David Fiorentino, MD, PhD

All Publications

• 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 Web of Science ID 000364481400021

• 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 Web of Science ID 000363416300004

• Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis Results From the Psoriasis Longitudinal Assessment and Registry (PSOLAR) JAMA DERMATOLOGY Kalb, R. E., Fiorentino, D. F., Lebwohl, M. G., Toole, J., Poulin, Y., Cohen, A. D., Goyal, K., Fakharzadeh, S., Calabro, S., Chevrier, M., Langholff, W., You, Y., Leonardi, C. L. 2015; 151 (9): 961-969

  View details for DOI 10.1001/jamadermatol.2015.0718

  View details for Web of Science ID 000361371100009

• 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

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

  View details for Web of Science ID 000357069900001

• 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

• 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 Web of Science ID 000355329400010

  View details for PubMedID 25331610

• 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

• 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

• 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 < .001). An association between calcinosis and both interstitial lung disease and anti-MDA-5 autoantibodies was identified, but this association did not persist in multivariate models that adjusted for fingertip ulcers. Fingertip ulcers and disease duration were strongly associated with calcinosis in all multivariate models, independent of the underlying autoantibody present. Autoantibodies to NXP-2 were associated with calcinosis (odds ratio, 15.52; 95% CI, 2.01-119.90), whereas anti-transcriptional intermediary factor 1-γ antibodies were protective (odds ratio, 0.2; 95% CI, 0.01-0.99) in multivariate analyses that adjusted for fingertip ulcers and other covariates.Calcinosis was a relatively uncommon clinical feature in our cohort of adults with DM. Our data suggest that calcinosis is positively associated with longer disease duration, fingertip ulcers, and NXP-2 autoantibodies and negatively associated with transcriptional intermediary factor 1-γ antibodies. A common vascular mechanism may underlie the development of both calcinosis and fingertip ulcers in patients with DM.

  View details for DOI 10.1001/jamadermatol.2013.10416

  View details for PubMedID 24869801

• 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

  View details for DOI 10.1001/jamadermatol.2013.10416

  View details for Web of Science ID 000339652400006

• 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

• A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-alpha monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients ANNALS OF THE RHEUMATIC DISEASES Higgs, B. W., Zhu, W., Morehouse, C., White, W. I., Brohawn, P., Guo, X., Rebelatto, M., Le, C., Amato, A., Fiorentino, D., Greenberg, S. A., Drappa, J., Richman, L., Greth, W., Jallal, B., Yao, Y. 2014; 73 (1): 256-262

  Abstract

  To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure.A phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab.The IFNGS was suppressed by a median of 53-66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle.Sifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecule's mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy.

  View details for DOI 10.1136/annrheumdis-2012-202794

  View details for Web of Science ID 000327835100044

  View details for PubMedID 23434567

• The Plasma Cell Signature in Autoimmune Disease ARTHRITIS & RHEUMATOLOGY Streicher, K., Morehouse, C. A., Groves, C. J., Rajan, B., Pilataxi, F., Lehmann, K. P., Brohawn, P. Z., Higgs, B. W., McKeever, K., Greenberg, S. A., Fiorentino, D., Richman, L. K., Jallal, B., Herbst, R., Yao, Y., Ranade, K. 2014; 66 (1): 173-184

  Abstract

  Production of pathogenic autoantibodies by self-reactive plasma cells (PCs) is a hallmark of autoimmune diseases. We undertook this study to investigate the prevalence of PCs and their relationship to known pathogenic pathways to increase our understanding of the role of PCs in disease progression and treatment response.We developed a sensitive gene expression-based method to overcome the challenges of measuring PCs using flow cytometry. Whole-genome microarray analysis of sorted cellular fractions identified a panel of genes, IGHA1, IGJ, IGKC, IGKV4-1, and TNFRSF17, expressed predominantly in PCs. The sensitivity of the PC signature score created from the combined expression levels of these genes was assessed through ex vivo experiments with sorted cells. This PC gene expression signature was used for monitoring changes in PC levels following anti-CD19 therapy, for evaluating the relationship between PCs and other autoimmune disease-related genes, and for estimating PC levels in affected blood and tissue from patients with multiple autoimmune diseases.The PC signature was highly sensitive and capable of detecting a change in as few as 360 PCs. The PC signature was reduced more than 90% in scleroderma patients following anti-CD19 treatment, and this reduction was highly correlated (r = 0.80) with inhibition of collagen gene expression. Evaluation of multiple autoimmune diseases revealed that 30-35% of lupus and rheumatoid arthritis patients had increased levels of PCs.This newly developed PC signature provides a robust and accurate method of measuring PC levels in the clinic. Our results highlight subsets of patients across multiple autoimmune diseases who may benefit from PC-depleting therapy.

  View details for DOI 10.1002/art.38194

  View details for Web of Science ID 000337356300021

  View details for PubMedID 24431284

• 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 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

• 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 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

• Improvements in patient-reported outcomes with apremilast, an oral phosphodiesterase 4 inhibitor, in the treatment of moderate to severe psoriasis: results from a phase IIb randomized, controlled study HEALTH AND QUALITY OF LIFE OUTCOMES Strand, V., Fiorentino, D., Hu, C., Day, R. M., Stevens, R. M., Papp, K. A. 2013; 11

  Abstract

  Apremilast, a specific inhibitor of phosphodiesterase 4, modulates pro-inflammatory and anti-inflammatory cytokine production.Apremilast's effect on patient-reported outcomes (PROs) in patients with moderate to severe psoriasis was evaluated in a phase IIb randomized, controlled trial (NCT00773734).In this 16-week, placebo-controlled study, 352 patients with moderate to severe plaque psoriasis received placebo or apremilast (10, 20, or 30 mg BID). PROs included Dermatology Life Quality Index (DLQI), pruritus visual analog scale (VAS), and Short-Form Health Survey (SF-36) to assess health-related quality of life (HRQOL). Changes from baseline and patients reporting improvements ≥minimum clinically important differences (MCID) were analyzed. Correlations between changes across various PRO instruments were explored.Baseline DLQI (>10 points) and SF-36 MCS and domain scores indicated impairments in HRQOL. At 16 weeks, greater improvements from baseline in DLQI scores were reported with apremilast 20 (-5.9) and 30 mg BID (-4.4) compared with placebo (1.9; P≤0.005 for both), and a greater proportion of patients reported improvements ≥MCID (20 mg BID, 49.4%, 30 mg BID, 44.3%) versus placebo (25.0%; P<0.04). Greater improvements from baseline in pruritus VAS scores were reported with apremilast 20 (-35.5%) and 30 mg BID (-43.7%) versus placebo (-6.1%; P≤0.005). Significant and clinically meaningful improvements in SF-36 mental component summary scores (P≤0.008) and Bodily Pain, Mental Health, and Role-Emotional domains were reported with all apremilast doses (P<0.05), and Social Functioning with 20 and 30 mg BID (P<0.05) and Physical Functioning with 20 mg BID (P<0.03). Correlations between SF-36 scores and DLQI were moderate (r>0.30 and ≤0.60) and low between SF-36 and pruritus VAS (r≤0.30), indicating they measure different aspects of the disease.Apremilast treatment resulted in improved HRQOL, including DLQI and pruritus VAS over 16 weeks of treatment, in patients with moderate to severe psoriasis.

  View details for DOI 10.1186/1477-7525-11-82

  View details for Web of Science ID 000319268200001

  View details for PubMedID 23663752

• Localized Cutaneous Fibrosing Disorders RHEUMATIC DISEASE CLINICS OF NORTH AMERICA Yaqub, A., Chung, L., Rieger, K. E., Fiorentino, D. F. 2013; 39 (2): 347-?

  View details for DOI 10.1016/j.rdc.2013.02.013

  View details for Web of Science ID 000318530000009

• 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

• Inflammatory arthritis following ustekinumab treatment for psoriasis: a report of two cases BRITISH JOURNAL OF DERMATOLOGY de Souza, A., Ali-Shaw, T., Reddy, S. M., Fiorentino, D., Strober, B. E. 2013; 168 (1): 210-212

  Abstract

  Psoriasis is a chronic inflammatory skin condition, characterized by T-helper (Th) 1 and Th17 cell activation. Ustekinumab is a fully human immunoglobulin G1κ monoclonal antibody that targets the common p40 subunit that is shared by both interleukin (IL)-12 and IL-23, consequently inhibiting T-cell differentiation along both Th1 and Th17 pathways. This is a report of two patients who developed psoriatic arthritis during ustekinumab treatment for psoriasis. Neither patient had a personal or family history of arthritis.

  View details for DOI 10.1111/j.1365-2133.2012.11206.x

  View details for Web of Science ID 000314469000060

• 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): R7-?

