Systemic sclerosis associated interstitial lung disease: a conceptual framework for subclinical, clinical and progressive disease.

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.

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma.

BACKGROUND: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

Safety and tolerability of nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from the SENSCIS trial.

OBJECTIVES: To characterise the safety and tolerability of nintedanib and the dose adjustments used to manage adverse events in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: In the SENSCIS trial, patients with SSc-ILD were randomised to receive nintedanib 150 mg two times per day or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg two times per day. We assessed adverse events and dose adjustments over 52 weeks. RESULTS: A total of 576 patients received nintedanib (n=288) or placebo (n=288). The most common adverse event was diarrhoea, reported in 75.7% of patients in the nintedanib group and 31.6% in the placebo group; diarrhoea led to permanent treatment discontinuation in 6.9% and 0.3% of patients in the nintedanib and placebo groups, respectively. In the nintedanib and placebo groups, respectively, 48.3% and 12.2% of patients had ≥1 dose reduction and/or treatment interruption, and adverse events led to permanent discontinuation of the trial drug in 16.0% and 8.7% of patients. The adverse events associated with nintedanib were similar across subgroups defined by age, sex, race and weight. The rate of decline in forced vital capacity in patients treated with nintedanib was similar irrespective of dose adjustments. CONCLUSIONS: The adverse event profile of nintedanib in patients with SSc-ILD is consistent with its established safety and tolerability profile in patients with idiopathic pulmonary fibrosis. Dose adjustment is important to minimise the impact of adverse events and help patients remain on therapy.

Factors associated with disease progression in early-diagnosed pulmonary arterial hypertension associated with systemic sclerosis: longitudinal data from the DETECT cohort.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc). In this longitudinal study, we aimed to identify factors associated with an unfavourable outcome in patients with SSc with early PAH (SSc-PAH) from the DETECT cohort. METHODS: Patients with SSc-PAH enrolled in DETECT were observed for up to 3 years. Associations between cross-sectional variables and disease progression (defined as the occurrence of any of the following events: WHO Functional Class worsening, combination therapy for PAH, hospitalisation or death) were analysed by univariable logistic regression. RESULTS: Of 57 patients with PAH (median observation time 12.6 months), 25 (43.9%) had disease progression. The following factors (OR (95% CI)) were associated with disease progression: male gender (4.1 (1.2 to 14.1)), high forced vital capacity % predicted/carbon monoxide lung diffusion capacity (DLCO)% predicted ratio (3.6 (1.2 to 10.7)), high Borg Dyspnoea Index (1.7 (1.1 to 2.6)) and low DLCO% predicted (non-linear relationship). CONCLUSION: More than 40% of early-diagnosed patients with SSc-PAH had disease progression during a short follow-up time, with male gender, functional capacity and pulmonary function tests at PAH diagnosis being associated with progression. This suggests that even mild PAH should be considered a high-risk complication of SSc.

Pulmonary hypertension related to systemic sclerosis: points to consider for clinical trials.

There are proven successful approaches to clinical trial design in pulmonary arterial hypertension (PAH), which in turn have led to the licensing of a number of effective therapies. SSc has been included in trials of World Health Organization Group 1 PAH but has been under-represented. Responses in outcomes as diverse as exercise capacity, quality of life, durability of drug effect and survival have been reduced in comparison with those seen in idiopathic PAH. The PAH community has achieved international and interdisciplinary consensus guidelines for future studies. We consider the diverse outcome measures used in trials in the context of the complexities of scleroderma. An argument is advanced in favour of future trials focused exclusively on SSc but with adaptations of the core outcome measures and trial design templates applicable to more general studies of PAH.

Interstitial lung disease points to consider for clinical trials in systemic sclerosis.

Interstitial lung disease causes major morbidity and mortality in patients with systemic sclerosis (SSc-ILD). Large randomized clinical trials in SSc-ILD have provided important information regarding the feasibility, reliability and validity of outcome measures. Forced vital capacity percentage predicted should be considered as a primary outcome measure, with inclusion of appropriate radiological and patient-reported measures. We provide practical recommendations for trial design in SSc-ILD.

Reliability, validity and responsiveness to change of the Saint George's Respiratory Questionnaire in early diffuse cutaneous systemic sclerosis.

