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Part 2 of this 2-part CME introduces dermatologists to non-infectious inflammatory skin diseases associated with pulmonary involvement. In many cases, dermatologists may be the first physicians recognizing respiratory complications associated with these diagnoses. Because pulmonary involvement is often the leading cause of morbidity and mortality, dermatologists should be comfortable screening and monitoring for lung disease in high-risk patients, recognizing cutaneous stigmata of lung disease in these patients and referring to pulmonary specialists, when appropriate, for prompt treatment initiation. Some treatments used for skin disease may not be appropriate in the context of lung disease and hence, choosing a holistic approach is important. Interstitial lung disease (ILD) and pulmonary hypertension (PH) are the most common pulmonary complications and a significant cause of mortality in autoimmune connective tissue diseases (CTD), especially systemic sclerosis (SSc), dermatomyositis (DM), and mixed connective tissue disease (MCTD). Pulmonary complications, notably ILD, are also common and life-threatening in sarcoidosis and vasculitis, while they are variable in neutrophilic and auto-immune blistering diseases.

ObjectiveTo assess whether patient and physician global assessment of gastrointestinal tract (GIT) disease in systemic sclerosis (SSc) are associated with a meaningful change in disease status.MethodsOne hundred forty-three participants from the Australian Scleroderma Cohort Study were recruited to this study. Using logistic regression analysis, we evaluated the relationship between patient-reported and physician-assessed GIT disease status and symptoms, measures of health-related quality of life (36-item Short Form Health Survey [SF-36]) and GIT disease severity, measured by the Scleroderma Clinical Trials Consortium UCLA Gastrointestinal Tract 2.0 (GIT 2.0) score.ResultsPatient-reported worsening of GIT symptoms in the month preceding assessment was significantly associated with more severe GIT disease (odds ratio [OR] 6.14,P< 0.01) and progressive worsening GIT disease severity as measured by the GIT 2.0 score (OR 45.98,P< 0.01). The new onset of reflux was the only specific symptom associated with patient-reported GIT disease activity (OR 2.98,P= 0.04). Physician-assessed GIT disease activity was not significantly associated with higher GIT 2.0 scores or increasing severity of disease. Patient-reported and physician-assessed GIT activity was not associated with SF-36 scores.ConclusionIn the absence of objective measures of GIT disease activity in SSc, patient-reported symptoms of GIT disease could be used to indicate disease activity and should merit consideration for inclusion in a multisystem disease activity index.

Objective: To explore the trajectory of scleroderma disease activity in women who experienced a pregnancy after systemic sclerosis diagnosis compared to nulliparous women. Methods: We analyzed data from the Canadian Scleroderma Research Group registry by identifying nulliparous women and women with ⩾1 pregnancy after systemic sclerosis diagnosis. Patient characteristics were compared between groups at registry entry. Controlling for age, smoking, and time since systemic sclerosis diagnosis, generalized estimating equations tested the effect of pregnancy on force vital capacity, diffusing capacity of the lungs for carbon monoxide, right ventricular systolic pressure, glomerular filtration rate, antibody status, active digital ulcers, physician global assessment of activity, and severity over 9 years. Results: At registry entry, numbers of women in the nulliparous and pregnancy after systemic sclerosis diagnosis groups were 153 and 45, respectively. Corresponding numbers at 6 and 9 years were 48 and 21, and 18 and 9, respectively. The prevalence of anti-topoisomerase positivity was 18.3% in nulliparous and 12.5% in pregnancy after systemic sclerosis diagnosis. Baseline differences included mean (Standard deviation) age of diagnosis (nulliparous: 38.8 (14.0), pregnancy after systemic sclerosis diagnosis: 22.6 (6.8) years, p Conclusion: Results demonstrated that having ⩾1 pregnancy after systemic sclerosis diagnosis did not appear to significantly impact long-term renal, respiratory, or global function outcomes. While this offers a hopeful message to systemic sclerosis patients planning a pregnancy, physicians and patients should remain vigilant for potential post-partum complications.

Objective A close temporal relationship between SSc onset and cancer has been reported in anti-RNA polymerase III-positive patients. We investigated the association between cancer and other SSc autoantibodies in a national SSc registry. Methods SSc patients enrolled in the Canadian Scleroderma Research Group registry from 2004 to 2019 were characterized according to autoantibodies to centromere, topoisomerase I/Scl70, RNA polymerase III, fibrillarin, Th/To (hPOP1), PM/Scl, Ku, NOR90, Ro52/TRIM21 and U1RNP. Logistic regression was used to examine the association between a close cancer-SSc interval and autoantibody status, adjusted for age, sex, race and smoking history. Results Of 1698 SSc patients, 1481 (87%) had available autoantibody data. Cancer was diagnosed within 2, 3 and 5 years of the first non-Raynaud manifestation in 1.3%, 2.1% and 3.5% of patients. The most frequent cancers diagnosed within 2 years were breast (33%), gynaecological (19%) and haematological (14%) cancers. The risk of cancer within 2 years was increased among anti-topoisomerase I [odds ratio (OR) 3.43, 95% CI: 1.04, 10.05] and anti-U1-RNP-positive patients (OR 5.54, 95% CI: 1.16, 20.40), but not with anti-RNA polymerase III. None of the anti-fibrillarin, Th/To, PM/Scl, Ku and NOR90-positive patients had cancer within 2 years. Patients with anti-centromere or none of the tested autoantibodies had numerically lower risks of developing cancer within two years. Conclusion Synchronous cancer was rare in this large cohort of predominantly female and White SSc patients. The risk of cancer within 2 years was increased among anti-topoisomerase I and anti-U1-RNP-positive patients. Screening strategies guided by autoantibodies require further careful consideration.

