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ObjectivesResults from the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) clinical trial demonstrated significant benefits of haematopoietic stem cell transplant (HSCT) versus cyclophosphamide (CTX) in patients with systemic sclerosis. The objective of this study was to test the hypothesis that transplantation stabilises the autoantibody repertoire in patients with favourable clinical outcomes.MethodsWe used a bead-based array containing 221 protein antigens to profile serum IgG autoantibodies in participants of the SCOT trial.ResultsComparison of autoantibody profiles at month 26 (n=23 HSCT; n=22 CTX) revealed antibodies against two viral antigens and six self-proteins (SSB/La, CX3CL1, glycyl-tRNA synthetase (EJ), parietal cell antigen, bactericidal permeability-increasing protein and epidermal growth factor receptor (EGFR)) that were significantly different between treatment groups. Linear mixed model analysis identified temporal increases in antibody levels for hepatitis B surface antigen, CCL3 and EGFR in HSCT-treated patients. Eight of 32 HSCT-treated participants and one of 31 CTX-treated participants had temporally varying serum antibody profiles for one or more of 14 antigens. Baseline autoantibody levels against 20 unique antigens, including 9 secreted proteins (interleukins, IL-18, IL-22, IL-23 and IL-27), interferon-α2A, stem cell factor, transforming growth factor-β, macrophage colony-stimulating factor and macrophage migration inhibitory factor were significantly higher in patients who survived event-free to month 54.ConclusionsOur results suggest that HSCT favourably alters the autoantibody repertoire, which remains virtually unchanged in CTX-treated patients. Although antibodies recognising secreted proteins are generally thought to be pathogenic, our results suggest a subset could potentially modulate HSCT in scleroderma.

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.

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 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.

To investigate whether obstetric complications prior to systemic sclerosis (SSc) diagnosis are more common in SSc patients compared to the general obstetric population.A case-control study was performed at Kaiser Permanente Northern California to compare prior obstetric complications in adult women who later developed SSc (cases) with women from the general obstetric population who did not develop SSc (controls; matched 10:1 by age and year of delivery) from 2007 to 2016. Exposures included past hypertensive disorders of pregnancy (preeclampsia, eclampsia, gestational hypertension), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), maternal infections, neonatal intensive care unit (NICU) admission, and preterm birth. Fischer's exact tests were used to compare categorical variables. Conditional logistic regression models estimated the odds ratio (OR), and corresponding 95% confidence intervals (95% CIs) for the outcome SSc.Seventeen SSc cases and 170 non-SSc controls were identified, with median maternal age at delivery 34 years (range 23-46 years) and median time from delivery to SSc diagnosis 2 years (range 0.2-7.3 years). Women with SSc were more likely to be Hispanic and Black. Prior obstetric complications appeared higher in women with an eventual SSc diagnosis compared to controls (70.6% versus 50%), including hypertensive disorders (17.7% versus 9.4%), PROM (11.8% versus 4.1%), IUGR (5.9% versus 1.8%), maternal infection (29.4% versus 14.1%), NICU admissions (23.5% versus 7.7%), and preterm delivery (29.4% versus 21.8%). Women with SSc had a higher odds of delivering infants requiring NICU admission (OR 4.7 [95% CI 1.2-18.8]).Women who eventually develop SSc had trends toward more complicated pregnancy histories before overt diagnosis.

