Publications by authors named "Thomas A Medsger"

77 Publications

Defining the optimal disease duration of early diffuse systemic sclerosis for clinical trial design.

Rheumatology (Oxford) 2021 Jan 28. Epub 2021 Jan 28.

Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Objectives: Clinical trials in early diffuse cutaneous systemic sclerosis (SSc) using the modified Rodnan skin score (mRSS) as the primary outcome measure have most often been negative. We wanted to assess how the definition of disease onset (first SSc manifestation vs first non-Raynaud manifestation), and varying lengths of disease duration at trial entry as an inclusion criteria functioned. Our objective was to optimize trial inclusion criteria.

Methods: We used the prospective, observational University of Pittsburgh Scleroderma Cohort to identify early diffuse SSc patients first evaluated between 1980 and 2015. All had <3 years from first SSc (n = 481) or first non-Raynaud manifestation (n = 514) and 3 or more mRSS scores. We used descriptive, survival and group-based trajectory analyses to compare the different definitions of disease onset and disease duration as inclusion criteria for clinical trials.

Results: There was no appreciable difference between using first SSc manifestation compared with first non-Raynaud manifestation as the definition of disease onset. Compared with other disease durations, <18 months of disease had >70% of patients fitting into trajectories with worsening cutaneous disease over six months of follow-up. Longer disease durations demonstrated the majority of patients with trajectories showing an improvement in mRSS (regression to the mean) over six months.

Conclusions: Regardless of whether the first SSc or first non-Raynaud manifestation is used to define disease onset, duration of < 18 months at enrolment is preferable. Longer disease duration criteria more frequently results in regression to the mean of the mRSS score, and likely contributes to negative trial outcomes.
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http://dx.doi.org/10.1093/rheumatology/keab075DOI Listing
January 2021

and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry.

Proc Natl Acad Sci U S A 2020 01 23;117(1):552-562. Epub 2019 Dec 23.

Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant * and * alleles were associated with overall SSc risk, and the * allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the * and * alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of in defining autoantibody subtypes. The association of the * allele with the ATA subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and * allele frequency in multiple populations was observed ( = 0.98, = 3 × 10). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.
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http://dx.doi.org/10.1073/pnas.1906593116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955366PMC
January 2020

Integrative analysis of DNA methylation in discordant twins unveils distinct architectures of systemic sclerosis subsets.

Clin Epigenetics 2019 04 4;11(1):58. Epub 2019 Apr 4.

Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.

Background: Systemic sclerosis (SSc) is a rare autoimmune fibrosing disease with an incompletely understood genetic and non-genetic etiology. Defining its etiology is important to allow the development of effective predictive, preventative, and therapeutic strategies. We conducted this epigenomic study to investigate the contributions of DNA methylation to the etiology of SSc while minimizing confounding due to genetic heterogeneity.

Methods: Genomic methylation in whole blood from 27 twin pairs discordant for SSc was assayed over 450 K CpG sites. In silico integration with reported differentially methylated cytosines, differentially expressed genes, and regulatory annotation was conducted to validate and interpret the results.

Results: A total of 153 unique cytosines in limited cutaneous SSc (lcSSc) and 266 distinct sites in diffuse cutaneous SSc (dcSSc) showed suggestive differential methylation levels in affected twins. Integration with available data revealed 76 CpGs that were also differentially methylated in blood cells from lupus patients, suggesting their role as potential epigenetic blood biomarkers of autoimmunity. It also revealed 27 genes with concomitant differential expression in blood from SSc patients, including IFI44L and RSAD2. Regulatory annotation revealed that dcSSc-associated CpGs (but not lcSSc) are enriched at Encyclopedia of DNA Elements-, Roadmap-, and BLUEPRINT-derived regulatory regions, supporting their potential role in disease presentation. Notably, the predominant enrichment of regulatory regions in monocytes and macrophages is consistent with the role of these cells in fibrosis, suggesting that the observed cellular dysregulation might be, at least partly, due to altered epigenetic mechanisms of these cells in dcSSc.

Conclusions: These data implicate epigenetic changes in the pathogenesis of SSc and suggest functional mechanisms in SSc etiology.
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http://dx.doi.org/10.1186/s13148-019-0652-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449959PMC
April 2019

Estradiol levels are elevated in older men with diffuse cutaneous SSc and are associated with decreased survival.

Arthritis Res Ther 2019 04 2;21(1):85. Epub 2019 Apr 2.

Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA.

Background: Systemic sclerosis (SSc) is a female-predominant disease, characterized by excessive extracellular matrix deposition (ECM) with dermal and internal organ fibrosis. Considering the sex-based disparity in disease incidence, estradiol (E2), an estrogen form with pro-fibrotic effects, may play a role in SSc. We reported that post-menopausal women with diffuse cutaneous (dc)SSc have higher serum E2 levels compared to similar aged, healthy controls. Since males with SSc tend to have more severe disease, we examined serum E2 in dcSSc males in relation to disease characteristics and survival.

Methods: We measured serum E2 in 83 dcSSc men > 50 years old from the University of Pittsburgh Scleroderma Center and similar aged healthy controls. Using statistical modeling, we examined the associations between serum E2, internal organ involvement, autoantibody profiles, and survival.

Results: Male dcSSc patients had significantly higher serum E2 levels compared to healthy males and similar aged dcSSc post-menopausal women. Male dcSSc patients with high serum E2 had significantly more heart involvement, a trend for higher skin thickness progression rate, and worse survival. Using Cox regression modeling, increased serum E2 levels in anti-Scl-70 antibody-positive dcSSc males were associated with an increased risk of death.