Objective: The aim of this study was to determine the independent value of N-terminal pro b-type natriuretic peptide, high-sensitivity cardiac troponin T, and C-reactive protein to predict onset of cardiopulmonary disease in a large, multi-center systemic sclerosis cohort followed prospectively. Methods: Subjects from the Canadian Scleroderma Research Group registry with data on N-terminal pro b-type natriuretic peptide, high-sensitivity cardiac troponin T, and C-reactive protein were identified. Outcomes of interest were death, systolic dysfunction (left ventricular ejection fraction Results: A total of 675 subjects were included with a mean follow-up of 3.0 ± 1.8 years. Subjects were predominantly women (88.4%) with mean age of 58.2 ± 11.3 years and mean disease duration of 13.7 ± 9.1 years. One hundred and one (101, 15%) subjects died during follow-up, 37 (6.4 %) developed systolic dysfunction, 18 (2.9%) arrhythmias, 34 (5.1%) pulmonary arterial hypertension, 43 (7.3%) pulmonary hypertension, and 48 (12.3%) interstitial lung disease. In multivariate analyses, elevated levels of N-terminal pro b-type natriuretic peptide, high-sensitivity cardiac troponin T, and C-reactive protein were associated with increased risk of death, while elevated levels of N-terminal pro b-type natriuretic peptide and C-reactive protein were associated with increased risk of developing pulmonary hypertension. Conclusion: In systemic sclerosis, N-terminal pro b-type natriuretic peptide, high-sensitivity cardiac troponin T, and C-reactive protein have independent predictive value for death and pulmonary hypertension. A larger study would be required to determine the predictive value of these biomarkers for less common systemic sclerosis outcomes.

Global assessments of disease by both patients and physicians are widely used in clinical studies of systemic sclerosis (SSc). They are commonly secondary endpoints in randomised controlled trials (RCTs) and are considered important items in composite measures of treatment response. A comprehensive literature review was conducted of the formats, wording, and clinimetric properties of the patient global assessments (PtGA) and physician global assessments (PhGA) used in RCTs of SSc. Marked heterogeneity was found in the wording and measurement scales of the global assessments applied in RCTs. These instruments were not developed using rigorous methodology and have not been fully validated. There is a pressing need for standardisation and validation of patient and physician global assessment tools in SSc to enable universal application of these measures to across RCTs in SSc. This article is protected by copyright. All rights reserved.

We aimed to test the hypothesis that exposure to immunosuppression in early systemic sclerosis (SSc) could modify the risk of developing new onset severe gastrointestinal (GIT) involvement.A total of 762 subjects with3 years of disease duration and without severe GIT disease at baseline study visit were identified from combined longitudinal cohort data from the Canadian Scleroderma Research Group (CSRG) and Australian Scleroderma Interest Group (ASIG). The primary exposure was ever use of methotrexate, cyclophosphamide, mycophenolate mofetil and/or azathioprine during the study period. Severe GIT disease was defined as: 1-malabsorption, 2-hyperalimentation, 3-pseudo-obstruction, and/or 4-≥10% weight loss in association with the use of antibiotics for bacterial overgrowth or oesophageal stricture. The change in the hazard of severe GIT disease due to exposure was estimated using a marginal structural Cox proportional hazards model fit by inverse probability of treatment weights (IPTW) to address potential confounding.Study subjects were 81.5% female, had a mean age of 53.7±13.0 years and mean disease duration at baseline of 1.4±0.8 years. During a mean follow-up of 4.0±2.6 years, severe GIT involvement developed in 11.6% of the 319 subjects exposed to immunosuppression and in 6.8% of the 443 unexposed subjects. In an IPTW-adjusted analysis, exposure to immunosuppression was not associated with severe GIT disease (weighted hazard ratio 0.91, 95% confidence interval 0.52-1.58).In this large inception SSc cohort, the risk of severe GIT involvement was not modified by exposure to immunosuppression.

ObjectiveSystemic sclerosis (SSc) is a multisystem disease with heterogeneity in presentation and prognosis.An international collaboration to develop new SSc subset criteria is underway. Our objectives were to identify systems of SSc subset classification and synthesize novel concepts to inform development of new criteria.MethodsMedline, Cochrane MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, EMBASE, and Web of Science were searched from their inceptions to December 2019 for studies related to SSc subclassification, limited to humans and without language or sample size restrictions.ResultsOf 5686 citations, 102 studies reported original data on SSc subsets. Subset classification systems relied on extent of skin involvement and/or SSc-specific autoantibodies (n = 61), nailfold capillary patterns (n = 29), and molecular, genomic, and cellular patterns (n = 12). While some systems of subset classification confer prognostic value for clinical phenotype, severity, and mortality, only subsetting by gene expression signatures in tissue samples has been associated with response to therapy.ConclusionSubsetting on extent of skin involvement remains important. Novel disease attributes including SSc-specific autoantibodies, nailfold capillary patterns, and tissue gene expression signatures have been proposed as innovative means of SSc subsetting.

