Canadian Scleroderma Research Group Cohort Research Articles

Mammalian target of rapamycin is activated in the kidneys of patients with scleroderma renal crisis.

Scleroderma renal crisis is a rare but serious complication affecting 2%-15% of patients with systemic sclerosis. Despite treatment with angiotensin-converting enzyme inhibitors, outcomes for scleroderma renal crisis patients are still poor. The cellular signaling mechanisms in scleroderma renal crisis are not yet known. Mammalian target of rapamycin, comprised of the subunits mTORC1 and mTORC2, has been shown to be activated in vascular lesions of renal transplant patients with anti-phospholipid antibody syndrome. Given the similarities between the pathophysiology of scleroderma renal crisis and anti-phospholipid antibody syndrome, we hypothesized that the mammalian target of rapamycin pathway would also be activated in the renal vasculature of patients with scleroderma renal crisis. We retrospectively analyzed renal biopsies of five patients with scleroderma renal crisis in the Canadian Scleroderma Research Group cohort. Immunostaining was performed using anti-P-S6RP antibodies to evaluate the phosphorylation of mTORC1, and anti-Rictor and anti-S473 to determine activation of mTORC2. Four of the five patients showed mTORC1 activation in arteriolar endothelial cells, and three of the five patients showed mTORC1 activation in the arterial endothelial cells. Two of four samples showed Rictor expression in the arteriolar and arterial endothelial cells, showing mTORC2 activation. There was no expression of mTORC1 or mTORC2 in samples from two healthy controls. We demonstrate that both mTORC1 and mTORC2 are activated in renal biopsies with typical histologic features of scleroderma renal crisis. Dual mammalian target of rapamycin inhibitors are currently available and in development. These findings could inform further research into novel treatment targets for scleroderma renal crisis.

Clinical correlates of faecal incontinence in systemic sclerosis: identifying therapeutic avenues.

The aim was to establish the prevalence and severity of faecal incontinence (FI) in SSc, its association with other intestinal manifestations and potential predictors of FI, and its impact on quality of life. A multicentre, cross-sectional study of 298 SSc subjects followed in the Canadian Scleroderma Research Group cohort was performed using validated questionnaires: Jorge-Wexner score (an FI severity scale), Bristol stool scale (a visual scale of stool consistency) and FI Quality-of-Life scale. Constipation was defined by the Rome III criteria. Associations between the Jorge-Wexner score and other clinical variables were determined using multivariate regression analyses. Eighty-one (27.2%) subjects had FI, which was mild in 37 (12.4%) and moderate to severe in 44 (14.8%). Most patients had well-formed stools, 111 (38.8%) reported constipation and 38 (13.4%) had been previously treated for small intestinal bacterial overgrowth (SIBO). Variables independently associated with FI were: loose vs well-formed stools [odds ratio (OR) = 7.01, 95% CI: 2.09, 23.51)], constipation (OR = 3.64, 95% CI: 1.61, 8.27, P = 0.002), history of SIBO (OR = 2.97, 95% CI: 1.06, 8.27) and urinary incontinence (OR = 2.45, 95% CI: 1.14, 5.27). Quality of life measured with the FI Quality-of-Life scale was inversely correlated with FI severity (correlation coefficients between -0.602 and -0.702, P < 0.001). FI was common and often severe in SSc. Loose stools, SIBO, constipation and urinary incontinence were strongly associated with FI. Other than targeting anorectal dysfunction, concomitant treatment of clinical correlates could lead to improvement in FI and quality of life in SSc.

Anti-HMGCR antibodies in systemic sclerosis.

