients with SSc. These rhythm disorders may have several origins (i.e., related to primary heart involvement, pericardial disease, valvular regurgitation or pulmonary arterial hypertension) and may negatively affect the overall prognosis of these patients. It is therefore important to identify patients at high risk for cardiac arrhythmias with a complete cardiological evaluation and to identify the underlying heart disease, including SSc-related myocardial involvement. In addition, some therapeutic options in SSc patients may differ from those recommended in other populations.

View details for DOI 10.1093/rheumatology/ket377

View details for Web of Science ID 000338647000004

View details for PubMedCentralID PMC4065005
Identification of clinical features and autoantibodies associated with calcinosis in dermatomyositis. JAMA dermatology Valenzuela, A., Chung, L., Casciola-Rosen, L., Fiorentino, D. 2014; 150 (7): 724-729
Abstract

Prior studies have estimated that up to 20% of adults with dermatomyositis (DM) have calcinosis, which can lead to significant morbidity. Identification of risk factors may provide a better understanding of the pathogenesis and ultimately therapy for this difficult clinical problem. Risk factors for calcinosis in adults with DM have not been extensively studied.To determine the prevalence of calcinosis and to identify associated clinical features in a cohort of extensively phenotyped adults with DM.A cross-sectional study of 126 patients diagnosed as having DM from January 1, 2006, through January 1, 2013, was performed. Patients were adults (?18 years of age) attending the Stanford University Medical Center clinic.Calcinosis, defined as the presence of calcium deposition in the skin and subcutaneous tissues on physical examination.Fourteen patients (11.1%) had calcinosis, with the extremities most commonly involved. Patients with vs those without calcinosis had a longer disease duration (median, 6.9 years; range, 2.4-18.1; vs median, 3.9 years; range, 0.2-19.2 years; P?=?.003) and more fingertip ulcers (50.0% vs 9.3%, P?
View details for DOI 10.1001/jamadermatol.2013.10416

View details for PubMedID 24869801
Multicriteria decision analysis methods with 1000Minds for developing systemic sclerosis classification criteria JOURNAL OF CLINICAL EPIDEMIOLOGY Johnson, S. R., Naden, R. P., Fransen, J., van den Hoogen, F., Pope, J. E., Baron, M., Tyndall, A., Matucci-Cerinic, M., Denton, C. P., Distler, O., Gabrielli, A., van Laar, J. M., Mayes, M., Steen, V., Seibold, J. R., clements, P., Medsger, T. A., Carreira, P. E., Riemekasten, G., Chung, L., Fessler, B. J., Merkel, P. A., Silver, R., Varga, J., Allanore, Y., Mueller-Ladner, U., Vonk, M. C., Walker, U. A., Cappelli, S., Khanna, D. 2014; 67 (6): 706-714
Abstract

Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to develop an instrument for collating case data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement among experts on the probability that cases were classified as SSc.A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and reranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICCs).Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7), and puffy fingers (5). The ICC across experts was 0.73 [95% confidence interval (CI): 0.58, 0.86] and improved to 0.80 (95% CI: 0.68, 0.90).Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (range, 23-14) and weighted. Our methods reflect the rigors of measurement science and serve as a template for developing classification criteria.

View details for DOI 10.1016/j.jclinepi.2013.12.009

View details for Web of Science ID 000335610000015

View details for PubMedID 24721558
Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials THORAX Saketkoo, L. A., Mittoo, S., Huscher, D., Khanna, D., Dellaripa, P. F., Distler, O., Flaherty, K. R., Frankel, S., Oddis, C. V., Denton, C. P., Fischer, A., Kowal-Bielecka, O. M., LeSage, D., Merkel, P. A., Phillips, K., Pittrow, D., Swigris, J., Antoniou, K., Baughman, R. P., Castelino, F. V., Christmann, R. B., Christopher-Stine, L., Collard, H. R., Cottin, V., Danoff, S., Highland, K. B., Hummers, L., Shah, A. A., Kim, D. S., Lynch, D. A., Miller, F. W., Proudman, S. M., Richeldi, L., Ryu, J. H., Sandorfi, N., Sarver, C., Wells, A. U., Strand, V., Matteson, E. L., Brown, K. K., Seibold, J. R. 2014; 69 (5): 428-436
Abstract

Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities.The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF).A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed.Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

View details for DOI 10.1136/thoraxjnl-2013-204202

View details for Web of Science ID 000347648600009

View details for PubMedID 24368713

View details for PubMedCentralID PMC3995282
Abstract 46: surgical treatment of systemic sclerosis: re-thinking the role and timing of peripheral sympathectomy. Plastic and reconstructive surgery Momeni, A., Sorice, S. C., Valenzuela, A., Fiorentino, D. F., Chung, L., Chang, J. 2014; 133 (4): 1010-?
View details for DOI 10.1097/01.prs.0000445829.40020.04

View details for PubMedID 24675339
Reconciling Healthcare Professional and Patient Perspectives in the Development of Disease Activity and Response Criteria in Connective Tissue Disease-related Interstitial Lung Diseases JOURNAL OF RHEUMATOLOGY Saketkoo, L. A., Mittoo, S., Frankel, S., LeSage, D., Sarver, C., Phillips, K., Strand, V., Matteson, E. L. 2014; 41 (4): 792-798
Abstract

Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.

View details for DOI 10.3899/jrheum.131251

View details for Web of Science ID 000333906400024

View details for PubMedID 24488412

View details for PubMedCentralID PMC4369780
Survival and Predictors of Mortality in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: Outcomes From the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry ARTHRITIS CARE & RESEARCH Chung, L., Domsic, R. T., Lingala, B., Alkassab, F., Bolster, M., Csuka, M. E., Derk, C., Fischer, A., Frech, T., Furst, D. E., Gomberg-Maitland, M., Hinchcliff, M., Hsu, V., Hummers, L. K., Khanna, D., Medsger, T. A., Molitor, J. A., Preston, I. R., Schiopu, E., Shapiro, L., Silver, R., Simms, R., Varga, J., Gordon, J. K., Steen, V. D. 2014; 66 (3): 489-495
Abstract

To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US.The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma registry is a prospective registry of SSc patients at high risk for PAH or with definite pulmonary hypertension diagnosed by right-sided heart catheterization within 6 months of enrollment. Only patients with World Health Organization group I PAH (mean pulmonary artery pressure >25 mm Hg and pulmonary capillary wedge pressure <15 mm Hg without significant interstitial lung disease) were included in these analyses.In total, 131 SSc patients with incident PAH were followed for a mean � SD of 2.0 � 1.4 years. The 1-, 2-, and 3-year cumulative survival rates were 93%, 88%, and 75%, respectively. On multivariate analysis, age >60 years (hazard ratio [HR] 3.0, 95% confidence interval [95% CI] 1.1- 8.4), male sex (HR 3.9, 95% CI 1.1-13.9), functional class (FC) IV status (HR 6.5, 95% CI 1.8 -22.8), and diffusing capacity for carbon monoxide (DLCO) <39% predicted (HR 4.2, 95% CI 1.3-13.8) were significant predictors of mortality.This is the largest study describing survival in patients with incident SSc-associated PAH followed up at multiple SSc centers in the US who had undergone routine screening for PAH. The survival rates were better than those reported in other recently described SSc-associated PAH cohorts. Severely reduced DLCO and FC IV status at the time of PAH diagnosis portended a poor prognosis in these patients.

View details for DOI 10.1002/acr.22121

View details for Web of Science ID 000331684800019
Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry. Arthritis care & research Chung, L., Domsic, R. T., Lingala, B., Alkassab, F., Bolster, M., Csuka, M. E., Derk, C., Fischer, A., Frech, T., Furst, D. E., Gomberg-Maitland, M., Hinchcliff, M., Hsu, V., Hummers, L. K., Khanna, D., Medsger, T. A., Molitor, J. A., Preston, I. R., Schiopu, E., Shapiro, L., Silver, R., Simms, R., Varga, J., Gordon, J. K., Steen, V. D. 2014; 66 (3): 489-495
Abstract

To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US.The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma registry is a prospective registry of SSc patients at high risk for PAH or with definite pulmonary hypertension diagnosed by right-sided heart catheterization within 6 months of enrollment. Only patients with World Health Organization group I PAH (mean pulmonary artery pressure >25 mm Hg and pulmonary capillary wedge pressure <15 mm Hg without significant interstitial lung disease) were included in these analyses.In total, 131 SSc patients with incident PAH were followed for a mean � SD of 2.0 � 1.4 years. The 1-, 2-, and 3-year cumulative survival rates were 93%, 88%, and 75%, respectively. On multivariate analysis, age >60 years (hazard ratio [HR] 3.0, 95% confidence interval [95% CI] 1.1- 8.4), male sex (HR 3.9, 95% CI 1.1-13.9), functional class (FC) IV status (HR 6.5, 95% CI 1.8 -22.8), and diffusing capacity for carbon monoxide (DLCO) <39% predicted (HR 4.2, 95% CI 1.3-13.8) were significant predictors of mortality.This is the largest study describing survival in patients with incident SSc-associated PAH followed up at multiple SSc centers in the US who had undergone routine screening for PAH. The survival rates were better than those reported in other recently described SSc-associated PAH cohorts. Severely reduced DLCO and FC IV status at the time of PAH diagnosis portended a poor prognosis in these patients.

View details for DOI 10.1002/acr.22121

View details for PubMedID 23983198
International consensus criteria for the diagnosis of Raynaud's phenomenon. Journal of autoimmunity Maverakis, E., Patel, F., Kronenberg, D. G., Chung, L., Fiorentino, D., Allanore, Y., Guiducci, S., Hesselstrand, R., Hummers, L. K., Duong, C., Kahaleh, B., MacGregor, A., Matucci-Cerinic, M., Wollheim, F. A., Mayes, M. D., Gershwin, M. E. 2014; 48-49: 60-65
Abstract

Vasoconstriction accompanied by changes in skin color is a normal physiologic response to cold. The distinction between this normal physiology and Raynaud's phenomenon (RP) has yet to be well characterized. In anticipation of the 9th International Congress on Autoimmunity, a panel of 12 RP experts from 9 different institutes and four different countries were assembled for a Delphi exercise to establish new diagnostic criteria for RP. Relevant investigators with highly cited manuscripts in Raynaud's-related research were identified using the Web of Science and invited to participate. Surveys at each stage were administered to participants via the on-line SurveyMonkey software tool. The participants evaluated the level of appropriateness of statements using a scale of 1 (extremely inappropriate) through 9 (extremely appropriate). In the second stage, panel participants were asked to rank rewritten items from the first round that were scored as "uncertain" for the diagnosis of RP, items with significant disagreement (Disagreement Index > 1), and new items suggested by the panel. Results were analyzed using the Interpercentile Range Adjusted for Symmetry (IPRAS) method. A 3-Step Approach to diagnose RP was then developed using items the panelists "agreed" were "appropriate" diagnostic criteria. In the final stage, the panel was presented with the newly developed diagnostic criteria and asked to rate them against previous models. Following the first two iterations of the Delphi exercise, the panel of 12 experts agreed that 36 of the items were "appropriate", 12 items had "uncertain" appropriateness, and 13 items were "inappropriate" to use in the diagnostic criteria of RP. Using an expert committee, we developed a 3-Step Approach for the diagnosis of RP and 5 additional criteria for the diagnosis of primary RP. The committee came to an agreement that the proposed criteria were "appropriate and accurate" for use by physicians to diagnose patients with RP.

View details for DOI 10.1016/j.jaut.2014.01.020

View details for PubMedID 24491823
Consensus opinion of a North American Working Group regarding the classification of digital ulcers in systemic sclerosis CLINICAL RHEUMATOLOGY Baron, M., Chung, L., Gyger, G., Hummers, L., Khanna, D., Mayes, M. D., Pope, J. E., Shah, A. A., Steen, V. D., Steele, R., Tatibouet, S., Herrick, A., Mueller-Ladner, U., Hudson, M. 2014; 33 (2): 207-214
Abstract

The objectives of this study were to develop a standard classification of digital ulcers (DUs) in systemic sclerosis (SSc) for use in observational or therapeutic studies and to assess the reliability of these definitions as well as of the measurement of ulcer area. Ten North American rheumatologists with expertise in SSc reviewed multiple photos of DUs, examined four SSc subjects with DUs, and came to a consensus on the definitions for digital, active, healed, and indeterminate ulcers. These ten raters then examined the right hand of ten SSc subjects twice and the left hand once to classify ulcers and to measure ulcer area. Weighted and Fleiss kappa were used to calculate intra- and interrater agreement on classification of ulcers, and intraclass correlation coefficient (ICC) was used to assess agreement on ulcer area. Because the traditional ICC calculations relied on a small number of ulcers, ICCs were recalculated using the results of linear mixed models to evaluate the variance components of observations on all the data. Intrarater kappa for classifying DU as not an ulcer/healed ulcer versus active/indeterminate ulcer was substantial (0.76), and interrater kappa was moderate (0.53). The ICC for ulcer area using the linear mixed models was moderate both for intrarater (0.57) and interrater (0.48) measurements. A consensus for the classification of DUs in SSc was developed, and after a training session, rheumatologists with expertise in SSc are able to reliably classify DUs and to measure ulcer area.

