P. Clements

EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR)

Purpose: The optimal treatment of systemic sclerosis (SSc) is a challenge because the pathogenesis of SSc is unclear and it is an uncommon and clinically heterogeneous disease affecting multiple organ systems. The aim of the European League Against Rheumatism (EULAR) Scleroderma Trials and Research group (EUSTAR) was to develop evidence-based, consensus-derived recommendations for the treatment of SSc. Methods: To obtain and maintain a high level of intrinsic quality and comparability of this approach, EULAR standard operating procedures were followed. The task force comprised 18 SSc experts from Europe, the USA and Japan, two SSc patients and three fellows for literature research. The preliminary set of research questions concerning SSc treatment was provided by 74 EUSTAR centres. Results: Based on discussion of the clinical research evidence from published literature, and combining this with current expert opinion and clinical experience, 14 recommendations for the treatment of SSc were formulated. The final set includes the following recommendations: three on SSc-related digital vasculopathy (Raynaud’s phenomenon and ulcers); four on SSc-related pulmonary arterial hypertension; three on SSc-related gastrointestinal involvement; two on scleroderma renal crisis; one on SSc-related interstitial lung disease and one on skin involvement. Experts also formulated several questions for a future research agenda. Conclusions: Evidence-based, consensus-derived recommendations are useful for rheumatologists to help guide treatment for patients with SSc. These recommendations may also help to define directions for future clinical research in SSc.

Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial.

