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Patients with autoimmune disease-related interstitial lung disease may develop pulmonary fibrosis, which may become progressive. Progressive pulmonary fibrosis (PPF) is associated with poor outcomes. Antifibrotic therapies have shown efficacy as treatments for PPF in patients with autoimmune diseases, but new treatments are needed to slow or halt disease progression. Phosphodiesterases (PDEs) are enzymes that mediate the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Pre-clinical data suggest that preferential inhibition of PDE4B has the potential to slow the progression of pulmonary fibrosis by inhibiting inflammatory and fibrotic pathways, with a lower risk of gastrointestinal adverse events than associated with pan-PDE4 inhibitors. Nerandomilast (BI 1015550) is a preferential PDE4 inhibitor that has demonstrated anti-inflammatory and antifibrotic effects in pre-clinical studies. In a phase II trial in patients with idiopathic pulmonary fibrosis, nerandomilast (given alone or on top of background antifibrotic therapy) prevented a decrease in lung function over 12 weeks with an acceptable safety and tolerability profile. The phase III FIBRONEER-ILD trial is evaluating the efficacy and safety of nerandomilast, given alone or on top of nintedanib, in patients with PPF, including PPF associated with autoimmune diseases. In this article, we review the potential of PDE4B inhibition in the treatment of ILD associated with autoimmune diseases, including the pre-clinical and early clinical data available to date.

Introduction: In this study, we investigated the prevalence of depression, depression treatment, and symptom burden in patients with systemic sclerosis (SSc) and examined their associations with the center for epidemiologic studies depression scale revised (CESD-R) scores., Methods: The Prospective Registry in Scleroderma at Massachusetts General Hospital (PRISM) is a longitudinal registry of patients with SSc. Among participants with CESD-R score ≥ 16, indicating possible depression, a chart review was performed for mental health diagnoses and treatments. We examined the relation of demographic and clinical factors to the presence of mental health diagnoses or treatment using logistic regression. We evaluated the association of SSc symptoms and the COVID-19 pandemic with a CESD-R score using quantile regression., Results: Of 214 patients enrolled in PRISM, 129 participants (38% diffuse and 59% limited) completed at least one CESD-R questionnaire. In the first survey, 29% had possible depression (CESD - R ≥ 16) and 16% had probable depression (CESD - R ≥ 23). Of 20 participants with probable depression, 90% received treatment for a mood disorder. In a multivariable logistic regression model among participants with CESD - R ≥ 16, none of the evaluated variables (CESD-R score, age, gender, employment status, race, and ethnicity) was associated with mental health diagnosis or treatment. Higher baseline dyspnea index, modified Rodnan skin score, and the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal total score and subscores were associated with higher CESD-R score., Conclusion: In this single-center cross-sectional study, 16% of participants had significant depressive symptoms. Dyspnea, extent of skin involvement, and gastrointestinal symptoms were associated with depression symptoms., Competing Interests: The authors do not have any relevant conflicts of interest., (Copyright © 2023 Marissa B. Savoie et al.)

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 Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

Pulmonary hypertension (PH) is a leading cause of morbidity and mortality in systemic sclerosis (SSc). PH is a heterogenous condition and several different forms of PH are associated with SSc, including pulmonary arterial hypertension (PAH) resulting from a pulmonary arterial vasculopathy, PH due to interstitial lung disease, PH due to left heart disease, and PH due to thromboembolic disease. Extensive research has led to an improved understanding of the mediators involved in the pathogenesis of SSc-PH. Initial combination therapy is the preferred treatment approach for SSc-PAH and requires coordinated care with a multidisciplinary team including rheumatology, pulmonology, and cardiology., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Systemic sclerosis (SSc) is a rare, complex, connective tissue disorder. Interstitial lung disease (ILD) is common in SSc, occurring in 35-52% of patients and accounting for 20-40% of mortality. Evolution of therapeutic options has resulted in a lack of consensus on how to manage this condition. This Delphi study was initiated to develop consensus recommendations based on expert physician insights regarding screening, progression, treatment criteria, monitoring of response, and the role of recent therapeutic advances with antifibrotics and immunosuppressants in patients with SSc-ILD., Methods: A modified Delphi process was completed by pulmonologists (n = 13) and rheumatologists (n = 12) with expertise in the management of patients with SSc-ILD. Panelists rated their agreement with each statement on a Likert scale from - 5 (complete disagreement) to + 5 (complete agreement). Consensus was predefined as a mean Likert scale score of ≤  - 2.5 or ≥  + 2.5 with a standard deviation not crossing zero., Results: Panelists recommended that all patients with SSc be screened for ILD by chest auscultation, spirometry with diffusing capacity of the lungs for carbon monoxide, high-resolution computed tomography (HRCT), and/or autoantibody testing. Treatment decisions were influenced by baseline and changes in pulmonary function tests, extent of ILD on HRCT, duration and degree of dyspnea, presence of pulmonary hypertension, and potential contribution of reflux. Treatment success was defined as stabilization or improvement of signs or symptoms of ILD and functional status. Mycophenolate mofetil was identified as the initial treatment of choice. Experts considered nintedanib a therapeutic option in patients with progressive fibrotic ILD despite immunosuppressive therapy or patients contraindicated/unable to tolerate immunotherapy. Concomitant use of nintedanib with MMF/cyclophosphamide can be considered in patients with advanced disease at initial presentation, aggressive ILD, or significant disease progression. Although limited consensus was achieved on the use of tocilizumab, the experts considered it a therapeutic option for patients with early SSc and ILD with elevated acute-phase reactants., Conclusions: This modified Delphi study generated consensus recommendations for management of patients with SSc-ILD in a real-world setting. Findings from this study provide a management algorithm that will be helpful for treating patients with SSc-ILD and addresses a significant unmet need., (© 2023. The Author(s).)

