Systemic Sclerosis in Individuals With Exposure to World Trade Center Ground Zero Rescue and Recovery Efforts: A Case Series.

OBJECTIVE: The World Trade Center (WTC) attack in New York resulted in a dust plume containing silica, hydrocarbons, and asbestos. Autoimmune disorders have been reported among those with WTC site exposure. The characteristics of individuals developing systemic sclerosis (SSc) have not been previously described. The purpose of this study was to describe the features of patients with SSc with WTC exposure. METHODS: Data were collected from 11 patients with SSc or SSc spectrum conditions who reported exposure to the WTC site. Seven patients completed an exposure assessment. RESULTS: Of the 11 patients, the majority (n = 8) were female. The median (range) for age at diagnosis was 46 (36-75) years, time between exposure and first non-Raynaud phenomenon SSc symptom was 8 (1-19) years, and time between exposure and diagnosis was 11 (2-18) years. Fifty-five percent had SSc onset > 5 years from WTC exposure. Five patients had limited cutaneous SSc, 3 patients had diffuse cutaneous SSc, 1 patient with SSc features met criteria for mixed connective tissue disease (CTD), and 2 patients had undifferentiated CTD with features of SSc. Four patients had overlapping features with other CTDs. Interstitial lung disease (ILD) was present in 10 patients. Five of 11 patients had a history of tobacco use. Seven of 7 patients who completed the questionnaire reported other hazardous exposures outside of WTC. Of these, only 2 patients reported personal protective equipment use. CONCLUSION: A high frequency of ILD and overlap features were observed among patients with SSc with WTC exposure. Future studies are needed to characterize this association.

CONQUER Scleroderma: association of gastrointestinal tract symptoms in early disease with resource utilization.

OBJECTIVES: SSc is associated with increased health-care resource utilization and economic burden. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative that collects longitudinal follow-up data on SSc patients with <5 years of disease duration enrolled at scleroderma centres in the USA. The objective of this study was to investigate the relationship between gastrointestinal tract symptoms and self-reported resource utilization in CONQUER participants. METHODS: CONQUER participants who had completed a baseline and 12-month Gastrointestinal Tract Questionnaire (GIT 2.0) and a Resource Utilization Questionnaire (RUQ) were included in this analysis. Patients were categorized by total GIT 2.0 severity: none-to-mild (0-0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00). Clinical features and medication exposures were examined in each of these categories. The 12-month RUQ responses were summarized by GIT 2.0 score categories at 12 months. RESULTS: Among the 211 CONQUER participants who met the inclusion criteria, most (64%) had mild GIT symptoms, 26% had moderate symptoms, and 10% severe GIT symptoms at 12 months. The categorization of GIT total severity score by RUQ showed that more upper endoscopy procedures and inpatient hospitalization occurred in the CONQUER participants with severe GIT symptoms. These patients with severe GIT symptoms also reported the use of more adaptive equipment. CONCLUSION: This report from the CONQUER cohort suggests that severe GIT symptoms result in more resource utilization. It is especially important to understand resource utilization in early disease cohorts when disease activity, rather than damage, primarily contributes to health-related costs of SSc.

The Collaborative National Quality and Efficacy Registry for Scleroderma: association of medication use on gastrointestinal tract symptoms in early disease and the importance of tobacco cessation.

OBJECTIVES: Systemic Sclerosis (SSc) is frequently associated with gastrointestinal tract (GIT) involvement. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative study collecting longitudinal follow up data on SSc patients with less than 5-years disease duration enrolled at Scleroderma centres of excellence. This manuscript presents the GIT natural history and outcomes in relation to other scleroderma manifestations and medication exposures. METHODS: CONQUER participants that had completed a minimum of two serial Scleroderma Clinical Trials Consortium GIT Questionnaires (GIT 2.0) were included in this analysis. Patients were categorised by total GIT 2.0 severity at baseline, and by category change: none-to-mild (0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00) at the subsequent visit. Based on this data, four groups were identified: none-to-mild with no change, moderate-to-severe with no change, improvement, or worsening. Clinical features and medications, categorised as gastrointestinal tract targeted therapy, anti-fibrotic, immunosuppression, or immunomodulatory drugs, were recorded. Analysis included a proportional odds modelaccounting for linear and mixed effects of described variables. RESULTS: 415 enrolled CONQUER participants met project inclusion criteria. Most participants had stable mild GIT symptoms at baseline and were on immunomodulatory and anti-reflux therapy. In most patients, anti-reflux medication and immunosuppression initiation preceded the baseline visit, whereas anti-fibrotic initiation occurred at or after the baseline visit. In the proportional odds model, worsening GIT score at the follow-up visit was associated with current tobacco use (odds ratio: 3.48 (1.22, 9.98, p 0.020). CONCLUSIONS: This report from the CONQUER cohort, suggests that most patients with early SSc have stable and mild GIT disease. Closer follow-up was associated with milder, stable GIT symptoms. There was no clear association between immunosuppression or anti-fibrotic use and severity of GIT symptoms. However, active tobacco use was associated with worse GIT symptoms, highlighting the importance of smoking cessation counselling in this population.