View details for DOI 10.1007/s10067-013-2460-7

View details for Web of Science ID 000330780600006

View details for PubMedID 24357325
Atherosclerotic Cardiovascular Disease in Hospitalized Patients With Systemic Sclerosis: Higher Mortality Than Patients With Lupus and Rheumatoid Arthritis ARTHRITIS CARE & RESEARCH Dave, A. J., Fiorentino, D., Lingala, B., Krishnan, E., Chung, L. 2014; 66 (2): 323-327
Abstract

Systemic sclerosis (SSc; scleroderma) patients have an increased risk for atherosclerotic cardiovascular disease (ASCVD), possibly mediated through inflammatory and fibrotic mechanisms affecting the macrovasculature and microvasculature. We utilized the US Nationwide Inpatient Sample to assess the frequency of and mortality risk associated with ASCVD among hospitalized SSc patients.We examined the frequency and mortality associated with primary diagnoses and procedures related to ASCVD among adult SSc patients using data from 1993 to 2007. Using multivariate logistic regression (controlling for age, sex, nonelective admission, and modified Charlson Comorbidity Index), we compared the odds of death among hospitalized SSc patients with ASCVD to those with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), as well as to a control group that excluded patients with connective tissue diseases.A total of 308,452 hospitalizations of SSc patients were included, of which 5.4% were associated with a primary ASCVD diagnosis or procedure. ASCVD-related SSc hospitalizations were more likely to result in death compared with non-ASCVD SSc hospitalizations (odds ratio [OR] 1.3, 95% confidence interval [95% CI] 1.1-1.4). Multivariate analyses showed that ASCVD-related SSc hospitalizations were more likely to result in death than similar hospitalizations of SLE (OR 1.5, 95% CI 1.2-1.8), RA (OR 2.3, 95% CI 1.9-2.8), and control patients (OR 1.4, 95% CI 1.2-1.8) with ASCVD.SSc patients with ASCVD have higher in-hospital mortality than comparable groups of SLE and RA patients with ASCVD. Further research to elucidate the specific mechanisms underlying ASCVD in SSc is necessary.

View details for DOI 10.1002/acr.22152

View details for Web of Science ID 000330266100020

View details for PubMedID 24022876
Recommendations for Screening and Detection of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension ARTHRITIS AND RHEUMATISM Khanna, D., Gladue, H., Channick, R., Chung, L., Distler, O., Furst, D. E., Hachulla, E., Humbert, M., Langleben, D., Mathai, S. C., Saggar, R., Visovatti, S., Altorok, N., Townsend, W., Fitzgerald, J., McLaughlin, V. V. 2013; 65 (12): 3194-3201
Abstract

Pulmonary arterial hypertension (PAH) affects up to 15% of patients with connective tissue diseases (CTDs). Previous recommendations developed as part of larger efforts in PAH did not include detailed recommendations for patients with CTD-associated PAH. Therefore, we sought to develop recommendations for screening and early detection of CTD-associated PAH.We performed a systematic review of the literature on the screening and diagnosis of PAH in CTD. Using the RAND/University of California, Los Angeles consensus methodology, we developed case scenarios followed by 2 stages of voting. First, international experts from a variety of specialties voted anonymously on the appropriateness of each case scenario. The experts then met face-to-face to discuss and resolve discrepant votes to arrive at consensus recommendations.The key recommendation stated that all patients with systemic sclerosis (SSc) should be screened for PAH. In addition, patients with mixed connective tissue disease or other CTDs with scleroderma features (scleroderma spectrum disorders) should be screened for PAH. It was recommended that screening pulmonary function tests (PFTs) with single-breath diffusing capacity for carbon monoxide, transthoracic echocardiogram, and measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) be performed in all patients with SSc and scleroderma spectrum disorders. In patients with SSc and scleroderma spectrum disorders, transthoracic echocardiogram and PFTs should be performed annually. The full screening panel (transthoracic echocardiogram, PFTs, and measurement of NT-proBNP) should be performed as soon as any new signs or symptoms are present.We provide consensus-based, evidence-driven recommendations for screening and early detection of CTD-associated PAH. It is our hope that these recommendations will lead to earlier detection of CTD-associated PAH and ultimately improve patient outcomes.

View details for DOI 10.1002/art.38172

View details for Web of Science ID 000327692600022

View details for PubMedID 24022584

View details for PubMedCentralID PMC3883571
Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1?. Arthritis and rheumatism Fiorentino, D. F., Chung, L. S., Christopher-Stine, L., Zaba, L., Li, S., Mammen, A. L., Rosen, A., Casciola-Rosen, L. 2013; 65 (11): 2954-2962
Abstract

Since dermatomyositis (DM) is associated with an increased risk of malignancy, accurate identification of patients likely to harbor cancers is important. Using immunoprecipitations from radiolabeled cell lysates, several groups recently showed that anti-transcription intermediary factor 1? (anti-TIF-1?) antibodies are associated with malignancy in DM. We undertook this study to develop sensitive, specific assays to detect antibodies against TIF-1? and nuclear matrix protein NXP-2 and to evaluate their association with malignancy in DM.To detect anti-TIF-1? antibodies, immunoprecipitations were performed using lysates made from HeLa cells overexpressing TIF-1?, with detection by immunoblotting. Anti-NXP-2 antibodies were assayed by immunoprecipitation using (35) S-methionine-labeled NXP-2 generated by in vitro transcription/translation. We analyzed patient sera from DM cohorts seen at the Stanford University Dermatology Clinic (n = 111) and the Johns Hopkins Myositis Center (n = 102).A total of 17% and 38% of patients had antibodies against NXP-2 and TIF-1?, respectively. Reactivity against either NXP-2 or TIF-1? identified 83% of patients with cancer-associated DM. In addition to older age and male sex, cancer was associated with antibodies to NXP-2 or TIF-1? on multivariate analysis (odds ratio 3.78 [95% confidence interval 1.33-10.8]). Stratification by sex revealed that anti-NXP-2 was specifically associated with cancer in males (odds ratio 5.78 [95% confidence interval 1.35-24.7]).These studies demonstrate that anti-NXP-2 and anti-TIF-1? antibodies are frequent DM specificities (found in 55% of patients) and are present in most patients with cancer-associated DM.

View details for DOI 10.1002/art.38093

View details for PubMedID 24037894
2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative ANNALS OF THE RHEUMATIC DISEASES van den Hoogen, F., Khanna, D., Fransen, J., Johnson, S. R., Baron, M., Tyndall, A., Matucci-Cerinic, M., Naden, R. P., Medsger, T. A., Carreira, P. E., Riemekasten, G., Clements, P. J., Denton, C. P., Distler, O., Allanore, Y., Furst, D. E., Gabrielli, A., Mayes, M. D., van Laar, J. M., Seibold, J. R., Czirjak, L., Steen, V. D., Inanc, M., Kowal-Bielecka, O., Mueller-Ladner, U., Valentini, G., Veale, D. J., Vonk, M. C., Walker, U. A., Chung, L., Collier, D. H., Csuka, M. E., Fessler, B. J., Guiducci, S., Herrick, A., Hsu, V. M., Jimenez, S., Kahaleh, B., Merkel, P. A., Sierakowski, S., Silver, R. M., Simms, R. W., Varga, J., Pope, J. E. 2013; 72 (11): 1747-1755
Abstract

The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc.Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc.It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc.The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

View details for DOI 10.1136/annrheumdis-2013-204424

View details for Web of Science ID 000325532200006
2013 Classification Criteria for Systemic Sclerosis An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative ARTHRITIS AND RHEUMATISM van den Hoogen, F., Khanna, D., Fransen, J., Johnson, S. R., Baron, M., Tyndall, A., Matucci-Cerinic, M., Naden, R. P., Medsger, T. A., Carreira, P. E., Riemekasten, G., Clements, P. J., Denton, C. P., Distler, O., Allanore, Y., Furst, D. E., Gabrielli, A., Mayes, M. D., van Laar, J. M., Seibold, J. R., Czirjak, L., Steen, V. D., Inanc, M., Kowal-Bielecka, O., Mueller-Ladner, U., Valentini, G., Veale, D. J., Vonk, M. C., Walker, U. A., Chung, L., Collier, D. H., Csuka, M. E., Fessler, B. J., Guiducci, S., Herrick, A., Hsu, V. M., Jimenez, S., Kahaleh, B., Merkel, P. A., Sierakowski, S., Silver, R. M., Simms, R. W., Varga, J., Pope, J. E. 2013; 65 (11): 2737-2747
Abstract

The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc.Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc.It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc.The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

View details for DOI 10.1002/art.38098

View details for Web of Science ID 000326138200001

View details for PubMedID 24122180
Most Patients With Cancer-Associated Dermatomyositis Have Antibodies to Nuclear Matrix Protein NXP-2 or Transcription Intermediary Factor 1?. Arthritis and rheumatism Fiorentino, D. F., Chung, L. S., Christopher-Stine, L., Zaba, L., Li, S., Mammen, A. L., Rosen, A., Casciola-Rosen, L. 2013; 65 (11): 2954-2962
Abstract

Since dermatomyositis (DM) is associated with an increased risk of malignancy, accurate identification of patients likely to harbor cancers is important. Using immunoprecipitations from radiolabeled cell lysates, several groups recently showed that anti-transcription intermediary factor 1? (anti-TIF-1?) antibodies are associated with malignancy in DM. We undertook this study to develop sensitive, specific assays to detect antibodies against TIF-1? and nuclear matrix protein NXP-2 and to evaluate their association with malignancy in DM.To detect anti-TIF-1? antibodies, immunoprecipitations were performed using lysates made from HeLa cells overexpressing TIF-1?, with detection by immunoblotting. Anti-NXP-2 antibodies were assayed by immunoprecipitation using (35) S-methionine-labeled NXP-2 generated by in vitro transcription/translation. We analyzed patient sera from DM cohorts seen at the Stanford University Dermatology Clinic (n = 111) and the Johns Hopkins Myositis Center (n = 102).A total of 17% and 38% of patients had antibodies against NXP-2 and TIF-1?, respectively. Reactivity against either NXP-2 or TIF-1? identified 83% of patients with cancer-associated DM. In addition to older age and male sex, cancer was associated with antibodies to NXP-2 or TIF-1? on multivariate analysis (odds ratio 3.78 [95% confidence interval 1.33-10.8]). Stratification by sex revealed that anti-NXP-2 was specifically associated with cancer in males (odds ratio 5.78 [95% confidence interval 1.35-24.7]).These studies demonstrate that anti-NXP-2 and anti-TIF-1? antibodies are frequent DM specificities (found in 55% of patients) and are present in most patients with cancer-associated DM.

View details for DOI 10.1002/art.38093

View details for PubMedID 24037894
Recommendations For Screening and Detection Of Connective-Tissue Disease Associated Pulmonary Arterial Hypertension Khanna, D., Gladue, H., Fitzgerald, J. D., Channick, R. N., Chung, L., Distler, O., Furst, D., Hachulla, E., Humbert, M., Langleben, D., Mathai, S. C., Saggar, R., Visovatti, S. H., McLaughlin, V. WILEY-BLACKWELL. 2013: S1100?S1101
View details for Web of Science ID 000325359206012
Validation Of a Novel Radiographic Scoring System For Calcinosis Affecting The Hands Of Patients With Systemic Sclerosis. Chung, L., Vergara, A., Fiorentino, D., Stevens, K., Li, S., Harris, J., Hutchinson, C. E., Assassi, S., Beretta, L., Lakshminarayanan, S., Reyna, T., Denton, C. P., Taillefer, R. G., Tatibouet, S., Herrick, A., Baron, M. WILEY-BLACKWELL. 2013: S289?S290
View details for Web of Science ID 000325359202186
Pregnancy Outcomes In Adult Patients With Dermatomyositis and Polymyositis Chung, L., Fiorentino, D., Li, S., Chakravarty, E. WILEY-BLACKWELL. 2013: S886?S887
View details for Web of Science ID 000325359205028
Validation Of The Cutaneous Dermatomyositis Disease Area and Severity Index: Characterizing Severity and Assessing Responsiveness To Clinical Change Anyanwu, C. O., Fiorentino, D., Chung, L., Wang, Y., Propert, K. J., Werth, V. P. WILEY-BLACKWELL. 2013: S824
View details for Web of Science ID 000325359204393
Validation Of The ICD-CM-9 Code For Systemic Sclerosis Using Updated ACR/EULAR Classification Criteria Yaqub, A., Chung, L., Fiorentino, D., Krishnan, E. WILEY-BLACKWELL. 2013: S772?S773
View details for Web of Science ID 000325359204270
Identification Of Clinical Features and Risk Factors Associated With Calcinosis In Adult Patients With Dermatomyositis Valenzuela, A., Chung, L., Casciola-Rosen, L., Rosen, A., Fiorentino, D. WILEY-BLACKWELL. 2013: S889
View details for Web of Science ID 000325359205033
Near-infrared fluorescence and nuclear imaging and targeting of prostate cancer. Translational andrology and urology Wu, J., Pan, D., Chung, L. W. 2013; 2 (3): 254-264
Abstract

Despite advances in the treatment of castration-resistant and bone metastatic prostate cancer (PCa), there is still no clear demonstration that PCa growth and metastases can be unambiguously detected. We review recent advances including our own development of near-infrared fluorescence (NIRF) and near-infrared nuclear (NIRN) imaging approaches. We validated our results in experimental models of PCa bone and soft tissue metastases including PCa colonization at metastatic sites by injecting PCa cells either intratibially or intracardiacally. We describe our experience using noninvasive imaging and targeting modalities to probe PCa tumors grown at metastatic sites, molecular studies to understand the multiple molecular and cellular processes within tumor cells and their interactions with the tumor microenvironment, and targeting tumor growth at metastatic bone site. In this review, current knowledge and emerging technologies based on NIRF and NIRN disciplines will be summarized. Additionally the mechanisms of differential uptake of these agents by normal and cancerous cells will be described.