Explore trial participants’ and research team members’ perceptions of the impact of the videoconference-based, supportive care program (SPIN-CHAT Program) during early COVID-19 for individuals with systemic sclerosis (SSc). Data were collected cross-sectionally. A social constructivist paradigm was adopted, and one-on-one videoconference-based, semi-structured interviews were conducted with SPIN-CHAT Trial participants and research team members. A hybrid inductive-deductive approach and reflexive thematic analysis were used. Of the 40 SPIN-CHAT Trial participants and 28 research team members approached, 30 trial participants (Mean age = 54.9; SD = 13.0 years) and 22 research team members agreed to participate. Those who took part in interviews had similar characteristics to those who declined. Five themes were identified: (1) The SPIN-CHAT Program conferred a range of positive psychological health outcomes, (2) People who don’t have SSc don’t get it: The importance of SSc-specific programming, (3) The group-based format of the SPIN-CHAT Program created a safe space to connect and meet similar others, (4) The structure and schedule of the SPIN-CHAT Program reduced feelings of boredom and contributed to enhanced psychological health, (5) The necessity of knowledge, skills, and tools to self-manage SSc and navigate COVID-19. Participants’ and research team members’ perspectives elucidated SPIN-CHAT Program benefits and how these benefits may have been realized. Results underscore the importance of social support from similar others, structure, and self-management to enhance psychological health during COVID-19. clinicaltrials.gov (NCT04335279)IMPLICATIONS FOR REHABILITATIONThe videoconference-based, supportive care SPIN-CHAT Program enhanced psychological health amongst individuals affected by systemic sclerosis.SPIN-CHAT Program participants and research team members shared that being around similar others, program structure, and self-management support were important and may have contributed to enhanced psychological health.Further efforts are required to explore experiences within supportive care programs to better understand if and how psychological health is impacted. The videoconference-based, supportive care SPIN-CHAT Program enhanced psychological health amongst individuals affected by systemic sclerosis. SPIN-CHAT Program participants and research team members shared that being around similar others, program structure, and self-management support were important and may have contributed to enhanced psychological health. Further efforts are required to explore experiences within supportive care programs to better understand if and how psychological health is impacted.

Background Systemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. We completed an initial feasibility trial of an online self-administered version of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program using the cohort multiple randomized controlled trial (RCT) design. Due to low intervention offer uptake, we will conduct a new feasibility trial with progression to full-scale trial, using a two-arm parallel, partially nested RCT design. The SPIN-SELF Program has also been revised to include facilitator-led videoconference group sessions in addition to online material. We will test the group-based intervention delivery format, then evaluate the effect of the SPIN-SELF Program on disease management self-efficacy (primary) and patient activation, social appearance anxiety, and functional health outcomes (secondary). Methods This study is a feasibility trial with progression to full-scale RCT, pending meeting pre-defined criteria, of the SPIN-SELF Program. Participants will be recruited from the ongoing SPIN Cohort (http://www.spinsclero.com/en/cohort) and via social media and partner patient organizations. Eligible participants must have SSc and low to moderate disease management self-efficacy (Self-Efficacy for Managing Chronic Disease (SEMCD) Scale score ≤ 7.0). Participants will be randomized (1:1 allocation) to the group-based SPIN-SELF Program or usual care for 3 months. The primary outcome in the full-scale trial will be disease management self-efficacy based on SEMCD Scale scores at 3 months post-randomization. Secondary outcomes include SEMCD scores 6 months post-randomization plus patient activation, social appearance anxiety, and functional health outcomes at 3 and 6 months post-randomization. We will include 40 participants to assess feasibility. At the end of the feasibility portion, stoppage criteria will be used to determine if the trial procedures or SPIN-SELF Program need important modifications, thereby requiring a re-set for the full-scale trial. Otherwise, the full-scale RCT will proceed, and outcome data from the feasibility portion will be utilized in the full-scale trial. In the full-scale RCT, 524 participants will be recruited. Discussion The SPIN-SELF Program may improve disease management self-efficacy, patient activation, social appearance anxiety, and functional health outcomes in people with SSc. SPIN works with partner patient organizations around the world to disseminate its programs free-of-charge. Trial registration ClinicalTrials.govNCT04246528. Registered on 27 January 2020

BACKGROUND Hydroxychloroquine (HCQ) is commonly used for patients with autoimmune conditions. Long-term use of HCQ can cause retinal toxicity, but this risk can be reduced if high doses are avoided. OBJECTIVE We developed and piloted an electronic health record–based dashboard to improve the safe prescribing of HCQ within the Veterans Health Administration (VHA). We observed pilot facilities over a 1-year period to determine whether they were able to improve the proportion of patients receiving inappropriate doses of HCQ. METHODS Patients receiving HCQ were identified from the VHA corporate data warehouse. Using PowerBI (Microsoft Corp), we constructed a dashboard to display patient identifiers and the most recent HCQ dose and weight (flagged if ≥5.2 mg/kg/day). Six VHA pilot facilities were enlisted to test the dashboard and invited to participate in monthly webinars. We performed an interrupted time series analysis using synthetic controls to assess changes in the proportion of patients receiving HCQ ≥5.2 mg/kg/day between October 2020 and November 2021. RESULTS At the start of the study period, we identified 18,525 total users of HCQ nationwide at 128 facilities in the VHA, including 1365 patients at the 6 pilot facilities. Nationwide, at baseline, 19.8% (3671/18,525) of patients were receiving high doses of HCQ. We observed significant improvements in the proportion of HCQ prescribed at doses ≥5.2 mg/kg/day among pilot facilities after the dashboard was deployed (–0.06; 95% CI –0.08 to –0.04). The difference in the postintervention linear trend for pilot versus synthetic controls was also significant (–0.06; 95% CI –0.08 to –0.05). CONCLUSIONS The use of an electronic health record–based dashboard reduced the proportion of patients receiving higher than recommended doses of HCQ and significantly improved performance at 6 VHA facilities. National roll-out of the dashboard will enable further improvements in the safe prescribing of HCQ.