Background Clinical practice guidelines recommend screening all systemic sclerosis (SSc) patients for pulmonary arterial hypertension (PAH) with yearly echocardiograms. There is a paucity of evidence to support these guidelines. Research question Can a prediction model identify SSc patients with a very low probability of PAH and therefore not requiring annual screening echocardiogram? Study design and methods We performed a case-control study of 925 unselected SSc subjects nested in a multi-centered, longitudinal cohort. The probability of PAH for each subject was calculated using the results of multivariate logistic regression models. A cut-off was identified for the estimated probability of PAH below which no subject developed PAH (100% sensitivity). Results Study subjects were predominantly female (87.5%), with mean (SD) age 58.6 (11.7) years and disease duration of 18.2 (12.2) years. Thirty-seven subjects developed PAH during 5407.97 person-years of observation (incidence rate 0.68 per 100 person-years). Shortness of breath (SOB), diffusing capacity for carbon monoxide (DLCO) and NT-proBNP were independent predictors of PAH. All SSc-PAH cases had a probability of PAH of >1.1%. Subjects below this cut-off, none of whom had PAH, accounted for 46.2% of the study population. Interpretation A simple prediction model identified subjects at very low probability of PAH who could potentially forego annual screening echocardiogram. This represents almost half of SSc subjects in a general SSc population. This study, which is the first evidence-based study for the rational use of follow-up echocardiograms in an unselected SSc cohort, requires validation. The scoring system is freely available online at http://pahtool.ladydavis.ca.

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

ImportanceSystemic sclerosis (SSc) is a severe, chronic, and incurable autoimmune fibrotic skin disease with significant extracutaneous involvement. Low concordance rate in twin studies and unequal geographic distribution of SSc argues for importance of environment in disease initiation and progression.ObjectiveIn this manuscript we provide a summary of all investigated potential external risk factors for SSc.Data sourcesA literature search in PubMed and EMBASE database was performed for studies published until January 1, 2020 by 2 reviewers (EN and LO) independently.FindingsOccupational and/or environmental exposures to silica and organic solvents are associated with increased incidence and severity of SSc. Exposure to epoxy resins, asbestos, and particulate air pollution favors increased risk of SSc, but data are based on limited number of observational studies. There is insufficient evidence to conclude an association between SSc development and other occupational (eg, welding fumes) or personal exposures (eg, smoking, vitamin D deficiency). Association of SSc with silicone breast implants has been disproven. Infectious pathogens (eg, Helicobacter pylori and angiotropic viruses) and dysbiosis seem to play a role in SSc development and severity, but their role remains to be clarified.Conclusions and relevanceIt may be prudent to counsel our patients with SSc (or those at risk of SSc) to avoid occupations with exposure to silica, organic solvents, asbestos and epoxy resins; restraint from smoking, using cocaine or drugs with pro-fibrotic potential. While the association between low vitamin D and SSc remains to be confirmed, we believe that SSc patients should be encouraged to maintain healthy vitamin D levels as benefits outweigh the risks.

Summary Digital ulcers are a serious, recurrent complication in patients with systemic sclerosis. They are often slow to heal and exquisitely painful. Local wound care, such as debridement of the wound bed, is an essential component in the management of digital ulcers in systemic sclerosis. However, digital ulcer debridement is not a standard of care, and there is substantial international variation in the use of this approach. In this Viewpoint, we discuss the assessment of the wound bed and different methods of debridement using the model of tissue management, infection and inflammation, moisture control, and wound edge or epidermal advancement, known as TIME. We highlight the challenges in standard practice and the need for research into local wound care for this type of ulceration, before suggesting a potential roadmap to develop a standardised approach to support ulcer debridement in systemic sclerosis. Debridement might be the missing component in optimising the management of digital ulcers and we propose that the approach should be rigorously investigated as a standard of care in this common complication of systemic sclerosis.

Digital ulcers (DUs) occur in half of the patients with systemic sclerosis (SSc) and require health care interventions for treatment and monitoring for complications. Our objective was to assess the impact of DUs on resource utilization, including hospitalizations, outpatient visits, and procedures within a large SSc Canadian registry in a matched cohort study.A total of 1,698 SSc patients who completed 1 or more 84-item Resource Utilization Questionnaire (RUQ) for a 12-month recall period between September 2005 and February 2020 were included (9,077 questionnaires). Organ involvement was assessed by the Disease Severity Scale (DSS) on the Medsger scale. Unadjusted and adjusted regression analyses compared the association between DUs and resource utilization.RUQs in 104 SSc patients with active DUs at 2 consecutive annual visits were compared with 104 patients without DUs matched 1:1 for age, sex, disease subtype, and duration. Over 1 year, DUs were associated with a higher number of tests (P ˂ 0.05) and visits to health professionals, especially to a rheumatologist (P ˂ 0.0001) and internist (P = 0.003), a greater need for an accompanying person (P ˂ 0.05) and aids purchased/received (P ˂ 0.05). Having DUs was associated with more severe disease, even after excluding the peripheral vascular domain from a total DSS score (9.7 ± 4.5 versus 5.6 ± 2.7, P ˂ 0.0001). After adjustment for disease severity in other organs, the presence of DUs remained a significant predictor of more frequent physician visits and more tests (P for all ˂ 0.05) by linear regression analysis.SSc patients with DUs used significantly more health care resources per year even after adjustment for disease severity in other organ systems.

Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive organ damage, which can be measured using the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI). We aimed to identify whether distinct trajectories of damage accrual exist and to determine which variables are associated with different trajectory groups.Incident cases of SSc (2 years) were identified in the Australian Scleroderma Interest Group and Canadian Scleroderma Research Group prospective registries. Group-based trajectory modeling was used to identify SCTC-DI trajectories over the cohort's first 5 annual visits. Baseline variables associated with trajectory membership in a univariate analysis were examined in multivariable models.A total of 410 patients were included. Three trajectory groups were identified: low (54.6%), medium (36.2%), and high (10.3%) damage. Patients with faster damage accrual had higher baseline SCTC-DI scores. Older age (odds ratio [OR] 1.57 [95% confidence interval (95% CI) 1.18-2.10]), male sex (OR 2.55 [95% CI 1.10-5.88]), diffuse disease (OR 6.7 [95% CI 2.57-17.48]), tendon friction rubs (OR 5.4 [95% CI 1.86-15.66]), and elevated C-reactive protein level (OR 1.98 [95% CI 1.49-2.63]) increased the odds of being in the high-damage group versus the reference (low damage), whereas White ethnicity (OR 0.31 [95% CI 0.12-0.75]) and anticentromere antibodies (OR 0.24 [95% CI 0.07-0.77]) decreased the odds.We identified 3 trajectories of damage accrual in a combined incident SSc cohort. Several characteristics increased the odds of belonging to worse trajectories. These findings may be helpful in recognizing patients in whom early aggressive treatment is necessary.

Cardiac disease is a leading cause of death in systemic sclerosis (SSc) and sudden cardiac death (SCD) is thought to occur more commonly in SSc than in the general population. Diffuse myocardial fibrosis, myocarditis and ischaemic heart disease are all prevalent in SSc and can be reasonably hypothesised to contribute to an increased risk of SCD. Despite this, SCD remains a relatively understudied area of SSc with little understood about SSc-specific risk factors and opportunities for primary prevention. In this review, we present an overview of the possible mechanisms of SCD in SSc and our current understanding of how each of these mechanisms may contribute to cardiac death. This review highlights the need for a future research agenda that addresses the underlying epidemiology of SCD in SSc and identifies opportunities for intervention to modify the disease course of heart disease in SSc. ispartof: DIAGNOSTICS vol:11 issue:10 ispartof: location:Switzerland status: published

Objectives: Scleroderma renal crisis is a rare but serious complication affecting 2%–15% of patients with systemic sclerosis. Despite treatment with angiotensin-converting enzyme inhibitors, outcomes for scleroderma renal crisis patients are still poor. The cellular signaling mechanisms in scleroderma renal crisis are not yet known. Mammalian target of rapamycin, comprised of the subunits mTORC1 and mTORC2, has been shown to be activated in vascular lesions of renal transplant patients with anti-phospholipid antibody syndrome. Given the similarities between the pathophysiology of scleroderma renal crisis and anti-phospholipid antibody syndrome, we hypothesized that the mammalian target of rapamycin pathway would also be activated in the renal vasculature of patients with scleroderma renal crisis. Methods: We retrospectively analyzed renal biopsies of five patients with scleroderma renal crisis in the Canadian Scleroderma Research Group cohort. Immunostaining was performed using anti-P-S6RP antibodies to evaluate the phosphorylation of mTORC1, and anti-Rictor and anti-S473 to determine activation of mTORC2. Results: Four of the five patients showed mTORC1 activation in arteriolar endothelial cells, and three of the five patients showed mTORC1 activation in the arterial endothelial cells. Two of four samples showed Rictor expression in the arteriolar and arterial endothelial cells, showing mTORC2 activation. There was no expression of mTORC1 or mTORC2 in samples from two healthy controls. Conclusion: We demonstrate that both mTORC1 and mTORC2 are activated in renal biopsies with typical histologic features of scleroderma renal crisis. Dual mammalian target of rapamycin inhibitors are currently available and in development. These findings could inform further research into novel treatment targets for scleroderma renal crisis.