Objective: Patients with systemic autoimmune rheumatic diseases (SARDs) face illness-related uncertainty, but little is known about the psychological profiles and psychosocial and health needs associated with uncertainty among adults with SARDs., Methods: Patients from the Massachusetts General Hospital with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), IgG4-related disease (IgG4-RD), and systemic sclerosis (SSc) completed the Mishel Uncertainty in Illness Scale, 8-item Patient Health Questionnaire depression scale, 7-item General Anxiety Disorder scale, Sickness Impact Profile, and a survey of psychosocial needs. The associations of uncertainty and self-reported needs with depression, anxiety, and sickness impact were assessed., Results: One hundred thirty-two patients with AAV (n = 41, 31%), IgG4-RD (n = 61, 46%), or SSc (n = 30, 23%) participated. The mean age was 64 years, 52% were female, and 83% were White. Greater illness-related uncertainty was positively correlated with higher levels of depression ( r = 0.43, P < 0.001), anxiety ( r = 0.33, P < 0.001), and sickness impact ( r = 0.28, P = 0.001). We observed variations in these measures across SARDs, such that uncertainty was more strongly associated with depression and sickness impact in AAV or SSc compared to IgG4-RD. The primary needs that patients endorsed were services for managing physical symptoms (53%), self-care (37%), and emotional concerns (24%), with greater needs strongly associated with greater illness-related uncertainty., Conclusion: Among patients with SARDs, illness-related uncertainty is correlated with levels of depression, anxiety, and sickness impact, as well as psychosocial needs. Findings also implicate the need for targeted interventions to address uncertainty and needs among subgroups of patients with different illness profiles., (Copyright © 2022 by the Journal of Rheumatology.)

Objective: Although a high-resolution computed tomography (HRCT) scan of the chest is the gold standard test for the detection of interstitial lung disease (ILD), there is no consensus among rheumatologists regarding the use of HRCT to screen for ILD in their patients with systemic sclerosis (SSc). The aims of this study were to describe the HRCT ordering practices at SSc centers in the United States and to determine which patient characteristics are associated with HRCT performance., Methods: We performed a prospective cohort study of patients with SSc enrolled in the US-based Collaborative National Quality and Efficacy Registry (CONQUER). We performed univariate logistic regression followed by multivariable logistic regression to determine which patient characteristics were associated with HRCT performance., Results: Of the 356 patients with SSc enrolled in CONQUER, 286 (80.3%) underwent HRCT at some point during their disease course. On multivariable analyses, missing total lung capacity percent predicted (odds ratio [OR] 3.26, 95% confidence interval [CI]: 1.53-7.41, P = 0.007) was positively associated with ever having undergone HRCT, whereas a positive anti-centromere antibody (OR 0.27, 95% CI: 0.12-0.61, P = 0.008) and missing forced vital capacity percent predicted (OR 0.29, 95% CI: 0.10-0.80, P = 0.005) were negatively associated with ever having undergone HRCT. There was a trend toward a positive association between crackles on pulmonary exam and ever having undergone HRCT (OR 2.28, 95% CI: 0.97-6.05, P = 0.058), although this relationship did not reach statistical significance., Conclusion: The majority of patients with SSc enrolled in CONQUER underwent HRCT. A positive anti-centromere antibody was the key clinical variable inversely associated with performance of HRCT., (© 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Vaping, including the use of electronic cigarettes (e-cigarettes), has become increasingly prevalent, yet the associated long-term health risks are largely unknown. Given the prevalence of use, particularly among adolescents early in their lifespan, it is vital to understand the potential chronic pathologic sequelae of vaping., Methods: We present the cases of four patients with chronic lung disease associated with e-cigarette use characterized by clinical evaluation, with pulmonary function tests (PFTs), chest high-resolution computed tomography (HRCT), endobronchial optical coherence tomography (EB-OCT) imaging, and histopathologic assessment., Results: Each patient presented with shortness of breath and chest pain in association with a 3- to 8-year history of e-cigarette use, with mild progressive airway obstruction on PFTs and/or chest HRCT findings demonstrating evidence of air trapping and bronchial wall thickening. EB-OCT imaging performed in two patients showed small airway-centered fibrosis with bronchiolar narrowing and lumen irregularities. The predominant histopathologic feature on surgical lung biopsy was small airway-centered fibrosis, including constrictive bronchiolitis and MUC5AC overexpression in all patients. Patients who ceased vaping had a partial, but not complete, reversal of disease over 1 to 4 years., Conclusions: After thorough evaluation for other potential etiologies, vaping was considered to be the most likely common causal etiology for all patients due to the temporal association of symptomatic chronic lung disease with e-cigarette use and partial improvement in symptoms after e-cigarette cessation. In this series, we associate the histopathologic pattern of small airway-centered fibrosis, including constrictive bronchiolitis, with vaping, potentially defining a clinical and pathologic entity associated with e-cigarette use. (Funded in part by the National Institutes of Health.).