Relaxin, a heterodimer protein with a molecular weight of 6000, is secreted by the corpus luteum and placenta during pregnancy (1, 2). It is structurally related to insulin and insulin-like growth factor I, and its principal physiologic role seems to be fostering the growth and remodeling of the uterus. Relaxin also loosens the pelvic ligaments and ripens the uterine cervix in preparation for parturition (3). The availability of recombinant human relaxin has permitted focused investigations of its effects on connective tissue. Recombinant human relaxin alone reduces synthesis of dermal fibroblast collagen and enhances the effects of interferon- (4). Relaxin attenuates the actions of profibrotic cytokines, including transforming growth factor- and interleukin-1 (5), and increases secretion of dermal fibroblast collagenase while reducing levels of tissue inhibitor of metalloproteinase (5). Of interest, the effect of relaxin on reduced secretion of collagen and tissue inhibitor of metalloproteinase is dose-dependent, whereas its effect on collagenase is optimal in a narrow range of concentrations (5). Finally, recombinant human relaxin prevents the development of bleomycin-induced pulmonary fibrosis in rodents (6), as well as dermal fibrosis in rodent irritant models (7). In vitro and animal studies suggest that recombinant human relaxin might be therapeutically useful for diseases characterized by fibrosis. Systemic sclerosis (scleroderma) is the prototypical fibrosing disease in humans. Although the pathogenesis of systemic sclerosis is not completely understood, tissue fibrosis dominates the clinical features of the disease and largely determines its morbidity and mortality (8). Scleroderma-related fibrosis includes both the fibrotic intimal hyperplasia of small arteries and arterioles (the Raynaud phenomenon, renal crisis, and pulmonary hypertension), as well as extravascular tissue fibrosis (skin, interstitial lung disease, and tendon involvement) (8). The long-term clinical benefit of preventing or reversing fibrosis in systemic sclerosis has not been tested, and no therapies to date have demonstrated such effects (9). Before porcine relaxin was withdrawn from the market in the early 1960s in response to reformed policies of the U.S. Food and Drug Administration (FDA), open case studies showed that it improved scleroderma-related skin change and healed cutaneous ulcers (10). Phase I studies of recombinant human relaxin in patients with diffuse scleroderma have demonstrated that steady-state serum concentrations of relaxin up to 60 times higher than those seen in normal pregnancy could be safely achieved with continuous subcutaneous infusion (11, 12). The most common drug-related adverse events associated with relaxin treatment have been menometrorrhagia and moderate reversible reductions in hemoglobin. In phase I studies, extent and severity of skin thickening as well as patient global assessment and functional status improved over periods of up to 1 year. However, interpretation of these findings has been hampered by short duration of treatment (11) or inadequacies of open-label design (12). We report the results of a randomized, double-blind, controlled clinical trial comparing placebo with recombinant human relaxin, 25 g/kg of body weight per day and 100 g/kg per day, given for 24 weeks in patients with stable, diffuse, moderate to severe scleroderma. Methods Patients Before screening, all patients gave informed consent according to the principles of the Declaration of Helsinki and in compliance with FDA requirements. Patients were recruited through 13-member institutions of the Scleroderma Clinical Trials Consortium. Men and women 18 to 70 years of age were included if they had a history of systemic sclerosis with diffuse scleroderma (defined as skin involvement proximal to the elbows or knees, excluding the face and neck) and less than 5 years had elapsed since onset of the first non-Raynaud sign or symptom. A baseline modified Rodnan skin score of at least 20, or of at least 16 in the case of truncal involvement, was required for inclusion in the treatment phase of the study. Patients were excluded from this phase if their skin score varied by more than 5 points from screening to the first treatment day. We excluded patients who had systemic sclerosis with limited scleroderma (skin involvement restricted to face and neck and sites distal to elbows and knees); eosinophilic fasciitis; eosinophilia myalgia syndrome; or scleroderma in conjunction with any other definable connective tissue disease, such as rheumatoid arthritis, systemic lupus erythematosus, polymyositis, or dermatomyositis. We also excluded patients with a substantial history of environmental exposure to tainted rapeseed oil, vinyl chloride, trichloroethylene, or silica. In addition, patients with renal crisis in the previous 6 months; chronic renal failure; or severe cardiovascular, gastrointestinal, or pulmonary disease were excluded. Patients were required to discontinue putative disease-modifying treatments for scleroderma (including d-penicillamine, cyclophosphamide, cyclosporine, azathioprine, methotrexate, potassium aminobenzoate, photopheresis, colchicine, or any other experimental treatment) at least 4 weeks before beginning treatment with the study drug. Patients were excluded if they were receiving more than 10 mg of prednisone per day or an equivalent dose of another glucocorticoid. Intervention We administered recombinant human relaxin, 25 g/kg per day or 100 g/kg per day, or placebo for 24 weeks by continuous subcutaneous infusion, using microinfusion pumps (Panomat T-Series 5 mL, Disetronic Medical Systems, Inc., Minneapolis, Minnesota). Recombinant human relaxin was produced by Connetics Corp. (Palo Alto, California) in Escherichia coli (13). The placebo was a sterile acetate buffer solution that was identical in composition to the buffer used for relaxin. Patients were randomly assigned to receive placebo or recombinant human relaxin (25 g/kg per day or 100 g/kg per day). Randomization was performed at a centralized data management organization (Pacific Research Associates, Los Altos, California). Biased coin randomization (14, 15) was used to stratify patients on the basis of disease duration ( 2.5 years or>2.5 to 5 years) and use of d-penicillamine in the previous 6 months (16). The same randomization procedure was used to replace patients who withdrew before completing 4 weeks of treatment. Patient prescriptions for the study medication were forwarded to a centralized pharmacy (Coram Healthcare of Northern California, Hayward, California) for preparation of blinded supplies of the study drug. Each patients dose was based on screening body weight. The dose was adjusted only if body weight changed by 10% or more during the study. Treatment was administered over 24 hours for 24 weeks. The infusion site and needle were changed at least every 72 hours. The dosage of 25 g/kg per day was selected on the basis of pharmacokinetic results from earlier studies. We anticipated that it would be safe and well tolerated and would produce steady-state serum concentrations of relaxin that were approximately three- to fivefold greater than those found in human pregnancy (11). On the basis of preclinical and earlier clinical studies, we hypothesized that this serum concentration would have antifibrotic effects. To measure the potential for a doseresponse effect, we selected the dosage of 100 g/kg per day on the basis of safety and tolerability data from earlier clinical studies (11, 12). Continuous subcutaneous infusion was chosen as the mode of administration to eliminate the need for six daily subcutaneous injections, to conserve drug supply, and to mimic the constancy of relaxin concentrations that are usually seen in pregnancy (11). Study Design The objectives of the study were to assess the efficacy, safety, and doseresponse effect of recombinant human relaxin in patients with diffuse scleroderma. The study was conducted as a randomized, double-blind, placebo-controlled, parallel-treatment clinical trial. Assessments The primary measure of efficacy was the modified Rodnan skin score, a clinical evaluation by palpation of skin thickness in 17 body areas (face, chest, abdomen, right and left fingers, hands, forearms, upper arms, thighs, legs, and feet). Each area receives a score of 0 to 3 for degree of thickness (0=normal, 1=mild thickening, 2=moderate thickening, and 3=severe thickening). The total score ranges from 0 to 51. The modified Rodnan skin score has been the standard measure of outcome in recent clinical trials involving scleroderma (16-18). Many recent studies have confirmed that total skin scoring is both accurate (with an interobserver variability of 4.6 units) and reproducible (with an intraobserver variability of 3.1 units) (19, 20). Skin scoring is in many ways an ideal outcome measure for scleroderma because it is accessible, cost-effective, sensitive to change, and, as a measure of fibrosis, directly relevant to the biological process of disease (21). Before the study began, investigators were trained according to the standards of one experienced observer. All skin scoring for each individual patient was performed by a single investigator. Secondary measures of efficacy were the following: maximal oral aperture; maximal hand extension (18); tenderness and swelling of metacarpophalangeal joints (as a unit), wrists, and knees; enumeration of cutaneous ulcers; functional status according to the Health Assessment Questionnaire (HAQ) (22); global disease assessments by patients and investigators; and pulmonary function tests, including lung diffusion capacity and forced vital capacity. Serum relaxin levels were determined by using enzyme immunoassay (6). The presence of antirelaxin antibody was measured in an enzyme immunoassay that used purified recombinant relaxin and affinity-purified antihuman immunoglobulin as the