Systemic sclerosis is a multi-organ autoimmune disease characterized by vasculopathy and fibrosis, and it is arguably the most devastating of the rheumatological diseases. The gastrointestinal tract is the most commonly involved internal organ in systemic sclerosis. Gastrointestinal tract involvement is reported in up to 90% of SSc patients, is the leading cause of morbidity, and is the third most common cause of mortality in this disease. Among all gastrointestinal tract manifestations, small intestinal bacterial overgrowth is one manifestation that may be ameliorated and even eradicated with appropriate treatment, if recognized early. Small intestinal bacterial overgrowth occurs with a prevalence of approximately 39% in systemic sclerosis and presents with a range of non-specific gastrointestinal tract symptoms, including diarrhea, flatulence, abdominal pain, bloating, and early satiety. These manifestations occur due to an alteration and overgrowth of small intestinal bacteria occurring in the setting of gastrointestinal tract dysmotility and slow transit time. The clinical diagnosis of small intestinal bacterial overgrowth is commonly based on the presence of characteristic clinical symptoms together with a positive hydrogen breath test and response to a therapeutic trial of oral antibiotics used sequentially. Almost two-thirds of systemic sclerosis patients with small intestinal bacterial overgrowth have an improvement in their gastrointestinal tract symptoms with rotating antibiotics. Untreated small intestinal bacterial overgrowth can lead to malnutrition, and thus an important aspect of treatment is the identification and treatment of any associated vitamin and mineral deficiencies. This article focuses on small intestinal bacterial overgrowth, an important and understudied area in systemic sclerosis that remains a diagnostic and therapeutic challenge for both patients and clinicians alike.

Objective To determine whether skin score changes are associated with changes in overall disease severity, function and quality of life in early dcSSc patients. Methods A total of 154 and 128 dcSSc patients from the Canadian Scleroderma Research Group database with 1 and 2 year follow-up and a disease duration ⩽5 years without end-stage organ damage and/or significant comorbidity at the initial visit were included. Skin was assessed using the modified Rodnan skin score (mRSS) and disease severity by the summed Medsger disease severity score (DSS) (without skin domain), physician and patient global assessments, function [HAQ disability index (HAQ-DI)] and quality of life [36-item Short Form Health Survey (SF-36) physical component summary (PCS)]. Analyses were repeated in patients with a disease duration ⩽3 years. Results At 2 years, 64 (50%) patients had improved skin (mRSS decrease of ⩾5 points and/or ⩾25%). Skin improvers had improved summed DSS (P = 0.002); better physician global assessments of disease activity, severity and damage (all P ⩽ 0.003); better HAQ-DI (P = 0.001) and SF-36 PCS (P = 0.005). Changes in the mRSS were positively correlated with changes in summed DSS (P = 0.006) and other disease outcomes. In the 26 (20.3%) patients with worsened skin (mRSS increase of ⩾5 points and/or ⩾25%), the summed DSS and physician global assessments were worse (P = 0.01 and P ⩽ 0.009, respectively). In the subgroup with a disease duration ⩽3 years, similar associations were found. Conclusion At 1 and 2 years, overall disease improvement parallels skin improvement in early dcSSc. This is important for prognosis and reflects the value of mRSS as an outcome measure in trials with these patients.

Background: Clinically evident primary heart involvement due to systemic sclerosis (SHI) is considered a poor prognostic factor and is a leading cause of systemic sclerosis (SSc) related death. Yet, there remains no consensus definition of SHI and poor understanding of the natural history and risk factors for the development of SHI. Methods: We performed a scoping literature review of published articles with a primary focus of SHI to capture previously used definitions of SHI and items used to measure SHI. Any factors reported to be associated with an increased risk of SHI were recorded. Results: Of the 2436 records identified in a search of MEDLINE, EMBASE and PubMed databases, 295 were included in the final scoping review. Analysis of the literature revealed studies of variable quality, generally low patient numbers and highly heterogeneous definitions of SHI within studies. There is no clear consensus from the literature as to the scope of SHI and the prognostic significance of sub-clinical investigation abnormalities commonly detected. Conclusion: The lack of a standardised definition of SHI remains a significant unmet need in SSc. The results of this review will assist in the development of consensus classification criteria to enable more accurate quantification of the burden of SHI, identification of factors associated with increased risk of developing SHI, and evaluation of the efficacy of any novel therapeutic strategies.

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

Background: Immunosuppression remains the main treatment for progressing skin involvement, interstitial lung disease and inflammatory joint or muscle disease in systemic sclerosis. This study investigated the pattern and trends in immunosuppressive agents used in early systemic sclerosis (diagnosed before and after 2007) to determine whether the changes in the preferred type, timing and combination of immunosuppression took place over the past decade. Methods: In total, 397 Canadian Scleroderma Research Group database patients (183 diffuse cutaneous systemic sclerosis and 214 limited cutaneous systemic sclerosis) who had baseline and follow-up visits within 3 years (mean: 1.8 ± 0.8) after disease onset were included: 82% females, age at diagnosis 53 ± 13 years. Bivariate, chi-square, analysis of variance and adjusted regression analyses were used. Results: In total, 115 diffuse cutaneous systemic sclerosis patients (63%) and 62 limited cutaneous systemic sclerosis (29%) received immunosuppressive drugs, most commonly methotrexate, followed by mycophenolate mofetil and cyclophosphamide. In diffuse cutaneous systemic sclerosis, immunosuppressants were prescribed after 2007 more often (74% vs 50%, p = 0.001), especially methotrexate ( p = 0.02) and mycophenolate mofetil ( p = 0.04), and earlier (peak at 2 years after onset). Immunosuppressive therapy was associated with male gender, interstitial lung disease, anti-Scl70 positivity, ACA negativity and inflammatory joint disease in limited cutaneous systemic sclerosis and with ACA negativity and a higher modified Rodnan skin score in diffuse cutaneous systemic sclerosis. Multivariate regression analysis showed that the use of immunosuppressants after 2007 was predicted only by ACA negativity in limited cutaneous systemic sclerosis and by younger age in diffuse cutaneous systemic sclerosis. Conclusion: Over the past decade, there has been a trend to prescribe immunosuppressants more often and earlier in diffuse cutaneous systemic sclerosis patients, regardless of modified Rodnan skin score. Methotrexate is being more frequently used, and mycophenolate mofetil has gained favour over cyclophosphamide. Autoantibody status was the most consistent predictor of immunosuppressive therapy.

