Early Mortality in a Multinational Systemic Sclerosis Inception Cohort.

OBJECTIVE: To determine mortality and causes of death in a multinational inception cohort of subjects with systemic sclerosis (SSc). METHODS: We quantified mortality as standardized mortality ratio (SMR), years of life lost, and percentage mortality in the first decade of disease. The inception cohort comprised subjects recruited within 4 years of disease onset. For comparison, we used a prevalent cohort, which included all subjects irrespective of disease duration at recruitment. We determined a single primary cause of death (SSc related or non-SSc related) using a standardized case report form, and we evaluated predictors of mortality using multivariable Cox regression. RESULTS: In the inception cohort of 1,070 subjects, there were 140 deaths (13%) over a median follow-up of 3.0 years (interquartile range 1.0-5.1 years), with a pooled SMR of 4.06 (95% confidence interval [95% CI] 3.39-4.85), up to 22.4 years of life lost in women and up to 26.0 years of life lost in men, and mortality in the diffuse disease subtype of 24.2% at 8 years. In the prevalent cohort of 3,218 subjects, the pooled SMR was lower at 3.39 (95% CI 3.06-3.71). In the inception cohort, 62.1% of the primary causes of death were SSc related. Malignancy, sepsis, cerebrovascular disease, and ischemic heart disease were the most common non-SSc-related causes of death. Predictors of early mortality included male sex, older age at disease onset, diffuse disease subtype, pulmonary arterial hypertension, and renal crisis. CONCLUSION: Early mortality in SSc is substantial, and prevalent cohorts underestimate mortality in SSc by failing to capture early deaths, particularly in men and those with diffuse disease.

Clinical correlates of monospecific anti-PM75 and anti-PM100 antibodies in a tri-nation cohort of 1574 systemic sclerosis subjects.

OBJECTIVE: Autoantibodies directed against the two principal antigens of the human exosome complex, PM75 and PM100, are present in systemic sclerosis (SSc) sera and have been associated with myositis and calcinosis. However, there is a paucity of data on the clinical correlates of these autoantibodies separately and in the absence of other SSc-specific antibodies. The aim of this study was to assess the clinical correlates of monospecific anti-PM75 and anti-PM100 in SSc. METHODS: A tri-nation cohort of 1574 SSc subjects was formed, clinical variables were harmonized and sera were tested for anti-PM75 and anti-PM100 antibodies using a line immunoassay. RESULTS: Forty-eight (3.0%) subjects had antibodies against PM75 and 18 (1.1%) against PM100. However, only 16 (1%) had monospecific anti-PM75 antibodies and 11 (0.7%) monospecific anti-PM100 antibodies (i.e. in isolation of each other and other SSc-specific antibodies). Monospecific profiles of each autoantibody included more calcinosis. An increased frequency of myositis was only seen in subjects positive for both anti-PM75 and anti-PM100 antibodies. Lung disease was only associated with anti-PM75 and subjects with anti-PM100 antibodies had better survival compared to other antibody subsets. CONCLUSION: The prevalence of monospecific anti-PM75 and anti-PM100 antibodies in this large SSc cohort was low. Disease features associated with anti-PM/Scl antibodies may depend on particular and possibly multiple antigen specificities. However, due to the small samples, these results need to be interpreted with caution. International collaborations are key to understanding the clinical correlates of uncommon serological profiles in SSc.

The Canadian Systemic Sclerosis Oral Health Study IV: oral radiographic manifestations in systemic sclerosis compared with the general population.

OBJECTIVE: The aim of this study was to compare oral radiologic abnormalities associated with systemic sclerosis (SSc) against abnormalities in the general population. STUDY DESIGN: Patients with SSc and healthy controls were enrolled in a multi-site cross-sectional study. Included in the radiology examination were a panoramic radiograph, four bitewings, and an anterior mandibular periapical radiograph. Radiographs were evaluated by two oral and maxillofacial radiologists tested for interobserver and intraobserver reliability. Chi-squared tests, Fisher exact tests, and Mann Whitney U tests were used to summarize the radiologic manifestations of patients and controls. RESULTS: We assessed 163 SSc patients and 231 controls. Widening of the periodontal ligament space (PLS) (P < .001), with higher percentage of teeth with PLS widening (P < .001), was significantly more frequent in patients with SSc than in controls. The most significant differences between the two groups were found in the molars and premolars (P < .001). Moreover, 26% of the patients with SSc had a periapical PLS greater than 0.19 mm compared with 13% of the controls (P = .003). Patients with SSc had significantly more erosions compared with controls (14.5% vs. 3.6%; P < .001), mostly in the condyles (P = .022), coronoid processes (P = .005) and other locations (P = .012). CONCLUSION: Patients with SSc had more teeth with PLS widening and erosions of the mandible compared with controls.

Thinking outside the box--The associations with cutaneous involvement and autoantibody status in systemic sclerosis are not always what we expect.