View details for PubMedID 25285271
Functional Class Improvement and 3-Year Survival Outcomes in Patients With Pulmonary Arterial Hypertension in the REVEAL Registry CHEST Barst, R. J., Chung, L., Zamanian, R. T., Turner, M., Mcgoon, M. D. 2013; 144 (1): 160-168
Abstract

ABSTRACT OBJECTIVE: New York Heart Association/World Health Organization functional class (FC) is associated with outcomes in pulmonary arterial hypertension (PAH). We assessed whether patients with PAH who improve from FC III to FC I/II have improved survival versus patients who remain at FC III or worsen to FC IV. METHODS: Patients aged ?19 years with FC III PAH from the REVEAL Registry (N=982) were categorized as improved, unchanged, or worsened according to their change in FC from enrollment to first follow-up assessment within 1 year of enrollment. Kaplan-Meier estimates of 3-year survival from first follow-up and changes in 6-minute walk distance (6MWD) from enrollment to first follow-up were determined. Subgroup analyses were conducted by etiology (ie, idiopathic/familial, connective tissue disease [CTD], congenital heart disease) and time of diagnosis (ie, newly and previously diagnosed [diagnostic right heart catheterization within or ?3 months of enrollment, respectively]). RESULTS: Overall, 27% of patients improved FC. Survival was better in patients whose FC improved (84%�2%; n=263) versus those who remained unchanged (66%�2%; n=645) or worsened (29%�6%; n=74) (all P<.001). Survival was also better in patient subgroups whose FC improved versus those who remained unchanged (idiopathic/familial [P<.001], CTD-associated PAH [P=.009], whether newly [P=.004] or previously diagnosed [P<.001]. 6MWD improvements were greater in patients whose FC improved versus those who remained unchanged in the overall (P<.001) and CTD (P=.028) cohorts. CONCLUSION: Patients with PAH who improve from FC III to I/II, whether newly or previously diagnosed and regardless of PAH etiology, have better survival versus patients who remain FC III.ClinicalTrials.gov Registration Number: NCT00370214.

View details for DOI 10.1378/chest.12-2417

View details for PubMedID 23429998
Management of the hand in systemic sclerosis. journal of hand surgery Fox, P., Chung, L., Chang, J. 2013; 38 (5): 1012-1016
View details for DOI 10.1016/j.jhsa.2013.02.012

View details for PubMedID 23561724
Localized cutaneous fibrosing disorders. Rheumatic diseases clinics of North America Yaqub, A., Chung, L., Rieger, K. E., Fiorentino, D. F. 2013; 39 (2): 347-364
View details for DOI 10.1016/j.rdc.2013.02.013

View details for PubMedID 23597968
Localized cutaneous fibrosing disorders. Rheumatic diseases clinics of North America Yaqub, A., Chung, L., Rieger, K. E., Fiorentino, D. F. 2013; 39 (2): 347-364
Abstract

This article acquaints the reader with disorders of the skin that might mimic systemic sclerosis but whose pathology is localized to the skin and/or has extracutaneous manifestations that are different than systemic sclerosis. These disorders include localized scleroderma (morphea), eosinophilic fasciitis, scleredema, scleromyxedema, nephrogenic systemic fibrosis, and chronic graft-versus-host disease. Particular emphasis is placed on clinical and histopathologic features that help the clinician differentiate between these disorders. Treatment options are briefly reviewed.

View details for DOI 10.1016/j.rdc.2013.02.013

View details for PubMedID 23597968
Dyspnea Assessment and Pulmonary Hypertension in Patients With Systemic Sclerosis: Utility of the University of California, San Diego, Shortness of Breath Questionnaire ARTHRITIS CARE & RESEARCH Chung, L., Chen, H., Khanna, D., Steen, V. D. 2013; 65 (3): 454-463
Abstract

The University of California in San Diego Shortness of Breath Questionnaire (UCSD SOBQ) has been used to assess dyspnea-related activity limitation in patients with airway and parenchymal lung disease. We sought to assess the construct validity and responsiveness of the UCSD SOBQ in systemic sclerosis (SSc; scleroderma) patients with incident pulmonary hypertension (PH) and those at high risk of developing PH.We used data from 179 patients enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry with pre-PH (defined by criteria on pulmonary function tests and/or echocardiogram) or definite PH with mean pulmonary artery pressure ?25 mm Hg by right-sided heart catheterization within 6 months of enrollment. For this analysis, we included those subjects with complete data for self-reported measures at baseline and at 12 months.At baseline, the UCSD SOBQ had strong correlations in the expected direction with the disability index (DI) of the Health Assessment Questionnaire (HAQ) (r = 0.71, P < 0.0001), dyspnea assessment by visual analog scale (r = 0.71, P < 0.0001), and the Short Form 36 (SF-36) health survey physical component summary (PCS) score (r = -0.77, P < 0.0001), as well as a moderate correlation with the 6-minute walk test distance (r = -0.33, P < 0.0001), Borg dyspnea score (r = 0.47, P < 0.0001), and diffusing capacity of carbon monoxide (r = -0.33, P < 0.0001). Change in the UCSD SOBQ at 12 months correlated in the expected direction with change in the HAQ DI (r = 0.54, P < 0.0001) and change in the SF-36 PCS (r = -0.44, P < 0.0001). Multivariate analysis adjusting for age, sex, and race identified male sex as a significant predictor of death (odds ratio [OR] 7.00, 95% confidence interval [95% CI] 1.55-31.76), while the UCSD SOBQ showed a strong trend toward significance (OR 1.82, 95% CI 0.97-3.41).The UCSD SOBQ demonstrates good construct validity and responsiveness to change in SSc patients with pulmonary vascular disease.

View details for DOI 10.1002/acr.21827

View details for Web of Science ID 000316907700015

View details for PubMedID 23042670
Epidemiology and risk factors for pulmonary hypertension in systemic sclerosis. Current rheumatology reports Yaqub, A., Chung, L. 2013; 15 (1): 302-?
Abstract

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy and excessive collagen production leading to fibrosis of the skin and internal organs. SSc patients are at risk of developing pulmonary hypertension (PH), a debilitating, progressive condition of the pulmonary vasculature that leads to right heart failure and death. This review is an updated summary of the epidemiology and risk factors for PH in SSc. We describe the current literature examining the incidence, prevalence, and demographic and clinical risk factors associated with PH in SSc. We also discuss classical and novel autoantibodies and potential biomarkers that may be helpful in the assessment of risk and prognosis of PH in SSc patients. The ultimate objective in understanding the risk of developing PH in SSc is early diagnosis and early initiation of appropriate therapy with the hope for improved outcomes for patients with SSc-PH.

View details for DOI 10.1007/s11926-012-0302-2

View details for PubMedID 23292818
Molecular Profiling to Diagnose a Case of Atypical Dermatomyositis. The Journal of investigative dermatology 2013
View details for PubMedID 23732751
Atherosclerotic cardiovascular disease and dermatomyositis: an analysis of the Nationwide Inpatient Sample survey ARTHRITIS RESEARCH & THERAPY Linos, E., Fiorentino, D., Lingala, B., Krishnan, E., Chung, L. 2013; 15 (1)
Abstract

ABSTRACT: INTRODUCTION: Increased rates of cardiovascular disease are implicated in several rheumatologic diseases. Our aim was to characterize dermatomyositis hospitalizations and evaluate cardiovascular-associated mortality in this patient population. METHODS: We examined the frequency and mortality rates of several atherosclerotic cardiovascular diagnoses and procedures among hospitalized adult patients with dermatomyositis using data from the US Nationwide Inpatient Sample (NIS) from 1993 to 2007. We compared the odds of death among hospitalized dermatomyositis patients with each cardiovascular diagnosis or procedure to those without, as well as to controls with cardiovascular diagnoses, using logistic regression. RESULTS: A total of 50,322 hospitalizations of dermatomyositis patients occurred between 1993 and 2007 (mean age 58 years, and 73% female). Of all dermatomyositis hospitalizations, 20% were associated with a concurrent atherosclerotic cardiovascular diagnosis or procedure. The overall in-hospital mortality was 5.7%. Dermatomyositis patients with any associated atherosclerotic cardiovascular diagnosis or procedure were twice as likely to die during the inpatient stay compared to dermatomyositis patients who did not have atherosclerotic cardiovascular disease (OR = 2.0 95% CI 1.7-2.5, p < 0.0001). The odds ratio for death in patients with both dermatomyositis and cardiovascular disease compared to controls with cardiovascular disease alone was 1.98 (95% CI 1.57-2.48) in multivariate adjusted models. CONCLUSIONS: Approximately one fifth of dermatomyositis hospitalizations in the US were associated with an atherosclerotic cardiovascular diagnosis or procedure. These patients have double the risk of in-hospital death in comparison with controls and dermatomyositis patients without a cardiovascular diagnosis, making identification of these groups important for both prognostic purposes and clinical care.

View details for DOI 10.1186/ar4135

View details for Web of Science ID 000317932600021
Immune Responses to NXP-2 and TIF-g Are Associated with Distinct Clinical Phenotypes and Prognosis for Skin Disease in Dermatomyositis Patients. Annual Scientific Meeting of the American-College-of-Rheumatology (ACR) and Association-of-Rheumatology-Health-Professionals (ARHP) Fiorentino, D., Chung, L., Zaba, L., Lingala, B., Rosen, A., Casciola-Rosen, L. WILEY-BLACKWELL. 2012: S828?S828
View details for Web of Science ID 000309748304231
Excess Mortality From Atherosclerotic Cardiovascular Disease in Systemic Sclerosis Compared to Lupus and Rheumatoid Arthritis Dave, A. J., Lingala, B., Fiorentino, D., Krishnan, E., Chung, L. WILEY-BLACKWELL. 2012: S302?S303
View details for Web of Science ID 000309748301244
Cutaneous Ulceration in Dermatomyositis: Association with MDA-5 and Interstitial Lung Disease. Narang, N., Casciola-Rosen, L., Rosen, A., Fiorentino, D., Chung, L. WILEY-BLACKWELL. 2012: S326
View details for Web of Science ID 000309748301295
Antibodies to NXP-2 and Transcriptional Intermediary Factor-Gamma Identify Patients with Cancer-Associated Dermatomyositis. Fiorentino, D., Christopher-Stine, L., Chung, L., Lingala, B., Mammen, A. L., Rosen, A., Casciola-Rosen, L. WILEY-BLACKWELL. 2012: S828
View details for Web of Science ID 000309748304230
World Health Organization Classification of Pulmonary Hypertension and Survival in Systemic Sclerosis Patients in the Pharos Cohort Gordon, J. K., Chung, L., Domsic, R. T., Huang, W., Lyman, S. L., Horn, E. M., Steen, V. D., PHAROS Investigators WILEY-BLACKWELL. 2012: S629
View details for Web of Science ID 000309748303186
Survival, Hospitalization or Need for Combination Therapy At One Year in Patients with Scleroderma-Associated Pulmonary Arterial Hypertension Domsic, R. T., Chung, L., Gordon, J. K., Cloonan, Y., Steen, V. D., PHAROS Investigators WILEY-BLACKWELL. 2012: S310?S311
View details for Web of Science ID 000309748301261
Pulmonary Hypertension and Interstitial Lung Disease within Pharos: Impact of Extent of Fibrosis and Pulmonary Physiology On Cardiac Hemodynamic Parameters Fischer, A., Mathai, S. C., Bolster, M. B., Chung, L., Csuka, M., Domsic, R. T., Frech, T. M., Hinchcliff, M. E., Hsu, V. M., Hummers, L. K., Kolfenbach, J. R., Gomberg-Maitland, M., Manu, A., Simms, R. W., Steen, V. D. WILEY-BLACKWELL. 2012: S628
View details for Web of Science ID 000309748303184
Differential Expression of Hepatocyte Growth Factor (HGF) in Patients with Systemic Sclerosis-Associated Pulmonary Arterial Hypertension Chung, L., Cramb, C., Robinson, W. H., Steen, V. D., Zamanian, R. T. WILEY-BLACKWELL. 2012: S632
View details for Web of Science ID 000309748303192
Clinical presentation and evaluation of dermatomyositis. Indian journal of dermatology Marvi, U., Chung, L., Fiorentino, D. F. 2012; 57 (5): 375-381
Abstract