Objectives Although interstitial lung disease (ILD) occurs in over half of systemic sclerosis (SSc) patients and represents a leading cause of mortality, there are currently no preventative strategies. We evaluated if gastroprotective agents were associated with a lower incident risk of SSc-ILD. Methods An SSc cohort without clinically apparent ILD at baseline was constructed from the Canadian Scleroderma Research Group registry. The primary exposure was any use of gastroprotective agents. Treatment with promotility agents was assessed as a secondary exposure. Time to development of clinically apparent ILD was compared between exposed and unexposed person-time, using a multivariable marginal structural Cox model incorporating inverse probability of treatment weights to address time-varying confounding. Results In total, 798 subjects met inclusion criteria. At cohort entry, median disease duration was 7.6 (IQR 3.9–15.6) years. During a median 4.4 (IQR 2.6–7.2) years of follow-up, 158 new ILD cases were diagnosed, for a crude incidence of 4.4 (95% CI 3.8–5.1) events per 100 person-years. Most (2085, 73.4%) person-visits were exposed to gastroprotective agents, 579 (20.4%) were exposed to promotility agents, and 554 (19.5%) were exposed to both agents. The marginal structural weighted hazard ratio (HR) for incident ILD related to gastroprotective agents was 0.86 (95% CI 0.52–1.41). When exposure was defined as treatment with promotility agents, the weighted adjusted HR was 0.79 (95% CI: 0.35–1.77). Conclusion In this large retrospective cohort study, we were unable to demonstrate a protective role for gastroprotective and promotility agents in preventing clinically apparent SSc-ILD.

Involvement of the pericardium in systemic sclerosis (SSc) is common, but rarely clinically apparent. Pericardial involvement consists of fibrinous pericarditis, pericardial adhesions, and acute or chronic pericarditis with or without effusion. Most pericardial effusions are small and asymptomatic, and are typically exudative; tamponade is rare. Patients typically present with dyspnea, chest pain, and fever.

Objective SSc is an autoimmune connective tissue disorder characterized by inflammation and fibrosis. Although constitutive activation of fibroblasts is proposed to be responsible for the fibrotic and inflammatory features of the disease, the underlying mechanism remains elusive, and effective therapeutic targets are still lacking. The aim of this study was to evaluate the role of oxidative stress-induced senescence and its contribution to the pro-fibrotic and pro-inflammatory phenotypes of fibroblasts from SSc patients. Methods Dermal fibroblasts were isolated from SSc (n = 13) and healthy (n = 10) donors. Fibroblasts’ intracellular and mitochondrial reactive oxygen species (ROS) were determined by flow cytometry. Mitochondrial function was measured by Seahorse XF24 analyser. Fibrotic and inflammatory gene expressions were assessed by qPCR and key pro-inflammatory components of the fibroblasts’ secretome (IL-6 and IL-8) were quantified by ELISA. Results Compared with healthy fibroblasts, SSc fibroblasts displayed higher levels of both intracellular and mitochondrial ROS. Oxidative stress in SSc fibroblasts induced the expression of fibrotic genes and activated the TGF-β-activated kinase 1 (TAK1)–IκB kinase β (IKKβ)–IFN regulatory factor 5 (IRF5) inflammatory signalling cascade. These cellular responses paralleled the presence of a DNA damage response, a senescence-associated secretory phenotype and a fibrotic response. Treatment of SSc fibroblasts with ROS scavengers reduced their pro-inflammatory secretome production and fibrotic gene expression. Conclusions Oxidative stress-induced cellular senescence in SSc fibroblasts underlies their pro-inflammatory and pro-fibrotic phenotypes. Targeting redox imbalance of SSc fibroblasts enhances their in vitro functions and could be of relevance for SSc therapy.