Esophagitis in scleroderma: Prevalence and risk factors

Of 53 patients with scleroderma (43 women and 10 men) evaluated by esophagoscopy and biopsy, 32 (60%) had erosive esophagitis. Symptoms of heartburn and dysphagia were significantly more frequent in the patients who had erosive esophagitis but often were present in those without this condition. Abnormal motility characterized by loss of peristalsis in the distal esophagus was present in all patients with erosive esophagitis, including the 5 who were asymptomatic. No patient with normal esophageal motility had erosive esophagitis at endoscopy. The patients with erosive esophagitis also had significantly diminished lower esophageal sphincter pressures and increased frequency and duration of gastroesophageal reflux episodes. Stricture was present in 13 of 32 patients with erosive esophagitis and was absent in the other 21 patients. The duration of disease, rate of gastric emptying, and fungal smear and culture were not significantly different in those with or without esophagitis. Treatment of fungal infection for a month had little beneficial effect. The pattern of esophageal motility in scleroderma identifies high and low risk groups for esophagitis and stricture, and can be used to select those who require further investigation, irrespective of symptoms.

European League Against Rheumatism (EULAR) Scleroderma Trial and Research group (EUSTAR) recommendations for the treatment of systemic sclerosis: methods of elaboration and results of systematic literature research