Introduction: 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., Materials and Methods: 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 as >25% 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 by >25%. Nineteen SSc patients from an independent cohort were used for validation., Results: 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., Conclusions: 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., (Published by Elsevier Inc.)

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) <80% or total lung capacity (TLC) <80% predicted., Results: There were 160 (45%) SSc subjects characterized as having RLD. There was no significant difference in age, gender or disease duration. RLD subjects had a mean disease duration from date of first non-Raynaud's symptom of 2.6 years and a mean FVC% predicted of 67% at baseline. In multivariable analysis, non-White race, higher physician global health assessment and modified Medical Research Council (mMRC) dyspnea scores, were independently associated with RLD. In the subgroup of RLD subjects with ILD, ILD had a negative correlation with RNA polymerase III antibody., Conclusion: CONQUER is the largest, multi-center, prospective cohort of early SSc patients in the US. Non-White race was independently associated with RLD. In addition, 45% of CONQUER subjects already had RLD, highlighting the importance of screening for SSc-ILD at initial diagnosis., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objectives: Many patients with interstitial lung disease (ILD) have autoimmune manifestations but do not meet criteria for a systemic rheumatic disease. A subset meets criteria for interstitial pneumonia with autoimmune features (IPAF) and have ILD requiring therapy. We conducted a multicentre observational study to examine the use of rituximab (RTX) in IPAF., Methods: Patients from Mass General Brigham (MGB) and University of Chicago Medicine (UCM) were included if they were ≥18 years old, met the 2015 classification criteria for IPAF and were treated with RTX. Clinical improvement was defined as improvement in four out of four domains at 1 year after RTX initiation: documented clinician global assessment; oxygen requirement; need for respiratory-related hospitalization; and survival., Results: At MGB, 36 IPAF patients (mean age 61 years, 44% female) were treated with RTX. At 1 year, 18 (50%) were clinically improved, 12 (33%) were stable, and 6 (17%) died from progressive respiratory failure. At UCM, 14 IPAF patients (mean age 53 years, 71% female) were treated with RTX. At 1 year, eight (57%) were improved, two (14%) were stable, three (21%) died from progressive respiratory failure, and one (7%) was lost to follow-up. Two patients experienced minor infusion reactions, and two patients discontinued therapy owing to adverse events (infections)., Conclusion: In patients with IPAF treated with RTX at two medical centres, the majority (40 [80%]) demonstrated improvement/stability at 1 year. These findings call for prospective studies, including randomized clinical trials, to determine the risks, benefits and cost effectiveness of RTX in IPAF., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Early diffuse cutaneous systemic sclerosis (dcSSc) has the highest case fatality among rheumatic diseases. We report baseline characteristics, current immunosuppressive therapies, progression of skin and internal organ involvement, and mortality in a multicenter prospective cohort from the United States (US) of America., Methods: We performed a longitudinal analysis of participants from 12 US centers, from April 2012 to July 2020. All participants had early dcSSc or were at-risk for dcSSc, with ≤2 years since the first non-Raynaud's phenomenon (RP) symptom., Results: Three hundred one patients were included with a baseline median disease duration of 1.2 years since RP and a mean modified skin score of 21.1 units. At baseline, 263 (87.3%) had definite dcSSc and 38 (12.7%) were classified as at-risk; 112 (49.6%) patients were positive for anti-RNA polymerase III antibodies. The median follow-up duration was 24.5 months (IQR = 10.3-40.7 months). One hundred ninety (63.1%) participants were treated with an immunosuppressive therapy, of which mycophenolate mofetil was most used at baseline and follow-up. Of 38 who were classified as at-risk at baseline, 27 (71%) went on to develop dcSSc; these patients were characterized by higher baseline mean HAQ-DI (0.8 versus 0.4, p = 0.05) and higher baseline mRSS (8.8 versus 4.4, p < 0.01) in comparison with those who remained as limited cutaneous SSc. In the overall cohort, 48 participants (21.1%) had clinically significant worsening of skin fibrosis, mainly occurring in the first year of follow-up; 41 (23.3%) had an absolute forced vital capacity decline of ≥10%. Twenty participants (6.6%) died, of which 18 died in the first 3 years of follow-up. Cardiac involvement (33.3%), gastrointestinal dysmotility (22.2%), and progressive interstitial lung disease (ILD) (16.7%) were the main causes of death., Conclusion: This US cohort highlights the management of early SSc in the current era, demonstrating progression of skin and lung involvement despite immunosuppressive therapy and high mortality due to cardiac involvement.