  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 PubMedID 23298514

• 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

• Genomic signatures characterize leukocyte infiltration in myositis muscles BMC MEDICAL GENOMICS Zhu, W., Streicher, K., Shen, N., Higgs, B. W., Morehouse, C., Greenlees, L., Amato, A. A., Ranade, K., Richman, L., Fiorentino, D., Jallal, B., Greenberg, S. A., Yao, Y. 2012; 5

  Abstract

  Leukocyte infiltration plays an important role in the pathogenesis and progression of myositis, and is highly associated with disease severity. Currently, there is a lack of: efficacious therapies for myositis; understanding of the molecular features important for disease pathogenesis; and potential molecular biomarkers for characterizing inflammatory myopathies to aid in clinical development.In this study, we developed a simple model and predicted that 1) leukocyte-specific transcripts (including both protein-coding transcripts and microRNAs) should be coherently overexpressed in myositis muscle and 2) the level of over-expression of these transcripts should be correlated with leukocyte infiltration. We applied this model to assess immune cell infiltration in myositis by examining mRNA and microRNA (miRNA) expression profiles in muscle biopsies from 31 myositis patients and 5 normal controls.Several gene signatures, including a leukocyte index, type 1 interferon (IFN), MHC class I, and immunoglobulin signature, were developed to characterize myositis patients at the molecular level. The leukocyte index, consisting of genes predominantly associated with immune function, displayed strong concordance with pathological assessment of immune cell infiltration. This leukocyte index was subsequently utilized to differentiate transcriptional changes due to leukocyte infiltration from other alterations in myositis muscle. Results from this differentiation revealed biologically relevant differences in the relationship between the type 1 IFN pathway, miR-146a, and leukocyte infiltration within various myositis subtypes.Results indicate that a likely interaction between miR-146a expression and the type 1 IFN pathway is confounded by the level of leukocyte infiltration into muscle tissue. Although the role of miR-146a in myositis remains uncertain, our results highlight the potential benefit of deconvoluting the source of transcriptional changes in myositis muscle or other heterogeneous tissue samples. Taken together, the leukocyte index and other gene signatures developed in this study may be potential molecular biomarkers to help to further characterize inflammatory myopathies and aid in clinical development. These hypotheses need to be confirmed in separate and sufficiently powered clinical trials.

  View details for DOI 10.1186/1755-8794-5-53

  View details for Web of Science ID 000313563800001

  View details for PubMedID 23171592

• Skin disease in dermatomyositis CURRENT OPINION IN RHEUMATOLOGY Zaba, L. C., Fiorentino, D. F. 2012; 24 (6): 597-601

  Abstract

  This review will provide the clinician with an update on the pathogenesis, clinical manifestations, and therapy for skin disease in dermatomyositis. Recent insights into the role for interferon in skin disease as well as the development and validation of quantitative tools to measure skin disease activity allow the possibility that, for the first time, dermatomyositis skin disease can serve as a valid outcome for clinical trials of targeted therapies. Also, the increasing appreciation of the heterogeneity of skin disease in dermatomyositis has already provided evidence that clinical subtypes of disease can provide important prognostic and diagnostic information to the clinician.It is becoming apparent that the skin inflammation alone has implications for systemic and malignancy risk in dermatomyositis patients, and that there may be several pathogenic similarities between muscle and skin inflammation in dermatomyositis. Recent data on therapy for calcinosis cutis highlights that more prospective studies are needed to evaluate how best to manage all manifestations of skin inflammation in dermatomyositis.A more careful description and classification of skin disease in dermatomyositis may allow the clinician to predict more accurately which patients will be at higher risk for cancer, lung disease, or muscle inflammation. In addition, given the similarities in perturbed gene expression between skin and muscle tissue, it is likely that analysis of a more readily evaluable target organ such as skin might shed light on mechanisms of disease propagation throughout the body.

  View details for DOI 10.1097/BOR.0b013e3283585748

  View details for Web of Science ID 000309545600002

  View details for PubMedID 22907594

• Immune Responses to NXP-2 and TIF-g Are Associated with Distinct Clinical Phenotypes and Prognosis for Skin Disease in Dermatomyositis Patients. 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

• Homology of Cytokine Synthesis Inhibitory Factor (IL-10) to the Epstein-Barr Virus Gene BCRFI JOURNAL OF IMMUNOLOGY Moore, K. W., Vieira, P., Fiorentino, D. F., Trounstine, M. L., Khan, T. A., Mosmann, T. R. 2012; 189 (5): 1230-1234

  View details for DOI 10.1126/science.2161559

  View details for Web of Science ID 000308083600002

• Treatment of Recalcitrant Eosinophilic Cellulitis With Adalimumab ARCHIVES OF DERMATOLOGY Sarin, K. Y., Fiorentino, D. 2012; 148 (9): 990-992

  View details for Web of Science ID 000308883500002

  View details for PubMedID 22986848

• 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

• A Novel Dermato-Pulmonary Syndrome Associated With MDA-5 Antibodies Report of 2 Cases and Review of the Literature MEDICINE Chaisson, N. F., Paik, J., Orbai, A., Casciola-Rosen, L., Fiorentino, D., Danoff, S., Rosen, A. 2012; 91 (4): 220-228

  Abstract

  Melanoma differentiation-associated protein 5 (MDA-5) is a novel autoantibody frequently characterized by interstitial lung disease and a distinct cutaneous phenotype with palmar papules, ulceration, and rash. Virtually all patients have underlying dermatomyositis, but many lack the characteristic clinical myopathy associated with it. In the setting of amyopathic disease, the absence of clinically available biomarkers or clear pathologic diagnosis can complicate effective prognostic and therapeutic intervention. Until recently the presence of MDA-5 antibody associated dermato-pulmonary syndrome was described only in Asian populations. We present 2 cases of MDA-5-associated dermato-pulmonary syndrome and provide a comprehensive review of available literature.

  View details for DOI 10.1097/MD.0b013e3182606f0b

  View details for Web of Science ID 000306113300006

  View details for PubMedID 22732950

• Comparison of health-related quality of life in rheumatoid arthritis, psoriatic arthritis and psoriasis and effects of etanercept treatment ANNALS OF THE RHEUMATIC DISEASES Strand, V., Sharp, V., Koenig, A. S., Park, G., Shi, Y., Wang, B., Zack, D. J., Fiorentino, D. 2012; 71 (7): 1143-1150

  Abstract

  To compare health-related quality of life (HRQoL) before and after treatment with etanercept in patients with moderate to severe rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis using spydergram representations.Data from randomised, controlled trials of etanercept in patients with RA, PsA and psoriasis were analysed. HRQoL was assessed by the medical outcomes survey short form 36 (SF-36) physical (PCS) and mental (MCS) component summary and domain scores. Baseline comparisons with age and gender-matched norms and treatment-associated changes in domain scores were quantified using spydergrams and the health utility SF-6D measure.Mean baseline PCS scores were lower than age and gender-matched norms in patients with RA and PsA, but near normative values in patients with psoriasis; MCS scores at baseline were near normal in PsA and psoriasis but low in RA. Treatment with etanercept resulted in improvements in PCS and MCS scores as well as individual SF-36 domains across all indications. Mean baseline SF-6D scores were higher in psoriasis than in RA or PsA; clinically meaningful improvements in SF-6D were observed in all three patient populations following treatment with etanercept.Patients with RA, PsA and psoriasis demonstrated unique HRQoL profiles at baseline. Treatment with etanercept was associated with improvements in PCS and MCS scores as well as individual domain scores in patients with RA, PsA and psoriasis.

  View details for DOI 10.1136/annrheumdis-2011-200387

  View details for Web of Science ID 000305293400007

  View details for PubMedID 22258482

• Autoantibodies to transcription intermediary factor 1 in dermatomyositis shed insight into the cancer-myositis connection ARTHRITIS AND RHEUMATISM Fiorentino, D., Casciola-Rosen, L. 2012; 64 (2): 346-349

  View details for DOI 10.1002/art.33402

  View details for Web of Science ID 000299625700004

  View details for PubMedID 21987176

• Identification of activated cytokine pathways in the blood of systemic lupus erythematosus, myositis, rheumatoid arthritis, and scleroderma patients INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES Higgs, B. W., Zhu, W., Richman, L., Fiorentino, D. F., Greenberg, S. A., Jallal, B., Yao, Y. 2012; 15 (1): 25-35

  Abstract

  To develop genomic signatures of seven cytokines involved in the pathogenesis of rheumatic diseases such as systemic lupus erythematosus (SLE), dermatomyositis (DM), polymyositis (PM), rheumatoid arthritis (RA), or systemic scleroderma (SSc) that could potentially help identify patients likely to respond to therapies that target these individual cytokines.Over-expressed transcripts in the whole blood (WB) were identified from 262 SLE, 44 DM, 33 PM, 38 SSc and 89 RA subjects and compared to 24 healthy subjects using Affymetrix arrays. Cytokine-inducible gene signatures such as type I interferon (IFN), tumor necrosis factor alpha (TNF-?), interleukin (IL)-1?, IL-10, IL-13, IL-17, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were assessed in the WB of these subjects to identify subpopulations showing activation of specific cytokine pathways.Significant activation of the type I IFN pathway in a population of five diseases studied was universally observed. The TNF-? and IL-1? pathways were activated in subgroups of PM and RA subjects, respectively, with another subgroup of RA subjects showing activation of the IL-13 pathway. The GM-CSF pathway was activated in a subgroup of SSc subjects and the IL-17 pathway was activated in subgroups of all diseases except SLE.A novel gene expression measurement of activated cytokines in five different rheumatic diseases is presented. Characterizing the cytokine pathways most activated in specific patient subpopulations has the potential to help target the appropriate patient populations for corresponding anti-cytokine therapies.

  View details for DOI 10.1111/j.1756-185X.2011.01654.x

  View details for Web of Science ID 000300446600014

  View details for PubMedID 22324944

• Interferon and Biologic Signatures in Dermatomyositis Skin: Specificity and Heterogeneity across Diseases PLOS ONE Wong, D., Kea, B., Pesich, R., Higgs, B. W., Zhu, W., Brown, P., Yao, Y., Fiorentino, D. 2012; 7 (1)

  Abstract

  Dermatomyositis (DM) is an autoimmune disease that mainly affects the skin, muscle, and lung. The pathogenesis of skin inflammation in DM is not well understood.We analyzed genome-wide expression data in DM skin and compared them to those from healthy controls. We observed a robust upregulation of interferon (IFN)-inducible genes in DM skin, as well as several other gene modules pertaining to inflammation, complement activation, and epidermal activation and differentiation. The interferon (IFN)-inducible genes within the DM signature were present not only in DM and lupus, but also cutaneous herpes simplex-2 infection and to a lesser degree, psoriasis. This IFN signature was absent or weakly present in atopic dermatitis, allergic contact dermatitis, acne vulgaris, systemic sclerosis, and localized scleroderma/morphea. We observed that the IFN signature in DM skin appears to be more closely related to type I than type II IFN based on in vitro IFN stimulation expression signatures. However, quantitation of IFN mRNAs in DM skin shows that the majority of known type I IFNs, as well as IFN g, are overexpressed in DM skin. In addition, both IFN-beta and IFN-gamma (but not other type I IFN) transcript levels were highly correlated with the degree of the in vivo IFN transcriptional response in DM skin.As in the blood and muscle, DM skin is characterized by an overwhelming presence of an IFN signature, although it is difficult to conclusively define this response as type I or type II. Understanding the significance of the IFN signature in this wide array of inflammatory diseases will be furthered by identification of the nature of the cells that both produce and respond to IFN, as well as which IFN subtype is biologically active in each diseased tissue.