OBJECTIVE: Dyspnoea is a common, multifactorial source of functional impairment among patients with dcSSc. Our objective was to assess the reliability, construct validity and responsiveness to change of the Saint George's Respiratory Questionnaire (SGRQ) in patients with early dcSSc participating in a multicentre prospective study. METHODS: At enrolment and 1 year, patients completed the SGRQ (a multi-item instrument with four scales: symptoms, activity, impact and total), a visual analogue scale (VAS) for breathing and the HAQ Disability Index (HAQ-DI) and underwent 6 min walk distance and pulmonary function tests, physician and patient global health assessments and high-resolution CT (HRCT). We assessed internal consistency reliability using Cronbach's α. For validity we examined the ability of the SGRQ to differentiate the presence vs absence of interstitial lung disease (ILD) on HRCT or restrictive lung disease and evaluated the 1 year responsiveness to change using pulmonary function tests and patient- and physician-reported anchors. Correlation coefficients of 0.24-0.36 were considered moderate and >0.37 was considered large. RESULTS: A total of 177 patients were evaluated. Reliability was satisfactory for all SGRQ scales (0.70-0.93). All scales showed large correlations with the VAS for breathing and diffusing capacity of the lung for carbon monoxide in the overall cohort and in the subgroup with ILD. Three of the four scales in the overall cohort and the total scale in the ILD subgroup showed moderate to large correlation with the HAQ-DI and the predicted forced vital capacity (r = 0.33-0.44). Each scale discriminated between the presence and absence of ILD and restrictive lung disease (P ≤ 0.0001-0.03). At follow-up, all scales were responsive to change using different anchors. CONCLUSION: The SGRQ has acceptable reliability, construct validity and responsiveness to change for use in a dcSSc population and differentiates between patients with and without ILD.

Twenty-two points to consider for clinical trials in systemic sclerosis, based on EULAR standards.

OBJECTIVE: SSc is clinically and aetiopathogenically heterogeneous. Consensus standards for more uniform trial design and selection of outcome measures are needed. The objective of this study was to develop evidence-based points to consider (PTCs) for future clinical trials in SSc. METHODS: Thirteen international SSc experts experienced in SSc clinical trial design were invited to participate. One researcher with experience in systematic literature review and three trainees were also included. A systematic review using PubMed and the Cochrane Central Register of Controlled Trials was conducted and PTCs when designing clinical trials in SSc were developed. As part of that development we conducted an Internet-based Delphi exercise regarding the main points to be made in the consensus statement. Consensus was defined as achieving a median score of ≥7 of 9. RESULTS: By consensus, the experts decided to develop PTCs for each individual organ system. The current document provides a unifying outline on PTCs regarding general trial design, inclusion/exclusion criteria and analysis. Consensus was achieved regarding all the main points of the PTCs. CONCLUSION: Using European League Against Rheumatism suggestions for PTCs, a general outline for PTCs for controlled clinical trials in SSc was developed. Specific outlines for individual organ systems are to be published separately. This general outline should lead to more uniform and higher-quality trials and clearly delineate areas where further research is needed.

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials.

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.

Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study.

OBJECTIVE: Earlier detection of pulmonary arterial hypertension (PAH), a leading cause of death in systemic sclerosis (SSc), facilitates earlier treatment. The objective of this study was to develop the first evidence-based detection algorithm for PAH in SSc. METHODS: In this cross-sectional, international study conducted in 62 experienced centres from North America, Europe and Asia, adults with SSc at increased risk of PAH (SSc for >3 years and predicted pulmonary diffusing capacity for carbon monoxide <60%) underwent a broad panel of non-invasive assessments followed by diagnostic right heart catheterisation (RHC). Univariable and multivariable analyses selected the best discriminatory variables for identifying PAH. After assessment for clinical plausibility and feasibility, these were incorporated into a two-step, internally validated detection algorithm. Nomograms for clinical practice use were developed. RESULTS: Of 466 SSc patients at increased risk of PAH, 87 (19%) had RHC-confirmed PAH. PAH was mild (64% in WHO functional class I/II). Six simple assessments in Step 1 of the algorithm determined referral to echocardiography. In Step 2, the Step 1 prediction score and two echocardiographic variables determined referral to RHC. The DETECT algorithm recommended RHC in 62% of patients (referral rate) and missed 4% of PAH patients (false negatives). By comparison, applying European Society of Cardiology/European Respiratory Society guidelines to these patients, 29% of diagnoses were missed while requiring an RHC referral rate of 40%. CONCLUSIONS: The novel, evidence-based DETECT algorithm for PAH detection in SSc is a sensitive, non-invasive tool which minimises missed diagnoses, identifies milder disease and addresses resource usage.

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

OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

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

OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSIONS: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

Effect of oxidative stress on protein tyrosine phosphatase 1B in scleroderma dermal fibroblasts.