Objectives We evaluated the safety and efficacy of oral treprostinil in preventing progression of SSc-associated calcinosis. Methods This prospective open-label study enrolled 12 SSc patients meeting 2013 ACR/EULAR classification criteria with confirmed clinical and radiographic evidence of one or more calcinosis deposit in the hands. Patients received oral treprostinil for 1 year. Primary endpoints were safety/tolerability and percentage of patients without radiographic progression of calcinosis at 1 year ( Results Twelve female patients were enrolled, half with diffuse cutaneous disease; median age was 55 years (range 35–68 years). Five patients completed the study. Seven patients withdrew due to intolerable adverse effects (n = 3), intercurrent unrelated illness (n = 2, cirrhosis, cancer), progressive SSc (n = 1) and personal reasons (n = 1). Most patients developed headaches and gastrointestinal adverse effects. Four of 11 (36%) patients with 1-year follow-up hand radiographs experienced progression of calcinosis. Of five who completed treatment, calcinosis was stable in four (80%) with progression in one. Based on SF-36 Physical and Mental Component and Domain scores, transition question and SF-6D utility score, all patients who finished the trial reported overall improvement or no change compared with baseline. Conclusion Oral treprostinil was poorly tolerated in SSc patients with calcinosis. Of five patients who completed treatment, most (80%) had documented stability of calcinosis on hand radiographs at 1 year. ClinicalTrials.gov identifier NCT02663895.

Systemic sclerosis (SSc) patients are classified according to degree of skin fibrosis (limited and diffuse cutaneous) and serum autoantibodies. We undertook the present multicenter study to determine if intrinsic subset (IS) classification based upon skin gene expression yields additional valuable clinical information.SSc patients and healthy participants (HP) were classified as Normal-like, Limited, Fibroproliferative and Inflammatory IS using a previously trained classifier. Clinical data were obtained (serum autoantibodies, pulmonary function testing, modified Rodnan Skin scores [mRSS], and high-resolution chest computed tomography [HRCT]). Statistical analyses were performed to compare patients classified by IS, traditional cutaneous classification, and serum autoantibodies.223 participants (165 SSc [115 dcSSc and 50 lcSSc] and 58 HP) were classified. Inflammatory IS patients had higher mRSS (22.1±9.9, p0.001) than other IS and dcSSc (19.4±9.4, p= 0.05) despite similar disease duration (median [IQR] months 14.9[19.9] vs 18.4[31.6], p=0.48). In multivariable modeling, no significant association between mRSS and RNA Pol III (p=0.07) or Scl-70 (p=0.09) was found. Radiographic ILD was more prevalent in Fibroproliferative IS compared to other IS (91%, p=0.04) with similar prevalence between lcSSc and dcSSc (67% vs. 76%, p=0.73). Positive Scl-70 antibody was the strongest ILD predictor (p0.001). Interestingly, all lcSSc/Fibroproliferative patients were demonstrated radiographic ILD.Classification by IS identifies patients with distinct clinical phenotypes versus traditional cutaneous or autoantibody classification. IS classification identifies subgroups of SSc patients with more radiographic ILD (Fibroproliferative), higher mRSS (Inflammatory) and milder phenotype (Normal-like), and may provide additional clinically useful information to current SSc classification systems. This article is protected by copyright. All rights reserved.