Objective: Response to immunosuppression is highly variable in systemic sclerosis (SSc)-related interstitial lung disease (ILD). This study was undertaken to determine whether a composite serum interferon (IFN)-inducible protein score exhibits predictive significance for the response to immunosuppression in SSc-ILD., Methods: Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC), were examined. Results were validated in an independent observational cohort receiving active treatment. A composite score of 6 IFN-inducible proteins IFNγ-inducible 10-kd protein, monokine induced by IFNγ, monocyte chemotactic protein 2, β 2 -microglobulin, tumor necrosis factor receptor type II, and macrophage inflammatory protein 3β) was calculated, and its predictive significance for longitudinal forced vital capacity percent predicted measurements was evaluated., Results: Higher baseline IFN-inducible protein score predicted better response over 3 to 12 months in the MMF arm (point estimate = 0.41, P = 0.001) and CYC arm (point estimate = 0.91, P = 0.009). In contrast, higher baseline C-reactive protein (CRP) levels were predictive of a worse ILD course in both treatment arms. The predictive significance of the IFN-inducible protein score and CRP levels remained after adjustment for baseline demographic and clinical predictors. During the second year of treatment, in which patients in the CYC arm were switched to placebo, a higher IFN-inducible protein score at 12 months showed a trend toward predicting a worse ILD course (point estimate = -0.61, P = 0.068), while it remained predictive of better response to active immunosuppression in the MMF arm (point estimate = 0.28, P = 0.029). The predictive significance of baseline IFN-inducible protein score was replicated in the independent cohort (r s = 0.43, P = 0.028)., Conclusion: A higher IFN-inducible protein score in SSc-ILD is predictive of better response to immunosuppression and could potentially be used to identify patients who may derive the most benefit from MMF or CYC., (© 2020, American College of Rheumatology.)

Interstitial lung disease (ILD) is a common manifestation of connective tissue diseases (CTDs). A proportion of patients with CTD-ILDs develop progressive fibrosing ILD, which is characterized by worsening fibrotic abnormalities on high-resolution computed tomography scan, decline in lung function, worsening symptoms, and early mortality. Here, we review the impact of ILD in patients with CTDs, the importance of prompt diagnosis and close monitoring, and the evidence available to guide the management of CTD-ILDs. Management of patients with CTD-ILDs should be individualized and involve close collaboration between rheumatologists and pulmonologists. Immunosuppression is the mainstay of therapy for CTDs, but evidence for its effectiveness in slowing the progression of ILD is limited. Recently, nintedanib has been approved to slow decline in lung function in patients with systemic sclerosis-associated ILD and chronic fibrosing ILDs with a progressive phenotype. The results of ongoing clinical trials will help clinicians take a more evidence-based approach to the treatment of CTD-ILDs., (© 2021 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The objective of this analysis is to examine whether the severity of systemic sclerosis (SSc)-hand involvement influences patient-reported outcome measure (PROM) completion rate in a US cohort of early disease. Participants included SSc patients with less than 5 years disease duration consented and enrolled in the Collaborative, National, Quality, and Efficacy Registry (CONQUER) between June 2018 and December 2019. Participants' socio-demographics, hand clinical features (severe modified Rodnan skin score, presence of small joint contractures, acro-osteolysis, calcinosis, and digital ulcers), and completion rates of seven PROMs including a Resource Use Questionnaire were analyzed. Cohort characteristics and baseline PROM completion were evaluated. Multivariable logistic regression assessed the relationship between hand limitations and PROM incompletion at several time points using generalized estimating equations. At the time of data lock, 339 CONQUER subjects had a total of 600 visits available for analysis. Calcinosis (odds ratio [OR] 6.35, confidence interval [CI] 2.41-16.73 and acro-osteolysis OR 3.88 (1.57-9.55) were significantly associated with incomplete PROM. The Resource Use Questionnaire was the PROM most commonly not completed. Increasing age was correlated with resource use questionnaire incompletion rate. Acro-osteolysis and calcinosis were associated with lower PROM completion rates in a US SSc cohort, independent of the length of the questionnaires or the modality of administration (electronic or paper). Resource Use Questionnaires are important for understanding the economic impact and burden of chronic disease; however, in this study, it had lower completion rates than PROMs devoted to clinical variables. Key points •Multiple strategies are needed to ensure optimal completion of PROM in longitudinal cohort studies. Even if patients request electronic surveys, we have found it is important to follow up incomplete surveys with paper forms provided at the time of a clinical visit. •The Resource Utilization Questionnaire was lengthy and prone to non-completion in the younger population. •Acro-osteolysis and calcinosis were associated with reduced PROM completion rates.

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 DiffuseCutaneous Systemic Sclerosis), which is a double-blind trial at 22 sites in Canada, the UK, and the USA. Aftercompletion of 12 months of treatment with either abatacept or placebo, patients received a further 6 months ofabatacept (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-labelextension. 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 theabatacept-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.

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests: DK reports consultancy fees from Acceleron, Actelion, Bayer, Blade Therapeutics, BMS, Galapagos, Genentech/Roche, GSK, Mitsubishi Tanabi, Sanofi-A ventis/Genzyme, and UCB Pharma, and reports grants from Bayer, BMS, and Genentech/Roche outside the submitted work, and reports ownership interest in Eicos Sciences, Inc. WRS reports consulting fees from UT Health Science Center at Houston. JKG reports grants from Corbus Pharmaceuticals, Cumberland Pharmaceuticals and Eicos Pharmaceuticals outside the submitted work. AAS reports support from Sanofi outside the submitted work. MLW reports grants and personal fees from Celdara Medical, LLC and personal fees from Abbvie, Acceleron, BMS, Corbus Pharmaceuticals and Boehringer Ingelheim outside the submitted work. JLB reports grants from Hoffman La Roche and the Scleroderma Foundation outside the submitted work. SB and PB are employees of Boehringer Ingelheim. FVC reports personal fees from Boehringer Ingelheim outside the submitted work. EJB reports a grant from Pfizer and support from Bohringer Ingelheim, Corbus Pharmaceuticals and Eicos outside the submitted work. MDM reports personal fees from Medtelligence, Actelion Pharma, Astellas, Mitsubishi-Tanabe, and Boehringer Ingelheim and grants from Bayer, Reata, Sanofi, Corbus, Eicos and Boehringer Ingelheim outside the submitted work. SA reports personal fees from Boehringer Ingelheim and grants from Boehringer Ingelheim, Bayer and Momenta outside the submitted work., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc)., Methods: In this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets., Results: Among 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively., Conclusion: In this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial., (© 2019, American College of Rheumatology.)