Dermatomyositis (DM) is a chronic inflammatory disorder of the skin and muscles. Evidence supports that DM is an immune-mediated disease and 50-70% of patients have circulating myositis-specific auto-antibodies. Gene expression microarrays have demonstrated upregulation of interferon signaling in the muscle, blood, and skin of DM patients. Patients with classic DM typically present with symmetric, proximal muscle weakness, and skin lesions that demonstrate interface dermatitis on histopathology. Evaluation for muscle inflammation can include muscle enzymes, electromyogram, magnetic resonance imaging, and/or muscle biopsy. Classic skin manifestations of DM include the heliotrope rash, Gottron's papules, Gottron's sign, the V-sign, and shawl sign. Additional cutaneous lesions frequently observed in DM patients include periungual telangiectasias, cuticular overgrowth, "mechanic's hands", palmar papules overlying joint creases, poikiloderma, and calcinosis. Clinically amyopathic DM is a term used to describe patients who have classic cutaneous manifestations for more than 6 months, but no muscle weakness or elevation in muscle enzymes. Interstitial lung disease can affect 35-40% of patients with inflammatory myopathies and is often associated with the presence of an antisynthetase antibody. Other clinical manifestations that can occur in patients with DM include dysphagia, dysphonia, myalgias, Raynaud phenomenon, fevers, weight loss, fatigue, and a nonerosive inflammatory polyarthritis. Patients with DM have a three to eight times increased risk for developing an associated malignancy compared with the general population, and therefore all patients with DM should be evaluated at the time of diagnosis for the presence of an associated malignancy. This review summarizes the immunopathogenesis, clinical manifestations, and evaluation of patients with DM.

View details for DOI 10.4103/0019-5154.100486

View details for PubMedID 23112358

View details for PubMedCentralID PMC3482801
Change in diffusing capacity for carbon monoxide as a predictor of outcomes in connective tissue disease-associated pulmonary arterial hypertension: Analysis from the REVEAL registry Zamanian, R., Kudelko, K., Miller, D., McGoon, M., Benza, R., Hassoun, P., Nicolls, M., Chung, L. EUROPEAN RESPIRATORY SOC JOURNALS LTD. 2012
View details for Web of Science ID 000449650903554
Baseline characteristics and follow-up in patients with normal haemodynamics versus borderline mean pulmonary arterial pressure in systemic sclerosis: results from the PHAROS registry ANNALS OF THE RHEUMATIC DISEASES Bae, S., Saggar, R., Bolster, M. B., Chung, L., Csuka, M. E., Derk, C., Domsic, R., Fischer, A., Frech, T., Goldberg, A., Hinchcliff, M., Hsu, V., Hummers, L., Schiopu, E., Mayes, M. D., McLaughlin, V., Molitor, J., Naz, N., Furst, D. E., Maranian, P., Steen, V., Khanna, D. 2012; 71 (8): 1335-1342
Abstract

Patients with normal (mean pulmonary arterial pressure (mPAP) ?20 mm Hg) and borderline mean pulmonary pressures (21-24 mm Hg) are "at risk" of developing pulmonary hypertension (PH). The objectives of this analysis were to examine the baseline characteristics in systemic sclerosis (SSc) with normal and borderline mPAP and to explore long-term outcomes in SSc patients with borderline mPAP versus normal haemodynamics.PHAROS is a multicentre prospective longitudinal cohort of patients with SSc "at risk" or recently diagnosed with resting PH on right heart catheterisation (RHC). Baseline clinical characteristics, pulmonary function tests, high-resolution CT, 2-dimensional echocardiogram and RHC results were analysed in normal and borderline mPAP groups.206 patients underwent RHC (results showed 35 normal, 28 borderline mPAP, 143 resting PH). There were no differences in the baseline demographics. Patients in the borderline mPAP group were more likely to have restrictive lung disease (67% vs 30%), fibrosis on high-resolution CT and a higher estimated right ventricular systolic pressure on echocardiogram (46.3 vs 36.2 mm Hg; p<0.05) than patients with normal haemodynamics. RHC revealed higher pulmonary vascular resistance and more elevated mPAP on exercise (?30; 88% vs 56%) in the borderline mPAP group (p<0.05 for both). Patients were followed for a mean of 25.7 months and 24 patients had a repeat RHC during this period. During follow-up, 55% of the borderline mPAP group and 32% of the normal group developed resting PH (p=NS).Patients with borderline mPAP have a greater prevalence of abnormal lung physiology, pulmonary fibrosis and the presence of exercise mPAP ?30 mm Hg.

View details for DOI 10.1136/annrheumdis-2011-200546

View details for Web of Science ID 000306407700012

View details for PubMedID 22307943

View details for PubMedCentralID PMC3398226
Hyperuricemia in Young Adults and Risk of Insulin Resistance, Prediabetes, and Diabetes: A 15-Year Follow-up Study AMERICAN JOURNAL OF EPIDEMIOLOGY Krishnan, E., Pandya, B. J., Chung, L., Hariri, A., Dabbous, O. 2012; 176 (2): 108-116
Abstract

The objective of this study was to assess the utility of hyperuricemia as a marker for diabetes and prediabetes (impaired fasting glucose) and insulin resistance in young adults. Using Cox proportional hazards regression models, the authors analyzed 15-year follow-up data on 5,012 persons in 4 US cities who were aged 18-30 years and diabetes-free at the time of enrollment. At baseline (1986), 88% of participants had a body mass index (weight (kg)/height (m)(2)) less than 30. During the follow-up period (through 2001), the incidence rates of diabetes and prediabetes (insulin resistance and impaired fasting glucose) were higher among persons with greater serum urate concentrations. In multivariable Cox regression analyses that adjusted for age, gender, race, body mass index, family history of diabetes, diastolic blood pressure, total cholesterol, smoking, and alcohol use, the hazard ratios for diabetes, insulin resistance, and prediabetes among persons with hyperuricemia (serum urate level >7 mg/dL vs. ?7.0 mg/dL) were 1.87 (95% confidence interval (CI): 1.33, 2.62), 1.36 (95% CI: 1.23, 1.51), and 1.25 (95% CI: 1.04, 1.52), respectively. This observation was generally consistent across subgroups. The authors conclude that hyperuricemia in the midtwenties is an independent marker for predicting diabetes and prediabetes among young adults in the subsequent 15 years.

View details for DOI 10.1093/aje/kws002

View details for Web of Science ID 000306406500005

View details for PubMedID 22753829
Clinical trial design in scleroderma: where are we and where do we go next? CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Chung, L., Denton, C. P., Distler, O., Furst, D. E., Khanna, D., Merkel, P. A. 2012; 30 (2): S97-S102
Abstract

Drug development for SSc has been hindered by the relative paucity of validated outcome measures and biomarkers for use in clinical trials. The Scleroderma Clinical Trials Consortium (SCTC) conducted an interactive session at the Scleroderma International Workshop in Cambridge, UK in July 2011 to discuss clinical trial design in SSc. The following issues were discussed: 1) primary outcome for trials of SSc - skin vs. lung vs. composite; 2) ischaemic digital ulcers in SSc - healing vs. repair vs. composite; 3) pulmonary arterial hypertension in SSc; and 4) neglected aspects of SSc - opportunities for study or of lower priority and feasibility. Randomised controlled trials with collection of biospecimens are necessary to assess efficacy of therapeutic agents, validate novel outcome measures, and discover and validate potential biomarkers for each of these areas. Although SSc is a rare, heterogeneous disease, collaborative efforts led by the SCTC and other international networks will ultimately improve the design of clinical trials of promising therapies for SSc.

View details for Web of Science ID 000304976600016

View details for PubMedID 22691217
Items for developing revised classification criteria in systemic sclerosis: Results of a consensus exercise ARTHRITIS CARE & RESEARCH Fransen, J., Johnson, S. R., van den Hoogen, F., Baron, M., Allanore, Y., Carreira, P. E., Czirjak, L., Denton, C. P., Distler, O., Furst, D. E., Gabrielli, A., Herrick, A., Inanc, M., Kahaleh, B., Kowal-Bielecka, O., Medsger, T. A., Mueller-Ladner, U., Riemekasten, G., Sierakowski, S., Valentini, G., Veale, D., Vonk, M. C., Walker, U., Chung, L., Clements, P. J., Collier, D. H., Csuka, M. E., Jimenez, S., Merkel, P. A., Seibold, J. R., Silver, R., Steen, V., Tyndall, A., Matucci-Cerinic, M., Pope, J. E., Khanna, D. 2012; 64 (3): 351-357
Abstract

Classification criteria for systemic sclerosis (SSc; scleroderma) are being updated. Our objective was to select a set of items potentially useful for the classification of SSc using consensus procedures, including the Delphi and nominal group techniques (NGT).Items were identified through 2 independent consensus exercises performed by the Scleroderma Clinical Trials Consortium and the European League Against Rheumatism Scleroderma Trials and Research Group. The first-round items from both exercises were collated and redundancies were removed, leaving 168 items. A 3-round Delphi exercise was performed using a 1-9 scale (where 1 = completely inappropriate and 9 = completely appropriate) and a consensus meeting using NGT was conducted. During the last Delphi round, the items were ranked on a 1-10 scale.In round 1, 106 experts rated the 168 items. Those with a median score of <4 were removed, resulting in a list of 102 items. In round 2, the items were again rated for appropriateness and subjected to a consensus meeting using NGT by European and North American SSc experts (n = 16), resulting in 23 items. In round 3, SSc experts (n = 26) then individually scored each of the 23 items in a last Delphi round using an appropriateness score (1-9) and ranking their 10 most appropriate items for the classification of SSc. Presence of skin thickening, SSc-specific autoantibodies, abnormal nailfold capillary pattern, and Raynaud's phenomenon ranked highest in the final list that also included items indicating internal organ involvement.The Delphi exercise and NGT resulted in a set of 23 items for the classification of SSc that will be assessed for their discriminative properties in a prospective study.

View details for DOI 10.1002/acr.20679

View details for Web of Science ID 000300831500006

View details for PubMedID 22052558

View details for PubMedCentralID PMC3288452
Classification and Diagnosis of Systemic Slerosis: Towards Early Recognition of the Disease Scleroderma: From Pathogenesis to Comprehensive Management Chung, L., Fransen, J., van den Hoogen, F. Dordrecht, Heidelberg, London, Springer. 2012; 1: 53?69
Evolving Concepts of Diagnosis and Classification SCLERODERMA: FROM PATHOGENESIS TO COMPREHENSIVE MANAGEMENT Chung, L., Fransen, J., Van den Hoogen, F. J., Varga, J., Denton, C. P., Wigley, F. M. 2012: 53?69
View details for DOI 10.1007/978-1-4419-5774-0_7

View details for Web of Science ID 000303688600007
A Pilot Study of Abatacept for the Treatment of Patients with Diffuse Cutaneous Systemic Sclerosis. 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) Chakravarty, E. F., Fiorentino, D., Bennett, M., Chung, L. WILEY-BLACKWELL. 2011: S274?S275
View details for Web of Science ID 000297621500703
Effect of the ETA Selective Endothelin Receptor Antagonist Ambrisentan on Digital Ulcers in Patients with Systemic Sclerosis: Results of a Prospective Pilot Study. Chung, L., Arefiev, K., Yaqub, A., Strahs, D., Lingala, B., Fiorentino, D. WILEY-BLACKWELL. 2011: S259?S260
View details for Web of Science ID 000297621500664
International Classification of Diseases-Clinical Modification-9 Codes for the Diagnosis of Dermatomyositis and Polymyositis in Discharge Summaries: Evidence of Acceptable Validity Narang, N., Fiorentino, D., Krishnan, E., Chung, L. WILEY-BLACKWELL. 2011: S90
View details for Web of Science ID 000297621500244
Better Survival in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension Patients Enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry Chung, L., Domsic, R. T., Lingala, B., Steen, V. D., PHAROS Investigators WILEY-BLACKWELL. 2011: S673
View details for Web of Science ID 000297621502101
Functional Class Change in Patients with Connective Tissue Disease-Associated Pulmonary Arterial Hypertension: Associations with Survival and Exercise Capacity Chung, L., Parsons, L. S., Hassoun, P. M., McGoon, M. D., Badesch, D. B., Miller, D. P., Nicolls, M. R., Zamanian, R. T. WILEY-BLACKWELL. 2011: S575
View details for Web of Science ID 000297621501665
Digital Ischemic Ulcers in Scleroderma Treated with Oral Treprostinil Diethanolamine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Seibold, J. R., Wigley, F. M., Schiopu, E., Denton, C. D., Silver, R. M., Steen, V. D., Medsger, T. A., Mayes, M. D., Chatterjee, S., Chung, L., Csuka, M., Khanna, D., Frech, T. M., Molitor, J. A., Rothfield, N. F., Herrick, A. L., Simms, R. W., Pope, J. E., Rollins, K. D., Arneson, C., Wade, M., DISTOL Investigators WILEY-BLACKWELL. 2011: S968?S969
View details for Web of Science ID 000297621503054
Tyrosine kinases in inflammatory dermatologic disease JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Paniagua, R. T., Fiorentino, D. F., Chung, L., Robinson, W. H. 2011; 65 (2): 389-403
Abstract

Tyrosine kinases (TKs) are enzymes that catalyze the phosphorylation of tyrosine residues on protein substrates. They are key components of signaling pathways that drive an array of cellular responses including proliferation, differentiation, migration, and survival. Specific TKs have recently been identified as critical to the pathogenesis of several autoimmune and inflammatory diseases. Small-molecule inhibitors of TKs are emerging as a novel class of therapy that may provide benefit in certain patient subsets. In this review, we highlight TK signaling implicated in inflammatory dermatologic diseases, evaluate strategies aimed at inhibiting these aberrant signaling pathways, and discuss prospects for future drug development.