OBJECTIVE: Platelet-derived growth factor (PDGF) and its receptor, PDGFR, promote fibrosis in systemic sclerosis (SSc; scleroderma) dermal fibroblasts, and such cells in scleroderma skin lesions produce excessive reactive oxygen species (ROS). PDGFR is phosphorylated upon PDGF stimulation, and is dephosphorylated by protein tyrosine phosphatases (PTPs), including PTP1B. This study was undertaken to determine whether the thiol-sensitive PTP1B is affected by ROS in SSc dermal fibroblasts, thereby enhancing the phosphorylation of PDGFR and synthesis of type I collagen. This study also sought to investigate the effect of a thiol antioxidant, N-acetylcysteine (NAC), in SSc. METHODS: Fibroblasts were isolated from the skin of patients with diffuse SSc and normal healthy donors for cell culture experiments and immunofluorescence analyses. A phosphate release assay was used to determine the activity of PTP1B. RESULTS: Levels of ROS and type I collagen were significantly higher and amounts of free thiol were significantly lower in SSc fibroblasts compared to normal fibroblasts. After stimulation with PDGF, not only were PDGFR and ERK-1/2 phosphorylated to a greater extent, but also the ability to produce PTP1B was hampered in SSc fibroblasts. The activity of PTP1B was significantly inactivated in SSc fibroblasts as a result of cysteine oxidation by the raised levels of ROS, which was confirmed by the oxidation of multiple PTPs, including PTP1B, in SSc fibroblasts. Decreased expression of PTP1B in normal fibroblasts led to increased expression of type I collagen. Treatment of the cells with NAC restored the activity of PTP1B, improved the profile of PDGFR phosphorylation, decreased the numbers of tyrosine-phosphorylated proteins and levels of type I collagen, and scavenged ROS in SSc fibroblasts. CONCLUSION: This study describes a new mechanism by which ROS may promote a profibrotic phenotype in SSc fibroblasts through the oxidative inactivation of PTP1B, leading to pronounced activation of PDGFR. The study also presents a novel molecular mechanism by which NAC may act on ROS and PTP1B to provide therapeutic benefit in SSc.

Clinical course of lung physiology in patients with scleroderma and interstitial lung disease: analysis of the Scleroderma Lung Study Placebo Group.

OBJECTIVE: Patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) are thought to have the greatest decline in lung function (forced vital capacity [FVC]% predicted) in the early years after disease onset. The aim of this study was to assess the natural history of the decline in FVC% predicted in patients receiving placebo in the Scleroderma Lung Study and to evaluate possible factors for cohort enrichment in future therapeutic trials. METHODS: Patients randomized to receive placebo (n=79) were divided into 3 groups based on the duration of SSc (0-2 years, 2-4 years, and >4 years). Descriptive statistics and a mixed-effects model were used to analyze the rate of decline in the FVC% predicted over a 1-year period. Additional analyses stratified according to the severity of fibrosis on high-resolution computed tomography (HRCT) were performed, and interactions between disease severity and disease duration were explored. RESULTS: The mean±SD decline in the unadjusted FVC% predicted during the 1-year period was 4.2±12.8%. At baseline, 28.5%, 43.0%, and 28.5% of patients were in the groups with disease durations of 0-2 years, 2-4 years, and >4 years, respectively. The rate of decline in the FVC% predicted was not significantly different across the 3 disease groups (P=0.85). When stratified by baseline fibrosis on HRCT, the rate of decline in the FVC% predicted was statistically significantly greater in the group with severe fibrosis (mean annualized decline in the FVC% predicted 7.2% versus 2.7% in the groups with no or moderate fibrosis; P=0.008). The decline observed in the group with severe fibrosis was most pronounced in those with a relatively short disease duration (0-2 years; annualized decline 7.0%). CONCLUSION: Among patients with SSc-ILD in the Scleroderma Lung Study, the rates of progression of lung disease were similar irrespective of disease duration. The baseline HRCT fibrosis score is a predictor of a future decline in the FVC% predicted in the absence of effective treatment.

Nintedanib in Patients With Autoimmune Disease-Related Progressive Fibrosing Interstitial Lung Diseases: Subgroup Analysis of the INBUILD Trial.

OBJECTIVE: To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease-related interstitial lung diseases (ILDs) with a progressive phenotype. METHODS: The INBUILD trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity percent predicted (FVC%) ≥45%, and diffusing capacity of the lungs for carbon monoxide percent predicted ≥30% to <80%. Patients fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease-related ILDs. RESULTS: Among 170 patients with autoimmune disease-related ILDs, the rate of decline in FVC over 52 weeks was -75.9 ml/year with nintedanib versus -178.6 ml/year with placebo (difference 102.7 ml/year [95% confidence interval 23.2, 182.2]; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively. CONCLUSION: In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease-related ILDs, with AEs that were manageable for most patients.

Acute kidney injury in patients with systemic sclerosis participating in hematopoietic cell transplantation trials in the United States.