The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud's symptom. The data collection methodology incorporates successful models from other SSc registries. The cohort is designed to provide linked bio-specimen and clinical outcomes data on a longitudinal cohort of SSc patients for validation of hypothesis-driven research and to provide a platform for studying patient-reported outcomes in scleroderma. The CONQUER registry was developed using the guidelines of the International Society for Biological Repositories, and was an iterative process between physicians with an expertise in SSc, patient stakeholders, and information technology experts. Enrollment commenced in June 2018. During the first 6 months of the CONQUER Scleroderma study, 151 SSc patients with less than 5 years of disease duration (from first non-Raynaud's symptom) have been recruited. The mean age is 51 ± 14 years, 83% are female, and 60% of patients have diffuse disease. Survey completion rates are above 88% for all patient-reported outcome surveys. Bio-specimen collection rates are over 97%, and disease severity score completion rates are over 98%. Pulmonary function test data is available on 91% of patients, and echocardiography is available 80%. The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. KEY POINTS : • The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud's symptom. • The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. • CONQUER is innovative in its design in that it is focused on prospective collection of paired clinical and patient outcome data with bio-specimens.

Purpose of Review: Systemic sclerosis is a systemic autoimmune disorder wherein interstitial lung disease (ILD) is the major source or morbidity and mortality. Research into mechanisms of fibrosis and its intersection with autoimmunity, specifically lung fibrosis, has accelerated and been applied to autoimmune disorders such as scleroderma. This review highlights important emerging insights and treatment trials., Recent Findings: The important elements of this review focus on the challenges faced in identifying patients not only who develop lung disease but who are at a higher risk for progression given the heterogeneous natural history of ILD in scleroderma. Risk assessment scoring models using radiographic and physiologic parameters are highlighted and recent and ongoing clinical trials in scleroderma ILD are discussed., Summary: The implications of much of this ongoing work is a potential paradigm shift in our ability to identify those patients at risk for progression, and to offer novel therapies that can limit the progression of inflammatory and fibrotic lung disease in this challenging group of patients.

Objective: To determine perceived barriers and facilitators to effective mentoring for early career rheumatology investigators and to develop a framework for an inter-institutional mentoring program., Methods: Focus groups or interviews with rheumatology fellows, junior faculty, and mentors were conducted, audiorecorded, and transcribed. Content analysis was performed using NVivo software. Themes were grouped into categories (e.g., mentor-mentee relationship, barriers, and facilitators of a productive relationship). Rheumatology fellows and early career investigators were also surveyed nationwide to identify specific needs to be addressed through an inter-institutional mentoring program., Results: Twenty-five individuals participated in focus groups or interviews. Attributes of the ideal mentee-mentor relationship included communication, accessibility, regular meetings, shared interests, aligned goals, and mutual respect. The mentee should be proactive, efficient, engaged, committed, focused, accountable, and respectful of the mentor's time. The mentor should support/promote the mentee, shape the mentee's goals and career plan, address day-to-day questions, provide critical feedback, be available, and have team leadership skills. Barriers included difficulty with career path navigation, gaining independence, internal competition, authorship, time demands, funding, and work-life balance. Facilitators of a successful relationship included having a diverse network of mentors filling different roles, mentor-mentee relationship management, and confidence. Among 187 survey respondents, the primary uses of an inter-institutional mentoring program were career development planning and oversight, goal-setting, and networking., Conclusions: In this mixed-methods study, tangible factors for optimizing the mentor-mentee relationship were identified and will inform the development of an adult rheumatology inter-institutional mentoring program., (© 2017, American College of Rheumatology.)

Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are leading causes of morbidity and mortality in systemic sclerosis (SSc). As symptoms are often under-reported in SSc, early screening of ILD and PAH is of paramount importance, and early treatment may be associated with better clinical outcomes. Serologies are particularly helpful in identifying patients at risk for pulmonary involvement. Pulmonary function testing, high-resolution computed tomography of the chest and echocardiography are important tools in the initial screening of these patients. Extensive research has also led to an improved understanding of the mediators involved in the pathogenesis of ILD and PAH. As a result, there have been significant advances in the development of novel targeted therapeutics and an increase in the number of early-phase clinical trials in SSc.