The objective of this study was to investigate the frequency of autoantibodies to hydroxymethylglutaryl coenzyme A reductase (HMGCR) in systemic sclerosis (SSc) and associations with inflammatory myositis and statin exposure.This was a cross-sectional, multicenter study of 306 subjects from the Canadian Scleroderma Research Group cohort who had complete data on statin exposure and serology for anti-HMGCR antibodies assayed by an addressable laser bead immunoassay (ALBIA). Descriptive statistics were used to summarize the baseline characteristics of the patients and to compare subjects with and without anti-HMGCR antibodies.Four (1.3%) subjects had anti-HMGCR antibodies. None of the subjects with anti-HMGCR antibodies titers had a history of an inflammatory myositis or overlap with polymyositis/dermatomyositis, compared to 8.6% and 2.0% of those without anti-HMGCR antibodies, respectively. In addition, none of the subjects with anti-HMGCR antibodies had past or current exposure to statins compared to 12% of those with negative titers.Anti-HMGCR antibodies are rare in SSc and are not associated with inflammatory myopathy or statin exposure. Larger studies will be required to confirm these preliminary observations. Nevertheless, we conclude that anti-HMGCR antibodies are unlikely to play a major role in inflammatory myopathy in SSc and anti-HMGCR antibodies can be present in subjects without exposure to statins.

Relationship Between Disease Characteristics and Oral Radiologic Findings in Systemic Sclerosis: Results From a Canadian Oral Health Study.

Systemic sclerosis (SSc; scleroderma) is associated with a wide periodontal ligament (PDL) and mandibular erosions. We investigated the clinical correlates of SSc with these radiologic abnormalities. Subjects from the Canadian Scleroderma Research Group cohort underwent detailed radiologic examinations. Associations between radiologic abnormalities and clinical manifestations of SSc were examined with univariate and multivariate analyses. The study included 159 subjects; 90.6% were women, the mean ± SD age was 56 ± 10 years, diffuse disease was present in 28.3%, and mean ± SD disease duration was 13.7 ± 8.4 years. Widening of the PDL involving at least 1 tooth was present in 38% of subjects, and 14.5% had at least 1 site in the mandible with an erosion. In analyses adjusting for age, disease duration, sex, smoking, and education, we found significant associations between the number of teeth with widening of the PDL and disease severity assessed by the physician global assessment (PGA) (relative risk [RR] 1.19, 95% confidence interval [95% CI] 1.02-1.39, P = 0.028). Analyses replacing the PGA with the skin score, disease subset, or anti-topoisomerase I antibodies confirmed the relationship with indices of disease severity. There was no relationship between either the number of teeth with periodontal disease or the number of missing teeth, and the number of teeth with wide PDL. A smaller interdental distance (RR 0.89, 95% CI 0.82-0.97, P = 0.006), but not disease severity, facial skin score, or ischemia was associated with a larger number of erosions. In SSc, a wide PDL may reflect generalized overproduction of collagen, and mandibular erosions are related to local factors in the oral cavity.

Relationship between disease characteristics and orofacial manifestations in systemic sclerosis: Canadian Systemic Sclerosis Oral Health Study III.

Systemic sclerosis (SSc; scleroderma) is associated with decreased saliva production and interincisal distance, more missing teeth, and periodontal disease. We undertook this study to determine the clinical correlates of SSc with these oral abnormalities. Subjects were recruited from the Canadian Scleroderma Research Group cohort. Detailed dental and clinical examinations were performed according to standardized protocols. Associations between dental abnormalities and selected clinical and serologic manifestations of SSc were examined. One hundred sixty-three SSc subjects were included: 90% women, mean ± SD age 56 ± 11 years, mean ± SD disease duration 14 ± 8 years, 72% with limited cutaneous disease, and 28% with diffuse cutaneous disease. Decreased saliva production was associated with Sjögren's syndrome-related autoantibodies (β = -43.32; 95% confidence interval [95% CI] -80.89, -5.75), but not with disease severity (β = -2.51; 95% CI -8.75, 3.73). Decreased interincisal distance was related to disease severity (β = -1.02; 95% CI -1.63, -0.42) and the modified Rodnan skin thickness score (β = -0.38; 95% CI -0.53, -0.23). The number of missing teeth was associated with decreased saliva production (relative risk [RR] 0.97; 95% CI 0.94, 0.99), worse hand function (RR 1.52; 95% CI 1.13, 2.02), and the presence of gastroesophageal reflux disease (GERD; RR 1.68 [95% CI 1.14, 2.46]). No clinical or serologic variables were correlated with periodontal disease. In SSc, diminished interincisal distance is related to overall disease severity. Decreased saliva production is related to concomitant Sjögren's syndrome antibodies. Tooth loss is associated with poor upper extremity function, GERD, and decreased saliva. The etiology of excess periodontal disease is likely multifactorial and remains unclear.