ImportanceDegos-like lesions are cutaneous manifestations of a small-vessel vasculopathy that appear as atrophic, porcelain-white papules with red, telangiectatic borders. No study has adequately examined Degos-like lesions in patients with systemic sclerosis (SSc).ObjectiveTo characterize the serologic, cutaneous, and internal organ manifestations associated with Degos-like lesions in a large cohort of patients with SSc.Design, Settings, and ParticipantsThis retrospective cohort study involved adult patients with SSc who were seen at Stanford Rheumatologic Dermatology Clinic between January 1, 1998, and December 31, 2018. Participants fulfilled the 2013 classification criteria for SSc. Data analysis was conducted from February 1 to June 1, 2019.Main Outcomes and MeasuresData on demographic characteristics; autoantibody status; clinical characteristics, including cutaneous and systemic manifestations of SSc; and presence of Degos-like lesions were collected.ResultsThe cohort comprised 506 patients with SSc (447 females [88.3%]; mean [SD] age at first non–Raynaud disease symptoms, 46.1 [15.2] years). Twenty-seven patients (5.3%) had Degos-like lesions, of whom 24 (89.0%) had lesions affecting the fingers. Patients with Degos-like lesions were more likely to have diffuse cutaneous SSc compared with patients without lesions (15 [55.6%] vs 181 [37.8%]; P = .04). Degos-like lesions were also associated with acro-osteolysis (10 [37.0%] vs 62 [12.9%]; P P = .04), and calcinosis (15 [55.6%] vs 115 [24.0%]; P P Conclusions and RelevanceResults of this study suggest an association of Degos-like lesions with diffuse cutaneous SSc and other cutaneous manifestations of vasculopathy, including acro-osteolysis, calcinosis, and digital ulcers. A prospective longitudinal study is warranted to examine the onset of Degos-like lesions and to elucidate whether these lesions play a role in SSc.

Objectives The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process. Methods This multicentre, randomized, double-blind, placebo-controlled study enrolled participants ≥18 years of age with active dcSSc. Participants were randomized 3:1 (GSK2330811:placebo) in one of two sequential cohorts to receive GSK2330811 (cohort 1: 100 mg; cohort 2: 300 mg) or placebo s.c. every other week for 12 weeks. The primary endpoint was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory endpoint. Results Thirty-five participants were randomized to placebo (n = 8), GSK2330811 100 mg (n = 3) or GSK2330811 300 mg (n = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated following GSK2330811 treatment. There were no meaningful differences between GSK2330811 and placebo for any efficacy endpoints. The safety and tolerability of GSK2330811 were not favourable in the 300 mg group, with on-target, dose-dependent adverse events related to decreases in haemoglobin and platelet count that were not observed in the 100 mg or placebo groups. Conclusion Despite a robust and novel experimental medicine approach and evidence of target engagement, anticipated SSc-related biologic effects of GSK2330811 were not different from placebo and safety was unfavourable, suggesting OSM inhibition may not be a useful therapeutic strategy in SSc. Trial registration number ClinicalTrials.gov, NCT03041025; EudraCT, 2016-003417-95.

Objectives To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). Methods A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. Results Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. Conclusions Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Summary Background Abatacept was well tolerated by patients with early diffuse cutaneous systemic sclerosis in a phase 2, double-blind randomised trial, with potential efficacy at 12 months. We report here the results of an open-label extension for 6 months. Methods Patients (aged ≥18 years) with diffuse cutaneous systemic sclerosis of less than 3 years' duration from their first non-Raynaud's symptom were enrolled into the ASSET trial (A Study of Subcutaneous Abatacept to Treat Diffuse Cutaneous Systemic Sclerosis), which is a double-blind trial at 22 sites in Canada, the UK, and the USA. After completion of 12 months of treatment with either abatacept or placebo, patients received a further 6 months of abatacept (125 mg subcutaneous every week) in an open-label extension. The primary endpoint of the double-blind trial was modified Rodnan Skin Score (mRSS) at 12 months, which was reassessed at 18 months in the open-label extension. The primary analysis included all participants who completed the double-blind trial and received at least one dose of open-label treatment (modified intention to treat). This trial is registered with ClinicalTrials.gov , NCT02161406 . Findings Between Sept 22, 2014, and March 15, 2017, 88 participants were randomly allocated in the double-blind trial either abatacept (n=44) or placebo (44); 32 patients from each treatment group completed the 6-month open-label extension. Among patients assigned abatacept, a mean improvement from baseline in mRSS was noted at 12 months (−6·6 [SD 6·4]), with further improvement seen during the open-label extension period (−9·8 [8·1] at month 18). Participants assigned placebo had a mean improvement from baseline in mRSS at 12 months (−3·7 [SD 7·6]), with a further improvement at month 18 (−6·3 [9·3]). Infections during the open-label extension phase occurred in nine patients in the placebo–abatacept group (12 adverse events, one serious adverse event) and in 11 patients in the abatacept–abatacept group (14 adverse events, one serious adverse event). Two deaths occurred during the 12-month double-blind period in the abatacept group, which were related to scleroderma renal crisis; no deaths were recorded during the open-label extension. Interpretation During the 6-month open-label extension, no new safety signals for abatacept were identified in the treatment of diffuse cutaneous systemic sclerosis. Clinically meaningful improvements in mRSS and other outcome measures were observed in both the abatacept and placebo groups when patients transitioned to open-label treatment. These data support further studies of abatacept in diffuse cutaneous systemic sclerosis. Funding Bristol-Myers Squibb and National Institutes of Health.