Objective: We previously implicated the lipid mediator lysophosphatidic acid (LPA) as having a role in dermal fibrosis in systemic sclerosis (SSc). The aim of this study was to identify the role of the LPA-producing enzyme autotaxin (ATX), and to connect the ATX/LPA and interleukin-6 (IL-6) pathways in SSc., Methods: We evaluated the effect of a novel ATX inhibitor, PAT-048, on fibrosis and IL-6 expression in the mouse model of bleomycin-induced dermal fibrosis. We used dermal fibroblasts from SSc patients and control subjects to evaluate LPA-induced expression of IL-6, and IL-6-induced expression of ATX. We next evaluated whether LPA-induced ATX expression is dependent on IL-6, and whether baseline IL-6 expression in fibroblasts from SSc patients is dependent on ATX. Finally, we compared ATX and IL-6 expression in the skin of patients with SSc and healthy control subjects., Results: PAT-048 markedly attenuated bleomycin-induced dermal fibrosis when treatment was initiated before or after the development of fibrosis. LPA stimulated expression of IL-6 in human dermal fibroblasts, and IL-6 stimulated fibroblast expression of ATX, connecting the ATX/LPA and IL-6 pathways in an amplification loop. IL-6 knockdown abrogated LPA-induced ATX expression in fibroblasts, and ATX inhibition attenuated IL-6 expression in fibroblasts and the skin of bleomycin-challenged mice. Expression of both ATX and IL-6 was increased in SSc skin, and LPA-induced IL-6 levels and IL-6-induced ATX levels were increased in fibroblasts from SSc patients compared with controls., Conclusion: ATX is required for the development and maintenance of dermal fibrosis in a mouse model of bleomycin-induced SSc and enables 2 major mediators of SSc fibrogenesis, LPA and IL-6, to amplify the production of each other. Our results suggest that concurrent inhibition of these 2 pathways may be an effective therapeutic strategy for dermal fibrosis in SSc., Competing Interests: Drs. Bain and Goulet receive income from and own equity in PharmAkea Inc. Dr. Tager is a member of the scientific advisory board of PharmAkea Inc., (© 2016, American College of Rheumatology.)

Background: IgG4-related disease (IgG4-RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4(+) T cells constitute the major inflammatory cell population in IgG4-RD lesions., Objective: We used an unbiased approach to characterize CD4(+) T-cell subsets in patients with IgG4-RD based on their clonal expansion and ability to infiltrate affected tissue sites., Methods: We used flow cytometry to identify CD4(+) effector/memory T cells in a cohort of 101 patients with IgG4-RD. These expanded cells were characterized by means of gene expression analysis and flow cytometry. Next-generation sequencing of the T-cell receptor β chain gene was performed on CD4(+)SLAMF7(+) cytotoxic T lymphocytes (CTLs) and CD4(+)GATA3(+) TH2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined by using quantitative multicolor imaging., Results: CD4(+) effector/memory T cells with a cytolytic phenotype were expanded in patients with IgG4-RD. Next-generation sequencing revealed prominent clonal expansions of these CD4(+) CTLs but not CD4(+)GATA3(+) memory TH2 cells in patients with IgG4-RD. The dominant T cells infiltrating a range of inflamed IgG4-RD tissue sites were clonally expanded CD4(+) CTLs that expressed SLAMF7, granzyme A, IL-1β, and TGF-β1. Clinical remission induced by rituximab-mediated B-cell depletion was associated with a reduction in numbers of disease-associated CD4(+) CTLs., Conclusions: IgG4-RD is prominently linked to clonally expanded IL-1β- and TGF-β1-secreting CD4(+) CTLs in both peripheral blood and inflammatory tissue lesions. These active, terminally differentiated, cytokine-secreting effector CD4(+) T cells are now linked to a human disease characterized by chronic inflammation and fibrosis., Competing Interests: The authors declare that they have no relevant conflict of interest., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Lysophosphatidic acid (LPA) is an important mediator of pulmonary fibrosis. In blood and multiple tumor types, autotaxin produces LPA from lysophosphatidylcholine (LPC) via lysophospholipase D activity, but alternative enzymatic pathways also exist for LPA production. We examined the role of autotaxin (ATX) in pulmonary LPA production during fibrogenesis in a bleomycin mouse model. We found that bleomycin injury increases the bronchoalveolar lavage (BAL) fluid levels of ATX protein 17-fold. However, the LPA and LPC species that increase in BAL of bleomycin-injured mice were discordant, inconsistent with a substrate-product relationship between LPC and LPA in pulmonary fibrosis. LPA species with longer chain polyunsaturated acyl groups predominated in BAL fluid after bleomycin injury, with 22:5 and 22:6 species accounting for 55 and 16% of the total, whereas the predominant BAL LPC species contained shorter chain, saturated acyl groups, with 16:0 and 18:0 species accounting for 56 and 14% of the total. Further, administration of the potent ATX inhibitor PAT-048 to bleomycin-challenged mice markedly decreased ATX activity systemically and in the lung, without effect on pulmonary LPA or fibrosis. Therefore, alternative ATX-independent pathways are likely responsible for local generation of LPA in the injured lung. These pathways will require identification to therapeutically target LPA production in pulmonary fibrosis.-Black, K. E., Berdyshev, E., Bain, G., Castelino, F. V., Shea, B. S., Probst, C. K., Fontaine, B. A., Bronova, I., Goulet, L., Lagares, D., Ahluwalia, N., Knipe, R. S., Natarajan, V., Tager, A. M. Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis., (© FASEB.)