View details for DOI 10.1016/j.jaad.2010.04.026

View details for PubMedID 20584561
The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): A retrospective study JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Fiorentino, D., Chung, L., Zwerner, J., Rosen, A., Casciola-Rosen, L. 2011; 65 (1): 25-34
Abstract

Dermatomyositis (DM) is a multisystem autoimmune disease, in which serologic evidence of immune responses to disease-specific antigenic targets is found in approximately 50% to 70% of patients. Recently, melanoma differentiation-associated gene 5 (MDA5) has been identified as a DM-specific autoantigen that appears to be targeted in patients with DM and mild or absent muscle inflammation and with an increased risk of interstitial lung disease.We wished to understand the role of MDA5 in DM skin inflammation by testing it to determine if a specific cutaneous phenotype is associated with MDA5 reactivity.We retrospectively screened plasma from 77 patients with DM in the outpatient clinics at the Stanford University Department of Dermatology in California.We found that 10 (13%) patients had circulating anti-MDA5 antibodies, and had a characteristic cutaneous phenotype consisting of skin ulceration, tender palmar papules, or both. Typical areas of skin ulceration included the lateral nailfolds, Gottron papules, and elbows. Biopsy specimens of the palmar papules showed a vasculopathy characterized by vascular fibrin deposition with variable perivascular inflammation. Patients with anti-MDA5 antibodies also had an increased risk of oral pain and/or ulceration, hand swelling, arthritis/arthralgia, and diffuse hair loss. Consistent with previous reports, these patients had little or no myositis and had increased risk of interstitial lung disease.This study was conducted at a tertiary referral center. Multiple associations with MDA5 antibodies were tested retrospectively on a relatively small cohort of 10 anti-MDA5-positive patients.We suggest that MDA5 reactivity in DM characterizes a patient population with severe vasculopathy.

View details for DOI 10.1016/j.jaad.2010.09.016

View details for Web of Science ID 000292222200003

View details for PubMedID 21531040

View details for PubMedCentralID PMC3167687
Pathogenesis of dermatomyositis: role of cytokines and interferon. Current rheumatology reports Kao, L., Chung, L., Fiorentino, D. F. 2011; 13 (3): 225-232
Abstract

Dermatomyositis is a systemic autoimmune disease that primarily affects skeletal muscle, skin, and the lungs. Dermatomyositis is characterized by autoantibodies, tissue inflammation, parenchymal cell damage and death, and vasculopathy. This review focuses on recent advances regarding the role of cytokines and interferon in the pathogenesis of the disease. Evidence for the role of a particular cytokine is based on data showing dysregulated levels in tissue and/or blood; correlation with histopathologic or clinical markers of disease activity; and, rarely, clinical efficacy of targeted cytokine inhibitors. Many of the recent advances pertain to elucidation of the role of interferons in both muscle and skin disease in dermatomyositis. Although a great deal of progress has been made regarding the role of interferon in the disease, many critical questions remain unanswered.

View details for DOI 10.1007/s11926-011-0166-x

View details for PubMedID 21318338
Pathogenesis of Dermatomyositis: Role of Cytokines and Interferon CURRENT RHEUMATOLOGY REPORTS Kao, L., Chung, L., Fiorentino, D. F. 2011; 13 (3): 225-232
Abstract

Dermatomyositis is a systemic autoimmune disease that primarily affects skeletal muscle, skin, and the lungs. Dermatomyositis is characterized by autoantibodies, tissue inflammation, parenchymal cell damage and death, and vasculopathy. This review focuses on recent advances regarding the role of cytokines and interferon in the pathogenesis of the disease. Evidence for the role of a particular cytokine is based on data showing dysregulated levels in tissue and/or blood; correlation with histopathologic or clinical markers of disease activity; and, rarely, clinical efficacy of targeted cytokine inhibitors. Many of the recent advances pertain to elucidation of the role of interferons in both muscle and skin disease in dermatomyositis. Although a great deal of progress has been made regarding the role of interferon in the disease, many critical questions remain unanswered.

View details for DOI 10.1007/s11926-011-0166-x

View details for Web of Science ID 000208771200007
Survival in Pulmonary Hypertension Registries The Importance of Incident Cases Response CHEST Chung, L., Liu, J., Parsons, L. S., Hassoun, P. M., McGoon, M. D., Badesch, D. B., Miller, D. P., Nicolls, M. R., Zamanian, R. T. 2011; 139 (6): 1548-1549
View details for DOI 10.1378/chest.11-0341

View details for Web of Science ID 000291511100050
An Analysis of Connective Tissue Disease-associated Interstitial Lung Disease at a US Tertiary Care Center: Better Survival in Patients with Systemic Sclerosis JOURNAL OF RHEUMATOLOGY Su, R., Bennett, M., Jacobs, S., Hunter, T., Bailey, C., Krishnan, E., Rosen, G., Chung, L. 2011; 38 (4): 693-701
Abstract

To compare survival of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD) versus idiopathic pulmonary fibrosis (IPF) and patients with systemic sclerosis-associated ILD (SSc-ILD) versus other CTD-ILD followed at our center.We used the Stanford ILD database, which contains prospectively collected information on patients with ILD evaluated at our tertiary care center from 2002 to 2009. Survival at last followup from time of ILD diagnosis was calculated using the Kaplan-Meier estimator. Prognostic factors for survival in the overall cohort (IPF and CTD-ILD) and in the CTD-ILD group were identified with univariate and multivariate Cox regression models.Of 427 patients with ILD, 148 (35%) had IPF and 76 (18%) had CTD-ILD at the baseline visit. The cumulative incidence of CTD was 4%. After a median followup of 4 years, 67 patients (36.4%) had died and 4 (2.2%) were lost to followup. Patients with IPF (n = 122) and CTD-ILD (n = 62) experienced similar survival rates (5-year survival about 50%). Patients with SSc-ILD (n = 24) experienced better survival than those with other CTD-ILD (n = 38), with 1-year, 3-year, and 5-year survival rates of 100%, 90%, and 77%, respectively, versus 78%, 42%, and 38% (p = 0.01). The presence of SSc in patients with CTD-ILD decreased the risk of death by > 80% even after correcting for age at ILD diagnosis, sex, and ethnicity (HR = 0.17, 95% CI 0.04-0.83).Survival in patients with SSc-ILD was better than in patients with other CTD-ILD, potentially related to routine screening for and early detection of ILD in patients with SSc at our center.

View details for DOI 10.3899/jrheum.100675

View details for Web of Science ID 000289333800018

View details for PubMedID 21285162
Colonic ulceration as an unusual manifestation of vasculopathy in systemic sclerosis RHEUMATOLOGY Kao, L., Myer, P., Nguyen, L., Zamanian, R. T., Chung, L. 2011; 50 (3): 626-628
View details for DOI 10.1093/rheumatology/keq276

View details for Web of Science ID 000287745600030

View details for PubMedID 21172924
Endothelin Receptor Antagonists for the Treatment of Raynaud's Phenomenon and Digital Ulcers in Systemic Sclerosis. International journal of rheumatology Arefiev, K., Fiorentino, D. F., Chung, L. 2011; 2011: 201787-?
Abstract

Systemic sclerosis is a connective tissue disease characterized by fibrosis of the skin, internal organs, and widespread vasculopathy. Raynaud's phenomenon and digital ulcers are vascular manifestations of this disease and cause significant morbidity. Current treatments are only moderately effective in reducing the severity of Raynaud's in a portion of patients and typically do not lead to substantial benefit in terms of the healing or prevention of digital ulcers. Several studies have evaluated the efficacy of targeting the vasoconstrictor endothelin-1 for the treatment of systemic sclerosis-associated vascular disease. The purpose of this paper is to summarize the published studies and case reports evaluating the efficacy of endothelin receptor antagonists in the treatment of Raynaud's phenomenon and digital ulcers associated with systemic sclerosis.

View details for DOI 10.1155/2011/201787

View details for PubMedID 22121371

View details for PubMedCentralID PMC3205679
Endothelin Receptor Antagonists for the Treatment of Raynaud's Phenomenon and Digital Ulcers in Systemic Sclerosis INTERNATIONAL JOURNAL OF RHEUMATOLOGY Arefiev, K., Fiorentino, D. F., Chung, L. 2011
View details for DOI 10.1155/2011/201787

View details for Web of Science ID 000214704300003
Systemic Sclerosis 2011 INTERNATIONAL JOURNAL OF RHEUMATOLOGY Chung, L., Distler, O., Hummers, L., Krishnan, E., Steen, V. 2011
View details for DOI 10.1155/2011/308231

View details for Web of Science ID 000214704300011
Systemic sclerosis 2011. International journal of rheumatology Chung, L., Distler, O., Hummers, L., Krishnan, E., Steen, V. 2011; 2011: 308231-?
View details for DOI 10.1155/2011/308231

View details for PubMedID 22577388

View details for PubMedCentralID PMC3332200
Emerging therapies in systemic sclerosis International Joural of Rheumatology Chung, L., Distler, O., Hummers, L., Krishnan, E., Steen, V. 2011
Hyperuricemia and the risk for subclinical coronary atherosclerosis - data from a prospective observational cohort study ARTHRITIS RESEARCH & THERAPY Krishnan, E., Pandya, B. J., Chung, L., Dabbous, O. 2011; 13 (2)
Abstract

Our purpose was to test the hypothesis that hyperuricemia is associated with coronary artery calcification (CAC) among a relatively healthy population, and that the extent of calcification is directly proportional to the serum uric acid (sUA) concentration.Data from 2,498 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were analyzed using logistic regression models. Subjects were free of clinical heart disease, diabetes, and renal impairment. The main measure was the presence of any CAC by computerized tomography (Agatston score >0).Forty-eight percent of the study participants were male and 45% were African-American. Mean (� SD) age was 40 � 4 years, body mass index 28 � 6 kg/m2, Framingham risk score -0.7 � 5%, blood pressure 113 � 14/75 � 11 mmHg, alcohol consumption 12 � 27 ml/day, and sUA 297 � 89 ?mol/L (5.0 � 1.5 mg/dL). Prevalence of CAC increased with sUA concentration among both men and women. Adjusted for age, gender, race, lipoproteins, triglycerides, smoking, blood pressure, presence of metabolic syndrome, C-reactive protein, waist circumference, alcohol use, creatinine, and serum albumin, the highest quartile of sUA (>393 ?mol/L [6.6 mg/dL] for men and >274 ?mol/L [4.6 mg/dL] for women) was associated with an odds ratio of 1.87 (1.19-2.93) compared to the lowest quartile (<291 ?mol/L [4.9 mg/dL] for men and <196 ?mol/L [3.3 mg/dL] for women). Among those with any CAC, each unit increase in sUA was associated with a 22% increase in Agatston score (P = 0.008) after adjusting for the above covariates.Hyperuricemia is an independent risk factor for subclinical atherosclerosis in young adults.

