Clinical Focus

  • Rheumatology
  • Connective Tissue Diseases
  • Immunology and Rheumatology
  • Scleroderma, Systemic

Academic Appointments

Professional Education

  • Fellowship:Stanford University School of Medicine (2006) CA
  • Board Certification: Rheumatology, American Board of Internal Medicine (2005)
  • Residency:Stanford University School of Medicine (2003) CA
  • Medical Education:Ohio State University College of Medicine (2000) OH
  • AB, Princeton University, Molecular Biology (1996)
  • MD, Ohio State University, Medicine (2000)
  • MS, Stanford University, Epidemiology (2007)

Research & Scholarship

Clinical Trials

  • Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH) Recruiting

    Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is a serious, life-threatening manifestation of systemic sclerosis (SSc), an autoimmune disease of the connective tissue characterized by scarring (fibrosis) and atrophy of the skin, joints and tendons, skeletal muscles, and internal organs, and immunological disturbances. One-year survival for patients with SSc-PAH ranges from 50-81%. There is currently no cure for SSc-PAH and treatment is limited to vasodilator therapy used in all forms of PAH. In recent studies, immunotherapy was shown to be effective in treating SSc-interstitial lung disease, another serious, life-threatening manifestation of SSc. In addition, there are compelling pre-clinical data and anecdotal clinical reports that suggest modulation of the immune system may be an effective strategy for treating SSc-PAH. To test this approach, this trial will determine if rituximab, an immunotherapy, has a marked beneficial effect on clinical disease progression, with minimal toxicity, in patients with SSc-PAH when compared to placebo.

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  • A Study of RoActemra/Actemra (Tocilizumab) Versus Placebo in Patients With Systemic Sclerosis Recruiting

    This multicenter, randomized, double-blind, placebo-controlled, two-arm, parallel-group study will evaluate the efficacy and safety of RoActemra/Actemra (tocilizumab) in patients with systemic sclerosis. Patients will be randomized to receive either RoActemra/Actemra 162 mg subcutaneously weekly or placebo for 48 weeks. From Week 49 to Week 96, all patients will receive open-label RoActemra/Actemra 162 mg subcutaneously weekly. Anticipated time on study treatment is 96 weeks.

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2013-14 Courses

Postdoctoral Advisees


Journal Articles

  • 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


    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

  • 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


    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

  • 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


    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

  • 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


    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 1γ (anti-TIF-1γ) antibodies are associated with malignancy in DM. We undertook this study to develop sensitive, specific assays to detect antibodies against TIF-1γ and nuclear matrix protein NXP-2 and to evaluate their association with malignancy in DM.To detect anti-TIF-1γ antibodies, immunoprecipitations were performed using lysates made from HeLa cells overexpressing TIF-1γ, 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-1γ, respectively. Reactivity against either NXP-2 or TIF-1γ 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-1γ 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-1γ 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
  • 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


    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

  • 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 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 Registration Number: NCT00370214.

    View details for DOI 10.1378/chest.12-2417

    View details for Web of Science ID 000321605500026

    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


    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


    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-?


    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

  • 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)

    View details for DOI 10.1186/ar4135

    View details for Web of Science ID 000317932600021

  • Clinical presentation and evaluation of dermatomyositis. Indian journal of dermatology Marvi, U., Chung, L., Fiorentino, D. F. 2012; 57 (5): 375-381


    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

  • 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


    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

  • 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


    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

  • 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


    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

  • 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


    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 Web of Science ID 000293311200017

    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


    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

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


    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

  • 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


    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-?


    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

  • 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)


    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

  • 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


    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. Trial registry:; No.: NCT00370214; URL:

    View details for DOI 10.1378/chest.10-0260

    View details for Web of Science ID 000285494000017

    View details for PubMedID 20507945

  • 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

  • Digital ischemic loss in systemic sclerosis. International journal of rheumatology Marvi, U., Chung, L. 2010; 2010


    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

  • 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

  • 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
  • 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


    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


    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

  • 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


    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 Web of Science ID 000263276400032

    View details for PubMedID 19180499

  • 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


    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

  • 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


    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

  • 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


    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

  • 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


    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


    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

  • 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


    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

  • 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


    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 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


    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 AUTOIMMUNITY REVIEWS Chung, L., Fiorentino, D. 2006; 5 (2): 125-128


    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


    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

  • Bleeding complications in patients on celecoxib and warfarin JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS Chung, L., Chakravarty, E. F., Kearns, P., Wang, C., Bush, T. M. 2005; 30 (5): 471-477


    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


    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

  • Antibodies in scleroderma: direct pathogenicity and phenotypic associations. Current rheumatology reports Chung, L., Utz, P. J. 2004; 6 (2): 156-163


    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

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