  View details for DOI 10.1371/journal.pone.0029161

  View details for Web of Science ID 000301123400030

  View details for PubMedID 22235269

• Consensus Guidelines for the Management of Plaque Psoriasis ARCHIVES OF DERMATOLOGY Hsu, S., Papp, K. A., Lebwohl, M. G., Bagel, J., Blauvelt, A., Duffin, K. C., Crowley, J., Eichenfield, L. F., Feldman, S. R., Fiorentino, D. F., Gelfand, J. M., Gottlieb, A. B., Jacobsen, C., Kalb, R. E., Kavanaugh, A., Korman, N. J., Krueger, G. G., Michelon, M. A., Morison, W., Ritchlin, C. T., Gold, L. S., Stone, S. P., Strober, B. E., Van Voorhees, A. S., Weiss, S. C., Wanat, K., Bebo, B. F. 2012; 148 (1): 95-102

  Abstract

  The Canadian Guidelines for the Management of Plaque Psoriasis were reviewed by the entire National Psoriasis Foundation Medical Board and updated to include newly approved agents such as ustekinumab and to reflect practice patterns in the United States, where the excimer laser is approved for psoriasis treatment. Management of psoriasis in special populations is discussed. In the updated guidelines, we include sections on children, pregnant patients or pregnant partners of patients, nursing mothers, the elderly, patients with hepatitis B or C virus infections, human immunodeficiency virus-infected patients, and patients with malignant neoplasms, as well as sections on tumor necrosis factor blockers, elective surgery, and vaccinations.

  View details for Web of Science ID 000299653900018

  View details for PubMedID 22250239

• Quality of life in dermatomyositis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Goreshi, R., Chock, M., Foering, K., Feng, R., Okawa, J., Rose, M., Fiorentino, D., Werth, V. 2011; 65 (6): 1107-1116

  Abstract

  Quality of life (QoL) for patients with inflammatory skin disease can be significant, but has been evaluated in just one study in dermatomyositis (DM).We sought to examine the relationship between the Cutaneous Dermatomyositis Area (CDASI) and Severity Index, a DM-specific cutaneous severity instrument, and various QoL study instruments and to determine the impact of DM on QoL.Skin-specific QoL instruments, the Skindex and the Dermatology Life Quality Index, and global medical QoL instruments, the Short Form 36 and the Health Assessment Questionnaire-Disability Index, were used. Pruritus was evaluated by a visual analog scale and a 0-to-10 scale in DM and cutaneous lupus erythematosus (CLE) populations, respectively.There was a significant correlation between the CDASI and all skin-specific QoL scores (lowest P = .0377). Using the Short Form 36, DM population was found to have significantly worse QoL scores than the general population with the exception of bodily pain (all subscore P values < .01). Furthermore, DM had a significantly lower vitality score, representing energy level, compared with CLE, hypertension, diabetes, and recent myocardial infarction scores (lowest P = .003). There was a significantly lower mental health score, representing overall mood, to all compared diseases except CLE and clinical depression (P values < .01 when significant). We found that DM produces more pruritus than CLE (P < .0001).A larger patient population needs to be studied to further assess QoL in patients with DM.We conclude that DM has a large impact on QoL, even when compared with other diseases, and that DM skin disease activity correlates with a poorer QoL.

  View details for DOI 10.1016/j.jaad.2010.10.016

  View details for Web of Science ID 000297717200004

  View details for PubMedID 21722989

• Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway ANNALS OF THE RHEUMATIC DISEASES Higgs, B. W., Liu, Z., White, B., Zhu, W., White, W. I., Morehouse, C., Brohawn, P., Kiener, P. A., Richman, L., Fiorentino, D., Greenberg, S. A., Jallal, B., Yao, Y. 2011; 70 (11): 2029-2036

  Abstract

  To characterise activation of the type I interferon (IFN) pathway in patients with systemic lupus erythematosus (SLE), dermatomyositis (DM), polymyositis (PM), rheumatoid arthritis (RA) and systemic scleroderma (SSc) and to evaluate the potential to develop a molecular diagnostic tool from the peripheral blood that reflects this activation in disease-affected tissues.Overexpressed transcripts were identified in the whole blood (WB) of 262 patients with SLE, 44 with DM, 33 with PM, 28 with SSc and 89 with RA and compared with 24 healthy subjects using Affymetrix microarrays. A five gene type I IFN signature was assessed in these subjects to identify subpopulations showing both activation and concordance of the type I IFN pathway in the peripheral blood and disease-affected tissues of each disease and to correlate activation of this pathway in the WB with clinical measurements.A common set of 36 type I IFN inducible transcripts were identified among the most overexpressed in the WB of all subjects. Significant activation of the type I IFN pathway in subgroups of each of the five diseases studied was observed. Baseline disease activity measurements correlated with a type I IFN gene signature in the WB of subjects with SLE, PM and SSc, as did various serum autoantibody levels in subjects with SLE and DM. This signature was also well correlated between disease-affected tissue and WB in subjects with SLE, DM, PM and SSc.The results indicate that the type I IFN pathway is activated in patient subsets of five rheumatic diseases and suggest that these subsets may benefit from anti-IFN therapy.

  View details for DOI 10.1136/ard.2011.150326

  View details for Web of Science ID 000295399700026

  View details for PubMedID 21803750

• 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 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

  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

• 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

• Prevalence of Children with Severe Fetal Alcohol Spectrum Disorders in Communities Near Rome, Italy: New Estimated Rates Are Higher than Previous Estimates May, P. A., Fiorentino, D., Coriale, G., Kalberg, W. O., Hoyme, H. E., Aragon, A. S., Buckley, D., Stellavato, C., Gossage, J. P., Robinson, L. K., Jones, K. L., Manning, M., Ceccanti, M. MDPI AG. 2011: 2331-2351

  Abstract

  To determine the population-based epidemiology of fetal alcohol syndrome (FAS) and other fetal alcohol spectrum disorders (FASD) in towns representative of the general population of central Italy.Slightly revised U.S. Institute of Medicine diagnostic methods were used among children in randomly-selected schools near Rome. Consented first grade children (n=976) were screened in Tier I for height, weight, or head circumference and all children?10th centile on one of these measurements were included in the study. Also, teachers referred children for learning or behavioral problems. Children meeting either of these two criteria, along with randomly-selected controls, advanced to Tier II which began with a dysmorphology examination. Children with a possible FASD, and controls, advanced to Tier III for neurobehavioral testing, and their mothers were interviewed for maternal risks. Final diagnoses using indicators of dysmorphology, neurobehavior, and maternal risk were made in formally-structured, interdisciplinary case conferences.Case control comparisons of physical, neurobehavioral, and maternal risk variables are presented for 46 children with an FASD and 116 randomly-selected controls without a diagnosis on the FASD continuum. Rates of diagnoses within the FASD continuum are then estimated from these in-school data via three different methods. The range of rates of FAS produced by these methods is between 4.0 to 12.0 per 1,000; Partial FAS ranges from 18.1 to 46.3 per 1,000; and an FASD was found in 2.3% to 6.3% of the children.These rates are substantially higher than previous estimates of FAS and overall FASD for the general populations of Western Europe and the U. S., and raise questions as to the total impact of FASD on mental deficit in mainstream populations of Western Europe and the United States where the majority are middle class and are not believed to be characterized by heavy episodic drinking.

  View details for DOI 10.3390/ijerph8062331

  View details for Web of Science ID 000292022500034

  View details for PubMedID 21776233

• The direct cellular target of topically applied pimecrolimus may not be infiltrating lymphocytes BRITISH JOURNAL OF DERMATOLOGY Fiorentino, D. F., Chen, R. O., STEWART, D. B., Brown, K. K., Sundram, U. N. 2011; 164 (5): 996-1003

  Abstract

  Topically applied calcineurin inhibitors have been shown to be effective in the treatment of atopic dermatitis. When systemically administered, these agents cause immunosuppression via inhibition of calcineurin in lymphocytes. As topical agents, the mechanism of action is poorly defined.To test the hypothesis that skin-infiltrating lymphocytes are directly targeted when calcineurin inhibitors are applied to the skin.Ten patients with atopic dermatitis were treated with 1% pimecrolimus cream twice daily to target lesions. Skin biopsies were performed before and 48 h after beginning therapy. We assessed the cellular localization of NFAT1 and NFAT2 as a surrogate measure of intracellular calcineurin activity (e.g. increasing cytoplasmic localization with increasing calcineurin inhibition).All patients showed a clinical response, at both 48 h and 2 weeks. As previously described, NFAT2 localized to the follicular keratinocytes, and its activation was partially inhibited by topical pimecrolimus. NFAT1 was found to be expressed by follicular and interfollicular keratinocytes, and its mostly nuclear localization was not affected by topical pimecrolimus therapy. Both NFAT1 and NFAT2 were found in the infiltrating lymphocytes. However, using both manual counting as well as an automated method to assess nuclear intensity of NFAT staining, we found that the proportion of infiltrating leucocytes with nuclear ('activated') NFAT did not change following therapy with pimecrolimus.Our results suggest that topical pimecrolimus does not act primarily by inhibiting the calcineurin/NFAT axis in lymphocytes but may instead act by other mechanisms, possibly by decreasing NFAT2 activity in follicular keratinocytes.