Recipients of hematopoietic cell transplantation may be at risk for developing acute kidney injury (AKI), and this risk may be increased in patients who undergo transplantation for severe systemic sclerosis (SSc) due to underlying scleroderma renal disease. AKI after transplantation can increase treatment-related mortality. To better define these risks, we analyzed 91 patients with SSc who were enrolled in 3 clinical trials in the United States of autologous or allogeneic hematopoietic cell transplantation (HCT). Eleven (12%) of the 91 patients with SSc in these studies (8 undergoing autologous HCT, 1 undergoing allogeneic HCT, 1 pretransplantation, 1 given i.v. cyclophosphamide on a transplantation trial) experienced AKI, of whom 8 required dialysis and/or therapeutic plasma exchange. AKI injury in the 9 HCT recipients developed a median of 35 days (range, 0-90 days) after transplantation. Ten of 11 patients with AKI received angiotensin-converting enzyme inhibitor (ACE-I) therapy. The etiology of AKI was attributed to scleroderma renal crisis in 6 patients (including 2 with normotensive renal crisis), to AKI of uncertain etiology in 2 patients, and to AKI superimposed on scleroderma kidney disease in 3 patients. Eight of the 11 patients died, one each because of progression of SSc, multiorgan failure, gastrointestinal and pulmonary bleeding, pericardial tamponade and pulmonary complications, diffuse alveolar hemorrhage, pulmonary embolism, graft-versus-host disease, and malignancy. Limiting nephrotoxins, cautious use of corticosteroids, renal shielding during total body irradiation, strict control of blood pressure, and aggressive use of ACE-Is may be of importance in preventing renal complications after HCT for SSc.

Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial.

OBJECTIVES: Ischaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin receptor antagonist, reduced the occurrence of new DUs by 48%. The present study (RAPIDS-2, for 'RAndomized, double-blind, Placebo-controlled study with bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis') was conducted to more fully evaluate the effects of bosentan treatment on DUs associated with SSc. METHODS: This double-blind, placebo-controlled trial conducted at 41 centres in Europe and North America randomised 188 patients with SSc with at least 1 active DU ('cardinal ulcer') to bosentan 62.5 mg twice daily for 4 weeks and 125 mg twice daily thereafter for 20 weeks (n=98) or matching placebo (n=90; total 24 weeks). The two primary end points were the number of new DUs and the time to healing of the cardinal ulcer. Secondary end points included pain, disability and safety. RESULTS: Over 24 weeks, bosentan treatment was associated with a 30% reduction in the number of new DUs compared with placebo (mean ± standard error: 1.9±0.2 vs 2.7±0.3 new ulcers; p=0.04). This effect was greater in patients who entered the trial with more DUs. There was no difference between treatments in healing rate of the cardinal ulcer or secondary end points of pain and disability. Peripheral oedema and elevated aminotransferases were associated with bosentan treatment. CONCLUSIONS: Bosentan treatment reduced the occurrence of new DUs in patients with SSc but had no effect on DU healing. Bosentan was well tolerated and may be a useful adjunct in the management of patients with SSc with recurrent DUs.

Association of gastrointestinal involvement and depressive symptoms in patients with systemic sclerosis.

OBJECTIVES: SSc-associated gastrointestinal tract involvement (SSc-GIT) is an important predictor of depressive symptoms. University of California at Los Angeles Scleroderma Clinical trial Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) is a 34-item valid instrument that captures GIT symptom severity and impact on quality of life. It has seven GI-specific scales and a total GIT score. The objectives were to assess: (i) whether there is an association between depressed mood with GI symptom scales as assessed by the UCLA SCTC GIT 2.0 instrument; and (ii) to explore which GI-specific symptom scales are associated with depressed mood in patients with SSc. METHODS: One hundred and fifty-two patients with SSc completed the UCLA SCTC GIT 2.0 and the Center for Epidemiologic Studies Short Depression scale (CES-D10). Patients were divided into depressed (CES-D ≥ 10) or non-depressed group (CES-D < 10) and compared using t-test or chi-square test. Multiple linear regression was used to determine associations between GI scales and depressed mood (CES-D). RESULTS: Study participants were 84% female, 78% Caucasian and 40% had depressed mood (CES-D10 ≥ 10). Patients with depressed mood had statistically worse GI scale scores (except fecal soilage) and worse total GIT score (P < 0.05). In the multivariable model reflux and constipation scales were independently associated with worse CES-D scores (P = 0.01-0.06) CONCLUSION: SSc-GIT involvement is associated with depressed mood. Reflux and constipation scales of UCLA-SCTC GIT 2.0 were independently associated with CES-D. Future studies should assess if treatment of GIT symptoms will improve depressed mood in patients with SSc-GIT.