Conclusions: dcSSc males > 50 years old have higher levels of serum E2 compared to healthy controls and dcSSc post-menopausal women. Elevated serum E2 levels in dcSSc males are associated with heart involvement, trend to progression of dermal fibrosis, and, if anti-Scl-70 antibody positive, worse survival. Our study expands on previous work implicating E2 in dermal fibrosis in SSc and associates E2 levels with internal organ involvement and survival. These data suggest a role for estrogen imbalance in dcSSc.
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http://dx.doi.org/10.1186/s13075-019-1870-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444502PMC
April 2019

Anti-RNPC-3 (U11/U12) Antibodies in Systemic Sclerosis in Patients With Moderate-to-Severe Gastrointestinal Dysmotility.

Arthritis Care Res (Hoboken) 2019 09 6;71(9):1164-1170. Epub 2019 Aug 6.

Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: To examine the association of anti-RNPC-3 antibodies in patients with systemic sclerosis (scleroderma or SSc) with selected gastrointestinal (GI) tract complications.

Methods: Sera from patients with SSc with or without severe GI dysfunction (total parenteral nutrition dependence) from the Johns Hopkins Scleroderma Center were screened for anti-RNPC-3 antibodies. We then examined anti-RNPC-3-positive cases and negative SSc controls from the University of Pittsburgh and the University of Pittsburgh Medical Center (UPMC) scleroderma cohort to confirm our findings and to examine whether specific GI features were associated with anti-RNPC-3 antibodies.

Results: In the discovery cohort, patients with SSc with severe GI dysfunction (n = 37) and without GI dysfunction (n = 38) were screened for anti-RNPC-3 antibodies. The former were more likely to have anti-RNPC-3 antibodies (14% versus 3%; P = 0.11). In the Pittsburgh cohort, moderate-to-severe GI dysfunction (Medsger GI score ≥2) was present in 36% of anti-RNPC-3-positive patients versus 15% of anti-RNPC-3-negative patients (P ≤ 0.01). Anti-RNPC-3-positive patients were more likely to be male (31% versus 15%; P = 0.04), African American (18% versus 6%; P = 0.02), have esophageal dysmotility (93% versus 62%; P < 0.01), and interstitial lung disease (ILD) (77% versus 35%; P < 0.01). After adjusting for relevant covariates and potential confounders, moderate-to-severe GI disease was associated with anti-RNPC-3 antibodies (odds ratio [OR] 3.8 [95% confidence interval (95% CI) 1.0-14.3]), and ILD trended toward significance (OR 2.8 [95% CI 1.0-8.2]).

Conclusion: Patients with SSc and anti-RNPC-3 antibodies are more likely to be male and African American and to have moderate-to-severe GI disease and ILD. Further studies on larger patient cohorts may be helpful in further defining subsets of patients with SSc at risk for severe GI involvement.
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http://dx.doi.org/10.1002/acr.23763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430701PMC
September 2019

Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans.

Arthritis Rheumatol 2018 10 29;70(10):1654-1660. Epub 2018 Aug 29.

Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients.

Methods: SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls.

Results: Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10 ).

Conclusion: In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility.
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http://dx.doi.org/10.1002/art.40541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160338PMC
October 2018

Clinical and serological features of systemic sclerosis in a multicenter African American cohort: Analysis of the genome research in African American scleroderma patients clinical database.

Medicine (Baltimore) 2017 Dec;96(51):e8980

Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD Division of Rheumatology, University of Texas-McGovern Medical School, Houston, TX Division of Rheumatology, University of Pittsburgh, PA Division of Rheumatology, Georgetown University School of Medicine, Washington, DC Division of Rheumatology, Northwestern University, Feinberg School of Medicine, Chicago, IL Division of Rheumatology, Medical University of South Carolina, Charleston, SC Division of Rheumatology, University of Michigan, Ann Arbor, MI Division of Rheumatology, Robert Wood Johnson University, New Brunswick, NJ Division of Rheumatology, Hospital for Special Surgery, New York, NY Department of Rheumatology, Arthritis and Osteoporosis Consultants of the Carolinas, Charlotte, NC Division of Rheumatology, Tulane University School of Medicine, New Orleans, LA Division of Rheumatology, University of California San Francisco, CA Division of Rheumatology, University of Pennsylvania, Philadelphia, PA Division of Rheumatology, Boston University School of Medicine, Boston, MA Division of Rheumatology, George Washington University, Washington, DC Division of Rheumatology, Stanford University School of Medicine, Stanford, CA Division of Rheumatology, University of Chicago Pritzker School of Medicine, Chicago, IL Division of Rheumatology, New York University Langone Medical Center, New York, NY National Human Genome Research Institute National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.

Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ± 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ≤50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry.
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http://dx.doi.org/10.1097/MD.0000000000008980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758130PMC
December 2017

14-3-3z sequesters cytosolic T-bet, upregulating IL-13 levels in T2 and CD8 lymphocytes from patients with scleroderma.

J Allergy Clin Immunol 2018 07 15;142(1):109-119.e6. Epub 2017 Nov 15.

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pa; Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Electronic address:

Background: IL-13-producing CD8 T cells have been implicated in the pathogenesis of type 2-driven inflammatory human conditions. We have shown that CD8IL-13 cells play a critical role in cutaneous fibrosis, the most characteristic feature of systemic sclerosis (SSc; scleroderma). However, the molecular mechanisms underlying production of IL-13 and other type 2 cytokines by CD8 T cells remain unclear.

Objective: We sought to establish the molecular basis of IL-13 overproduction by CD8 T cells from patients with SSc, focusing on T-bet modulation of GATA-3 activity, which we showed to underlie IL-13 overproduction in CD8IL-13 cells from patients with SSc.