2013 American College of Rheumatology/European League against rheumatism classification criteria for systemic sclerosis outperform the 1980 criteria: data from the Canadian Scleroderma Research Group.

The goal of this study was to determine the sensitivity of the new 2013 classification criteria for systemic sclerosis (SSc; scleroderma) in an independent cohort of SSc subjects and to assess the contribution of individual items of the criteria to the overall sensitivity. SSc subjects from the Canadian Scleroderma Research Group cohort were assessed. Sensitivity was determined in several subgroups of patients. In patients without the criterion of skin thickening proximal to the metacarpophalangeal (MCP) joints, we recalculated sensitivity after removing the individual criterion. A total of 724 SSc patients were included. Most were women (86%), mean age was 55.8 years, mean disease duration was 10.9 years, and 59% had limited cutaneous SSc (lcSSc). Overall, the sensitivity of the 2013 criteria was 98.3% compared to 88.3% for the 1980 criteria. This pattern was consistent among those with lcSSc (98.8% versus 85.6%), anticentromere antibodies (98.9% versus 79.8%), disease duration ≤3 years (98.7% versus 84.7%), and no skin involvement proximal to the MCP joints (97% versus 60%). In the latter subgroup, removing Raynaud's phenomenon and sclerodactyly from the criteria reduced the sensitivity to 77% and 79%, respectively. Removing both sclerodactyly and puffy fingers reduced the sensitivity to 62%. The 2013 SSc classification criteria classify more SSc patients than the 1980 criteria. The improvement in sensitivity is most striking in those with lcSSc, especially those without skin involvement proximal to the MCP joints. The addition of Raynaud's phenomenon and puffy fingers to the 2013 criteria accounts for important gains in sensitivity.

SAT0330 Juvenile Onset Raynaud's Predicts Good Survival in the Canadian Scleroderma Research Group Cohort

BackgroundJuvenile onset systemic sclerosis is thought to have distinct features compared to adult onset systemic sclerosis (SSc). There is currently little data on patients with juvenile onset of Raynaud's phenomenon...

Myopathy is a poor prognostic feature in systemic sclerosis: results from the Canadian Scleroderma Research Group (CSRG) cohort

Objective: To determine the clinical impact of muscle involvement in a large systemic sclerosis (SSc) cohort.Method: Using the Canadian Scleroderma Research Group (CSRG) database, SSc patients with either elevated creatine kinase (CK) or a prior history of myositis/myopathy were identified. Regression and Kaplan–Meier analyses were performed to determine characteristics associated with muscle involvement in SSc and survival outcome.Results: In 1145 patients with SSc, 5.6% had an elevated CK. This subset was more likely to be male (24.5% in elevated CK vs. 12.6% in normal CK, p < 0.013), younger (52 vs. 56 years, p < 0.045), have diffuse cutaneous SSc (dcSSc; 40.4% vs. 37.9%, p < 0.002), tendon friction rubs (30.0% vs. 13.4%, p < 0.001), and forced vital capacity (FVC) < 70% (23.9% vs. 13.1%, p < 0.039), be ribonucleoprotein (RNP) antibody positive (12.0% vs. 5.0%, p < 0.032), topoisomerase1 (topo1)-antibody positive (26.0% vs. 14.4%, p < 0.026), have a higher modified Rodnan skin score (MRSS; 16.14 vs. 9.81, p < 0.001), and a higher Health Assessment Questionnaire (HAQ) score (0.98 vs. 0.79, p < 0.011). Survival was reduced for patients with elevated CK (p < 0.025). Nearly 10% of patients in the CSRG cohort had a prior history of myositis/myopathy. This subset also had findings similar to those with elevated CK and increased mortality (p < 0.003).Conclusions: Muscle involvement in SSc has a poor prognosis impacting survival, especially in men with early dcSSc with topo1 and RNP autoantibodies and interstitial lung disease (ILD).

