Maureen D. Mayes

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.

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.

High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: Analysis of a two-year, double-blind, randomized, controlled clinical trial

OBJECTIVE To test the hypothesis that systemic sclerosis (SSc) patients taking high-dose D-penicillamine (D-Pen) would have greater softening of skin, lower frequency of renal crisis, and better survival than patients taking low-dose D-Pen. METHODS Seventeen centers enrolled 134 SSc patients with early (< or =18 months) diffuse cutaneous scleroderma into a 2-year, double-blind, randomized comparison of high-dose D-Pen (750-1,000 mg/day) versus low-dose D-Pen (125 mg every other day). All 134 patients were followed up for a mean+/-SD of 4.0+/-1.1 years to assess the frequencies of new-onset scleroderma renal crisis (SRC) and mortality. RESULTS Sixty-eight patients completed 24 months of drug treatment. The course of the modified Rodnan skin thickness score in the 32 high-dose and the 36 low-dose D-Pen completers was not different at 24 months: the skin score dropped 4.8+/-10.3 (mean+/-SD) units in the high-dose group and 6.9+/-8.4 units in the low-dose group (P = 0.384 by t-test; favoring low-dose D-Pen) from 20.4+/-10.3 in the high-dose and 19.9+/-6.6 in the low-dose D-Pen group at study entry. The incidences of SRC and mortality were not different (P > 0.38 by Cox proportional hazards and by chi-square test) in the 66 high-dose patients (8 developed SRC and 8 died) compared with the 68 low-dose patients (10 developed SRC and 12 died). Of the 20 adverse event-related withdrawals, 80% occurred in the high-dose D-Pen group. CONCLUSION The course of the skin score and the frequencies of SRC and mortality in the high-dose D-Pen group were not different from those in the low-dose D-Pen group. Eighty percent of the adverse event-related withdrawals occurred in the high-dose D-Pen patients. Although this study cannot answer the question of whether low-dose D-Pen is effective, it does suggest that there is no advantage to using D-Pen in doses higher than 125 every other day.

Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22–23, rs2056626, P = 2.09 × 10−7 in the discovery samples, P = 3.39 × 10−9 in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 × 10−18), IRF5 (P = 1.86 × 10−13) and STAT4 (P = 3.37 × 10−9) gene regions as SSc genetic risk factors.

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

Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts

OBJECTIVE To determine the frequency with which scleroderma (systemic sclerosis; SSc) recurs in families and the familial relative risk (lambda) in the US. METHODS Family histories of SSc were prospectively surveyed in 3 large US cohorts of SSc patients, 2 in Texas and 1 in Michigan. Diagnoses of familial SSc were verified by rheumatologist evaluation and/or review of medical records. Familial relative risks for first-degree relatives (lambda1) and siblings (lambdas) were calculated using actual reported counts of first-degree relatives in 2 cohorts and recent estimates of SSc prevalence in the US. RESULTS Compared with the estimated prevalence of SSc in the US (2.6 cases/10,000 population [0.026%]), the disease occurred in 1 or more first-degree relatives in 1.5-1.7% of SSc families in the 3 cohorts (or 11 of 703 families [1.6%]), a significant increase. Familial relative risks in first-degree relatives in the 3 cohorts ranged from 10 to 16 (13 combined), and in siblings they ranged from 10 to 27 (15 combined). CONCLUSION SSc occurs significantly more frequently in families with scleroderma (1.6%) than in the general population (0.026%). A positive family history of SSc is the strongest risk factor yet identified for SSc; however, the absolute risk for each family member remains quite low (<1%).

Skin thickness score as a predictor and correlate of outcome in systemic sclerosis: High-dose versus low-dose penicillamine trial

OBJECTIVE To study the clinical implications of a skin thickness score > or =20 at first visit and of softening of sclerodermatous skin in a cohort of systemic sclerosis (SSc) patients with diffuse cutaneous scleroderma. METHODS Skin and visceral involvement were assessed in 134 SSc patients with diffuse scleroderma (mean +/- SD duration of SSc 10 +/- 4 months) as they entered a multicenter drug trial and again at 2 years of followup. Advent of mortality and scleroderma renal crisis (SRC) were assessed during a followup of 4.0 +/- 1.1 years (mean +/- SD). Logistic and linear regression were used to examine the relationship of baseline skin score to morbidity, mortality, and visceral involvement and the relationship of changes in skin score to changes in physical examination, laboratory, and functional variables over 2 years. RESULTS A baseline skin score > or =20 was associated with heart involvement at baseline (odds ratio [OR] 3.10, 95% confidence interval [95% CI] 1.25-7.70) and was predictive of mortality (OR 3.59, 95% CI 1.23-10.55) and SRC (OR 10.00, 95% CI 2.21-45.91) over 4 years. Multivariate linear regression demonstrated that a model with skin score at baseline (P = 0.0078) and changes in large joint contractures (P = 0.0072), tender joint counts (P = 0.0119), handspread (P = 0.0242), and Health Assessment Questionnaire disability index (HAQ-DI) (P = 0.0244) explained the change in skin score over 2 years (R2 = 0.567). Multivariate logistic regression demonstrated that the investigators global assessment of improvement was best explained by a model with skin score and HAQ-DI (R2 = 0.455). CONCLUSION A baseline skin score > or =20 was associated with heart involvement at baseline and predicted mortality and SRC over the subsequent 4 years. Improvement in skin score in these patients with diffuse cutaneous scleroderma was associated with improvement in hand function, inflammatory indices, joint contractures, arthritis signs, overall functional ability, and the examining investigators global assessment of improvement.

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.

Proteome-wide Analysis and CXCL4 as a Biomarker in Systemic Sclerosis

BACKGROUND Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.).