Objective: To describe methods and procedures used for the development of the European League Against Rheumatism (EULAR)/EULAR Scleroderma Trial and Research group (EUSTAR) recommendations for the treatment of systemic sclerosis. In particular, the results of a web-based Delphi exercise aimed at selection of research questions and evidence from systematic literature research, as parts of the development of these recommendations, are presented in detail. Methods: In agreement with the EULAR standard operating procedures a Task Force was created that consisted of the EUSTAR board members, 10 systemic sclerosis (SSc) experts invited from outside the EUSTAR board and representing Europe, the USA and Japan, a clinical epidemiologist, 2 patients with SSc and 3 fellows for literature research. All EUSTAR centres were invited to contribute to the development of recommendations through submission and preliminary selection of the research questions. The systematic literature research was performed using the Pubmed, Medline, EMBASE and Cochrane databases. Retrieved trials were evaluated according to the Jadad classification, and the level of evidence was graded from 1 to 4. Outcome data for efficacy and adverse events were abstracted and effect size, number needed to treat (NNT) and number needed to harm (NNH) were calculated when appropriate. Results: In all, 65 EUSTAR Centres provided 304 research questions concerning SSc treatment. These questions were aggregated, subdivided into 19 treatment categories and then subjected to preliminary selection by a web-based Delphi technique. The final set of 26 research questions was created by the Expert Committee based on the results of the Delphi exercise and the expert’s experience. Conclusions: This paper is a comprehensive summary of the methods we used to build recommendations for the drug treatment of systemic sclerosis, combining an evidence based approach and expert opinion.

Measurement of clinical change in progressive systemic sclerosis: a 1 year double-blind placebo-controlled trial of N-acetylcysteine.

N-acetylcysteine was employed as a therapeutic agent in a 1-year, parallel, double-blind, placebo-controlled, prospective study of 22 patients with progressive systemic sclerosis (PSS). Patients were closely followed-up and were extensively evaluated at baseline, 6 and 12 months. Most parameters remained unchanged during 1 year of study in both the NAC and placebo groups, which showed the need for prolonged studies of drugs in PSS if definitive results are to be obtained. Over the year of the study the diffusing capacity decreased in both groups, while several other parameters measured both increased and decreased. Several simple measures of function and skin distensibility were tested and two (oral aperature and handspread) were reproducible and sensitive enough to measure moderate changes of disease activity. They may be useful in future trials of drug effect in PSS.

Brief report: effect of ambrisentan treatment on exercise-induced pulmonary hypertension in systemic sclerosis: a prospective single-center, open-label pilot study.

OBJECTIVE Exercise-induced pulmonary hypertension (ePH) may represent an early, clinically relevant phase in the spectrum of pulmonary vascular disease. The purpose of this pilot study was to describe the changes in hemodynamics and exercise capacity in patients with systemic sclerosis (SSc) spectrum-associated ePH treated with open-label daily ambrisentan. METHODS Patients were treated with ambrisentan, 5 mg or 10 mg once daily, for 24 weeks. At baseline and 24 weeks, patients with SSc spectrum disorders exercised in a supine position, on a lower extremity cycle ergometer. All patients had normal hemodynamics at rest. We defined baseline ePH as a mean pulmonary artery pressure of >30 mm Hg with maximum exercise and a transpulmonary gradient (TPG) of >15 mm Hg. The primary end point was change in pulmonary vascular resistance (PVR) with exercise. Secondary end points included an improvement from baseline in 6-minute walking distance, health-related quality of life assessments, and cardiopulmonary hemodynamics. RESULTS Of the 12 enrolled patients, 11 completed the study. At 24 weeks there were improvements in mean exercise PVR (85.8 dynes × second/cm(5) ; P = 0.003) and mean distance covered during 6-minute walk (44.5 meters; P = 0.0007). Improvements were also observed in mean exercise cardiac output (1.4 liters/minute; P = 0.006), mean pulmonary artery pressure (-4.1 mm Hg; P = 0.02), and total pulmonary resistance (-93.0 dynes × seconds/cm(5) ; P = 0.0008). Three patients developed resting pulmonary arterial hypertension during the 24 weeks. CONCLUSION Exercise hemodynamics and exercise capacity in patients with SSc spectrum-associated ePH improved over 24 weeks with exposure to ambrisentan. Placebo-controlled studies are needed to confirm whether this is a drug-related effect and to determine optimal therapeutic regimens for patients with ePH.