  View details for DOI 10.1111/j.1365-2133.2010.10190.x

  View details for Web of Science ID 000289898200012

  View details for PubMedID 21166661

• International consensus for a definition of disease flare in lupus LUPUS Ruperto, N., HANRAHAN, L. M., Alarcon, G. S., Belmont, H. M., Brey, R. L., Brunetta, P., Buyon, J. P., Costner, M. I., Cronin, M. E., Dooley, M. A., Filocamo, G., Fiorentino, D., Fortin, P. R., Franks, A. G., Gilkeson, G., Ginzler, E., Gordon, C., Grossman, J., Hahn, B., Isenberg, D. A., Kalunian, K. C., Petri, M., Sammaritano, L., Sanchez-Guerrero, J., Sontheimer, R. D., Strand, V., Urowitz, M., Von Feldt, J. M., Werth, V. P., Merrill, J. T. 2011; 20 (5): 453-462

  Abstract

  The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: "A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment." The LFA proposes this definition for lupus flare on the basis of its high face validity.

  View details for DOI 10.1177/0961203310388445

  View details for Web of Science ID 000290213800003

  View details for PubMedID 21148601

• 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

• A Pilot Study of Etanercept Treatment for Pemphigus Vulgaris ARCHIVES OF DERMATOLOGY Fiorentino, D. F., Garcia, M. S., Rehmus, W., Kimball, A. B. 2011; 147 (1): 117-118

  View details for Web of Science ID 000286229000031

  View details for PubMedID 21242406

• 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

• Modification of the Cutaneous Dermatomyositis Disease Area and Severity Index, an outcome instrument BRITISH JOURNAL OF DERMATOLOGY Yassaee, M., Fiorentino, D., Okawa, J., Taylor, L., Coley, C., Troxel, A. B., Werth, V. P. 2010; 162 (3): 669-673

  Abstract

  Validated outcome measures in dermatology help standardize and improve patient care. A scoring system of skin disease severity in dermatomyositis known as the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) has been developed.To simplify and improve the tool for clinical research and care, we modified the CDASI and validated the new version, v2.The original CDASI has four activity and two damage measures. The modified CDASI has three activity and two damage measures. The skin disease of 20 patients with dermatomyositis was evaluated by the same dermatologist using both the original and the modified CDASI. Global validation measures were implemented to assess overall skin disease state, skin disease activity and skin damage. Spearman's rho (r(sp)), adjusted for multiple observations on subjects, was used to determine the relationship between the two versions of the CDASI and their correlation with the physician global measures (PGMs).The total score and activity and damage subscores of the original and the modified CDASI correlated perfectly with each other (r(sp) = 0.99, 1.00, 1.00). The PGM-overall skin scale correlated with the total scores (r(sp) = 0.72, r(sp) = 0.76) and activity subscores (r(sp) = 0.68, r(sp) = 0.63) but not with the damage subscores (r(sp) = 0.14, r(sp) = 0.15) of the original and the modified CDASI, respectively. However, the PGM-activity and PGM-damage scales correlated with the activity (r(sp) = 0.76, r(sp) = 0.75) and damage subscores (r(sp) = 0.90, r(sp) = 0.90), respectively, of the original and the modified CDASI.The modified CDASI is perfectly correlated with the original CDASI. It has equally good concurrent validity with the PGM-overall skin and PGM-activity scales. The CDASI subscores have equally good concurrent validity with the PGM-activity and PGM-damage scales. We suggest that PGMs of skin disease activity and damage should be assessed separately for greater specificity. The modified CDASI is a refined and equally as useful outcome measure.

  View details for DOI 10.1111/j.1365-2133.2009.09521.x

  View details for Web of Science ID 000274550600031

  View details for PubMedID 19863510

• Conditioned Pharmacotherapeutic Effects: A Preliminary Study PSYCHOSOMATIC MEDICINE Ader, R., Mercurio, M. G., Walton, J., James, D., Davis, M., Ojha, V., Kimball, A. B., Fiorentino, D. 2010; 72 (2): 192-197

  Abstract

  To test the hypothesize that psoriasis patients treated under a partial schedule of pharmacologic (corticosteroid) reinforcement would show less severe symptoms and relapse than those given the same amount of drug under standard conditions. Behavioral conditioning as an inherent component of many pharmacotherapeutic protocols has never been examined.A double-blind, simple randomization intervention was conducted with 46 patients from California and New York. Initially, lesions were treated with 0.1% acetonide triamcinolone under standard treatment conditions. Thereafter, a Standard Therapy group continued on continuous reinforcement (active drug every treatment) with 100% of the initial dose; Partial Reinforcement patients received a full dose 25% to 50% of the time and placebo medication other times; Dose Control patients received continuous reinforcement with 25% to 50% of the initial dose.Severity of disease scores in California neither supported nor refuted the hypothesis. In New York, where there was no difference between Partial Reinforcement and Dose Control groups at baseline, partial reinforcement effected a greater reduction in lesion severity than Dose Control conditions and did not differ from Standard Therapy patients receiving two to four times more drug. For the entire population, the frequency of relapse under partial reinforcement (26.7%) was lower than in Dose Control patients (61.5%) and did not differ from full-dose treatment (22.2%).A partial schedule of pharmacotherapeutic reinforcement could maintain psoriasis patients with a cumulative amount of corticosteroid that was relatively ineffective when administered under standard treatment conditions. Conceivably, corticosteroid administration only one quarter or half as frequently as currently prescribed is sufficient to treat psoriasis. We posit, however, that these preliminary observations implicate conditioning processes in-and for the design of-regimens of pharmacotherapy.

  View details for Web of Science ID 000274797700013

  View details for PubMedID 20028830

• Treatment recommendations for psoriatic arthritis ANNALS OF THE RHEUMATIC DISEASES Ritchlin, C. T., Kavanaugh, A., Gladman, D. D., Mease, P. J., Helliwell, P., Boehncke, W., de Vlam, K., Fiorentino, D., Fitzgerald, O., Gottlieb, A. B., McHugh, N. J., Nash, P., Qureshi, A. A., Soriano, E. R., Taylor, W. J. 2009; 68 (9): 1387-1394

  Abstract

  To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion.Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire.Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective.Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available.

  View details for DOI 10.1136/ard.2008.094946

  View details for Web of Science ID 000268888600003

  View details for PubMedID 18952643

• 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

• 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 Web of Science ID 000263276400032

  View details for PubMedID 19180499

• Imatinib in the Treatment of Nephrogenic Systemic Fibrosis AMERICAN JOURNAL OF KIDNEY DISEASES Chandran, S., Petersen, J., Jacobs, C., Forentino, D., Doeden, K., Lafayette, R. A. 2009; 53 (1): 129-132

  Abstract

  Nephrogenic systemic fibrosis is a disabling progressive condition that is being reported with increased frequency in patients with kidney disease. Treatment is extremely limited and largely supportive. We report a case of severe nephrogenic systemic fibrosis in a dialysis patient exposed to multiple doses of gadolinium who improved clinically and histologically with treatment with imatinib.

  View details for DOI 10.1053/j.ajkd.2008.08.029

  View details for Web of Science ID 000262172200018

  View details for PubMedID 19012999

• Type I Interferon in the Induction or Exacerbation of Dermatomyositis What This Observation Tells Us About the Naturally Occurring Disease ARCHIVES OF DERMATOLOGY Fiorentino, D. F. 2008; 144 (10): 1379-1382

  View details for Web of Science ID 000260199400015

  View details for PubMedID 18936404

• Comparison of the reliability and validity of outcome instruments for cutaneous dermatomyositis BRITISH JOURNAL OF DERMATOLOGY Klein, R. Q., Bangert, C. A., Costner, M., Connolly, M. K., Tanikawa, A., Okawa, J., Rose, M., Fakharzadeh, S. S., Fiorentino, D., Lee, L. A., Sontheimer, R. D., Taylor, L., Troxel, A. B., Werth, V. P. 2008; 159 (4): 887-894

  Abstract

  Reliable and validated measures of skin disease severity are needed for cutaneous dermatomyositis (DM). Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Dermatomyositis Skin Severity Index (DSSI) and Cutaneous Assessment Tool (CAT) skin indices have been developed as outcome instruments.We sought to demonstrate reliability and validity of the CDASI, and to compare the CDASI with other potential tools for use in measuring disease severity in cutaneous dermatomyositis.CDASI has four activity and two damage measures, with scores from 0 to 148. DSSI assesses activity based on body surface area and severity on a scale of 0-72. CAT uses 21 activity and damage items, for a range of 0-175 for activity and 0-33 for damage. Ten dermatologists used the instruments to score the same 12-16 patients in one session. Global validation measures were administered to physicians and patients.Global validation measures correlated with the three outcome instruments (P < 0.0001). CAT displayed lower inter- and intrarater reliability relative to the CDASI. All scales correlate better with physician than patient global skin measures.It appears that the CDASI may be a useful outcome measure for studies of cutaneous DM. Further testing to compare responsiveness of all three measures is necessary.