View details for DOI 10.1186/ar3322

View details for Web of Science ID 000292449700031

View details for PubMedID 21501486

View details for PubMedCentralID PMC3132061
Characterization of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension From REVEAL Identifying Systemic Sclerosis as a Unique Phenotype CHEST Chung, L., Liu, J., Parsons, L., Hassoun, P. M., McGoon, M., Badesch, D. B., Miller, D. P., Nicolls, M. R., Zamanian, R. T. 2010; 138 (6): 1383-1394
Abstract

REVEAL (the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) is the largest US cohort of patients with pulmonary arterial hypertension (PAH) confirmed by right-sided heart catheterization (RHC), providing a more comprehensive subgroup characterization than previously possible. We used REVEAL to analyze the clinical features of patients with connective tissue disease-associated PAH (CTD-APAH).All newly and previously diagnosed patients with World Health Organization (WHO) group 1 PAH meeting RHC criteria at 54 US centers were consecutively enrolled. Cross-sectional and 1-year mortality and hospitalization analyses from time of enrollment compared CTD-APAH to idiopathic disease and systemic sclerosis (SSc) to systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis (RA).Compared with patients with idiopathic disease (n = 1,251), patients with CTD-APAH (n = 641) had better hemodynamics and favorable right ventricular echocardiographic findings but a higher prevalence of pericardial effusions, lower 6-min walk distance (300.5 � 118.0 vs 329.4 � 134.7 m, P = .01), higher B-type natriuretic peptide (BNP) levels (432.8 � 789.1 vs 245.6 � 427.2 pg/mL, P < .0001), and lower diffusing capacity of carbon monoxide (Dlco) (44.9% � 18.0% vs 63.6% � 22.1% predicted, P < .0001). One-year survival and freedom from hospitalization were lower in the CTD-APAH group (86% vs 93%, P < .0001; 67% vs 73%, P = .03). Compared with patients with SSc-APAH (n = 399), those with other CTDs (SLE, n = 110; MCTD, n = 52; RA, n = 28) had similar hemodynamics; however, patients with SSc-APAH had the highest BNP levels (552.2 � 977.8 pg/mL), lowest Dlco (41.2% � 16.3% predicted), and poorest 1-year survival (82% vs 94% in SLE-APAH, 88% in MCTD-APAH, and 96% in RA-APAH).Patients with SSc-APAH demonstrate a unique phenotype with the highest BNP levels, lowest Dlco, and poorest survival of all CTD-APAH subgroups.ClinicalTrials.gov; No.: NCT00370214; URL: clinicaltrials.gov.

View details for DOI 10.1378/chest.10-0260

View details for Web of Science ID 000285494000017

View details for PubMedID 20507945

View details for PubMedCentralID PMC3621419
A 39-Year-Old Woman With Lupus, Myositis, and a Recalcitrant Vasculopathy ARTHRITIS CARE & RESEARCH Sokolove, J., Copland, A., Shirvani, S., Brown, J., Posley, K., Chung, L. 2010; 62 (9): 1351-1356
View details for DOI 10.1002/acr.20236

View details for Web of Science ID 000281913400022

View details for PubMedID 20506174
Dyspnea in pcleroderma patients from the PHAROS Registry: a major contributor to disability Chung, L., Chen, H., Steen, V., PHAROS Investigators CLINICAL & EXPER RHEUMATOLOGY. 2010: S62
View details for Web of Science ID 000284028600027
Evaluation of an imatinib response gene signature in patients with systemic sclerosis Chung, L., Ruiz, P., Wood, T., Shoor, S., Robinson, W., Whitfield, M., Chang, H., Fiorentino, D. CLINICAL & EXPER RHEUMATOLOGY. 2010: S62?S62
View details for Web of Science ID 000284028600028
Digital ischemic loss in systemic sclerosis. International journal of rheumatology Marvi, U., Chung, L. 2010; 2010
Abstract

Digital ischemic loss is a cause of significant morbidity in patients with systemic sclerosis (SSc). Microvascular disease with intimal proliferation and luminal narrowing of small digital arteries, as well as macrovascular disease with narrowing or occlusion of larger digital arteries, contribute to the perfusion defects involved in digital ischemic loss. Immediate clinical evaluation and treatment are mandatory at the onset of critical digital ischemia to prevent digital loss. Hospitalization for medical therapies including intravenous prostacyclin therapy should be considered for all SSc patients who present with critical digital ischemia. Surgical interventions are typically reserved for patients who fail medical therapies and for those with late stage, necrotic tissue. This paper summarizes the current knowledge regarding the risk factors, pathogenesis, evaluation, and treatment of digital ischemic loss in SSc.

View details for DOI 10.1155/2010/130717

View details for PubMedID 20871838

View details for PubMedCentralID PMC2943156
Vascular disease in systemic sclerosis. International journal of rheumatology Chung, L., Distler, O., Hummers, L., Krishnan, E., Steen, V. 2010; 2010: 714172-?
View details for DOI 10.1155/2010/714172

View details for PubMedID 21048994

View details for PubMedCentralID PMC2964904
Prevalence of pulmonary arterial hypertension in an Australian scleroderma population: screening allows for earlier diagnosis INTERNAL MEDICINE JOURNAL Phung, S., Strange, G., Chung, L. P., Leong, J., Dalton, B., RODDY, J., Deague, J., Playford, D., Musk, M., Gabbay, E. 2009; 39 (10): 682-691
Abstract

We sought to determine the prevalence of pulmonary complications and especially pulmonary arterial hypertension (PAH) in an Australian scleroderma population.Between July 2005 and June 2007, physicians in Western Australia were asked to refer patients with scleroderma specifically for pulmonary hypertension screening. All patients were assessed for PAH and other respiratory conditions using echocardiography, lung function testing and clinical assessments. Right heart catheterization was carried out in patients with evidence of increased right ventricular systolic pressure.Of the 184 patients analysed, 44 had possible PAH on echocardiography. Right heart catheterization confirmed the diagnosis in 24 (13%). Diffuse interstitial lung disease was found in 32 patients representing a point prevalence of 17.4%. The severity of PAH at diagnosis varied according to whether the patients were referred for screening (group A) or for diagnostic (group B) purposes. The 6-min-walk test distance and median pulmonary vascular resistance were significantly worse in group B versus group A (324 vs 402 m; P= 0.02 and 884 dynes/s per cm(-5) vs 486 dynes/s per cm(-5); P < 0.01, respectively).Screening may result in earlier diagnosis of PAH with, in general more mild disease. This is important, given that early treatment for PAH while patients are less symptomatic is associated with improved exercise tolerance and pulmonary haemodynamics: indices indicative of disease progression and clinical worsening.

View details for DOI 10.1111/j.1445-5994.2008.01823.x

View details for Web of Science ID 000270901200009

View details for PubMedID 19220532
Characterizing systemic sclerosis in Northern California: focus on Asian and Hispanic patients CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Schmajuk, G., Bush, T. M., Burkham, J., Krishnan, E., Chung, L. 2009; 27 (3): S22-S25
View details for Web of Science ID 000270854500006
Characterizing systemic sclerosis in Northern California: focus on Asian and Hispanic patients. Clinical and experimental rheumatology Schmajuk, G., Bush, T. M., Burkham, J., Krishnan, E., Chung, L. 2009; 27 (3): 22-25
Abstract

Previous studies suggest that Asian and Hispanic patients with systemic sclerosis (SSc) may have more severe disease than their Caucasian counterparts. The purpose of this study is to compare the clinical features of a group of Asian, Hispanic, and Caucasian patients with SSc in Northern California.We performed a cross-sectional study of patients receiving care at Stanford University Medical Center, Palo Alto Veterans Affairs Hospital, Santa Clara Valley Medical Center and San Francisco General Hospital between 1996 and 2006. Patients included in the analyses fulfilled the American College of Rheumatology criteria for SSc and could be classified as Caucasian, Asian, or Hispanic. Analyses using Caucasians as the reference group were performed.One hundred and ninety-nine patients met the criteria for SSc, and 165 of these patients were classified as Caucasian (47%), Asian (26%), or Hispanic (27%). Disease subtype did not differ significantly among the three groups. Asian patients were less likely to have digital ulcers (26% vs. 47%, p=0.02) or anemia (26% vs. 45%, p=0.04) than Caucasians, and Hispanic patients had a lower frequency of lung disease than Caucasians (48% vs. 67%, p=0.04), but there were no other significant differences in disease manifestations.In our cohort of SSc patients living in Northern California, clinical manifestations in Asian and Hispanic patients did not differ substantially from Caucasians. Further research is necessary to confirm these results and to investigate gene-environment interactions which may affect the clinical expression of disease in different racial groups.

View details for PubMedID 19796557
MQX-503, a Novel Formulation of Nitroglycerin, Improves the Severity of Raynaud's Phenomenon A Randomized, Controlled Trial ARTHRITIS AND RHEUMATISM Chung, L., Shapiro, L., Fiorentino, D., Baron, M., Shanahan, J., Sule, S., Hsu, V., Rothfield, N., Steen, V., Martin, R. W., Smith, E., Mayes, M., Simms, R., Pope, J., Kahaleh, B., Csuka, M. E., Gruber, B., Collier, D., Sweiss, N., Gilbert, A., Dechow, F. J., Gregory, J., Wigley, F. M. 2009; 60 (3): 870-877
Abstract

Raynaud's phenomenon (RP) affects 3-9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX-503, in the treatment of RP in an ambulatory setting.We conducted a multicenter, randomized, placebo-controlled study with a 2-week single-blind run-in period to determine baseline severity, followed by a 4-week double-blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX-503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0-10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run-in period in terms of ambient temperature) compared with baseline.The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX-503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX-503 had a side effect profile similar to that of placebo.MQX-503 is well tolerated and more effective than placebo for the treatment of RP.

View details for DOI 10.1002/art.24351

View details for Web of Science ID 000264211900029

View details for PubMedID 19248104
Use of imatinib to treat systemic sclerosis: A prospective case series Arefiev, K., Fiorentino, D., Chung, L., Robinson, W. MOSBY-ELSEVIER. 2009: AB3
View details for Web of Science ID 000263934100010
Molecular Framework for Response to Imatinib Mesylate in Systemic Sclerosis ARTHRITIS AND RHEUMATISM Chung, L., Fiorentino, D. F., Benbarak, M. J., Adler, A. S., Mariano, M. M., Paniagua, R. T., Milano, A., Connolly, M. K., Ratiner, B. D., Wiskocil, R. L., Whitfield, M. L., Chang, H. Y., Robinson, W. H. 2009; 60 (2): 584-591
Abstract

Systemic sclerosis (SSc) is an autoimmune disease in which the tyrosine kinases platelet-derived growth factor receptor (PDGFR) and Abl are hypothesized to contribute to the fibrosis and vasculopathy of the skin and internal organs. Herein we describe 2 patients with early diffuse cutaneous SSc (dcSSc) who experienced reductions in cutaneous sclerosis in response to therapy with the tyrosine kinase inhibitor imatinib mesylate. Immunohistochemical analyses of skin biopsy specimens demonstrated reductions of phosphorylated PDGFRbeta and Abl with imatinib therapy. By gene expression profiling, an imatinib-responsive signature specific to dcSSc was identified (P < 10(-8)). The response of these patients and the findings of the analyses suggest that PDGFRbeta and Abl play critical, synergistic roles in the pathogenesis of SSc, and that imatinib targets a gene expression program that is frequently dysregulated in dcSSc.

View details for DOI 10.1002/art.24221

View details for PubMedID 19180499
Pulmonary arterial hypertension in systemic sclerosis Scleroderma: Modern aspects of pathogenesis, diagnosis and therapy Chung, L., Zamanian, R., Ghofrani, H. Unimed Publishers. 2009; 1: 37?43
Malignancy in the Setting of the Anti-Synthetase Syndrome JCR-JOURNAL OF CLINICAL RHEUMATOLOGY Rozelle, A., Trieu, S., Chung, L. 2008; 14 (5): 285-288
Abstract

Malignancy and interstitial lung disease (ILD) are 2 conditions associated with dermatomyositis (DM) that are responsible for a significant portion of the morbidity and mortality related to this disease; however, they rarely occur in the same patient. The antisynthetase syndrome consists of several characteristics, including ILD, arthritis, Raynaud phenomenon, "mechanic's hands," and positive antibodies to tRNA synthetases, which have each been negatively associated with cancer. When patients with DM present with such characteristics, clinicians may be falsely reassured that a thorough malignancy screen is unnecessary. We describe a patient who presented with the antisynthetase syndrome and was subsequently found to have colon cancer. Removal of the cancer led to resolution of the myositis and lung disease, but the patient's rash and arthritis persisted and ultimately required immunosuppressive therapy. We provide a review of the literature describing the concurrence of both this syndrome and ILD alone, with malignancy. We conclude that a thorough and expedited age-appropriate malignancy work up is indicated in all patients with a new diagnosis of DM, despite the presence of disease characteristics that are usually not associated with cancer.