Objective: To determine perceived barriers to and facilitators of a career in rheumatology research, examine factors leading rheumatologists to leave an academic research career, and solicit ways to best support young physician-scientists., Methods: A web-based survey was conducted among the domestic American College of Rheumatology (ACR) membership from January through March 2014. Inclusion criteria were ACR membership and an available e-mail address. Non-rheumatologists were excluded. The survey assessed demographics, research participation, barriers to and facilitators of a career in research, reasons for leaving a research career (when applicable), and ways in which the ACR could support junior investigators. Content analysis was used to extract relevant themes., Results: Among 5,448 domestic ACR members, 502 responses were obtained (9.2% response rate). After exclusions (38 incomplete, 2 duplicates, 32 non-rheumatologists), 430 responses were analyzed. Participants included fellows, young investigators, established investigators, mentors, clinicians, and those who previously pursued a research career but have chosen a different career path. Funding and mentoring were the most highly ranked barriers and facilitators. Protection from clinical and administrative duties, institutional support, and personal characteristics such as resilience and persistence were also ranked highly. The most commonly cited reasons for leaving an academic research career were difficulty obtaining funding and lack of department or division support., Conclusion: This is the first study to examine barriers to and facilitators of a career in rheumatology research from the perspectives of diverse groups of rheumatologists. Knowledge of such barriers and facilitators may assist in designing interventions to support investigators during vulnerable points in their career development., (© 2015, American College of Rheumatology.)

Objective: The impact and natural history of connective tissue disease related interstitial lung disease (CTD-ILD) are poorly understood; and have not been previously described from the patient's perspective. This investigation sought insight into CTD-ILD from the patients' perspective to add to our knowledge of CTD-ILD, identify disease-specific areas of unmet need and gather potentially meaningful information towards development of disease-specific patient-reported outcome measures (PROMs)., Methods: A mixed methods design incorporating patient focus groups (FGs) querying disease progression and life impact followed by questionnaires with items of importance generated by >250 ILD specialists were implemented among CTD-ILD patients with rheumatoid arthritis, idiopathic inflammatory myopathies, systemic sclerosis, and other CTD subtypes. FG data were analyzed through inductive analysis with five independent analysts, including a patient research partner. Questionnaires were analyzed through Fisher's Exact tests and hierarchal cluster analysis., Results: Six multicenter FGs included 45 patients. Biophysiologic themes were cough and dyspnea, both pervasively impacting health related quality of life (HRQoL). Language indicating dyspnea was unexpected, unique and contextual. Psycho-social themes were Living with Uncertainty, Struggle over Self-Identity, and Self-Efficacy - with education and clinician communication strongly emphasised. All questionnaire items were rated 'moderately' to 'extremely' important with 10 items of highest importance identified by cluster analysis., Conclusion: Patients with CTD-ILD informed our understanding of symptoms and impact on HRQoL. Cough and dyspnea are central to the CTD-ILD experience. Initial FGs have provided disease-specific content, context and language essential for reliable PROM development with questionnaires adding value in recognition of patients' concerns.

Systemic sclerosis is a heterogeneous disease of unknown etiology with limited effective therapies. It is characterized by autoimmunity, vasculopathy, and fibrosis and is clinically manifested by multiorgan involvement. Interstitial lung disease is a common complication of systemic sclerosis and is associated with significant morbidity and mortality. The diagnosis of interstitial lung disease hinges on careful clinical evaluation and pulmonary function tests and high-resolution computed tomography. Effective therapeutic options are still limited. Several experimental therapies are currently in early-phase clinical trials and show promise., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose of Review: To summarize the recent advances in understanding the novel cytokine pathways, intracellular signaling molecules, cell-fate decisions, cellular aging and senescence, and the cross-talk of effector cells and the extracellular matrix (ECM) in the pathogenesis of systemic sclerosis (SSc) fibrosis., Recent Findings: Studies from the animal models and human beings implicate novel molecular pathways such as Wnts, the chemokines, chemokine (C-X-C motif) ligand 4 and chemokine (C-C motif) ligand 2, and the lipid mediators lysophosphatidic acid and sphingosine-1-phosphate in the pathogenesis of SSc. These signals, coupled with the mesenchymal cell-fate decisions, contribute to aberrant fibroblast activation and myofibroblast accumulation. The resulting deposition and remodeling of ECM alters the biomechanical environment, and leads to further cross-talk of mechanical signals with biochemical mediators such as focal adhesion kinase, integrin signaling, and Yes-associated protein-transcriptional coactivator with PDZ-binding motif signaling pathways., Summary: Progress in understanding the cellular, molecular, and biomechanical regulators of fibrosis has led to the identification of novel targets for interrupting the fibrotic process in SSc. Efforts to antagonize cytokine pathways, affect mesenchymal cell fates, attenuate senescence, and clear activated myofibroblasts, along with modifying the ECM mechanical environment, may ultimately lead to effective therapies in SSc.

Rationale: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities., Methods: The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF)., Results: A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed., Conclusion: Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Systemic sclerosis (SSc) is a clinically heterogeneous orphan disease of unknown etiology and no effective therapy. It is characterized by protean manifestations, an unpredictable disease course and variable outcomes. Clinical manifestations reflect underlying autoimmunity, small vessel vasculopathy and progressive multi-organ fibrosis. Predicting disease progression, pattern and severity of complications and response to therapy in SSc remain major challenges both for the management of patients and for the development of effective disease-modifying therapies. This review summarizes contemporary understanding of novel and emerging biomarkers for SSc. We focus on the development of new classification criteria, the utility of SSc-specific autoantibodies as diagnostic and prognostic markers, and on biomarkers for skin and lung involvement. Finally, we review genome-wide expression analysis as a tool to predict therapeutic responses. We anticipate that the development, validation and application of these biomarkers, singly or more likely in combination, will have a transformative impact in SSc, informing early diagnosis, classification and management, as well as the design, execution and interpretation of clinical trials of novel therapeutic agents.