Is there an association between Ro52/TRIM21 antibodies and rheumatoid factor in systemic sclerosis?

Autoantibodies to Ro52/TRIM21 are among the most common autoantibodies detected in subjects with systemic autoimmune rheumatic autoimmune diseases (SARD), including systemic sclerosis (SSc) [1–3]. Ro52/TRIM21 is an immunoglobulin-binding protein [4]. It is also an extraordinarily prevalent and antigenic target of autoantibodies. It is part of the Ro/SSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. Recently, it has been shown that Ro52/TRIM21 plays a major role in the destruction of misfolded IgG1. Its C-terminal PRYSPRY domain, also known as B30.2 domain, has been found to be of great importance for its function as a highly specific IgG receptor. Studies have suggested a possible association between anti-Ro52/ TRIM21 antibodies and rheumatoid factor (RF) in Sjogren’s syndrome (SjS) [5, 6]. In a cohort of 187 SjS patients, 37 % were anti-Ro52/TRIM21 positive and 74 % had significantly high RF titers [5]. Similarly, in another study, the prevalence of anti-Ro52/TRIM21 varied from 14.1 % (n = 106) in SSc patients to 97.5 % (n = 40) in SjS, and the mean anti-Ro52/TRIM21 signal intensity was significantly higher in SjS patients who were RF positive [6]. The presence of RF in SSc patients has been described in several studies with a frequency that varies from 12 to 37 % [7–9] and higher in selected SSc subjects (66 % in subjects with rheumatoid arthritis overlap and 59 % in subjects with SjS overlap) [10]. Taking these reports into account, we set out to determine if there was an association between Ro52/TRIM21 and RF in SSc. Sera from 89 anti-Ro52/TRIM21 antibody positive and 89 antibody negative SSc subjects from the Canadian Scleroderma Research Group cohort were selected consecutively. Anti-Ro52/TRIM21 antibodies were detected by an addressable laser bead immunoassay (ALBIA) utilizing a commercially available kit (QUANTAPlex ENA 8, INOVA Diagnostics Inc., San Diego, CA) in a Luminex 100 (Luminex Corp., Austin, TX) platform, the results of which were cross-validated on another kit (Connective13, BMD/FIDIS, Paris, France) in a Luminex 200 (Luminex Corp.) platform, according to protocols previously described [2]. The sera of all study subjects were tested for IgM RF by ELISA (INOVA, San Diego, CA) using a cutoff value for RF set according to the manufacturer’s recommendations at 6 IU/ml. Descriptive statistics and logistic regression were used to analyze the data, using SAS v.9.2 (SAS Institute, USA). After excluding 4 subjects with incomplete datasets, 86 Ro52/TRIM21 autoantibody positive and 88 Ro52/ TRIM21 antibody negative subjects were available for this analysis (Table 1). The overall prevalence of RF was high (45 %), but there was no difference in either Ro52/ The Investigators of the Canadian Scleroderma Research Group is given in ‘‘Appendix’’.

Does cigarette smoking mitigate the severity of skin disease in systemic sclerosis?