Methods: Biochemical and biophysical methods were used to determine the expression and association of T-bet, GATA-3, and regulatory factors in CD8 T cells isolated from the blood and lesional skin of patients with SSc with severe skin thickening. Chromatin immunoprecipitation analysis determined GATA-3 binding to the IL-13 promoter. ImageStream analysis and confocal microscopy visualized the subcellular localization of T-bet and GATA-3. Transcript levels were decreased by small interfering RNAs.

Results: Interaction of T-bet with the adaptor protein 14-3-3z in the cytosol of CD8 T cells from patients with SSc reduces T-bet translocation into the nucleus and its ability to associate with GATA-3, allowing more GATA-3 to bind to the IL-13 promoter and inducing IL-13 upregulation. Strikingly, we show that this mechanism is also found during type 2 polarization of CD8 T cells (T2) from healthy donors.

Conclusions: We identified a novel molecular mechanism underlying type 2 cytokine production by CD8 T cells, revealing a more complete picture of the complex pathway leading to SSc disease pathogenesis.
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http://dx.doi.org/10.1016/j.jaci.2017.10.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953767PMC
July 2018

Skin-Resident Effector Memory CD8CD28 T Cells Exhibit a Profibrotic Phenotype in Patients with Systemic Sclerosis.

J Invest Dermatol 2017 05 22;137(5):1042-1050. Epub 2016 Dec 22.

Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Electronic address:

Loss of CD28 expression by CD8 T cells occurs with age and during chronic inflammatory conditions. CD8CD28 T cells are a heterogeneous cell subpopulation whose function ranges from immunosuppressive to effector. Here we analyzed the role of CD8CD28 T cells in the pathogenesis of systemic sclerosis (SSc), a connective tissue disorder characterized by autoimmunity, vasculopathy, and extensive cutaneous and visceral fibrosis. We show that the frequency of CD8CD28 T cells is increased in the blood and affected skin of SSc patients, independent of patient age, and correlates with the extent of skin fibrosis. We found that most skin-tropic CD8CD28 T cells are resident in the skin lesions of patients in the early stage of the disease, exhibit an effector memory phenotype, and present a strong cytolytic activity ex vivo. Skin-resident and circulating SSc CD8CD28 T cells produce high levels of the profibrotic cytokine IL-13, which induces collagen production by normal and SSc dermal fibroblasts. Thus, our findings indicate that CD8CD28 T cells represent a pathogenic T-cell subset in SSc and likely play a critical role in the early stage of SSc skin disease.
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http://dx.doi.org/10.1016/j.jid.2016.11.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433864PMC
May 2017

Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry.

Clin Exp Rheumatol 2017 Sep-Oct;35 Suppl 106(4):106-113. Epub 2016 Nov 10.

Stanford University, Stanford, CA, and Vera Moulton Wall Center for Pulmonary Vascular Disease, USA.

Objectives: To assess the utility of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) in detecting and monitoring pulmonary hypertension (PH) in systemic sclerosis (SSc).

Methods: PHAROS is a multicenter prospective cohort of SSc patients at high risk for developing pulmonary arterial hypertension (SSc-AR-PAH) or with a definitive diagnosis of SSc-PH. We evaluated 1) the sensitivity and specificity of BNP≥64 and NT-proBNP≥210 pg/mL for the detection of SSc-PAH and/ or SSc-PH in the SSc-AR-PAH population; 2) baseline and longitudinal BNP and NT-proBNP levels as predictors of progression to SSc-PAH and/or SSc-PH; 3) baseline BNP≥180, NT-proBNP≥553 pg/mL, and longitudinal changes in BNP and NT-proBNP as predictors of mortality in SSc-PH diagnosed patients.

Results: 172 SSc-PH and 157 SSc-AR- PAH patients had natriuretic peptide levels available. Median BNP and NT-proBNP were significantly higher in the SSc-PH versus SSc-AR-PAH group. The sensitivity and specificity for SSc-PAH detection using baseline BNP≥64 pg/mL was 71% and 59%; and for NT-proBNP≥210 pg/mL, 73% and 78%. NT-proBNP showed stronger correlations with haemodynamic indicators of right ventricular dysfunction than BNP. Baseline creatinine, RVSP > 40 mmHg, and FVC%:DLco% ratio ≥1.8 were associated with progression from SSc-AR-PAH to SSc-PH but no association with individual or combined baseline BNP and NT-proBNP levels was observed. Baseline and follow-up BNP or NT-proBNP levels were not predictive of death, however, a composite BNP/NT-proBNP group predicted mortality (HR 3.81 (2.08-6.99), p<.0001).

Conclusions: NT-proBNP may be more useful than BNP in the detection and monitoring of PAH in SSc patients, but additional studies are necessary.
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December 2017

Brief Report: HLA-DRB1, DQA1, and DQB1 in Juvenile-Onset Systemic Sclerosis.

Arthritis Rheumatol 2016 11 6;68(11):2772-2777. Epub 2016 Oct 6.

Fred Hutchinson Cancer Research Center and University of Washington, Seattle.

Objective: Systemic sclerosis (SSc) is a rare disease that is particularly uncommon in children. Specific HLA alleles have been associated with SSc in adults. This study was undertaken to investigate HLA class II alleles in juvenile-onset SSc.

Methods: DRB1, DQA1, and DQB1 alleles were determined by DNA-based HLA typing. Analyses were conducted comparing Caucasian patients with juvenile-onset SSc (n = 76) to healthy Caucasian controls (n = 581).