View details for DOI 10.1097/RHU.0b013e31817d116f

View details for Web of Science ID 000260154000008

View details for PubMedID 18664993
Molecular framework for response to imatinib mesylate in systemic sclerosis 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Chung, L., Fiorentino, D. F., Benbarak, M. J., Adler, A. S., Mariano, M. M., Paniagua, R. T., Milano, A., Connolly, M. K., Ratiner, B. D., Wiskocil, R. L., Whitfield, M. L., Chang, H. Y., Robinson, W. H. WILEY-BLACKWELL. 2008: S819?S820
View details for Web of Science ID 000259244202263
MQX-503, a novel topical nitroglycerin formulation, improves severity of symptoms associated with Raynaud's phenomenon Belch, J., Fiorentino, D., Denton, C., Herrick, A., Sule, S., Steen, V., Rothfield, N., Scheja, A., Shapiro, L., Shanahan, J., Emery, P., Chung, L., Gregory, J. K. WILEY-LISS. 2008: S622
View details for Web of Science ID 000259244201475
Comparison of responders and non-responders to MQX-503, a novel investigational topical nitroglycerin formulation, in treatment of scieroderma-related and non-scleroderma-related Raynaud'S phenomenon Herrick, A., Denton, C., Fiorentino, D., Sule, S., Rothfield, N., Belch, J., Shapiro, L., Scheja, A., Shanahan, J., Steen, V., Chung, L., Emery, P., Wigley, F., Gregory, J. WILEY-LISS. 2008: S822
View details for Web of Science ID 000259244202270
Pulmonary hypertension assessment and recognition of outcomes in scleroderma (PHAROS): Patients with pulmonary hypertension Hinchcliff, M. E., Hsu, V., Bolster, M., Hummers, L., Seibold, J., Csuka, M., Chung, L., Shapiro, L., Derk, C., Fischer, A., Wigley, F., Steen, V. WILEY-LISS. 2008: S948
View details for Web of Science ID 000259244202606
"PHAROS" pulmonary hypertension (PH) assessment and recognition of outcomes in systemic sclerosis (SSc): Pre-pulmonary arterial hypertension (PAH) preliminary outcomes Fischer, A., Impens, A., Hsu, V., Shapiro, L., Mayes, M., Hummers, L., Csuka, M., Chung, L., Hinchcliff, M., Varga, J., Derk, C., Seibold, J., Steen, V. WILEY-LISS. 2008: S377
View details for Web of Science ID 000259244200588
A clinical comparison of systemic sclerosis-versus systemic lupus erythematosus-pulmonary arterial hypertension using the REVEAL registry Chung, L., Liu, J., Parsons, L., McGoon, M., Badesch, D., Nicholls, M., Zamanian, R. WILEY-LISS. 2008: S948
View details for Web of Science ID 000259244202605
Safety and tolerability of MQX-503, a novel investigational topical formulation of nitroglycerin for the treatment of Raynaud's phenomenon Rothfield, N., Shapiro, L., Fiorentino, D., Chung, L., Denton, C., Herrick, A., Baron, M., Shanahan, J., Hsu, V., Belch, J., Steen, V., Scheja, A., Martin, R., Smith, E., Mayes, M., Simms, R., Pope, J., Kahaleh, B., Csuka, M., Gruber, B., Collier, D., Sweiss, N., Sule, S., Emery, P., Wigey, F. M. WILEY-LISS. 2008: S821
View details for Web of Science ID 000259244202266
Pregnancy outcomes in systemic sclerosis, primary pulmonary hypertension, and sickle cell disease OBSTETRICS AND GYNECOLOGY Chakravarty, E. F., Khanna, D., Chung, L. 2008; 111 (4): 927-934
Abstract

Systemic sclerosis, primary pulmonary hypertension, and sickle cell disease are uncommon vasculopathic diseases affecting women. We estimated the nationwide occurrence of pregnancies in women with these conditions and compared pregnancy outcomes to the general obstetric population.We studied the 2002-2004 Nationwide Inpatient Sample, of the Healthcare Cost and Utilization Project to estimate the number of obstetric hospitalizations and deliveries among women with systemic sclerosis, primary pulmonary hypertension, sickle cell disease, and women in the general population. Pregnancy outcomes included length of hospital stay, hypertensive disorders including preeclampsia, intrauterine growth restriction (IUGR), and cesarean delivery. Multivariable regression analyses were performed using maternal age, race or ethnicity, antiphospholipid antibody syndrome, diabetes mellitus, and renal failure as covariates.Of an estimated 11.2 million deliveries, 504 occurred in women with systemic sclerosis, 182 with primary pulmonary hypertension, and 4,352 with sickle cell disease. Systemic sclerosis, was associated with an increased risk of hypertensive disorders including preeclampsia (odds ratio [OR] 3.71, 95% confidence interval [CI] 2.25-6.15), IUGR (OR 3.74, 95% CI 1.51-9.28), and increased length of hospital stay. Primary pulmonary hypertension was associated with an increase in the odds of antenatal hospitalization (OR 4.67, 95% CI 2.88-7.57), hypertensive disorders including preeclampsia (OR 5.62, 95% CI 2.60-12.15) and a substantial increase in length of hospital stay. Sickle cell disease was associated with an increased odds of antenatal hospitalization (OR 5.56 95% CI 5.08-6.09), hypertensive disorders including preeclampsia (OR 1.78, 95% CI 1.48-2.14), and IUGR (OR 2.91, 95% CI 2.16-3.93), with a modest increase in length of hospital stay.Women with systemic sclerosis, primary pulmonary hypertension, and sickle cell disease have significantly increased rates of adverse pregnancy outcomes, requiring extensive preconceptional counseling about the risks of pregnancy.

View details for Web of Science ID 000254433700017

View details for PubMedID 18378753
Cutaneous Vasculitis Dermatology Chung, L., Kea, B., Fiorentino, D. Mosby. 2008; 2: 347?367
Hospitalizations and mortality in systemic sclerosis: results from the Nationwide Inpatient Sample RHEUMATOLOGY Chung, L., Krishnan, E., Chakravarty, E. F. 2007; 46 (12): 1808-1813
Abstract

To study the causes of hospitalizations and predictors of subsequent adverse outcomes for contemporary cohorts of patients with systemic sclerosis (SSc) in the USA.The data source was the 2002 and 2003 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS) databases. We identified all discharges with an International Classification of Diseases-Clinical Modification (ICD9-CM) code of 710.1 (limited and diffuse SSc), then excluded those with concomitant diagnoses for lupus or rheumatoid arthritis. We calculated hospitalization rates, in-hospital mortality rates and mean length of stay (LOS). Multivariate logistic and linear regression models for in-hospital death and LOS were performed adjusting for sociodemographic and comorbidity covariates.The overall in-hospital mortality rate was 6.3% and the mean LOS was 6.6 days. Hospitalization rates were 4.5 times higher in women than in men, but in-hospital mortality was approximately 25% lower (P = 0.005). SSc was the most common principal diagnosis for all SSc hospitalizations, with the most common secondary diagnosis (24%) being pulmonary fibrosis. After SSc, respiratory failure was the second most common principal diagnosis in patients who died. Pulmonary fibrosis increased the odds of in-hospital death by 2.63 [95% confidence interval (CI) 1.98-3.49] fold and increased LOS by 7.25% (95% CI 0.90-13.60).Women with SSc had higher rates of hospitalization but lower in-hospital mortality than men. Pulmonary fibrosis was the major predictor of poor hospitalization outcomes in SSc patients in recent years, emphasizing the importance of continuing to develop more effective therapies for this fatal complication of the disease.

View details for DOI 10.1093/rheumatology/kem273

View details for Web of Science ID 000251197900014

View details for PubMedID 17986481
Characterizing systemic sclerosis in an ethnically diverse population Schmajuk, G., Bush, T. M., Burkham, J., Chung, L. WILEY-LISS. 2007: 4302
View details for Web of Science ID 000251781200172
A multi-center crossover study of MQX-503, a topical formulation of nitroglycerin, in patients with Raynaud's phenomenon Denton, C. P., Fiorentino, D., Herrick, A., Sule, S., Rothfield, N., Belch, J., Shapiro, L., Scheja, A., Shanahan, J., Steen, V., Emery, P., Chung, L., Gregory, J., Batson, E., Dooley, T., Gilbert, A., Dechow, F., Wigley, F. M. WILEY-LISS. 2007: 4238
View details for Web of Science ID 000251781200057
A pilot study of tumor necrosis factor inhibition in erosive/inflammatory osteoarthritis of the hands JOURNAL OF RHEUMATOLOGY Magnano, M. D., Chakravarty, E. F., Broudy, C., Chung, L., Kelman, A., Hillygus, J., Genovese, M. C. 2007; 34 (6): 1323-1327
Abstract

To determine if anti-tumor necrosis factor (TNF) therapy (adalimumab) can safely improve symptoms of erosive/inflammatory osteoarthritis (EOA).This was an open-label pilot trial in 12 patients with EOA. Patients > 45 years old with EOA of the hands defined by > or = 2 tender and > or = 2 swollen joints (distal interphalangeal, proximal interphalangeal, first carpometacarpal) despite nonsteroidal antiinflammatory drug therapy were eligible. Patients were excluded for autoimmune arthritis, recent disease modifying antirheumatic drug use, prior use of anti-TNF therapy, infection, malignancy, or poorly controlled medical conditions. All patients received adalimumab 40 mg every other week for 12 weeks. Safety was assessed 4 weeks after the final dose. Primary endpoints included safety and American College of Rheumatology (ACR) response.Patients were predominantly female with a mean age of 60 years and 12 years of arthritis. All patients completed the study and safety followup. Adverse events were mild without necessitating discontinuation of study drug. After 12 weeks, there was a statistically significant improvement in the number of swollen joints compared to baseline (p < 0.01). One patient achieved an ACR20 response and 42% achieved an OMERACT-OARSI response. Although we detected no statistically significant improvement in the number of tender joints, grip strength, disability, pain, or global disease assessments, trends suggested modest improvement in all efficacy measures.This small open-label study of patients with EOA demonstrated that adalimumab was well tolerated. Treatment with adalimumab for 3 months did not significantly improve the signs and symptoms of EOA and most patients did not achieve an ACR20. Trends suggested improvement and individual patients had some benefit. Factors limiting interpretation of this study include the lack of a control group, outcomes chosen, number of patients treated, and the duration of treatment.

View details for Web of Science ID 000247116600019

View details for PubMedID 17516620
A pilot trial of rituximab in the treatment of patients with dermatomyositis ARCHIVES OF DERMATOLOGY Chung, L., Genovese, M. C., Fiorentino, D. F. 2007; 143 (6): 763-767
Abstract

Dermatomyositis is an autoimmune disease that is associated with muscle and skin inflammation. Using quantitative scales, we sought to evaluate the effects of rituximab therapy on muscle strength and skin disease in patients with dermatomyositis.An open-label trial of rituximab therapy was conducted in 8 adult patients with dermatomyositis. Patients received 2 infusions of rituximab (1 g each) 2 weeks apart without peri-infusional steroids. The primary outcome was partial remission at week 24 (prespecified reduction in elevated creatine phosphokinase levels, muscle strength deficit (Manual Muscle Test), or skin disease (Dermatomyositis Skin Severity Index). After the first infusion of rituximab, all patients achieved sustained depletion of peripheral B cells. One patient withdrew at week 16 owing to a lack of treatment efficacy. Three patients (38%) achieved partial remission at week 24, in each case by improvement in muscle strength. Muscle enzyme levels and skin scores at week 24 were not significantly changed from those at baseline. Rituximab infusions were well tolerated, with no serious infectious complications. One patient died of metastatic cancer 9 months after his last infusion.Depletion of peripheral B cells had modest effects on muscle disease and limited effects on skin disease in our cohort of patients with dermatomyositis.

View details for Web of Science ID 000247207400012

View details for PubMedID 17576943
Therapeutic options for digital ulcers in patients with systemic sclerosis. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG Chung, L. 2007; 5 (6): 460-465
Abstract

Digital ulcers (DU) affect up to half of all patients with systemic sclerosis at some point during their disease. These lesions are extremely painful, heal slowly, and lead to substantial disability. DU arise from recurrent ischemic injury and microtrauma. Treatments for DU include non-pharmacologic modalities such as avoiding cold,stress,and trauma,as well as smoking cessation. Possible pharmacologic therapies for the prevention of DU include vasodilating agents to treat Raynaud phenomenon, statins, and oral agents used in the treatment of pulmonary hypertension (endothelin receptor antagonists, phosphodiesterase-5 inhibitors). The treatment of existing DU includes hydrocolloid occlusion, wound care, pain control, antibiotics, and the use of vasodilating medications. Intravenous or subcutaneous prostacyclins and digital or cervical sympathectomy should be considered for severe cases.

View details for PubMedID 17537038
Outcome of pregnancies complicated by systemic sclerosis and mixed connective tissue disease. 70th Annual Scientific Meeting of the American-College-of-Rheumatology/41st Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Chung, L., Flyckt, R. L., Colon, I., Shah, A. A., Drusin, M., Chakravarty, E. F. WILEY-BLACKWELL. 2006: 4077?77
View details for Web of Science ID 000242780700143
Hospitalizations and in-hospital mortality in patients with systemic sclerosis in the United States. Chung, L., Krishnan, E., Friedman, G. D., Chakravarty, E. F. WILEY-LISS. 2006: 4075?76
View details for Web of Science ID 000242780700140
Successful use of rituximab for cutaneous vasculitis ARCHIVES OF DERMATOLOGY Chung, L., Funke, A. A., Chakravarty, E. F., Callen, J. P., Fiorentino, D. F. 2006; 142 (11): 1407-1410
View details for Web of Science ID 000242157600002

View details for PubMedID 17116830
Systemic and locatized scleroderma CLINICS IN DERMATOLOGY Chung, L., Lin, J., Furst, D. E., Fiorentino, D. 2006; 24 (5): 374-392
Abstract

Sclerosing conditions of the skin are manifested by a full spectrum of presentations that includes skin-limited forms as well as those which can involve internal organs and result in death. At this point, we are just beginning to understand the mechanisms of tissue fibrosis, and it is likely that the fibrotic processes are a heterogeneous group of disorders in which perturbation of multiple molecular pathways, including vascular and immunologically mediated pathways, can lead to fibrosis. We now have some moderately effective therapies for vascular aspects of systemic sclerosis (eg, bosentan for pulmonary arterial hypertension, calcium-channel blockers for Raynaud's, or angiotensin-converting enzyme inhibitors for renal crisis). We also are beginning to find treatments interrupting the immunologic pathways that manifest as systemic sclerosis (eg, methotrexate for the skin or cyclophosphamide for the lungs). The basic process of fibrosis, however, awaits proven, effective therapy.