  View details for DOI 10.1111/j.1365-2133.2008.08711.x

  View details for Web of Science ID 000259307700015

  View details for PubMedID 18616782

• Molecular framework for response to imatinib mesylate in systemic sclerosis 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

• Palisaded neutrophilic and granulomatous dermatitis associated with limited systemic sclerosis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Hantash, B. M., Chiang, D., Kohler, S., Fiorentino, D. 2008; 58 (4): 661-664

  Abstract

  Palisaded neutrophilic and granulomatous dermatitis (PNGD) is a condition that is characterized histopathologically by a characteristic pattern of granulomatous inflammation in the presence or absence of leukocytoclastic vasculitis. It has been associated with systemic diseases, especially autoimmune conditions such as rheumatoid arthritis and Behçet's disease. A 44-year-old woman with underlying limited systemic sclerosis presented with painful erythematous nodules located on her face and scalp. Histopathologic analysis confirmed a diagnosis of PNGD, which self-resolved within weeks of the biopsy. To our knowledge, this is the first report of a case of PNGD associated with systemic sclerosis. A review of the literature revealed that PNGD is a female-predominant disease that is most commonly associated with rheumatoid arthritis, followed closely by lupus erythematosus. Most patients with PNGD respond to treatment of the underlying systemic disease, although spontaneous resolution is not uncommonly observed.

  View details for DOI 10.1016/j.jaad.2007.09.019

  View details for Web of Science ID 000254315000018

  View details for PubMedID 17945384

• Capillary Regeneration in Scleroderma: Stem Cell Therapy Reverses Phenotype? PLOS ONE Fleming, J. N., Nash, R. A., McLeod, D. O., Fiorentino, D. F., Shulman, H. M., Connolly, M. K., Molitor, J. A., Henstorf, G., Lafyatis, R., Pritchard, D. K., Adams, L. D., Furst, D. E., Schwartz, S. M. 2008; 3 (1)

  Abstract

  Scleroderma is an autoimmune disease with a characteristic vascular pathology. The vasculopathy associated with scleroderma is one of the major contributors to the clinical manifestations of the disease.We used immunohistochemical and mRNA in situ hybridization techniques to characterize this vasculopathy and showed with morphometry that scleroderma has true capillary rarefaction. We compared skin biopsies from 23 scleroderma patients and 24 normal controls and 7 scleroderma patients who had undergone high dose immunosuppressive therapy followed by autologous hematopoietic cell transplant. Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels. The molecules defining this phenotype are: vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation (lost in the scleroderma tissue), antiangiogenic interferon alpha (overexpressed in the scleroderma dermis) and RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis (also overexpressed in scleroderma skin. Following high dose immunosuppressive therapy, patients experienced clinical improvement and 5 of the 7 patients with scleroderma had increased capillary counts. It was also observed in the same 5 patients, that the interferon alpha and vascular endothelial cadherin had returned to normal as other clinical signs in the skin regressed, and in all 7 patients, RGS5 had returned to normal.These data provide the first objective evidence for loss of vessels in scleroderma and show that this phenomenon is reversible. Coordinate changes in expression of three molecules already implicated in angiogenesis or anti-angiogenesis suggest that control of expression of these three molecules may be the underlying mechanism for at least the vascular component of this disease. Since rarefaction has been little studied, these data may have implications for other diseases characterized by loss of capillaries including hypertension, congestive heart failure and scar formation.

  View details for DOI 10.1371/journal.pone.0001452

  View details for Web of Science ID 000260503800022

  View details for PubMedID 18197262

• Dermatomyositis. Current directions in autoimmunity Krathen, M. S., Fiorentino, D., Werth, V. P. 2008; 10: 313-332

  Abstract

  Dermatomyositis (DM) is a chronic inflammatory disorder of the skin and muscles. Although thought to be autoimmune in origin, many questions remain as to the etiopathogenesis of this disease. DM has classically been considered a humorally mediated disease. Current evidence, however, seems to increasingly support alternative (though not mutually exclusive) mechanisms of pathogenesis, including cell-mediated and innate immune system dysfunction. Pathologic findings of DM in muscle include infarcts, perifascicular atrophy, endothelial cell swelling and necrosis, vessel wall membrane attack complex deposition, and myocyte-specific MHC I upregulation. As for the skin, histopathologic findings include hyperkeratosis, epidermal basal cell vacuolar degeneration and apoptosis, increased dermal mucin deposition, and a cell-poor interface dermatitis. Autoantibodies, particularly those that bind nuclear or cytoplasmic ribonucleoprotein antigens, are also commonly found in DM, although their importance in pathogenesis remains unclear. Defective cellular clearance, genetic predilection and environmental exposures, such as viral infection, may also play an important role in the pathogenesis of DM. The seminal work regarding the pathogenesis of DM is reviewed and an update on the recent basic and molecular advances in the field is provided.

  View details for DOI 10.1159/000131751

  View details for PubMedID 18460893

• Localized scleroderma and systemic sclerosis: Is there a connection? BEST PRACTICE & RESEARCH IN CLINICAL RHEUMATOLOGY Gupta, R. A., Fiorentino, D. 2007; 21 (6): 1025-1036

  Abstract

  Excess fibrosis of the skin is a clinical hallmark of both localized scleroderma and systemic sclerosis. Localized scleroderma is generally thought to be a skin-limited disease whereas systemic sclerosis can have a wide range of internal organ involvement. Recent data suggest that a subset of patients with juvenile localized scleroderma can go on to develop systemic involvement of their disease. This raises the question of what the connection is, if any, between localized scleroderma and systemic sclerosis.

  View details for DOI 10.1016/j.berh.2007.09.003

  View details for Web of Science ID 000252093900005

  View details for PubMedID 18068859

• Nephrogenic systemic fibrosis - Relationship to gadolinium and response to photopheresis ARCHIVES OF DERMATOLOGY Richmond, H., Zwerner, J., Kim, Y., Fiorentino, D. 2007; 143 (8): 1025-1030

  Abstract

  Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy, is an idiopathic condition seen in patients with renal disease that is characterized by cutaneous sclerosis that can often result in contractures, pain, and functional disability as well as systemic complications. Recent reports have suggested a possible link with exposure to gadolinium, a commonly used radiocontrast agent. No current therapy has clearly demonstrated efficacy for NSF, although case reports suggest that extracorporeal photopheresis (ECP) may be of benefit. The purpose of this study was to explore the plausibility of a gadolinium linkage with NSF as well as to assess the efficacy of ECP in the treatment of a cohort of patients with NSF.We report our experience with 8 consecutive patients with NSF seen at the Stanford Medical Center, Palo Alta, California, from 2004 to 2006. Of the 8 patients, 6 had a history of arterial or venous thrombotic disease and 7 had a documented exposure to gadolinium within 1 week to several months prior to the onset of NSF. Specifically, all patients were exposed to gadodiamide. We treated 5 of the patients with ECP. After a mean number of 34 treatment sessions over a mean of 8.5 months, 3 patients experienced a mild improvement in skin tightening, range of motion, and/or functional capacity.Our data support the hypothesis that exposure to gadolinium, perhaps specifically gadodiamide, plays a role in the pathogenesis of NSF. Larger epidemiologic studies will be needed to confirm this association. In addition, our experience suggests that, if used for extended periods, ECP might have some mild benefit for patients with NSF. Larger, randomized, placebo-controlled trials of ECP should be performed to more specifically assess the benefit of ECP in the treatment of NSF.

  View details for Web of Science ID 000248723900008

  View details for PubMedID 17709661

• Mycophenolate mofetil DERMATOLOGIC THERAPY Zwerner, J., Fiorentino, D. 2007; 20 (4): 229-238

  Abstract

  Mycophenolate mofetil (MMF) is a relatively new systemic immunosuppressive agent whose use is rapidly increasing within the field of dermatologic. Originally used in the 1970s for the treatment of psoriasis, MMF has demonstrated efficacy in multiple types of inflammatory skin diseases. Although the safety data within the dermatologic literature is sparse, MMF's extensive use within the field of organ transplantation has demonstrated a favorable safety profile. MMF's lack of hepatic or renal toxicity is a significant advantage over immunosuppressive medications currently used in dermatology and make MMF an attractive candidate for multidrug regimens. In this review the present authors discuss the pharmacology, mechanisms of action, side effects and current uses of MMF reported within the dermatologic literature. The present authors also provide practical information regarding the use of the MMF culled from the literature as well as from the present authors' own clinical experience with the medication.

  View details for Web of Science ID 000250497200007

  View details for PubMedID 17970888

• 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

• Comparison of the reliability & validity of outcome instruments for cutaneous dermatomyositis Quain, R. D., Bangert, C. C., Costner, M., Connolly, M. K., Dugan, E., Tanikawa, A., Okawa, J., Rose, M., Fakharzadeh, S. S., Fiorentino, D., Lee, L. A., Sontheimer, R. D., Taylor, L., Werth, V. P. NATURE PUBLISHING GROUP. 2007: S59-S59

  View details for Web of Science ID 000245387800346

• Update on cutaneous vasculitis SEMINARS IN CUTANEOUS MEDICINE AND SURGERY Grzeszkiewicz, T. M., Fiorentino, D. F. 2006; 25 (4): 221-225

  Abstract

  Vasculitis presents with a range of clinical manifestations, many of which affect the skin. Diagnosing and classifying vasculitis can prove challenging. Particularly given the lack of unified criteria that are both useful as a research tool and clinically relevant. Also, vasculitis may be secondary to a wide range of conditions, making the prompt recognition and treatment of associated disorders essential for appropriate patient management. This article will highlight the classification, pathogenesis, clinical presentation, diagnosis, evaluation, and treatment of the cutaneous vasculitides.