Results: Initial analyses focused on HLA class II associations previously reported in adult Caucasian patients with SSc. The frequency of DRB1*11 was not significantly increased in juvenile-onset SSc (22.4% of patients with juvenile-onset SSc versus 17.6% of controls; odds ratio [OR] 1.35, P = 0.34), nor were the specific DRB1*11:01 or *11:04 alleles. DQA1*05, a risk factor previously identified in adult men with SSc, was increased in patients with juvenile-onset SSc versus controls (57.9% versus 44.1%; OR 1.76, P = 0.027), as was DRB1*03 (34.2% versus 22.5%; OR 1.79, P = 0.031). Secondary analyses of all DRB1 allele groups revealed an association with DRB1*10 (10.5% of patients with juvenile-onset SSc versus 1.5% of controls; OR 7.48, P = 0.0002). As this is a new observation, correction was made for multiple comparisons of 13 different DRB1 allele groups; results nevertheless remained significant (P = 0.003). Also, a lower frequency of DRB1*01 was observed in patients with juvenile-onset SSc who were younger at disease onset (OR 0.06, P = 0.01) and in those with antibodies to topoisomerase (OR 0.14, P = 0.024).

Conclusion: Associations of HLA alleles with juvenile-onset SSc differed from associations with SSc in women, but were similar to associations with SSc in men. Additionally, a novel association with DRB1*10 was observed in children. The greatest proportion of genetic risk of SSc is contributed by the HLA complex, and the current study reveals the importance of the association of HLA class II genes in juvenile-onset SSc.
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http://dx.doi.org/10.1002/art.39765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594690PMC
November 2016

Reply.

Arthritis Rheumatol 2017 01;69(1):242

University of Pittsburgh School of Medicine, Pittsburgh, PA.

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http://dx.doi.org/10.1002/art.39853DOI Listing
January 2017

Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A Scleroderma Clinical Trials Consortium study.

Semin Arthritis Rheum 2016 12 2;46(3):344-349. Epub 2016 Jun 2.

Department of Immunology and Rheumatology, Stanford University School of Medicine, 1000 Welch Road, Suite 203 MC 5755, Palo Alto, CA 94304. Electronic address:

Objectives: We sought to identify the clinical factors associated with calcinosis in an international multicenter collaborative effort with the Scleroderma Clinical Trials Consortium (SCTC).

Methods: This is a retrospective cohort study of 5218 patients with systemic sclerosis (SSc). Logistic regression was used to obtain odds ratios (OR) relating calcinosis to various clinical features in multivariate analyses.

Results: A total of 1290 patients (24.7%) had calcinosis. In univariate analyses, patients with calcinosis were older than patients without calcinosis, more likely to be female, and had longer disease duration from the first non-Raynaud phenomenon symptom. Patients with calcinosis were more likely to have digital ulcers, telangiectasias, acro-osteolysis, cardiac disease, pulmonary hypertension, gastrointestinal involvement, arthritis, and osteoporosis, but less likely to have muscle disease. Anti-Scl-70, RNA-polymerase-III, and U1-RNP autoantibodies were significantly less common in patients with calcinosis, while anticentromere (ACA), anti-PM/Scl, and anticardiolipin antibodies were more frequent. In multivariate analysis, the strongest associations with calcinosis were digital ulcers (OR = 3.9; 95% CI: 2.7-5.5; p < 0.0001) and osteoporosis (OR = 4.2; 95% CI: 2.3-7.9; p < 0.0001).

Conclusion: One quarter of patients with SSc have calcinosis at some time during their illness. Our data confirm a strong association of calcinosis with digital ulcers, and support a novel association with osteoporosis.
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http://dx.doi.org/10.1016/j.semarthrit.2016.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500288PMC
December 2016

Gender differences in systemic sclerosis: relationship to clinical features, serologic status and outcomes.

J Scleroderma Relat Disord 2016 May-Aug;1(2):177-240. Epub 2016 Jul 23.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania - USA.

Introduction: There is a strong female preponderance reported in many connective tissue diseases and in almost all systemic sclerosis (SSc) case series.

Methods: We compared gender differences in SSc patients in a large single-center cohort, including demographic features, disease subtype, environmental exposures, disease-specific serum autoantibodies, organ system involvement (frequency and severity) and survival. Adjustment for cutaneous subset (diffuse cutaneous [dc] and limited cutaneous [lc]) was performed.

Results: We identified key characteristics which distinguished female from male SSc patients. Females were more frequently younger at disease onset with a longer disease duration at the time of their first visit. Females more often had lcSSc and, if an overlap syndrome was present, it was most often systemic lupus erythematosus. In contrast, males more frequently had dcSSc and overlap with myositis. Females more frequently had peripheral vascular involvement but in males it was more often severe. Males were more often cigarette smokers and more frequently had environmental exposures. Males more frequently had interstitial lung disease (ILD or pulmonary fibrosis) which was more severe. Females had a significantly increased frequency of anti-centromere antibody and males anti-topoisomerase I and anti-U3RNP antibody. Males had significantly reduced survival (73% at 5 years and 45% at 10 years after onset of SSc). The most frequent causes of death were ILD in males and pulmonary hypertension in females.

Conclusions: Gender differences may be important clues to understanding the natural history and pathogenesis of SSc.
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http://dx.doi.org/10.5301/jsrd.5000209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726425PMC
July 2016

Derivation and External Validation of a Prediction Rule for Five-Year Mortality in Patients With Early Diffuse Cutaneous Systemic Sclerosis.

Arthritis Rheumatol 2016 Apr;68(4):993-1003

University of Pittsburgh, Pittsburgh, Pennsylvania.

Objective: Although diffuse cutaneous systemic sclerosis (dcSSc) is associated with a reduction in life expectancy, there are no validated prognostic models for determining 5-year mortality in patients with dcSSc. The objective of this study was to derive and validate a rule for predicting 5-year mortality in patients with early dcSSc.