Purpose of Review: Lipid mediators including the lysophospholipids, sphingolipids and eicosanoids have long been implicated in inflammation, cancer and numerous other diseases. Over the last decade, new research suggests a role for these mediators in fibrosis., Recent Findings: Recent developments in the study of fibrotic mediators have centered on lysophospholipids and eicosanoids. New research is evaluating metabolic-profiling strategies to quantitatively measure lipid mediators in human plasma. Lysophosphatidic acid receptor antagonists are currently under development with early phase trials scheduled for idiopathic pulmonary fibrosis and scleroderma dermal fibrosis. Eicosanoids have long been implicated in maintaining tissue homeostasis, and the balance of profibrotic and antifibrotic effects has drawn attention in recent years. Targeting the prostanoids, specifically PGE2 and PGI2, as well as the leukotrienes is now being considered for antifibrotic therapies., Summary: Lipid mediators have significant roles in many disease processes. Significant research now suggests a critical role for these mediators in the pathogenesis of fibrosis. Targeting these mediators is a promising area of drug discovery.

Objective: Scleroderma (systemic sclerosis [SSc]), is characterized by progressive multiorgan fibrosis. We recently implicated lysophosphatidic acid (LPA) in the pathogenesis of pulmonary fibrosis. The purpose of the present study was to investigate the roles of LPA and two of its receptors, LPA₁ and LPA₂, in dermal fibrosis in a mouse model of SSc., Methods: Wild type (WT), and LPA₁-knockout (KO) and LPA₂-KO mice were injected subcutaneously with bleomycin or phosphate buffered saline (PBS) once daily for 28 days. Dermal thickness, collagen content, and numbers of cells positive for α-smooth muscle actin (α-SMA) or phospho-Smad2 were determined in bleomycin-injected and PBS-injected skin. In separate experiments, a novel selective LPA₁ antagonist AM095 or vehicle alone was administered by oral gavage to C57BL/6 mice that were challenged with 28 daily injections of bleomycin or PBS. AM095 or vehicle treatments were initiated concurrently with, or 7 or 14 days after, the initiation of bleomycin and PBS injections and continued to the end of the experiments. Dermal thickness and collagen content were determined in injected skin., Results: The LPA₁ -KO mice were markedly resistant to bleomycin-induced increases in dermal thickness and collagen content, whereas the LPA₂-KO mice were as susceptible as the WT mice. Bleomycin-induced increases in dermal α-SMA+ and phospho-Smad2+ cells were abrogated in LPA₁-KO mice. Pharmacologic antagonism of LPA₁ with AM095 significantly attenuated bleomycin-induced dermal fibrosis when administered according to either a preventive regimen or two therapeutic regimens., Conclusion: These results suggest that LPA/LPA₁ pathway inhibition has the potential to be an effective new therapeutic strategy for SSc, and that LPA₁ is an attractive pharmacologic target in dermal fibrosis., (Copyright © 2011 by the American College of Rheumatology.)

Objective: We hypothesized that multi-disciplinary assessment of patients with interstitial lung disease (ILD) would lead to improved diagnosis and management., Methods: Our multi-disciplinary ILD group evaluated 50 patients referred to our tertiary care practice over a 12-month period. Evaluation consisted of independent assessments by a pulmonologist and rheumatologist, including complete history and physical examination, review of laboratory data, as well as review of imaging and pathological specimens in conjunction with a radiologist and pathologist experienced in ILD. Therapy was initiated or changed in collaboration with the referring physicians., Results: Mean age was 65 years for patients with rheumatic or CTD-related ILD (CTD-ILD) and 70 years for those with idiopathic pulmonary fibrosis (IPF). The final diagnosis after evaluation in the clinic was 25 patients with CTD-ILD, 15 patients with IPF and 10 patients with other forms of lung disease. Of the patients with a final diagnosis of CTD-ILD, 28% were referred with a diagnosis of IPF. Among those referred with CTD-ILD, 36% had their diagnosis changed to an alternate CTD-ILD. In total, the diagnosis was changed in 54% of patients who presented to the ILD clinic. Changes in therapy occurred in 80% of patients with CTD-ILD and in 27% of patients with IPF., Conclusion: A multi-disciplinary ILD clinic offers patients an innovative mode of health-care delivery that can enhance diagnosis, affect treatment regimens and improve quality of care. Rheumatologists play a significant role in the clinical care of these patients and should evaluate all patients with ILD.

Interstitial lung disease (ILD) is a challenging clinical entity associated with multiple connective tissue diseases, and is a significant cause of morbidity and mortality. Effective therapies for connective tissue disease-associated interstitial lung disease (CTD-ILD) are still lacking. Multidisciplinary clinics dedicated to the early diagnosis and improved management of patients with CTD-ILD are now being established. There is rapid progress in understanding and identifying the effector cells, the proinflammatory and profibrotic mediators, and the pathways involved in the pathogenesis of CTD-ILD. Serum biomarkers may provide new insights as risk factors for pulmonary fibrosis and as measures of disease progression. Despite these recent advances, the management of patients with CTD-ILD remains suboptimal. Further studies are therefore urgently needed to better understand these conditions, and to develop effective therapeutic interventions.