Cigarette smoking has significant negative effects on vascular, pulmonary and gastrointestinal outcomes in systemic sclerosis (SSc). The objective of this study was to study the effect of cigarette smoking on the extent of skin disease in SSc. Subjects were patients enrolled in the Canadian Scleroderma Research Group cohort. Smoking history was obtained by patient self-reports. The extent of skin involvement was measured using the modified Rodnan skin score. The effect of smoking on the skin score was assessed using the comprehensive smoking index (CSI), which integrates smoking intensity, duration and time since cessation into a single covariate of smoking effect. The regression model was adjusted for gender, ethnicity and disease duration. This study included 606 SSc patients, of which 87 % were women and 90 % were white; mean disease duration was 11 (±9) years, and mean modified Rodnan skin score was 10 (±9). Of these, 16 % were current, 42 % past and 42 % never smokers. There was a 16 % reduction in skin score (odds ratio 0.84, 95 % confidence interval 0.75, 0.95, p = 0.0029) for every 0.1 unit change in CSI. The effect of smoking on skin disease appeared cumulative and irreversible. Smoking was significantly associated with less extensive skin disease in SSc. This hypothesis-generating study provides new avenues of research, especially insofar as the role of nicotine in SSc is concerned and given that safe nicotine replacement therapy exists.

Cigarette smoking in patients with systemic sclerosis

To determine the effects of cigarette smoking on vascular, gastrointestinal, and respiratory outcomes in patients with systemic sclerosis (SSc). Subjects were patients enrolled in the Canadian Scleroderma Research Group cohort. Smoking history was obtained by patient self-report. The effect of smoking was assessed using multiple regression analysis of each SSc clinical outcome of interest (vascular, gastrointestinal, and respiratory). Smoking was modeled both as categorical variables (current, past, and never) and using the Comprehensive Smoking Index (CSI), which integrates smoking intensity, duration of smoking, and time since cessation into a single covariate of smoking effect. All regression models were adjusted for age, sex, disease duration, and limited or diffuse skin involvement. This study included 606 patients with SSc, of whom 87% were women and 90% were white, and the mean age was 55 years, mean disease duration was 11 years, and 36% had diffuse disease. Of these patients, 16% were current smokers, 42% were past smokers, and 42% were never smokers. The regression analyses showed that smoking had a significant negative effect on almost all vascular, gastrointestinal, and respiratory outcomes. The effects of smoking were in some cases long-lasting (e.g., persistent respiratory abnormalities), and smoking cessation appeared beneficial with respect to some outcomes (e.g., reduced severity of Raynaud's phenomenon). Physicians caring for patients with SSc should prioritize smoking cessation as a recommendation to patients, and resources directed to supporting smoking cessation in patients with SSc should be more readily available.

Assessment of reproductive history in systemic sclerosis

To assess the number of live births in women whose systemic sclerosis (SSc) onset occurred during their reproductive years, and to compare this with general population rates. Within the Canadian Scleroderma Research Group cohort, we identified 320 women whose SSc symptoms began prior to age 50 years. We determined the number of children born in the years following first onset of symptoms. We summed the years of followup from the time of first symptoms in subjects up to age 50 years (or oldest age attained, if the subject was age <49 years). We applied age-specific birth rates for Canadian women to these years of followup in order to determine the expected number of live births for the period. We then calculated the standardized incidence ratio (SIR) of observed to expected live births. In the 320 women studied, the number of live births over the interval since symptom onset was below the expected number (111 live births observed versus 140 expected; SIR 0.79, 95% confidence interval [95% CI] 0.65-0.95). This finding was more prominent in women with diffuse cutaneous disease versus limited cutaneous disease. The mean and median numbers of live births were similar across SSc subgroups based on organ involvement or cyclophosphamide exposure. In repeat analyses, including the reproductive period before SSc symptom onset, the ratio of observed to expected births was 1.23 (95% CI 1.13-1.33). Compared with the general population, fewer live births were noted in women with SSc, but this phenomenon was only apparent in the period after symptom onset.