Methods: We studied an inception cohort of 388 US Caucasian patients with early dcSSc (<2 years from the appearance of the first symptom). Predefined baseline variables were analyzed in a stepwise logistic regression model in order to identify factors independently associated with 5-year all-cause mortality. We rounded the beta weights to the nearest integer and summed the points assigned to each variable in order to stratify patients into low-risk (<0 points), moderate-risk (1-2 points), and high-risk (≥3 points) groups. We then applied this rule to an external validation cohort of 144 Caucasian patients with early dcSSc from the Royal Free Hospital cohort and compared stratum-specific 5-year mortality.

Results: Six independent predictors (rounded beta weight) comprised the model: age at first visit (points allotted: -1, 0, or 1), male sex (points allotted: 0 or 1), tendon friction rubs (points allotted: 0 or 1), gastrointestinal involvement (points allotted: 0 or 1), RNA polymerase III antibodies (points allotted: 0 or 1), and anemia (points allotted: 0 or 1). The 3-level risk stratification model performed well, with no significant differences between the US derivation cohort and the UK validation cohort.

Conclusion: We derived and externally validated, in US and UK cohorts, an easy-to-use 6-variable prediction rule that assigns low-risk, moderate-risk, and high-risk categories for 5-year mortality in patients with early dcSSc. Only history, physical examination, and basic laboratory assessments are required.
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http://dx.doi.org/10.1002/art.39490DOI Listing
April 2016

Progress in the evolution of systemic sclerosis classification criteria and recommendation for additional comparative specificity studies.

J Rheumatol 2015 Jan;42(1):8-10

Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

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http://dx.doi.org/10.3899/jrheum.141020DOI Listing
January 2015

Multicriteria decision analysis methods with 1000Minds for developing systemic sclerosis classification criteria.

J Clin Epidemiol 2014 Jun 8;67(6):706-14. Epub 2014 Apr 8.

Scleroderma Program, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.

Objectives: Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to develop an instrument for collating case data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement among experts on the probability that cases were classified as SSc.

Study Design And Setting: A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and reranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICCs).

Results: Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7), and puffy fingers (5). The ICC across experts was 0.73 [95% confidence interval (CI): 0.58, 0.86] and improved to 0.80 (95% CI: 0.68, 0.90).

Conclusions: Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (range, 23-14) and weighted. Our methods reflect the rigors of measurement science and serve as a template for developing classification criteria.
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http://dx.doi.org/10.1016/j.jclinepi.2013.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134523PMC
June 2014

Localized scleroderma and regional inflammatory myopathy.

Neuromuscul Disord 2014 May 1;24(5):425-30. Epub 2014 Feb 1.

Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Inflammatory myopathy is rare in localized scleroderma. We report 2 new cases of regional inflammatory myopathy associated with localized scleroderma and review 10 reported cases of localized scleroderma associated with an inflammatory myopathy with regional muscle involvement, more often in the upper extremities. Serum creatine kinase was mildly elevated or normal. Histopathology often showed perimysial inflammation and plasma cell infiltration. These cases demonstrate that inflammatory myopathy should be considered in patients with localized scleroderma and regional muscle weakness, pain or atrophy. Muscle biopsy can confirm the diagnosis of myositis, which if identified, will require anti-inflammatory and/or immunosuppressive therapy.
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http://dx.doi.org/10.1016/j.nmd.2014.01.012DOI Listing
May 2014

Derivation and validation of a prediction rule for two-year mortality in early diffuse cutaneous systemic sclerosis.

Arthritis Rheumatol 2014 Jun;66(6):1616-24

University of Pittsburgh, Pittsburgh, Pennsylvania.

Objective: Systemic sclerosis (SSc) is associated with a reduction in life expectancy, but there are no validated prognostic models for determining short-term mortality. The objective of this study was to derive and validate a prediction rule for 2-year mortality in patients with early diffuse cutaneous SSc (dcSSc).

Methods: We studied a prospectively enrolled cohort of 387 US Caucasian patients with early dcSSc (<2 years from the appearance of the first symptom), randomly divided into a derivation cohort (n = 260) and a validation cohort (n = 127). Predefined baseline predictor variables were analyzed in a stepwise multivariable logistic regression model in order to identify factors independently associated with 2-year all-cause mortality using a cutoff of P < 0.05. We rounded the beta values to the nearest integer and summed the points assigned to each variable in order to stratify patients into low-risk, moderate-risk, and high-risk groups. We then applied this rule to an external validation cohort of 110 Caucasian patients with early dcSSc from a single UK center and compared stratum-specific mortality using chi-square statistics.

Results: Four independent predictor variables (with assigned integer values) comprised the model: age at first visit (points allotted: -1, 0, or 1), skin thickness progression rate (points allotted: 0 or 1), gastrointestinal tract severity (points allotted: 0, 1, or 2), and anemia (points allotted: 0 or 2). The prediction model performed well, with no significant differences between the derivation cohort and the US or UK validation cohorts in the low-risk and moderate-risk groups.

Conclusion: We derived a 4-variable prediction rule that can be used to stratify patients with early dcSSc into groups by risk of 2-year mortality, and we validated that prediction rule in US and UK cohorts.
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http://dx.doi.org/10.1002/art.38381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180237PMC
June 2014

2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative.

Arthritis Rheum 2013 Nov 3;65(11):2737-47. Epub 2013 Oct 3.

St. Maartenskliniek and Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Objective: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc.

Methods: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc.

Results: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc.

Conclusion: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.
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http://dx.doi.org/10.1002/art.38098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930146PMC
November 2013

2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative.