Clinical and serological comparison of 17 chronic progressive systemic sclerosis (PSS) and 17 CREST syndrome patients matched for sex, age, and disease duration.

This study compares the clinical and serological differences between 17 PSS and 17 carefully matched CREST patients. Patients were matched for sex, age by decade, and, importantly, disease duration (11.2 +/- 9.2 vs. 12.0 +/- 9.3 years). Muscular and skin involvement were greater for the PSS groups (p less than 0.02) and pulmonary involvement was also greater (p less than 0.05), at least for non-smoking PSS patients. On the other hand no clinically significant differences were found between groups for other visceral involvement--including comparisons of gastrointestinal, cardiovascular, and renal involvement. There were also no laboratory differences except in anti-RNP antibody (p less than 0.04).

Multicriteria decision analysis methods with 1000Minds for developing systemic sclerosis classification criteria

OBJECTIVES Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to develop an instrument for collating case data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement among experts on the probability that cases were classified as SSc. STUDY DESIGN AND SETTING A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and reranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICCs). RESULTS Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7), and puffy fingers (5). The ICC across experts was 0.73 [95% confidence interval (CI): 0.58, 0.86] and improved to 0.80 (95% CI: 0.68, 0.90). CONCLUSIONS Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (range, 23-14) and weighted. Our methods reflect the rigors of measurement science and serve as a template for developing classification criteria.

Classification Criteria for Systemic Sclerosis: An ACR-EULAR 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, Raynauds 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.

FRI0396 Double-blind comparison of mycophenolate mofetil and oral cyclophosphamide for treatment of scleroderma-related interstitial lung disease (scleroderma lung study [SLS] II): rationale, design, methods, baseline characteristics and patient disposition

Background Cyclophosphamide (CYC), is the only therapy that has been shown thus far to be efficacious in scleroderma-related interstitial lung disease (SSc-ILD). However, the utility of CYC is constrained by its toxicity, which limits treatment to only ≤1 year. Findings from several uncontrolled studies in small numbers of patients with SSc-ILD (n≤17) suggest that mycophenolate mofetil (MMF) is a safe and effective treatment for SSc-ILD. Methods SLS II is a double-blind, double-dummy, parallel-group randomized controlled trial (DB DD PG RCT) comparing the efficacy and safety of MMF (titrated to 3 g/d over 2 years) versus oral CYC (titrated to 2 mg/kg/d for 1 year followed by placebo for another year) in patients with active SSc-ILD (target enrollment 150 patients). Key eligibility criteria included adults, ≤ 7 yrs, any ground glass opacity (GGO) as an indication of “active” disease, and FVC% between 40-80% predicted. Procedures: Spirometry, lung volumes, DLCO, SGRQ, SF-12, modified Rodnan skin score (mRSS), and cough questionnaire at screening and/or baseline and every 3 months for 2 yrs; BDI (baseline); TDI every 3 months for 2 yrs; HRCT (screening and 2 years ;central reading center); toxicity monitoring. Statistical analysis: Primary endpoints: FVC % pred at 2 yrs, adjusted for baseline FVC % pred and “fibrosis” score on screening HRCT and toxicity outcomes over 2 yrs. Results Baseline results are presented in Table 1. Premature discontinuation of study drug (38/130) – due to drug toxicity (13/38); failure to return for 24-month visits (12/26 due); SAEs (38) – 5 felt to be study-related; 1/130 treatment failure (defined by 15% pred decrease in FVC sustained for ≥1 mo). Conclusions A DB DD RCT of oral CYC for 1 yr versus MMF for 2 yrs in patients with progressive SSc-ILD is feasible with a low rate (10%) of discontinuations due to drug toxicity overall. Extent of ILD on HRCT is significantly, albeit modestly, correlated with physiologic impairment, supporting the use of change in HRCT scores from baseline as a key endpoint. Disclosure of Interest: None Declared