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

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

Hospital readmission in systemic sclerosis associated pulmonary hypertension: Results from the PHAROS registry.

OBJECTIVE: To identify individual-level factors associated with hospital readmission among individuals with SSc-associated pulmonary hypertension (SSc-PH). METHODS: Individuals enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) registry contributed clinical data related to SSc-PH disease severity and hospital admissions. Readmission was defined as a subsequent hospitalization within 12 months of any hospital discharge. Characteristics were compared between individuals with and without readmissions using Fisher's exact test, Wilcoxon rank-sum test, or Kruskal-Wallis test. Logistic regression was used to estimate associations between clinical predictors and likelihood of readmission. RESULTS: Of 572 individuals with SSc-PH enrolled in PHAROS, 54% had ≥1 hospitalizations between 2005 and 2016. Among individuals ever-hospitalized, 34% had ≥1 readmission. Individuals with vs without readmissions had shorter median (IQR) time between index hospitalization date and next PHAROS visit [37 (3, 80) vs 81 (42, 136) days, P <0.001]. Index admissions related to PH or SSc (vs non-PH/SSc related) were associated with an increased odds of 12-month readmission [aOR 6.6 (95% CI 3.2, 13.6) and aOR 2.2 (95% CI 1.1, 4.5), respectively]. Readmission was less likely among home oxygen users (vs non-users) (aOR 0.44; 95% CI 0.22, 0.89). Race, age, sex, disease duration and disease subtype were not associated with readmission. CONCLUSION: The strongest predictor for 12-month readmission was an index hospitalization reason related to PH. Home oxygen use was associated with lower odds of readmission. Future studies should determine whether testing for the need for home oxygen mediates the risk of readmission in SSc-PH.

A genomic meta-analysis of clinical variables and their association with intrinsic molecular subsets in systemic sclerosis.

OBJECTIVES: Four intrinsic molecular subsets (inflammatory, fibroproliferative, limited, normal-like) have previously been identified in SSc and are characterized by unique gene expression signatures and pathways. The intrinsic subsets have been linked to improvement with specific therapies. Here, we investigated associations between baseline demographics and intrinsic molecular subsets in a meta-analysis of published datasets. METHODS: Publicly available gene expression data from skin biopsies of 311 SSc patients measured by DNA microarray were classified into the intrinsic molecular subsets. RNA-sequencing data from 84 participants from the ASSET trial were used as a validation cohort. Baseline clinical demographics and intrinsic molecular subsets were tested for statistically significant associations. RESULTS: Males were more likely to be classified in the fibroproliferative subset (P = 0.0046). SSc patients who identified as African American/Black were 2.5 times more likely to be classified as fibroproliferative compared with White/Caucasian patients (P = 0.0378). ASSET participants sera positive for anti-RNA pol I and RNA pol III autoantibodies were enriched in the inflammatory subset (P = 5.8 × 10-5, P = 9.3 × 10-5, respectively), while anti-Scl-70 was enriched in the fibroproliferative subset. Mean modified Rodnan Skin Score (mRSS) was statistically higher in the inflammatory and fibroproliferative subsets compared with normal-like (P = 0.0027). The average disease duration for inflammatory subset was less than fibroproliferative and normal-like intrinsic subsets (P = 8.8 × 10-4). CONCLUSIONS: We identified multiple statistically significant differences in baseline demographics between the intrinsic subsets that may represent underlying features of disease pathogenesis (e.g. chronological stages of fibrosis) and have implications for treatments that are more likely to work in certain SSc populations.