Ann Rheum Dis 2013 Nov;72(11):1747-55

St. Maartenskliniek and Radboud University Nijmegen Medical Centre, , Nijmegen, The Netherlands.

Objective: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc.

Methods: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc.

Results: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc.

Conclusions: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.
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http://dx.doi.org/10.1136/annrheumdis-2013-204424DOI Listing
November 2013

Autoantibodies to RuvBL1 and RuvBL2: a novel systemic sclerosis-related antibody associated with diffuse cutaneous and skeletal muscle involvement.

Arthritis Care Res (Hoboken) 2014 Apr;66(4):575-84

Kanazawa University Graduate School of Medical Sciences and Komatsu Municipal Hospital, Ishikawa, Japan.

Objective: To identify and characterize a novel systemic sclerosis (SSc)-related autoantibody directed against a complex consisting of RuvBL1 and RuvBL2 (RuvBL1/2) and to assess its clinical correlations.

Methods: We first analyzed 316 consecutive patients with SSc who were evaluated at Kanazawa University Hospital. Controls included 290 patients with other connective tissue diseases, interstitial lung disease alone, or autoimmune hepatitis, and 50 healthy subjects. Autoantibody specificities were analyzed using RNA and protein immunoprecipitation assays. Autoimmune targets were affinity purified using patients' sera and subjected to liquid chromatography mass spectrometry. SSc patients in another institution in Japan and the University of Pittsburgh cohort were also included in analysis for evaluating clinical correlations.

Results: By protein immunoprecipitation assay, 6 SSc sera (1.9%) reacted with doublets with molecular weights of ∼50 kd. Liquid chromatography mass spectrometry of the partially purified autoantigen and additional immunoblot-based analyses revealed that this antibody specificity recognized RuvBL1/2. Anti-RuvBL1/2 antibody was exclusively detected in SSc patients. SSc patients with anti-RuvBL1/2 in both the Japanese and Pittsburgh cohorts consistently had higher frequencies of SSc in overlap with myositis and diffuse skin thickening than those without anti-RuvBL1/2. Compared with other autoantibodies related to SSc/myositis overlap (anti-PM-Scl and anti-Ku), anti-RuvBL1/2 was distinctive in terms of its associations with older age at SSc onset, male sex, and a high frequency of diffuse cutaneous involvement.

Conclusion: Anti-RuvBL1/2 antibody is a novel SSc-related autoantibody associated with a unique combination of clinical features, including myositis overlap and diffuse cutaneous involvement.
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http://dx.doi.org/10.1002/acr.22163DOI Listing
April 2014

Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry.

Arthritis Care Res (Hoboken) 2014 Mar;66(3):489-95

Objective: To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US.

Methods: The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma registry is a prospective registry of SSc patients at high risk for PAH or with definite pulmonary hypertension diagnosed by right-sided heart catheterization within 6 months of enrollment. Only patients with World Health Organization group I PAH (mean pulmonary artery pressure >25 mm Hg and pulmonary capillary wedge pressure <15 mm Hg without significant interstitial lung disease) were included in these analyses.

Results: In total, 131 SSc patients with incident PAH were followed for a mean ± SD of 2.0 ± 1.4 years. The 1-, 2-, and 3-year cumulative survival rates were 93%, 88%, and 75%, respectively. On multivariate analysis, age >60 years (hazard ratio [HR] 3.0, 95% confidence interval [95% CI] 1.1- 8.4), male sex (HR 3.9, 95% CI 1.1-13.9), functional class (FC) IV status (HR 6.5, 95% CI 1.8 -22.8), and diffusing capacity for carbon monoxide (DLCO) <39% predicted (HR 4.2, 95% CI 1.3-13.8) were significant predictors of mortality.

Conclusion: This is the largest study describing survival in patients with incident SSc-associated PAH followed up at multiple SSc centers in the US who had undergone routine screening for PAH. The survival rates were better than those reported in other recently described SSc-associated PAH cohorts. Severely reduced DLCO and FC IV status at the time of PAH diagnosis portended a poor prognosis in these patients.
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http://dx.doi.org/10.1002/acr.22121DOI Listing
March 2014

Significance of palpable tendon friction rubs in early diffuse cutaneous systemic sclerosis.

Arthritis Care Res (Hoboken) 2013 Aug;65(8):1385-9

University of North Carolina, Chapel Hill, NC, USA.

Objective: Palpable tendon friction rubs (TFRs) in systemic sclerosis (SSc; scleroderma) have been associated with diffuse skin thickening, increased disability, and poor survival. Our objective was to quantify the prognostic implications of palpable TFRs on the development of disease complications and longer-term mortality in an incident cohort of early diffuse cutaneous SSc (dcSSc) patients.

Methods: We identified early dcSSc patients (disease duration <2 years from the first SSc symptom) first evaluated at the University of Pittsburgh Scleroderma Center between 1980 and 2006 and found to have palpable TFRs. These patients were matched 1:1 with the next consecutive early dcSSc patient without TFRs as a control. All had ≥2 clinic visits and 5 years of followup from the first visit.

Results: A total of 287 early dcSSc patients with TFR were identified and matched to 287 controls. The median disease duration was 0.83 years in TFR patients and 1.04 years in controls. The median followup was 10.1 years in TFR patients and 7.9 years in controls. Over the course of their illness, patients with TFRs had a >2-fold risk of developing renal crisis and cardiac and gastrointestinal disease complications, even after adjustment for other known risk factors. Patients with TFRs had poorer 5- and 10-year survival rates.

Conclusion: Patients with early dcSSc having ≥1 TFRs are at an increased risk of developing renal, cardiac, and gastrointestinal involvement before and after their first Scleroderma Center visit and have reduced survival. Patients presenting with TFRs should be carefully monitored for serious internal organ involvement.
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http://dx.doi.org/10.1002/acr.21964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817608PMC
August 2013

Estradiol promotes the development of a fibrotic phenotype and is increased in the serum of patients with systemic sclerosis.