AIM Interstitial lung disease (ILD) is the leading cause of disease-related death in systemic sclerosis (SSc). Here, we assess baseline characteristics of SSc subjects with and without restrictive lung disease (RLD) in a multi-center, US-based registry. METHODS SSc patients within 5 years of disease onset were enrolled in the Collaborative National Quality and Efficacy Registry (CONQUER), a multi-center US-based registry of SSc study participants (age ≥ 18 years) enrolled at 13 expert centers. All subjects met 2013 American College of Rheumatology / European League Against Rheumatism criteria. Subjects with a pulmonary function test (PFT) at baseline before April 1, 2020 were included. High-resolution computed tomography scan of the chest was not available to characterize ILD for all subjects. RLD was defined as forced vital capacity (FVC)

Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It is a manifestation of several autoimmune connective tissue diseases, most frequently with systemic sclerosis and juvenile dermatomyositis, followed by adult dermatomyositis. Autoimmune connective tissue disease–associated calcinosis is of the dystrophic subtype, which occurs at sites of damaged tissue in the setting of normal serum calcium and phosphate levels. In juvenile dermatomyositis, calcinosis is considered a marker of ongoing disease activity and possibly inadequate treatment, while in adult dermatomyositis, it is a hallmark of skin damage due to chronic rather than active disease. Calcinosis is associated with long disease duration in systemic sclerosis and dermatomyositis, anti-polymyositis/sclerosis autoantibodies in systemic sclerosis and NXP-2 and melanoma differentiation-associated gene 5 in dermatomyositis. Calcinosis in systemic sclerosis occurs most frequently in the hands, particularly the fingers, whereas in dermatomyositis, it affects mainly the trunk and extremities. The primary mineral component of calcinosis is hydroxyapatite in systemic sclerosis and carbonate apatite in dermatomyositis. Calcinosis in dermatomyositis and systemic sclerosis share some pathogenic mechanisms, but vascular hypoxia seems to play a more important role in systemic sclerosis, whereas the release of calcium from mitochondria in muscle cells damaged by myopathy may be a primary mechanism contributing to dermatomyositis-related calcinosis. Multiple treatment strategies for dermatomyositis and systemic sclerosis-related calcinosis have been used with variable results. Early aggressive treatment of underlying myositis in patients with dermatomyositis may improve long-term outcomes of calcinosis. A better understanding of the pathogenesis of calcinosis is needed to improve treatment options.

Calcinosis, insoluble calcium compounds deposited in skin and other tissues, is a crippling sequela of dermatomyositis. Prolonged disease associated with ongoing inflammation, ischemia, repetitive trauma, and certain autoantibodies are associated with calcinosis. Herein, we describe potential pathogenic mechanisms including the role of mitochondrial calcification. There are no widely effective treatments for calcinosis. We review available pharmacologic therapies for calcinosis including those targeting calcium and phosphorus metabolism; immunosuppressive/anti-inflammatory therapies; and vasodilators. Mounting evidence supports the use of various formulations of sodium thiosulfate in the treatment of calcinosis. Although the early institution of aggressive immunosuppression may prevent calcinosis in juvenile dermatomyositis, only limited data support improvement once it has developed. Minocycline can be useful particularly for lesions associated with surrounding inflammation. Powerful vasodilators, such as prostacyclin analogs, may have promise in the treatment of calcinosis, but further studies are necessary. Surgical removal of lesions when amenable is our treatment of choice.

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.