Machine learning integration of scleroderma histology and gene expression identifies fibroblast polarisation as a hallmark of clinical severity and improvement.

OBJECTIVE: We sought to determine histologic and gene expression features of clinical improvement in early diffuse cutaneous systemic sclerosis (dcSSc; scleroderma). METHODS: Fifty-eight forearm biopsies were evaluated from 26 individuals with dcSSc in two clinical trials. Histologic/immunophenotypic assessments of global severity, alpha-smooth muscle actin (aSMA), CD34, collagen, inflammatory infiltrate, follicles and thickness were compared with gene expression and clinical data. Support vector machine learning was performed using scleroderma gene expression subset (normal-like, fibroproliferative, inflammatory) as classifiers and histology scores as inputs. Comparison of w-vector mean absolute weights was used to identify histologic features most predictive of gene expression subset. We then tested for differential gene expression according to histologic severity and compared those with clinical improvement (according to the Combined Response Index in Systemic Sclerosis). RESULTS: aSMA was highest and CD34 lowest in samples with highest local Modified Rodnan Skin Score. CD34 and aSMA changed significantly from baseline to 52 weeks in clinical improvers. CD34 and aSMA were the strongest predictors of gene expression subset, with highest CD34 staining in the normal-like subset (p<0.001) and highest aSMA staining in the inflammatory subset (p=0.016). Analysis of gene expression according to CD34 and aSMA binarised scores identified a 47-gene fibroblast polarisation signature that decreases over time only in improvers (vs non-improvers). Pathway analysis of these genes identified gene expression signatures of inflammatory fibroblasts. CONCLUSION: CD34 and aSMA stains describe distinct fibroblast polarisation states, are associated with gene expression subsets and clinical assessments, and may be useful biomarkers of clinical severity and improvement in dcSSc.

Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile.

OBJECTIVES: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease. METHODS: Skin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated. RESULTS: SSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression. CONCLUSIONS: Skin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

Skin Histology in Systemic Sclerosis: a Relevant Clinical Biomarker.

PURPOSE OF REVIEW: Systemic sclerosis (SSc) is a life-threatening autoimmune disease that causes debilitating skin fibrosis. The skin in SSc is easily accessible, and skin biopsies may provide rich biological data regarding underlying disease pathophysiology. Here, we review literature relevant to the potential for skin histology to serve as a diagnostic, pharmacokinetic/response, and predictive biomarker in SSc. RECENT FINDINGS: Multiple histologic parameters correlate with SSc severity, including alpha smooth muscle actin (aSMA), CD34, collagen density, thickness, and inflammatory cell infiltration. Recent clinical trials incorporate skin histology as exploratory outcome measurements; however, a standard approach is not yet established. The possibility that skin histology may be useful as a predictive biomarker was suggested by a recent study that identified genes related to skin aSMA and CD34 staining intensity that were increased at baseline among improvers versus nonimprovers. Current literature supports skin histology as a mechanism to measure treatment response, but future work is needed to define minimally meaningful changes in key SSc skin histologic features.

Randomised, double-blind, placebo-controlled trial of IL1-trap, rilonacept, in systemic sclerosis. A phase I/II biomarker trial.

OBJECTIVES: This clinical trial was designed to study the safety and efficacy of blocking IL-1 in skin fibrosis of patients with diffuse cutaneous systemic sclerosis (dcSSc), and to test the hypothesis that inhibition of IL-1 by rilonacept will downregulate expression of the 2G SSc gene biomarker as a surrogate for the modified Rodnan skin score (MRSS). METHODS: 19 dcSSc patients were randomised 2:1 active treatment:placebo in this double blinded trial. Study patients received weekly treatments with either subcutaneous rilanocept 320 mg loading dose at day 0 and then 160 mg for each of the 5 subsequent weekly doses, or placebo. Skin biopsies were taken to test 2G SSc biomarker gene expression at day 0 before treatment and one week after the final study drug dose, comparing gene expression changes between rilonacept- and placebo-treated patients, as well as the change in gene expression at week 6 compared to baseline in rilonacept-treated patients. Safety assessments extended to 6 weeks after the final dose of study drug or placebo. Other secondary outcome measures included global and IL-1-regulated gene expression, serum biomarkers and the MRSS. RESULTS: Rilonacept compared to placebo-treated patients did not show any treatment-related effect on the 2G SSc biomarker. Rilonacept treatment also failed to alter IL-6 expression in skin, serum IL-6, C-reactive protein, or CCL18, a marker of IL-6 activity in SSc. CONCLUSIONS: In this small trial we did not observe any effect of blocking IL-1 on clinical skin disease or biomarkers of IL-1 activity.

