Mary Ellen Csuka

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, 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.

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, 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. 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.

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

Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: A multicenter, placebo-controlled, double-blind study

OBJECTIVE To evaluate the efficacy and tolerability of an oral preparation of iloprost, a prostacyclin analog, in patients with Raynauds phenomenon (RP) secondary to systemic sclerosis (scleroderma). METHODS A multicenter, randomized, parallel-group, placebo-controlled double-blind study was performed at university and community-based medical centers. Patients were randomly assigned to receive either 50 microg of iloprost orally twice daily or an identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures included average total daily duration of RP attacks, average number of RP attacks, and RP condition scored via a standardized daily diary. RESULTS Three hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years [range 18-80]) were enrolled. One hundred fifty seven were assigned to receive iloprost and 151 to receive placebo. One hundred forty-three patients in the iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed to complete all of the followup visits. The mean reduction in the average duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynauds condition score, a patient-completed assessment of the severity of RP attacks, was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P = 0.323). The lack of significant difference between treatment groups did not change when a variety of factors, including use of other vasodilators, duration of disease, classification of scleroderma (limited versus diffuse), or number of baseline digital ulcers were taken into account. Premature withdrawal from the study due to adverse events occurred in 10 patients (6.4%) in the iloprost group and 3 (2.0%) in the placebo group (P = 0.058). CONCLUSION Oral iloprost at a dosage of 50 microg twice daily is no better than placebo for management of RP secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of posttreatment followup.

Recombinant Human Relaxin in the Treatment of Systemic Sclerosis With Diffuse Cutaneous Involvement : A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE A phase II randomized controlled trial of recombinant human relaxin suggested that a dosage of 25 microg/kg/day was safe and clinically effective in improving skin disease and reducing functional disability in scleroderma (systemic sclerosis; SSc). We undertook a large randomized, double-blind, placebo-controlled clinical trial to compare placebo with 10 microg/kg/day and 25 microg/kg/day recombinant human relaxin, given for 24 weeks in patients with stable, diffuse, moderate-to-severe SSc. METHODS Men and women ages 18-70 years with diffuse cutaneous SSc (dcSSc) were administered recombinant human relaxin (10 microg/kg/day or 25 microg/kg/day) or placebo for 24 weeks as a continuous subcutaneous infusion. There was a followup safety visit at week 28. RESULTS The primary outcome measure, the modified Rodnan skin thickness score, was similar among the 3 groups at baseline and at weeks 4, 12, and 24. Secondary outcomes such as functional disability were similar in all 3 groups, while the forced vital capacity decreased significantly in the relaxin groups. The discontinuation of both doses of relaxin at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as doubling of serum creatinine, renal crisis, or grade 3 or 4 essential hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo. CONCLUSION Recombinant relaxin was not significantly better than placebo in improving the total skin score or pulmonary function or in reducing functional disability in patients with dcSSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.

MQX-503, a novel formulation of nitroglycerin, improves the severity of Raynaud's phenomenon: A randomized, controlled trial†

OBJECTIVE Raynauds phenomenon (RP) affects 3-9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX-503, in the treatment of RP in an ambulatory setting. METHODS We conducted a multicenter, randomized, placebo-controlled study with a 2-week single-blind run-in period to determine baseline severity, followed by a 4-week double-blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX-503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynauds Condition Score (RCS; scale 0-10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run-in period in terms of ambient temperature) compared with baseline. RESULTS The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX-503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX-503 had a side effect profile similar to that of placebo. CONCLUSION MQX-503 is well tolerated and more effective than placebo for the treatment of RP.

Infusion of iloprost, a prostacyclin analogue, for treatment of Raynaud's phenomenon in systemic sclerosis.

Iloprost, a stable prostacyclin analogue, was given by intravenous infusion to 29 patients with severe Raynauds phenomenon, 26 of whom had systemic sclerosis (SS), and compared with placebo infusion in a double blind crossover trial. Iloprost significantly lessened the number and the severity of attacks compared with placebo. Nine patients expressed a preference for effectiveness of treatment, eight of these in favour of Iloprost. Thermography failed to show any long term effect of Iloprost. Side effects of headache, flushing, nausea, and vomiting were common, and the inconvenience of intravenous administration may limit its routine use.

Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry.

To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)–associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US.

Exposure to ACE inhibitors prior to the onset of scleroderma renal crisis-results from the international scleroderma renal crisis survey

OBJECTIVE To determine whether exposure to angiotensin-converting enzyme (ACE) inhibitors prior to the onset of scleroderma renal crisis (SRC) leads to worse outcomes of SRC. METHODS Prospective cohort study of incident SRC subjects. The exposure of interest was ACE inhibitors prior to the onset of SRC. The outcomes of interest were death or dialysis during the first year after the onset of SRC. RESULTS A total of 87 subjects with incident SRC were identified and 1-year follow-up data were obtained in 75 (86%) subjects. Overall, 27 (36%) subjects died within the first year and an additional 19 (25%) remained on dialysis 1 year after the onset of SRC. In adjusted analyses, exposure to ACE inhibitors prior to the onset of SRC was associated with an increased risk of death (hazard ratio 2.42, 95% CI 1.02, 5.75, p < 0.05 in the primary analysis and 2.17, 95% CI 0.88, 5.33, p = 0.09 after post-hoc adjustment for pre-existing hypertension). CONCLUSION Overall, the 1-year outcomes of SRC were poor. Prior exposure to ACE inhibitors was associated with an increased risk of death after the onset of SRC, although there was uncertainty around the magnitude of the risk and the possibility of residual confounding could not be ruled out. Further studies will be needed to confirm these findings.

Baseline characteristics and follow-up in patients with normal haemodynamics versus borderline mean pulmonary arterial pressure in systemic sclerosis: results from the PHAROS registry

Background Patients with normal (mean pulmonary arterial pressure (mPAP) ≤20 mm Hg) and borderline mean pulmonary pressures (21–24 mm Hg) are “at risk” of developing pulmonary hypertension (PH). The objectives of this analysis were to examine the baseline characteristics in systemic sclerosis (SSc) with normal and borderline mPAP and to explore long-term outcomes in SSc patients with borderline mPAP versus normal haemodynamics. Methods PHAROS is a multicentre prospective longitudinal cohort of patients with SSc “at risk” or recently diagnosed with resting PH on right heart catheterisation (RHC). Baseline clinical characteristics, pulmonary function tests, high-resolution CT, 2-dimensional echocardiogram and RHC results were analysed in normal and borderline mPAP groups. Results 206 patients underwent RHC (results showed 35 normal, 28 borderline mPAP, 143 resting PH). There were no differences in the baseline demographics. Patients in the borderline mPAP group were more likely to have restrictive lung disease (67% vs 30%), fibrosis on high-resolution CT and a higher estimated right ventricular systolic pressure on echocardiogram (46.3 vs 36.2 mm Hg; p<0.05) than patients with normal haemodynamics. RHC revealed higher pulmonary vascular resistance and more elevated mPAP on exercise (≥30; 88% vs 56%) in the borderline mPAP group (p<0.05 for both). Patients were followed for a mean of 25.7 months and 24 patients had a repeat RHC during this period. During follow-up, 55% of the borderline mPAP group and 32% of the normal group developed resting PH (p=NS). Conclusions Patients with borderline mPAP have a greater prevalence of abnormal lung physiology, pulmonary fibrosis and the presence of exercise mPAP ≥30 mm Hg.