Arthritis Res Ther 2013 Jan 10;15(1):R10. Epub 2013 Jan 10.

Introduction: Systemic sclerosis (SSc) is more prevalent in women. Our goal is to determine the effects of 17β-estradiol (E2) on the development of fibrosis and to compare circulating levels of estrogens in SSc patients and healthy controls.

Methods: Using primary human dermal fibroblasts, we evaluated the effect of E2 on fibronectin (FN) expression with and without the estrogen receptor (ER) antagonist ICI 182,780, inhibitors of signaling, propyl-pyrazole-triol, an ERα specific ligand, and genistein, an ERβ selective ligand, to identify the signaling pathways mediating E2's effect. We confirmed the fibrotic effect of E2 in human skin using an ex vivo organ culture model. Lastly, we measured levels of E2 and estrone in serum samples from SSc patients with diffuse cutaneous involvement and healthy controls using mass spectrometry.

Results: E2 increased expression of FN in dermal fibroblasts. ICI 182,780, inositol-1,4,5-triphosphate inhibitor, and p38 mitogen-activated protein kinase inhibitor blocked the effects of E2 on FN. Propyl-pyrazole-triol, but not genistein, significantly increased FN expression. Ex vivo, E2 induced fibrosis of human skin. The effects of E2 were abrogated by ICI 182,780. Circulating levels of E2 and estrone were significantly increased in sera of patients with diffuse cutaneous SSc.

Conclusion: Our findings implicate estrogens in the fibrotic process and may explain the preponderance of SSc in women. ICI 182,780 or other ER signaling antagonists may be effective agents for the treatment of fibrosis.
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http://dx.doi.org/10.1186/ar4140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672719PMC
January 2013

Interleukin-13-producing CD8+ T cells mediate dermal fibrosis in patients with systemic sclerosis.

Arthritis Rheum 2013 Jan;65(1):236-46

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.

Objective: Fibrosis is a major contributor to morbidity and mortality in systemic sclerosis (SSc). T cells are the predominant inflammatory infiltrate in affected tissue and are thought to produce cytokines that drive the synthesis of extracellular matrix (ECM) proteins by fibroblasts, resulting in excessive fibrosis. We have previously shown that aberrant interleukin-13 (IL-13) production by peripheral blood effector CD8+ T cells from SSc patients correlates with the extent of skin fibrosis. The present study was undertaken to investigate the role of IL-13 production by CD8+ T cells in dermal fibrosis, an early and specific manifestation of SSc.

Methods: ECM protein production by normal dermal fibroblasts cocultured with SSc CD8+ T cell supernatants was determined by quantitative polymerase chain reaction and Western blotting. Skin-homing receptor expression and IL-13 production by CD8+ T cells in the peripheral blood of SSc patients were measured by flow cytometry. IL-13+ and CD8+ cells in sclerotic skin were identified by immunohistochemistry.

Results: IL-13-producing circulating CD8+ T cells from patients with SSc expressed skin-homing receptors and induced a profibrotic phenotype in normal dermal fibroblasts, which was inhibited by an anti-IL-13 antibody. High numbers of CD8+ T cells and IL-13+ cells were found in the skin lesions of SSc patients, particularly during the early inflammatory phase of the disease.

Conclusion: These findings show that IL-13-producing CD8+ T cells are directly involved in modulating dermal fibrosis in SSc. The demonstration that CD8+ T cells homing to the skin early in the course of SSc are associated with accumulation of IL-13 is an important mechanistic contribution to the understanding of the pathogenesis of dermal fibrosis in SSc and may represent a potential target for therapeutic intervention.
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http://dx.doi.org/10.1002/art.37706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535505PMC
January 2013

A clinical and serologic comparison of African American and Caucasian patients with systemic sclerosis.

Arthritis Rheum 2012 Sep;64(9):2986-94

Georgetown University School of Medicine, Washington, DC 20007, USA.

Objective: Epidemiology studies suggest that systemic sclerosis (SSc) is more common, occurs at a younger age, and is more severe in African Americans than Caucasians. However, the scleroderma autoantibody profile is very different between these 2 ethnic groups. This study was undertaken to examine the demographic and disease features, frequency and severity of internal organ system involvement, and survival in African American patients compared to Caucasian patients with SSc, giving particular attention to their serum autoantibody profiles.

Methods: Demographic features, clinical characteristics, autoantibody profile, organ involvement, and survival were studied in consecutive African American and Caucasian patients with SSc whose visits were recorded between 1972 and 2007 as part of the Pittsburgh Scleroderma Database. The Medsger Severity Score for SSc was used to determine the severity of disease.

Results: African American patients were more likely to have anti-topoisomerase I (anti-topo I), anti-U1 RNP, and anti-U3 RNP autoantibodies. In comparing African American and Caucasian patients with these antibodies, pulmonary fibrosis was found to be more frequent and more severe, and the rate of survival was decreased, in African American patients with anti-topo I antibodies compared to Caucasian patients with anti-topo I. Pulmonary fibrosis was also more severe in the anti-U1 RNP-positive patients, but this was not associated with a difference in survival between African Americans and Caucasians. Anti-U3 RNP was associated with more severe gastrointestinal involvement in African Americans compared to Caucasians.

Conclusion: African Americans with SSc have more severe disease complications compared to Caucasians with SSc, and this is associated with both the type of autoantibody present and the severity of interstitial lung disease. Thus, it is hoped that early aggressive intervention in African Americans with interstitial lung disease will improve outcomes.
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http://dx.doi.org/10.1002/art.34482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557827PMC
September 2012

Anti-PM-Scl antibody in patients with systemic sclerosis.