Comparison of change in end tidal carbon dioxide after three minutes of step exercise between systemic sclerosis patients with and without pulmonary hypertension.

OBJECTIVES: Pulmonary hypertension (PH) is an important cause of morbidity and mortality in patients with SSc. The submaximal heart and pulmonary evaluation (step test) is a non-invasive, submaximal stress test that could be used to identify SSc patients with PH. Our aims were to determine whether change in end tidal carbon dioxide ([Formula: see text]) from rest to end-exercise, and the minute ventilation to carbon dioxide production ratio ([Formula: see text]), both as measured by the step test, differ between SSc patients with and without PH. We also examined differences in validated self-report questionnaires and potential PH biomarkers between SSc patients with and without PH. METHODS: We performed a cross-sectional study of 27 patients with limited or dcSSc who underwent a right heart catheterization within 24 months prior to study entry. The study visit consisted of questionnaire completion; history; physical examination; step test performance; and phlebotomy. [Formula: see text], [Formula: see text], self-report data and biomarkers were compared between patients with and without PH. RESULTS: SSc patients with PH had a statistically significantly lower median (interquartile range) [Formula: see text] than SSc patients without PH [-2.1 (-5.1 to 0.7) vs 1.2 (-0.7 to 5.4) mmHg, P = 0.035], and a statistically significantly higher median (interquartile range) [Formula: see text] [53.4 (39-64.1) vs 36.4 (31.9-41.1), P = 0.035]. There were no statistically significant differences in self-report data or biomarkers between groups. CONCLUSION: [Formula: see text] and [Formula: see text] as measured by the step test are statistically significantly different between SSc patients with and without PH. [Formula: see text] and [Formula: see text] may be useful screening tools for PH in the SSc population.

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

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.

Clinical characteristics and survival of systemic sclerosis patients with pulmonary hypertension and elevated wedge pressure: Observations from the PHAROS cohort.

BACKGROUND AND OBJECTIVE: Systemic sclerosis (SSc) is a complex autoimmune disease commonly associated with pulmonary hypertension (PH). When associated with elevated pulmonary artery wedge pressure (PAWP), pulmonary artery pressure (PAP) is either in-proportion (post-capillary PH) or higher than expected (combined PH) relative to the increased PAWP. METHODS: Patients from the PHAROS registry (a prospective observational cohort of SSc-PH patients) who had mean PAP ≥ 25 and PAWP > 15 on right heart catheterization were stratified based on diastolic pressure gradient (DPG). Kaplan-Meier analysis was performed to compare survival and PH-related hospitalization. Baseline factors were compared between patients dying and those who survived using Cox regression analysis. RESULTS: A total of 59 patients were included, of whom 21 (36%) patients were classified as combined PH and 38 (64%) had post-capillary PH. No baseline characteristics were significantly different between the two groups. There were no differences in survival or PH-related hospitalization between the groups. The only baseline factor independently associated with death was lower 6-min walk distance (6MWD) (hazard ratio (HR): 1.33 per 25 m decrease, 95% CI: 1.11-1.59, P = 0.002). PH-specific medications were started during follow-up in significantly more patients in the combined PH group compared with the post-capillary group (86% vs 50%, P = 0.01). CONCLUSION: Outcomes were similar between SSc patients with post-capillary PH and combined pre- and post-capillary PH. 6MWD at baseline can predict risk for death in SSc patients with PH and an elevated PAWP. More patients with combined PH were started on PH-specific medications, and the clinical benefit of treating this subgroup specifically in SSc patients needs further exploration.

African American race associated with body image dissatisfaction among patients with systemic sclerosis.