View details for DOI 10.1016/j.clindermatol.2006.07.004

View details for Web of Science ID 000240864500004

View details for PubMedID 16966019
A pilot study of TNF inhibition in Erosive/Inflammatory osteoarthritis of the hands. 70th Annual Scientific Meeting of the American-College-of-Rheumatology/41st Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Magnano, M. D., Chakravarty, E. F., Broudy, C., Chung, L., Kelman, A., Hillygus, J. J., Genovese, M. C. WILEY-BLACKWELL. 2006: S674?S674
View details for Web of Science ID 000240877203402
A pilot trial of treprostinil for the treatment and prevention of digital ulcers in patients with systemic sclerosis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Chung, L., Fiorentino, D. 2006; 54 (5): 880-882
Abstract

We performed a pilot trial of subcutaneous treprostinil for the treatment of digital ulcers in scleroderma. Of the 5 patients completing therapy, ulcer size significantly decreased and no new ulcers occurred on continuous therapy. Although effective, the high rate of injection site reactions may limit the utility of this therapy.

View details for DOI 10.1016/j.jaad.2006.02.004

View details for Web of Science ID 000237119600019

View details for PubMedID 16635673
Digital ulcers in patients with systemic sclerosis CIS Spring School on Systemic Autoimmune Diseases Chung, L., Fiorentino, D. ELSEVIER SCIENCE BV. 2006: 125?28
Abstract

Digital ulcers (DU), defined as necrotic lesions located at distal digits or overlying bony prominences, occur in up to 50% of patients with limited or diffuse systemic sclerosis (SSc). These lesions are extremely painful and lead to substantial functional disability. The pathogenesis of DU differs depending on their location. DU located at distal aspects of digits are thought to be related to tissue ischemia from several processes, including vasospasm secondary to Raynaud's phenomenon, intimal fibro-proliferation, and thrombosis of digital arteries. DU located over bony prominences, such as the phalangeal joints and elbows, are thought to be due to repetitive microtrauma and difficulty healing due to atrophic, avascular tissue overlying the joints. Management of DU include non-pharmacologic and pharmacologic modalities. This review summarizes the current available and investigational therapies for the treatment and prevention of DU in patients with SSc.

View details for DOI 10.1016/j.autrev.2005.08.004

View details for Web of Science ID 000235349400011

View details for PubMedID 16431342
Outcome of pregnancies complicated by systemic sclerosis and mixed connective tissue disease LUPUS Chung, L., Flyckt, R. L., Colon, I., Shah, A. A., Druzin, M., Chakravarty, E. F. 2006; 15 (9): 595-599
Abstract

Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are rare autoimmune diseases which share the common feature of non-inflammatory vasculopathy. Studies evaluating pregnancy outcomes in these patients have yielded conflicting results. We sought to describe the outcomes of pregnancies associated with SSc and MCTD followed at our center utilizing a retrospective review of all pregnant women with SSc and MCTD followed at Stanford University from 1993 to 2003. We identified 20 pregnancies occurring in 13 women with SSc or MCTD. Twelve pregnancies occurred in seven women with SSc and eight pregnancies occurred in six women with MCTD. The overall preterm delivery rate was 39% and small for gestational age infants occurred in 50% and 63% of pregnancies associated with SSc and MCTD, respectively. Fetal loss complicated two pregnancies in women with severe diffuse SSc and the antiphospholipid antibody syndrome. There were no cases of congenital heartblock among infants, and only one case of pre-eclampsia was observed. Maternal flares of disease during pregnancy were generally mild. Most pregnancies in women with SSc and MCTD in this cohort were uncomplicated. The high rates of prematurity and small for gestational age infants underscore the risk for growth restriction consistent with the vasculopathy associated with these diseases.

View details for DOI 10.1177/0961203306071915

View details for Web of Science ID 000241996300007

View details for PubMedID 17080915
Current and future trends in systemic lupus erythematosus The Rheumatology Report Chung, L. 2006; 1 (2)
Systemic and localized scleroderma Clinics in Dermatology Chung, L., Lin, J., Furst, D., Fiorentino, D. 2006; 24 (5)
Rituximab in the treatment of patients with dermatomyositis: 12 week interim analysis of a pilot trial. Chung, L., Genovese, M. C., Fiorentino, D. WILEY-LISS. 2005: 4088
View details for Web of Science ID 000234131500136
Coronary artery disease in patients with systemic lupus erythematosus NATURE CLINICAL PRACTICE RHEUMATOLOGY Galindo, M., Chung, L., Crockett, S. D., Chakravarty, E. F. 2005; 1 (1): 55-59
Abstract

A 24-year-old woman with an 11-year history of systemic lupus erythematosus presented with exacerbation of chronic abdominal pain followed by substernal chest pain. She had a history of pericarditis secondary to systemic lupus erythematosus and of varicella-zoster reactivation secondary to immunosuppression. Long-term medications included prednisolone, hydroxychloroquine, aspirin, and mycophenolate mofetil.Physical examination, mesenteric angiography, CT of the abdomen, esophagogastroduodenoscopy, colonoscopy, pelvic ultrasound, laboratory testing, serologic testing, cardiac echocardiography, electrocardiography and coronary angiography.Acute myocardial infarction secondary to severe multivessel atherosclerotic coronary artery disease.Intra-aortic balloon pump followed by emergent four-vessel coronary artery bypass grafting. Aspirin, hydroxychloroquine, and mycophenolate mofetil were continued and a judicious tapering of prednisolone was initiated.

View details for DOI 10.1038/ncprheum0037

View details for Web of Science ID 000235082200008

View details for PubMedID 16932628
Bleeding complications in patients on celecoxib and warfarin 68th Annual Scientific Meeting of the American-College-of-Rheumatology/39th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Chung, L., Chakravarty, E. F., Kearns, P., Wang, C., Bush, T. M. WILEY-BLACKWELL PUBLISHING, INC. 2005: 471?77
Abstract

Non-selective non-steroidal anti-inflammatory drugs (nNSAIDs) used in combination with warfarin are associated with an approximately 3-fold increased risk of upper gastrointestinal bleeding (UGIB) compared with warfarin alone. Celecoxib, a selective inhibitor of cyclo-oxygenase 2 (COX-2), is associated with less gastric mucosal injury and platelet dysregulation than nNSAIDs. We compared rates of bleeding complications in patients taking celecoxib and warfarin with those taking warfarin alone.We performed a retrospective analysis using data from our Protime Clinic and pharmacy databases from January 2001 to April 2004. We identified 123 patients who took celecoxib and warfarin concurrently (overlap group). We compared rates of bleeding complications in this group with 1022 control patients who were taking warfarin alone. Bleeding complications were defined as major if they resulted in hospitalization, blood transfusion or death.During approximately 1063 months of exposure to both celecoxib and warfarin, 10 bleeding complications were identified, only one of which was considered major. No patients had UGIB. In the control group, 116 bleeding complications were identified over approximately 16 520 months of exposure to warfarin alone, with 101 minor and 15 major events, including six episodes of UGIB. The relative risk of all bleeding complications was 1.34 (95% CI: 0.70-2.57) in the overlap vs. control groups, and for major bleeds was 1.04 (95% CI: 0.14-7.85).There is a mild but non-significant increase in bleeding complications in patients taking celecoxib and warfarin compared with those taking warfarin alone.

View details for Web of Science ID 000231677200010

View details for PubMedID 16164494
Giant cell myocarditis: a rare cardiovascular manifestation in a patient with systemic lupus erythematosus. Lupus Chung, L., Berry, G. J., Chakravarty, E. F. 2005; 14 (2): 166-169
Abstract

Giant cell myocarditis (GCM) is a rare form of myocarditis with a median survival of less than one year. It has been reported to occur in patients with various underlying autoimmune diseases; however, no cases of GCM have been described in patients with clear evidence of underlying systemic lupus erythematosus (SLE). The presentation of GCM may mimic that of lupus myocarditis, including an initial response to immunosuppression. Despite initial clinical similarities, lupus myocarditis and GCM are histologically distinct entities with dramatic differences in prognosis. We report herein a patient with a longstanding history of SLE, who presented acutely with myocarditis, responded well to initial immunosuppression and then subsequently died of progressive heart failure that was found to be due to GCM. Endomyocardial biopsy can help define diagnosis and prognosis of lupus patients presenting with myocarditis, and early referral for cardiac transplantation should be considered in patients diagnosed with GCM.

View details for PubMedID 15751823
Cutaneous vasculitis Orphanet encyclopedia Chung, L., Fiorentino, D. 2005
Incidence of bleeding complications in patients on celecoxib and warfarin. 68th Annual Scientific Meeting of the American-College-of-Rheumatology/39th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Chung, L., Wang, C., Kearns, P., Chakravarty, E. F., Bush, T. M. WILEY-BLACKWELL. 2004: 4087?88
View details for Web of Science ID 000225750200073
A pilot trial of treprostinil (Remodulin (R)) for the treatment and prevention of digital ischemic lesions in patients with systemic sclerosis. Chung, L., Fiorentino, D. WILEY-LISS. 2004: 4086
View details for Web of Science ID 000225750200068
Antibodies in scleroderma: direct pathogenicity and phenotypic associations. Current rheumatology reports Chung, L., Utz, P. J. 2004; 6 (2): 156-163
Abstract

Scleroderma is an autoimmune disease involving endothelial cell damage and fibroblast overproduction of extracellular matrix. Several autoantibodies present in the sera of patients with scleroderma, including anti-endothelial cell, antifibroblast, anti-matrix metalloproteinase, and antifibrillin-1 antibodies, may directly contribute to disease pathogenesis. Scleroderma also is characterized by the presence of antinuclear and antinucleolar antibodies, which correlate with particular phenotypes. These include antitopoisomerase-I, anticentromere, antihistone, anti-polymyositis/scleroderma, anti-Th/To, anti-U3-small nucleolar ribonucleoprotein particle, anti-U1-small nuclear ribonucleoprotein particle, anti-RNA polymerase, and anti-B23 antibodies. Other antibodies classically associated with other autoimmune diseases, such as antiphospholipid, antineutrophil cytoplasmic, and antimitochondrial antibodies, also have been described in patients with scleroderma. This review will summarize the various autoantibodies associated with scleroderma, their putative pathogenic roles, and their phenotypic correlations.

View details for PubMedID 15016347
EXTRACELLULAR-MATRIX AND ANDROGEN RECEPTOR EXPRESSION ASSOCIATED WITH SPONTANEOUS TRANSFORMATION OF RAT PROSTATE FIBROBLASTS CANCER RESEARCH Freeman, M. R., Song, Y., Carson, D. D., Guthrie, P. D., Chung, L. W. 1991; 51 (7): 1910-1916
Abstract

Spontaneous transformation in continuous culture of the androgen-sensitive rat prostate fibroblast cell line, NbF-1, resulted in an aggressively tumorigenic nonmetastatic phenotype that coincided with few gross chromosome abnormalities. This study identified transformation-associated alterations in extracellular matrix and androgen receptor expression in the NbF-1 cell line. Substantial levels of procollagens I, III, and IV and fibronectin mRNAs were detected in nontumorigenic NbF-1 cells. Laminin B1 and B2 mRNAs were also detectable, but at lower levels. Expression of all six extracellular matrix mRNAs was nonuniformly lower in tumorigenic NbF-1 cells. This decrease in expression was greatest for alpha 2 procollagen IV mRNA, which was reduced 17-fold. Proteoglycans and glycosaminoglycans synthesized by the NbF-1 cultures were also characterized. The NbF-1 cell line expressed chondroitin sulfate proteoglycans predominantly, and expression was reduced 5- to 10-fold in tumorigenic cultures. In contrast to the extensive alterations in the extracellular matrix, measurement of high-affinity androgen binding and androgen receptor mRNA levels showed substantial expression of androgen receptors in both NbF-1 cultures. Cultures of early and late passage NbF-1 cells demonstrated a mitogenic response to dihydrotestosterone. These data indicate (a) that alterations in expression of extracellular matrix components may represent early markers for tumorigenic transformation in prostatic mesenchymal cells and (b) that these changes can occur without disrupting androgen receptor expression and androgen sensitivity.

View details for Web of Science ID A1991FE04100025

View details for PubMedID 2004375

Lorinda Chung

Professor of Medicine (Immunology and Rheumatology) and, by courtesy, of Dermatology at the Palo Alto Veterans Affairs Health Care Center

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