Introduction No studies have examined factors associated with fear in any group of people vulnerable during COVID-19 due to pre-existing medical conditions. Objective To investigate factors associated with fear of consequences of COVID-19 among people living with a pre-existing medical condition, the autoimmune disease systemic sclerosis (SSc; scleroderma), including country. Methods Pre-COVID-19 data from the Scleroderma Patient-centered Intervention Network (SPIN) Cohort were linked to COVID-19 data collected in April 2020. Multivariable linear regression was used to assess factors associated with continuous scores of the 10-item COVID-19 Fears Questionnaire for Chronic Medical Conditions, controlling for pre-COVID-19 anxiety symptoms. Results Compared to France (N = 156), COVID-19 Fear scores among participants from the United Kingdom (N = 50) were 0.12 SD (95% CI 0.03 to 0.21) higher; scores for Canada (N = 97) and the United States (N = 128) were higher, but not statistically significant. Greater interference of breathing problems was associated with higher fears due to COVID-19 (Standardized regression coefficient = 0.12, 95% CI 0.01 to 0.23). Participants with higher financial resources adequacy scores had lower COVID-19 Fear scores (Standardized coefficient = −0.18, 95% CI −0.28 to −0.09). Conclusions Fears due to COVID-19 were associated with clinical and functional vulnerabilities in this chronically ill population. This suggests that interventions may benefit from addressing specific clinical issues that apply to specific populations. Financial resources, health policies and political influences may also be important. The needs of people living with chronic illness during a pandemic may differ depending on the social and political context in which they live., Highlights • People with chronic diseases may experience high levels of fear due to COVID-19. • We examined factors associated with fears due to COVID-19 in an at-risk population. • We used the validated COVID-19 Fears Questionnaire for Chronic Medical Conditions. • Fears due to COVID-19 among people with SSc differed substantially by country. • Interference of breathing problems and financial adequacy were related to fears.

Systemic sclerosis (SSc) is a severe, chronic, and incurable autoimmune fibrotic skin disease with significant extracutaneous involvement. Low concordance rate in twin studies and unequal geographic distribution of SSc argues for importance of environment in disease initiation and progression.In this manuscript we provide a summary of all investigated potential external risk factors for SSc.A literature search in PubMed and EMBASE database was performed for studies published until January 1, 2020 by 2 reviewers (EN and LO) independently.Occupational and/or environmental exposures to silica and organic solvents are associated with increased incidence and severity of SSc. Exposure to epoxy resins, asbestos, and particulate air pollution favors increased risk of SSc, but data are based on limited number of observational studies. There is insufficient evidence to conclude an association between SSc development and other occupational (eg, welding fumes) or personal exposures (eg, smoking, vitamin D deficiency). Association of SSc with silicone breast implants has been disproven. Infectious pathogens (eg,It may be prudent to counsel our patients with SSc (or those at risk of SSc) to avoid occupations with exposure to silica, organic solvents, asbestos and epoxy resins; restraint from smoking, using cocaine or drugs with pro-fibrotic potential. While the association between low vitamin D and SSc remains to be confirmed, we believe that SSc patients should be encouraged to maintain healthy vitamin D levels as benefits outweigh the risks.

Although trigeminal neuralgia (TN) has been associated with systemic sclerosis (SSc), there is a paucity of evidence and pathophysiological processes remain unknown. We undertook a nested case-control study to identify associations between TN and SSc in a large multi-centered cohort and identify possible pathophysiological links.Data were derived from a longitudinal cohort of 1652 SSc subjects. Cases with a physician-reported diagnosis of TN were identified at baseline visit (prevalent) and during follow-up (incident). Each case was matched on study visit to four SSc patients without TN. Sociodemographic, clinical and serological characteristics of cases and controls were compared.At enrolment, 43/1652 (2.6%) subjects had a history of TN. During follow-up, an additional 36 subjects developed TN over 6193 person-years of observation (incidence rate 5.8 per 1000 person-years). Cases were identified and matched to 172 and 144 controls, respectively. Compared to controls, prevalent cases had more inflammatory myositis (24.4% versus 5.2%, p0.001) and inflammatory arthritis (46.5% versus 30.2%, p = 0.043). Incident cases also had more inflammatory myositis (19.4% versus. 6.3%, p = 0.033) and inflammatory arthritis (50.0% versus. 16.2%, p0.001) compared to controls. There was a trend towards more interstitial lung disease in prevalent (32.6% versus 23.8%, p = 0.241) and incident (55.6% versus 40.6%, p = 0.105) cases compared to controls.This study provides novel evidence for a clinical association linking TN, inflammatory myositis, inflammatory arthritis and possibly interstitial lung disease. In addition to ischemia, we propose that TN in SSc could also be a consequence of inflammatory and possibly fibrotic processes.

Diffuse cutaneous systemic sclerosis (dcSSc) is a multifaceted disease for which the Composite Response Index in dcSSc (CRISS) was developed as a global outcome measure. We aimed to further validate the CRISS by examining its association with other disease measures, patient reported quality of life (QoL), and mortality.DcSSc patients with ≤5 year disease duration were recruited from multinational registries. CRISS improvers (score ≥0.6) and non-improvers (score0.6) were identified after one year. Median changes in European Scleroderma Group Activity Index (EScSG-AI), Medsger Disease Severity Scale (DSS), Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI), and Short Form 36 physical component score (SF-36 PCS) after one year was compared between CRISS groups. Kaplan Meier and adjusted Cox analyses compared SCTC-DI damage accrual and mortality between CRISS groups.Of 212 patients, 68 (32.1%) were CRISS improvers. CRISS improvers had improved median EScSG-AI (-1.1 points [IQR -2.6, -0.3] vs. 0 [-1.1, 1.0], p0.001), DSS (-1 [-3, 1] vs. 0 [-2, 2], p = 0.015), and SF-36 PCS (+3.6 [-1.0, 8.9] vs. -0.3 [-5.9, 4.5], p0.001) compared to non-improvers. CRISS improvers were less likely to accumulate damage on the SCTC-DI (hazard ratio [95% confidence interval] 0.68 [0.47, 0.96]) adjusting for age, sex, disease duration, and immunosuppression use. CRISS improvers had a trend towards better survival.CRISS improvers had more favourable changes in measures of disease activity, disease severity, and QoL compared to non-improvers. These findings support the construct validity of a CRISS outcome after one year in early dcSSc.