OBJECTIVES: Studies have shown a high degree of body image dissatisfaction among patients with systemic sclerosis (SSc). We aimed to identify demographic and phenotypic characteristics that correlate with body image dissatisfaction. METHODS: Ninety-eight patients with SSc were recruited from Georgetown University Medical Center 2003-2004. Anonymous surveys collected demographic information (age, race, gender, duration/type of SSc) and assessed degree of body image dissatisfaction on a scale of 0-3 in relation to phenotypic features of SSc (hand contractures, finger ulcers, pigmentation changes, lip wrinkling/thinning, telangiectasias). A composite total distress score was derived. Parametric and nonparametric T tests were used to compare groups. RESULTS: Of 98 patients, 86 were female and 12 male. The majority of patients were 30-60 years old. The sample was 62% Caucasian, 27% African American, and the rest identified as "other". Twenty-seven percent had limited SSc, 48% diffuse, and 25% "other". African American patients had greater total body image dissatisfaction (p=0.002), specifically with respect to digital ulcers, pruritus, and pigmentation changes, than Caucasian participants. Patients with diffuse SSc had greater body image dissatisfaction than those with limited disease (p=0.002). CONCLUSIONS: Our results suggest that African American patients with SSc and those with diffuse subtype suffer a higher degree of body image dissatisfaction. Screening for and addressing this issue in SSc patients is prudent. Further study is needed to understand racial differences in body image dissatisfaction among patients with SSc.

Clinical Trial Design Issues in Systemic Sclerosis: an Update.

Systemic sclerosis (scleroderma, SSc) is a multisystem disease characterized by vasculopathy, autoimmunity, and fibrosis. SSc has the highest disease-related mortality rate among the rheumatologic illnesses. In the USA, there remains no FDA-approved therapy. As our understanding of SSc pathogenesis improves, targeted therapies interrupting key pathways and mediators will be studied in clinical trials. However, clinical trials in SSc are fraught with challenges. Validated clinical outcome measures do not exist for all disease manifestations. It can be difficult to discern disease activity from damage. SSc is highly heterogeneous, with multiple different phenotypes, and predicting who will have progressive disease is not currently well understood. Biomarkers are in early stages of development and do not represent surrogate outcomes at this time. Given that SSc is uncommon, studies of similar disease aspects or populations can lead to competition for patients. This review will focus on current issues in SSc clinical trial design.

COVID-19 vaccinations and infections among individuals with systemic sclerosis: A Scleroderma Patient-centered Intervention Network (SPIN) Cohort study.

BACKGROUND/PURPOSE: We previously surveyed adults with systemic sclerosis (SSc) regarding COVID-19 vaccination in April-May 2021. The objective of the present study was to update through June-July 2022 and assess self-reported (1) COVID-19 vaccination rates, including boosters; (2) vaccine-related adverse events; (3) peri­vaccination immunosuppressive medication management; (4) vaccine hesitancy; and (5) prevalence and severity of COVID-19 infections. METHODS: In April-May 2021 and June-July 2022, SPIN Cohort participants completed surveys on COVID-19 vaccination and infection. Primary vaccine series was defined according to the standard for each COVID-19 vaccine; additional vaccine administrations were considered booster doses. Fully vaccinated was defined as having completed a primary vaccine series and at least one booster dose. RESULTS: 544 participants completed the 2021 survey only, 101 the 2022 survey only, and 388 both surveys. Among 489 participants with 2022 data, 437 (89 %) had received both primary and booster vaccines. Among all 1,033 participants, 960 (93 %) received at least one dose. At least one adverse reaction was reported by 34 % (330 of 960 participants) following first, 48 % (314 of 657 participants) following second, and 34 % (147 of 437 participants) following booster vaccine doses (primarily sore arm and fatigue); no severe adverse reactions were reported. SSc symptom worsening was reported in 6 % (53 of 960) after the first, 6 % after the second (39 of 657), and 4 % (17 of 437) after the booster dose. Of participants taking methotrexate or mycophenolate (including Cellcept or Myfortic), 34 of 266 (13 %) reported that they temporarily stopped or decreased their medication at the first dose, 32 of 215 (15 %) at the second dose, and 28 of 148 (19 %) for booster vaccination. Of 52 individuals not fully vaccinated with primary and booster doses in 2022, 29 (56 %) reported worry about vaccine related SSc flares. 172 of 489 (35 %) 2022 participants reported a history of at least one COVID-19 infection; 114 (66 %) occurred after receiving at least a primary vaccine series. Among initial COVID-19 infections, 9 (5 %) were asymptomatic, 66 (38 %) involved mild symptoms, 82 (48 %) moderate symptoms, and 15 (9 %) required hospitalization. CONCLUSION: Most people with SSc in the study were fully vaccinated, and most continued their methotrexate or mycophenolate post-primary and booster vaccinations. Over half of vaccine-hesitant participants were concerned regarding risk of SSc flare; however, few vaccinated participants reported this. These data may be useful for counselling people with SSc regarding COVID-19 vaccine safety and outcomes.