  View details for DOI 10.1016/j.sder.2006.08.005

  View details for Web of Science ID 000243158300007

  View details for PubMedID 17174842

• 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

• Epidemiology of FASD in a province in Italy: Prevalence and characteristics of children in a random sample of schools ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH May, P. A., Fiorentino, D., Gossage, J. P., Kalberg, W. O., Hoyme, H. E., Robinson, L. K., Coriale, G., Jones, K. L., del Campo, M., Tarani, L., Romeo, M., Kodituwakku, P. W., Deiana, L., Buckley, D., Ceccanti, M. 2006; 30 (9): 1562-1575

  Abstract

  Accurate estimates of the prevalence and characteristics of fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD) in a Western European population are lacking and are of particular interest in settings where the usual pattern of alcohol consumption is thought to be daily drinking with meals. To address these issues, an epidemiology study of FAS and other FASD was undertaken in Italian schools.Primary schools (n = 25) in 2 health districts of the Lazio region were randomly selected and recruited for the study. Five hundred forty-three children, 50% of those enrolled in first-grade classes, received parental permission to participate in a 2-tiered, active case ascertainment screening process. Detailed evaluation of children selected in a preliminary screening phase was carried out on those who were small for height, weight, and head circumference and/or referred by teachers for suspected learning and behavioral problems. Detailed evaluation was carried out on each child's: (1) physical growth and dysmorphology, (2) psychological development and behavior, and (3) prenatal exposure to alcohol and other risk factors for FASD via maternal interviews. A group of 67 randomly selected children without FASD from the same classes was utilized as a comparison group.Using 2 denominators for prevalence estimation, a conservative one and a strict sample-based estimate, the prevalence of FAS in this province of Italy was 3.7 to 7.4 per 1,000 children. When cases of partial FAS (PFAS) and a case of alcohol-related neurodevelopmental deficits (ARND) were added to FAS cases, the rate of FASD was 20.3 to 40.5 per 1,000 and estimated at 35 per 1,000 overall or between 2.3 and 4.1% of all children. This exceeds previously published estimates of both FAS and FASD for the western world. Detailed data are presented that demonstrate the utility of the guidelines of the revised Institute of Medicine diagnostic criteria for FASD. Children with FASD are significantly more impaired/affected (p < 0.05) than randomly selected comparison children on all measures of growth deficiency, key facial features of FASD, overall dysmorphology scores, language comprehension, nonverbal IQ, and behavior. Maternal reports of current drinking were significantly higher for mothers of FASD children than comparison mothers, but reported rates of overall drinking during pregnancy were not significantly different. In contrast to expectations, daily drinking among mothers of the comparison group was not common. However, dysmorphology scores of the children were significantly correlated with drinking in the second and third trimesters, drinks per current drinking day, and current drinks per month. Finally, children with the physical features of FASD had lower IQs; nonverbal IQ was significantly correlated with head circumference and negatively correlated with overall dysmorphology score, smooth philtrum, and several other facial and physical anomalies characteristic of FAS.Using careful measures of ascertainment in a primary school setting, these results provide relatively high estimates of the prevalence of FASD and raise the question of whether FASD is more common in the western world than previously estimated.

  View details for DOI 10.1111/j.1530-0277.2006.00188.x

  View details for Web of Science ID 000239939500013

  View details for PubMedID 16930219

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

  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

• Liver enzyme abnormalities in patients with atopic dermatitis treated with mycophenolate mofetil ARCHIVES OF DERMATOLOGY Hantash, B., Fiorentino, D. 2006; 142 (1): 109-110

  View details for Web of Science ID 000234605500021

  View details for PubMedID 16415398

• Muir-Torre syndrome: Confirmation of diagnosis by immunohistochemical analysis of cutaneous lesions JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Fiorentino, D. F., Nguyen, J. C., Egbert, B. M., Swetter, S. M. 2004; 50 (3): 476-478

  View details for DOI 10.1016/j.jaad.2003.07.027

  View details for Web of Science ID 000220080500026

  View details for PubMedID 14988697

• Cutaneous vasculitis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Fiorentino, D. F. 2003; 48 (3): 311-340

  Abstract

  Vasculitis can range in severity from a self-limited single-organ disorder to a life-threatening disease with the prospect of multiple-organ failure. This condition presents many challenges to the physician, including classification and diagnosis, appropriate laboratory workup, treatment, and the need for careful follow-up. The physician must not only be able to recognize vasculitis but also be able to provide a specific diagnosis (if possible) as well as recognize and treat any underlying etiologic condition. Most diagnostic criteria are based on the size of vessel involvement, which often correlates with specific dermatologic findings. This may allow the dermatologist to provide an initial diagnosis and direct the medical evaluation. This article reviews the classification and diagnosis of cutaneous vasculitic syndromes and current treatment options; it also presents a comprehensive approach to diagnosing and treating the patient with suspected cutaneous vasculitis. (J Am Acad Dermatol 2003;48:311-40.)At the completion of this learning activity, participants should be familiar with the classification and clinical features of the various forms of cutaneous vasculitis. They should also have a rational approach to diagnosing and treating a patient with vasculitis.

  View details for DOI 10.1067/mjd.2003.212

  View details for Web of Science ID 000181643900001

  View details for PubMedID 12637912

• Characterization of Saccharomyces cerevisiae dna2 mutants suggests a role for the helicase late in S phase MOLECULAR BIOLOGY OF THE CELL Fiorentino, D. F., Crabtree, G. R. 1997; 8 (12): 2519-2537

  Abstract

  The TOR proteins, originally identified as targets of the immunosuppressant rapamycin, contain an ATM-like "lipid kinase" domain and are required for early G1 progression in eukaryotes. Using a screen to identify Saccharomyces cerevisiae mutants requiring overexpression of Tor1p for viability, we have isolated mutations in a gene we call ROT1 (requires overexpression of Tor1p). This gene is identical to DNA2, encoding a helicase required for DNA replication. As with its role in cell cycle progression, both the N-terminal and C-terminal regions, as well as the kinase domain of Tor1p, are required for rescue of dna2 mutants. Dna2 mutants are also rescued by Tor2p and show synthetic lethality with tor1 deletion mutants under specific conditions. Temperature-sensitive (Ts) dna2 mutants arrest irreversibly at G2/M in a RAD9- and MEC1-dependent manner, suggesting that Dna2p has a role in S phase. Frequencies of mitotic recombination and chromosome loss are elevated in dna2 mutants, also supporting a role for the protein in DNA synthesis. Temperature-shift experiments indicate that Dna2p functions during late S phase, although dna2 mutants are not deficient in bulk DNA synthesis. These data suggest that Dna2p is not required for replication fork progression but may be needed for a later event such as Okazaki fragment maturation.

  View details for Web of Science ID A1997YK93000013

  View details for PubMedID 9398673

• The mechanism of action of cyclosporin A and FK506 Ho, S., Clipstone, N., Timmermann, L., Northrop, J., Graef, I., Fiorentino, D., Nourse, J., Crabtree, G. R. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1996: S40-S45

  Abstract

  The immunosuppressants cyclosporin A (CsA), FK506, and rapamycin suppress the immune response by inhibiting evolutionary conserved signal transduction pathways. CsA, FK506, and rapamycin bind to their intracellular receptors, immunophilins, creating composite surfaces that block the activity of specific targets. For CsA/cyclophilin and FK506/FKBP the target is calcineurin. Because of the large surface area of interaction of the drug-immunophilin complex with calcineurin, FK506 and CsA have a specificity for their biologic targets that is equivalent to growth factor-receptor interactions. To date, all the therapeutic as well as toxic effects of these drugs have been shown to be due to inhibition of calcineurin. Inhibition of the action of calcineurin results in a complete block in the translocation of the cytosolic component of the nuclear factor of activated T cells (NF-AT), resulting in a failure to activate the genes regulated by the NF-AT transcription factor. These genes include those required for B-cell help such as interleukin (IL-4) and CD40 ligand as well as those necessary for T-cell proliferation such as IL-2. The purpose of this article is to illustrate the means by which these drugs produce immunosuppression.

  View details for Web of Science ID A1996VG75000006

  View details for PubMedID 8811062

• TOR KINASE DOMAINS ARE REQUIRED FOR 2 DISTINCT FUNCTIONS, ONLY ONE OF WHICH IS INHIBITED BY RAPAMYCIN CELL Zheng, X. F., Fiorentino, D., Chen, J., Crabtree, G. R., Schreiber, S. L. 1995; 82 (1): 121-130

  Abstract

  The rapamycin-sensitive signaling pathway is required to transduce specific mitogenic signals to the cell cycle machinery responsible for G1 progression. Genetic studies in yeast identified two related genes on this pathway, TOR1 and TOR2, thought to encode novel phosphatidylinositol kinases. We now show that an intact kinase domain is required for the G1 cell cycle functions of both proteins, for the ability of a mutation in a neighboring FKBP12-rapamycin-binding domain of the TOR1 protein to inhibit the growth of yeast cells when overexpressed, and for the essential function of the TOR2 protein. The G1 function of both TOR proteins is sensitive to rapamycin, but the essential function of TOR2 is not. Thus, FKBP12-rapamycin does not appear to inhibit the kinase activity of TOR proteins in a general way; instead, it may interfere selectively with TOR protein binding to or phosphorylation of G1 effectors.

  View details for Web of Science ID A1995RK42400015

  View details for PubMedID 7606777

• IMMUNOPHILINS INTERACT WITH CALCINEURIN IN THE ABSENCE OF EXOGENOUS IMMUNOSUPPRESSIVE LIGANDS EMBO JOURNAL Cardenas, M. E., Hemenway, C., Muir, R. S., Ye, R., Fiorentino, D., Heitman, J. 1994; 13 (24): 5944-5957

  Abstract

  The peptidyl-prolyl isomerases FKBP12 and cyclophilin A (immunophilins) form complexes with the immunosuppressants FK506 and cyclosporin A that inhibit the phosphatase calcineurin. With the yeast two hybrid system, we detect complexes between FKBP12 and the calcineurin A catalytic subunit in both the presence and absence of FK506. Mutations in FKBP12 surface residues or the absence of the calcineurin B regulatory subunit perturb the FK506-dependent, but not the ligand-independent, FKBP12-calcineurin complex. By affinity chromatography, both FKBP12 and cyclophilin A bind calcineurin A in the absence of ligand, and FK506 and cyclosporin A respectively potentiate these interactions. Both in vivo and in vitro, the peptidyl-prolyl isomerase active sites are dispensable for ligand-independent immunophilin-calcineurin complexes. Lastly, by genetic analyses we demonstrate that FKBP12 modulates calcineurin functions in vivo. These findings reveal that immunophilins interact with calcineurin in the absence of exogenous ligands and suggest that immunosuppressants may take advantage of the inherent ability of immunophilins to interact with calcineurin.