Calcinosis cutis is a debilitating complication of systemic sclerosis (SSc). We previously developed a radiographic scoring system to assess severity of calcinosis affecting the hands in patients with SSc. We sought to further validate our radiographic scoring system to assess for change over 1 year and to identify factors associated with improvement or progression.Baseline and 1-year antero-posterior hand radiographs were obtained in 39 SSc patients with calcinosis prospectively enrolled at 6 centers within the US, Canada, Mexico and Australia. Two readers (one radiologist and one rheumatologist) scored all radiographs using the calcinosis scoring system and a 5-point Likert scale (1 = A lot better, 2 = A little better, 3=No change, 4 = A little worse, 5 = A lot worse) on follow-up. By maximizing the Kappa coefficient of agreement between grouped Likert scale (better/no change/worse) and the percentage of change of calcinosis in the radiographic scoring system, we defined progressive calcinosis as25% increase in score from baseline at 1-year, stable calcinosis as change in score between -25% to 25%, and improvement of calcinosis as decrease in score by25%. Nineteen SSc patients from an independent cohort were used for validation.Inter-rater reliability of the calcinosis scoring system was high with intra-class correlation coefficient of 0.93 (0.89-0.95). The median percentage of change from baseline to 1 year was 12.8% (range -89.3 to 290.2%). Sixteen patients (41%) experienced progression of calcinosis over 1 year; 18 (46%) remained stable; and 5 (13%) had improvement. Patients with progressive calcinosis had lower T-score on bone densitometry (-3.3 vs -1.7, p = 0.044) and higher prevalence of loss of digital pulp on physical exam (56% vs 22%, p = 0.027), with a trend towards lower baseline modified Rodnan skin score (mRSS) (3.8 vs. 5.9, p = 0.057), than patients who did not progress. Patients who experienced improvement in calcinosis had lower prevalence of digital pitting scars (20% vs 71%, p = 0.047) than patients whose calcinosis did not improve. In multivariable analysis, loss of digital pulp remained a predictor of calcinosis progression (OR 5.8, p = 0.023, CI 1.27 - 26.36). In the validation cohort, 2 (11%) patients improved, 10 (53%) remained stable, and 7 (37%) progressed.We confirmed the excellent inter-rater reliability of our radiographic calcinosis scoring system and demonstrated its usefulness to detect change over time. Approximately 40% of patients experienced progression of calcinosis over 1 year. Loss of digital pulp was predictive of progressive calcinosis providing further evidence that digital ischemia contributes to the progression of calcinosis.

BackgroundDifferent diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.AimsTo evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.MethodData collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.ResultsA total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15–3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98–10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7–15) (OR = 0.96; 95% CI = 0.56–1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26–0.97).ConclusionsThe MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.Declaration of interestDrs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

Maladaptive wound healing responses to chronic tissue injury result in organ fibrosis. Fibrosis, which entails excessive extracellular matrix (ECM) deposition and tissue remodeling by activated myofibroblasts, leads to loss of proper tissue architecture and organ function; however, the molecular mediators of myofibroblast activation have yet to be fully identified. Here we identify soluble ephrin-B2 (sEphrin-B2) as a new profibrotic mediator in lung and skin fibrosis. We provide molecular, functional and translational evidence that the ectodomain of membrane-bound ephrin-B2 is shed from fibroblasts into the alveolar airspace after lung injury. Shedding of sEphrin-B2 promotes fibroblast chemotaxis and activation via EphB3 and/or EphB4 receptor signaling. We found that mice lacking ephrin-B2 in fibroblasts are protected from skin and lung fibrosis and that a disintegrin and metalloproteinase 10 (ADAM10) is the major ephrin-B2 sheddase in fibroblasts. ADAM10 expression is increased by transforming growth factor (TGF)-β1, and ADAM10-mediated sEphrin-B2 generation is required for TGF-β1-induced myofibroblast activation. Pharmacological inhibition of ADAM10 reduces sEphrin-B2 levels in bronchoalveolar lavage and prevents lung fibrosis in mice. Consistent with the mouse data, ADAM10-sEphrin-B2 signaling is upregulated in fibroblasts from human subjects with idiopathic pulmonary fibrosis. These results uncover a new molecular mechanism of tissue fibrogenesis and identify sEphrin-B2, its receptors EphB3 and EphB4 and ADAM10 as potential therapeutic targets in the treatment of fibrotic diseases.