Low prevalence of coeliac disease in patients with systemic sclerosis: a cross-sectional study of a registry cohort.

OBJECTIVES: Two prior studies suggested that coeliac disease (CD) has a higher prevalence rate (8%) in SSc than in the general population (1%), but these studies were limited by small numbers and the use of traditional coeliac screening antibody tests, where newer ones with improved accuracy have since emerged. Our aim was to determine the prevalence of CD in a larger SSc population using a more modern serological approach to coeliac testing and to correlate coeliac antibody status with gastrointestinal symptoms. METHODS: Stored sera from 72 SSc patients in the Scleroderma Registry at the Hospital for Special Surgery were tested for anti-tissue transglutaminase (traditional) and anti-deamidated gliadin peptide (novel) antibodies. If any of these antibodies were positive, anti-endomysial antibodies were tested and confirmatory small-bowel endoscopy and biopsy were obtained. Registry clinical data were used to determine whether antibody status correlated with gastrointestinal symptoms. RESULTS: The prevalence of coeliac antibodies in our SSc population was 3/72 (4%). No significant differences with respect to gastrointestinal symptoms were seen in the coeliac antibody-positive compared with -negative SSc patients. No cases of confirmed CD were seen in our cohort. CONCLUSION: Contrary to the only two previously published studies, the low prevalence of CD that we found does not suggest that concurrent CD is a common cause of gastrointestinal complaints in SSc patients.

Treatment of early diffuse systemic sclerosis skin disease.

Diffuse systemic sclerosis carries a high morbidity and mortality. The Prospective Registry of Early Systemic Sclerosis (PRESS), a multicentre incident cohort study of patients with early diffuse cutaneous systemic sclerosis, has the goal of advancing the understanding of disease pathogenesis and identifying novel biomarkers. In this review, PRESS investigators discuss the evidence pertaining to the more commonly used treatments for early diffuse SSc skin disease including methotrexate, mycophenolate, cyclophosphamide, azathioprine, and intravenous immunoglobulin. This review highlights the unmet need for effective treatment in early diffuse SSc as well as its more rigorous study. Nonetheless, the PRESS investigators aim to decrease intra- and inter-institutional variability in prescribing in order to improve the understanding of the clinical course of early diffuse SSc skin disease.

Magnetic Resonance Angiography of the Hand Vasculature in Patients With Systemic Sclerosis and Systemic Lupus Erythematosus.

BACKGROUND: When patients with systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) develop digital ischemia, conventional angiography (CA) is traditionally used to assess hand vasculature. Recently, Chang et al described an angiographic classification system for patients with SSc. Conventional angiography uses intravascular contrast agents that are nephrotoxic and vasoconstrictive. Owing to these limitations, this study assesses the use of contrast-enhanced magnetic resonance angiography (MRA) as an alternative to CA to evaluate hand vasculature in patients with digital ischemia. METHODS: This retrospective case series reports on 38 contrast-enhanced MRAs of hand vasculature from 30 symptomatic patients with SSc (N = 21) or SLE (N = 9). The radial and ulnar arteries (RA, UA) and the superficial and deep palmar arches were evaluated at standard reference points both quantitatively and qualitatively for their diameter, patency, and Chang classification. RESULTS: In SSc MRAs (n = 26), the UA was significantly smaller than the RA and was occluded in 46%. In SLE MRAs (n = 12), the UA and RA had no difference in diameter and the UA was occluded in 25%. In SSc, the most common Chang classification was type 2 (UA involvement) in 44%. In SLE, the most common Chang classification was type 4 (UA and RA involvement) in 45%, with 18% classified as type 2. CONCLUSIONS: Contrast-enhanced MRA used to assess hand vasculature in SSc patients with digital ischemia shows similar patterns of vascular involvement as previously demonstrated by CA. While vascular involvement in SSc predominantly involves the UA, the RA is also frequently involved in SLE.