  View details for Web of Science ID A1994QA63700018

  View details for PubMedID 7529175

• MOLECULAR ANALYSIS OF THE INTERACTION OF CALCINEURIN WITH DRUG-IMMUNOPHILIN COMPLEXES JOURNAL OF BIOLOGICAL CHEMISTRY Clipstone, N. A., Fiorentino, D. F., Crabtree, G. R. 1994; 269 (42): 26431-26437

  Abstract

  The calcium/calmodulin-regulated phosphatase calcineurin (CN) is the site of action of the immunosuppressive drugs cyclosporin A (CsA) and FK506. CN has recently been established as a key signaling enzyme in the T cell signal transduction cascade and an important regulator of transcription factors such as NF-AT and OAP/Oct-1, which are involved in the expression of a number of important T cell early genes. CsA and FK506 act by forming complexes with their respective intracellular receptors cyclophilin and FKBP (immunophilins), which can then bind to CN, inhibiting its enzymatic activity and thereby preventing early gene expression. CN is comprised of two subunits: a 59-kDa catalytic subunit (CNA), which contains a calmodulin binding domain and autoinhibitory region, and a 19-kDa intrinsic calcium binding regulatory subunit (CNB). In this study, we have utilized a series of deletion mutants of the CNA subunit to investigate the subunit and molecular requirements that govern the interaction of CN with drug-immunophilin complexes. The calmodulin binding and autoinhibitory domains of the CNA subunit were found to be dispensable for the binding of CN to drug-immunophilin complexes. In contrast, we found that the regulatory CNB subunit appears to play an obligatory role in this interaction and have defined an amino acid sequence of the CNA subunit which forms the binding site for CNB. Although necessary, the CNB subunit per se is not sufficient to mediate an interaction with drug-immunophilin complexes; amino acid residues of the CNA subunit, specifically a region located within the putative catalytic domain, are also required for the interaction of CN with both FKBP-FK506 and cyclophilin A-CsA.

  View details for Web of Science ID A1994PQ93000075

  View details for PubMedID 7523407

• RAPAMYCIN SELECTIVELY INHIBITS INTERLEUKIN-2 ACTIVATION OF P70 S6 KINASE NATURE Kuo, C. J., Chung, J. K., Fiorentino, D. F., Flanagan, W. M., Blenis, J., Crabtree, G. R. 1992; 358 (6381): 70-73

  Abstract

  The macrolide rapamycin induces cell cycle G1 arrest in yeast and in mammalian cells, which suggests that an evolutionarily conserved, rapamycin-sensitive pathway may regulate entry into S phase. In mammals, rapamycin inhibits interleukin-2 receptor-induced S phase entry and subsequent T-cell proliferation, resulting in immunosuppression. Here we show that interleukin-2 selectively stimulates the phosphorylation and activation of p70 S6 kinase but not the erk-encoded MAP kinases and rsk-encoded S6 kinases. Rapamycin completely and rapidly inhibits interleukin-2-induced phosphorylation and activation of p70 S6 kinase at concentrations comparable to those blocking S phase entry of T cells (0.05-0.2 nM). The structurally related macrolide FK506 competitively antagonizes the actions of rapamycin, indicating that these effects are mediated by FKBP, which binds the transition-state mimic structure common to both rapamycin and FK506 (refs 4, 6, 9-11). The selective blockade of the p70 S6 kinase activation cascade by the rapamycin-FKBP complex implicates this signalling pathway in the regulation of T cell entry into S phase.

  View details for Web of Science ID A1992JB34100056

  View details for PubMedID 1614535

• IL-10 INHIBITS CYTOKINE PRODUCTION BY ACTIVATED MACROPHAGES JOURNAL OF IMMUNOLOGY Fiorentino, D. F., Zlotnik, A., Mosmann, T. R., Howard, M., OGARRA, A. 1991; 147 (11): 3815-3822

  Abstract

  IL-10 inhibits the ability of macrophage but not B cell APC to stimulate cytokine synthesis by Th1 T cell clones. In this study we have examined the direct effects of IL-10 on both macrophage cell lines and normal peritoneal macrophages. LPS (or LPS and IFN-gamma)-induced production of IL-1, IL-6, and TNF-alpha proteins was significantly inhibited by IL-10 in two macrophage cell lines. Furthermore, IL-10 appears to be a more potent inhibitor of monokine synthesis than IL-4 when added at similar concentrations. LPS or LPS- and IFN-gamma-induced expression of IL-1 alpha, IL-6, or TNF-alpha mRNA was also inhibited by IL-10 as shown by semiquantitative polymerase chain reaction or Northern blot analysis. Inhibition of LPS-induced IL-6 secretion by IL-10 was less marked in FACS-purified peritoneal macrophages than in the macrophage cell lines. However, IL-6 production by peritoneal macrophages was enhanced by addition of anti-IL-10 antibodies, implying the presence in these cultures of endogenous IL-10, which results in an intrinsic reduction of monokine synthesis after LPS activation. Consistent with this proposal, LPS-stimulated peritoneal macrophages were shown to directly produce IL-10 detectable by ELISA. Furthermore, IFN-gamma was found to enhance IL-6 production by LPS-stimulated peritoneal macrophages, and this could be explained by its suppression of IL-10 production by this same population of cells. In addition to its effects on monokine synthesis, IL-10 also induces a significant change in morphology in IFN-gamma-stimulated peritoneal macrophages. The potent action of IL-10 on the macrophage, particularly at the level of monokine production, supports an important role for this cytokine not only in the regulation of T cell responses but also in acute inflammatory responses.

  View details for Web of Science ID A1991GQ83700021

  View details for PubMedID 1940369

• PRODUCTION OF IL-10 BY CD4+ LYMPHOCYTES-T CORRELATES WITH DOWN-REGULATION OF TH1 CYTOKINE SYNTHESIS IN HELMINTH INFECTION JOURNAL OF IMMUNOLOGY Sher, A., Fiorentino, D., Caspar, P., Pearce, E., Mosmann, T. 1991; 147 (8): 2713-2716

  Abstract

  After the onset of parasite egg deposition, mice infected with the helminth Schistosoma mansoni mount strong Th2 cytokine responses in the absence of significant Th1 cytokine synthesis. To examine the basis of this immunoregulatory state, spleen or lymph node cells from schistosome-infected mice were stimulated with parasite-specific Ag and the supernatants tested for their capacity to suppress IFN-gamma synthesis by a Th1 cell line. Strong inhibition was observed that was neutralized by a mAb against IL-10, a cytokine previously shown to down-regulate Th1 cytokine synthesis. By means of ELISA measurements the production of IL-10 in schistosome infection was confirmed and shown to depend on CD4+ T cells. IL-10 synthesis stimulated by either mitogen or Ag was observed only at those stages of infection when Th2 response induction and Th1 cytokine down-regulation also occurred and was not detected in mice vaccinated with attenuated parasites. Moreover, the addition of the neutralizing anti-IL-10 mAb to Ag-stimulated spleen cell cultures from infected mice caused a dramatic augmentation in IFN-gamma synthesis. These findings suggest that IL-10 is responsible for the down-regulation of Th1 responses observed in schistosome infections, a phenomenon that may enable the parasite to escape potentially harmful cell-mediated responses.

  View details for Web of Science ID A1991GK97200042

  View details for PubMedID 1680917

• DIVERSITY OF CYTOKINE SYNTHESIS AND FUNCTION OF MOUSE CD4+ T-CELLS IMMUNOLOGICAL REVIEWS Mosmann, T. R., SCHUMACHER, J. H., STREET, N. F., Budd, R., OGARRA, A., Fong, T. A., Bond, M. W., MOORE, K. W., Sher, A., Fiorentino, D. F. 1991; 123: 209-229

  View details for Web of Science ID A1991GP27300010

  View details for PubMedID 1684780

• IL-10 ACTS ON THE ANTIGEN-PRESENTING CELL TO INHIBIT CYTOKINE PRODUCTION BY TH1 CELLS JOURNAL OF IMMUNOLOGY Fiorentino, D. F., Zlotnik, A., Vieira, P., Mosmann, T. R., Howard, M., Moore, K. W., OGARRA, A. 1991; 146 (10): 3444-3451

  Abstract

  Murine IL-10 (cytokine synthesis inhibitory factor) inhibits cytokine production by Th1 cell clones when they are activated under conditions requiring the presence of APC. By preincubating APC with IL-10, we demonstrate that IL-10 acts principally on APC to inhibit IFN-gamma production by Th1 clones. Moreover, IL-10 is not active when Th1 cells are stimulated with glutaraldehyde-fixed APC, which also indicates that its action involves regulation of APC function. Furthermore, IL-10 inhibits cytokine synthesis by Th1 cells stimulated with the super-antigen Staphylococcus enterotoxin B, which does not appear to require processing. Flow microfluorimetry purified splenic or peritoneal B cells and macrophages, and B cell and macrophage cell lines can present Ag to Th1 clones. However, IL-10 acts only on sorted macrophages and the macrophage cell line to suppress IFN-gamma production by Th1 clones. IL-10 does not show this effect when B cells are used as APC. In contrast, IL-10 does not impair the ability of APC to stimulate cytokine production by Th2 cells. IL-10 does not decrease IFN-gamma-induced I-Ad levels on a macrophage cell line. Inasmuch as IL-10 also inhibits IL-2-induced IFN-gamma production by Th1 cells in an Ag-free system requiring only the presence of accessory cells, these data suggest that IL-10 may inhibit macrophage accessory cell function which is independent of TCR-class II MHC interactions.