Clin Exp Rheumatol 2012 Mar-Apr;30(2 Suppl 71):S12-6. Epub 2012 May 29.

Drexel University College of Medicine, PA, USA.

Objectives: To compare systemic sclerosis (SSc) patients with and without anti-PM-Scl antibody.

Methods: We reviewed the medical records of 76 anti-PM-Scl antibody positive SSc patients and 2349 anti-PMScl negative SSc patients first evaluated during 1980-2004. Patients were included if they had a clinical diagnosis of SSc either alone or in overlap with another connective tissue disease. Anti-PM-Scl antibody was screened for by indirect immunofluorescence and tested by Ouchterlony double immunodiffusion.

Results: Anti-PM-Scl antibody positive patients had a significantly higher frequency of a positive ANA with nucleolar staining (87% vs. 32%, p<0.0001) and were younger at both symptom onset (p=0.004) and first physician diagnosis of SSc (p<0.001). They were classified more often as having overlap with another connective tissue disease, particularly polymyositis-dermatomyositis, and more frequently had limited cutaneous involvement (72% vs. 52%, p=0.001). Maximal skin thickening was less in anti-PM-Scl antibody patients (mean modified Rodnan total skin score 6.0±6.3 vs. 15.9±14.2, p<0.001). Anti-PM-Scl antibody positive patients less frequently had peripheral vascular (91% vs. 98%, p=0.0002) and gastrointestinal (52% vs. 79%, p=0.0001) disease. Lung involvement overall had a similar distribution between both groups. However, radiographic evidence of pulmonary fibrosis was more frequent in anti-PM-Scl antibody positive patients (50% vs. 37%, p=0.05) and pulmonary arterial hypertension was less often detected (5% vs. 15%, p<0.04). Skeletal muscle involvement (51% vs. 14%, p<0.0001) and subcutaneous calcinosis (p<0.003) were both significantly more often observed in anti-PM-Scl antibody positive patients. Joint, heart, and kidney involvement were similar in both groups. Overall survival was significantly better for anti-PM-Scl antibody positive patients (10 year cumulative survival rate 91% vs. 65%, p=0.0002). After adjustment for age, sex and limited vs. diffuse cutaneous involvement, patients with anti-PM-Scl antibody were significantly less likely to die (HR=0.32, 95% CI, [0.14, 0.72] p=0.006).

Conclusions: SSc patients with anti-PM-Scl antibody are younger and significantly more often have limited cutaneous involvement, skeletal muscle disease, pulmonary fibrosis and calcinosis compared to anti-PM-Scl antibody negative SSc patients. Ten-year cumulative survival is significantly better in anti-PM-Scl antibody positive SSc patients.
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August 2012

Commentary on myofascial release therapy in systemic lupus erythematosus and scleroderma.

J Bodyw Mov Ther 2012 Jan 2;16(1):2-4; author reply 4-6. Epub 2011 Oct 2.

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http://dx.doi.org/10.1016/j.jbmt.2011.09.001DOI Listing
January 2012

Validation of potential classification criteria for systemic sclerosis.

Arthritis Care Res (Hoboken) 2012 Mar;64(3):358-67

Toronto Western Hospital, Mount Sinai Hospital, and University of Toronto, Toronto, Ontario, Canada.

Objective: Classification criteria for systemic sclerosis (SSc; scleroderma) are being updated jointly by the American College of Rheumatology and European League Against Rheumatism. Potential items for classification were reduced to 23 using Delphi and nominal group techniques. We evaluated the face, discriminant, and construct validity of the items to be further studied as potential criteria.

Methods: Face validity was evaluated using the frequency of items in patients sampled from the Canadian Scleroderma Research Group, 1000 Faces of Lupus, and the Pittsburgh, Toronto, Madrid, and Berlin connective tissue disease (CTD) databases. Patients with SSc (n = 783) were compared to 1,071 patients with diseases similar to SSc (mimickers): systemic lupus erythematosus (n = 499), myositis (n = 171), Sjögren's syndrome (n = 95), Raynaud's phenomenon (RP; n = 228), mixed CTD (n = 29), and idiopathic pulmonary arterial hypertension (PAH; n = 49). Discriminant validity was evaluated using odds ratios (ORs). For construct validity, empirical ranking was compared to expert ranking.

Results: Compared to mimickers, patients with SSc were more likely to have skin thickening (OR 427); telangiectasias (OR 91); anti-RNA polymerase III antibody (OR 75); puffy fingers (OR 35); finger flexion contractures (OR 29); tendon/bursal friction rubs (OR 27); anti-topoisomerase I antibody (OR 25); RP (OR 24); fingertip ulcers/pitting scars (OR 19); anticentromere antibody (OR 14); abnormal nailfold capillaries (OR 10); gastroesophageal reflux disease symptoms (OR 8); antinuclear antibody, calcinosis, dysphagia, and esophageal dilation (all OR 6); interstitial lung disease/pulmonary fibrosis (OR 5); and anti-PM-Scl antibody (OR 2). Reduced carbon monoxide diffusing capacity, PAH, and reduced forced vital capacity had ORs of <2. Renal crisis and digital pulp loss/acroosteolysis did not occur in SSc mimickers (OR not estimated). Empirical and expert ranking were correlated (Spearman's ρ = 0.53, P = 0.01).

Conclusion: The candidate items have good face, discriminant, and construct validity. Further item reduction will be evaluated in prospective SSc and mimicker cases.
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http://dx.doi.org/10.1002/acr.20684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376721PMC
March 2012