  View details for Web of Science ID A1991FL83600024

  View details for PubMedID 1827484

• ISOLATION AND EXPRESSION OF HUMAN CYTOKINE SYNTHESIS INHIBITORY FACTOR CDNA CLONES - HOMOLOGY TO EPSTEIN-BARR-VIRUS OPEN READING FRAME BCRFI PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vieira, P., DEWAALMALEFYT, R., Dang, M. N., Johnson, K. E., Kastelein, R., Fiorentino, D. F., deVries, J. E., Roncarolo, M. G., Mosmann, T. R., Moore, K. W. 1991; 88 (4): 1172-1176

  Abstract

  We have demonstrated the existence of human cytokine synthesis inhibitory factor (CSIF) [interleukin 10 (IL-10)]. cDNA clones encoding human IL-10 (hIL-10) were isolated from a tetanus toxin-specific human T-cell clone. Like mouse IL-10, hIL-10 exhibits strong DNA and amino acid sequence homology to an open reading frame in the Epstein-Barr virus, BCRFI. hIL-10 and the BCRFI product inhibit cytokine synthesis by activated human peripheral blood mononuclear cells and by a mouse Th1 clone. Both hIL-10 and mouse IL-10 sustain the viability of a mouse mast cell line in culture, but BCRFI lacks comparable activity in this assay, suggesting that BCRFI may have conserved only a subset of hIL-10 activities.

  View details for Web of Science ID A1991EY61700019

  View details for PubMedID 1847510

• EXPRESSION OF INTERLEUKIN-10 ACTIVITY BY EPSTEIN-BARR-VIRUS PROTEIN BCRF1 SCIENCE Hsu, D. H., Malefyt, R. D., Fiorentino, D. F., Dang, M. N., Vieira, P., Devries, J., Spits, H., Mosmann, T. R., Moore, K. W. 1990; 250 (4982): 830-832

  Abstract

  Cytokine synthesis inhibitory factor (CSIF; interleukin-10), a product of mouse TH2 T cell clones that inhibits synthesis of cytokines by mouse TH1 T cell clones, exhibits extensive sequence similarity to an uncharacterized open reading frame in the Epstein-Barr virus BCRF1. Recombinant BCRF1 protein mimics the activity of interleukin-10, suggesting that BCRF1 may have a role in the interaction of the virus with the host's immune system.

  View details for Web of Science ID A1990EG88300043

  View details for PubMedID 2173142

• ISOLATION OF MONOCLONAL-ANTIBODIES SPECIFIC FOR IL-4, IL-5, IL-6, AND A NEW TH2-SPECIFIC CYTOKINE (IL-10), CYTOKINE SYNTHESIS INHIBITORY FACTOR, BY USING A SOLID-PHASE RADIOIMMUNOADSORBENT ASSAY JOURNAL OF IMMUNOLOGY Mosmann, T. R., SCHUMACHER, J. H., Fiorentino, D. F., LEVERAH, J., Moore, K. W., Bond, M. W. 1990; 145 (9): 2938-2945

  Abstract

  Hybridomas were produced from a rat that was immunized with partially purified proteins from supernatants of induced Th2 cells. These preparations were enriched for cytokine synthesis inhibitory factor (CSIF, IL-10). The mAb in the supernatants were screened by a solid phase radioimmunoadsorbent assay using 35S-methionine-labeled secreted proteins from a lectin-stimulated Th2 clone. A total of 18 anticytokine mAb were isolated, comprising 6 anti-CSIF, 1 anti-IL-4, 1 anti-IL-5, and 10 anti-IL-6 mAb. The anti-CSIF mAb were separable into three groups. mAb in groups A and B neutralized and depleted bioactivity, and bound to overlapping but nonidentical subpopulations of CSIF molecules. The 2 mAb in group C did not neutralize CSIF activity, and bound to CSIF molecules not recognized by mAb from groups A or B. A two-site sandwich ELISA for CSIF could be established with the group A antibody, SXC1, combined with any of the three group B antibodies. The sensitivity of this assay was equivalent to that of the CSIF bioassay. These antibodies have been used to show that CSIF is responsible for most or all of the ability of Th2 supernatants to inhibit cytokine synthesis by Th1 cells. In addition, the ELISA has been used to confirm that CSIF is produced by Th2 but not Th1 clones.

  View details for Web of Science ID A1990EF11800023

  View details for PubMedID 2145365

• HOMOLOGY OF CYTOKINE SYNTHESIS INHIBITORY FACTOR (IL-10) TO THE EPSTEIN-BARR-VIRUS GENE BCRFI SCIENCE Moore, K. W., Vieira, P., Fiorentino, D. F., TROUNSTINE, M. L., Khan, T. A., Mosmann, T. R. 1990; 248 (4960): 1230-1234

  Abstract

  Complementary DNA clones encoding mouse cytokine synthesis inhibitory factor (CSIF; interleukin-10), which inhibits cytokine synthesis by TH1 helper T cells, were isolated and expressed. The predicted protein sequence shows extensive homology with an uncharacterized open reading frame, BCRFI, in the Epstein-Barr virus genome, suggesting the possibility that this herpes virus exploits the biological activity of a captured cytokine gene to enhance its survival in the host.

  View details for Web of Science ID A1990DH14400037

  View details for PubMedID 2161559

• HETEROGENEITY OF MOUSE HELPER T-CELLS - EVIDENCE FROM BULK CULTURES AND LIMITING DILUTION CLONING FOR PRECURSORS OF TH1 AND TH2 CELLS JOURNAL OF IMMUNOLOGY Street, N. E., SCHUMACHER, J. H., Fong, T. A., Bass, H., Fiorentino, D. F., LEVERAH, J. A., Mosmann, T. R. 1990; 144 (5): 1629-1639

  Abstract

  Many long term mouse Th clones express either the type 1 or type 2 Th cell (Th1 or Th2) cytokine secretion phenotype. In this report we present two lines of evidence for the existence of additional Th differentiation states. Lectin-stimulated spleen cells secreted moderate levels of IL-2 compared with long term Th1 clones, whereas the levels of other cytokines were more than 100-fold lower than those produced by either Th1 or Th2 clones. This suggests that many spleen cells produce substantial amounts of IL-2 but little or no IL-4, IL-5, IFN-gamma, IL-3, and granulocyte/macrophage-CSF. In contrast to long term Th clones, many short term alloreactive clones displayed cytokine secretion phenotypes intermediate between the Th1 and Th2 patterns. The proportion of recognizable Th1 and Th2 clones at early times in culture was greatly increased by immunization of the mice from which the responder and stimulator cells were derived; Brucella abortus immunization resulted in the isolation of exclusively Th1 clones, whereas infection with Nippostrongylus brasiliensis resulted in a strong trend toward the isolation of Th2 clones. The immunization of mice from which responder cells were derived strongly affected the type of Th clone obtained, whereas the source of stimulator cells had much less effect, suggesting that the commitment of Th cells to the Th1 or Th2 phenotypes occurred mainly in vivo. A model for the possible relationships of the various Th cells is presented.

  View details for Web of Science ID A1990CR42900012

  View details for PubMedID 1968485

• 2 TYPES OF MOUSE T-HELPER CELL .4. TH2 CLONES SECRETE A FACTOR THAT INHIBITS CYTOKINE PRODUCTION BY TH1 CLONES JOURNAL OF EXPERIMENTAL MEDICINE Fiorentino, D. F., Bond, M. W., Mosmann, T. R. 1989; 170 (6): 2081-2095

  Abstract

  A cytokine synthesis inhibitory factor (CSIF) is secreted by Th2 clones in response to Con A or antigen stimulation, but is absent in supernatants from Con A-induced Th1 clones. CSIF can inhibit the production of IL-2, IL-3, lymphotoxin (LT)/TNF, IFN-gamma, and granulocyte-macrophage CSF (GM-CSF) by Th1 cells responding to antigen and APC, but Th2 cytokine synthesis is not significantly affected. Transforming growth factor beta (TGF-beta) also inhibits IFN-gamma production, although less effectively than CSIF, whereas IL-2 and IL-4 partially antagonize the activity of CSIF. CSIF inhibition of cytokine synthesis is not complete, since early cytokine synthesis (before 8 h) is not significantly affected, whereas later synthesis is strongly inhibited. In the presence of CSIF, IFN-gamma mRNA levels are reduced slightly at 8, and strongly at 12 h after stimulation. Inhibition of cytokine expression by CSIF is not due to a general reduction in Th1 cell viability, since actin mRNA levels were not reduced, and proliferation of antigen-stimulated cells in response to IL-2, was unaffected. Biochemical characterization, mAbs, and recombinant or purified cytokines showed that CSIF is distinct from IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IFN-gamma, GM-CSF, TGF-beta, TNF, LT, and P40. The potential role of CSIF in crossregulation of Th1 and Th2 responses is discussed.

  View details for Web of Science ID A1989CD27200022

  View details for PubMedID 2531194

• HETEROGENEITY OF MOUSE HELPER T-CELLS AND CROSS-REGULATION OF TH1 AND TH2 CLONES Mosmann, T. R., Street, N. E., Fiorentino, D. F., Bond, M. W., Fong, T. A., Schumacher, J., LEVERAH, J. A., Trounstine, M., Vieira, P., Moore, K. W. SPRINGER-VERLAG BERLIN. 1989: 611-618

  View details for Web of Science ID A1989BP83Z00082