OBJECTIVE: To describe the clinical characteristics and survival of anti-topoisomerase antibody positive (ATA+) limited cutaneous systemic sclerosis (lcSSc) and anti-centromere antibody positive (ACA+) diffuse cutaneous systemic sclerosis (dcSSc) patients in a large, multicenter SSc cohort. METHODS: Data from subjects in the Canadian Scleroderma Research Group (CSRG) cohort were extracted. Descriptive statistics were used to summarize the baseline characteristics, including sociodemographic, clinical and serological features of lcSSc and dcSSc, according to ATA+ and ACA+ subsets. Kaplan-Meier analysis was performed to investigate survival by subsets. RESULTS: Of the 551 subjects included in this study, 52 (9.4%) had ATA+ lcSSc and 91 (16.5%) had ACA+ dcSSc. Demographic and visceral organ involvement (e.g., gastrointestinal symptoms, interstitial lung disease, pulmonary hypertension, and scleroderma renal crisis) was associated with serologic status more so than with skin subset. On the other hand, calcinosis, joint and peripheral vascular manifestations were associated with skin rather than antibody status. Survival was associated with both skin and autoantibody subsets, with ATA + dcSSc associated with the worse survival compared to ATA+ lcSSc (p = 0.0115), ACA+ lcSSc (p = 0.0216) and ACA+ dcSSc (p = 0.0313). CONCLUSION: This study provides evidence that subsetting using antibody markers in addition to extent of skin involvement may predict clinical outcomes better than skin or serology alone in SSc. These findings can inform ongoing efforts to define more robust SSc subsets compared to those based on the extent of skin involvement or serology alone.

The Canadian systemic sclerosis oral health study II: the relationship between oral and global health-related quality of life in systemic sclerosis.

OBJECTIVE: Both oral and global health-related quality of life (HRQoL) are markedly impaired in SSc. In this study we aimed to determine the degree of association between oral HRQoL and global HRQoL in SSc. METHODS: Subjects were recruited from the Canadian Scleroderma Research Group registry. Global HRQoL was measured using the Medical Outcomes Trust 36-item Short Form Health Survey (SF-36) and oral HRQoL with the Oral Health Impact Profile (OHIP). The Medsger Disease Severity Score was used to determine organ involvement. Multivariate regression models determined the independent association of the OHIP with the SF-36 after adjusting for confounders. RESULTS: This study included 156 SSc subjects. The majority (90%) were women, with a mean age of 56 years, mean disease duration 13.8 years (s.d. 8.5) and 29% of the subjects had dcSSc. Mean total OHIP score was 40.8 (s.d. 32.4). Mean SF-36 mental component summary (MCS) score was 49.7 (s.d. 11.1) and physical component summary (PCS) score was 37.0 (s.d. 10.7). In adjusted analyses, the total OHIP score was significantly associated with the SF-36 MCS and PCS, accounting for 9.7% and 5.6% of their respective variances. Measures of disease severity were not related to OHIP score. CONCLUSION: Oral HRQoL in SSc is independently associated with global HRQoL. Oral HRQoL, however, is not related to physician-assessed disease severity. This suggests that physicians may be disregarding issues related to oral health. HRQoL is an additional dimension of HRQoL not captured by generic instruments such as the SF-36.

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.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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%. CONCLUSION: 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.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 (ß = -43.32; 95% confidence interval [95% CI] -80.89, -5.75), but not with disease severity (ß = -2.51; 95% CI -8.75, 3.73). Decreased interincisal distance was related to disease severity (ß = -1.02; 95% CI -1.63, -0.42) and the modified Rodnan skin thickness score (ß = -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. CONCLUSION: 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.

Systemic sclerosis sine scleroderma: a multicenter study of 1417 subjects.

OBJECTIVE: To describe the clinical and serological features of systemic sclerosis sine scleroderma (ssSSc) in a multicentered SSc cohort. METHODS: Data from 1417 subjects in the Canadian Scleroderma Research Group registry were extracted to identify subjects with ssSSc, defined as SSc diagnosed by an expert rheumatologist, but without any sclerodactyly or skin involvement prior to baseline study visit or during followup. Clinical and serological features of ssSSc subjects were compared to limited (lcSSc) and diffuse cutaneous SSc (dcSSc) subjects. RESULTS: At the first registry visit, only 57 subjects (4.0%) were identified as having ssSSc. Of these, 30 (2.1%) were reclassified as lcSSc within 1.9 years. Thus, only 27 ssSSc subjects (1.9%) remained, with mean followup of 2.4 years. Clinical profiles of ssSSc were generally similar or milder compared to lcSSc, and milder than dcSSc, including rates of interstitial lung disease (25.9% ssSSc, 25.4% lcSSc, 40.3% dcSSc). Patients with ssSSc had serological profiles similar to those with lcSSc, including high rates of anticentromere antibodies (50.0% ssSSc, 47.5% lcSSc, 12.1% dcSSc), and low rates of antitopoisomerase I (16.7% ssSSc, 7.0% lcSSc, 21.8% dcSSc) and anti-RNA polymerase III (0 ssSSc, 11.1% lcSSc, 34.9% dcSSc). CONCLUSION: The condition ssSSc is rare and resembles lcSSc. These observations suggest that ssSSc is most likely a forme fruste of lcSSc, and that the absence of skin involvement may in part be related to misclassification arising from early or subtle skin involvement. There is little evidence to consider ssSSc as a distinct clinical or serological subset of SSc.

Absence of an association between anti-Ro antibodies and prolonged QTc interval in systemic sclerosis: a multicenter study of 689 patients.

OBJECTIVE: To examine the association between anti-Ro antibodies, namely anti-Ro60/SS-A and anti-Ro52/TRIM21, together and separately, and a prolonged QT interval corrected for heart rate (QTc) in systemic sclerosis (SSc) patients. METHODS: A total of 689 SSc patients enrolled in a multicenter cohort study underwent a 12-lead resting EKG at baseline. The QTc interval was measured, and a QTc ≥ 440ms was considered prolonged. Detailed clinical data and sera of these patients were collected and positivity for anti-Ro60/SS-A and anti-Ro52/TRIM21 antibodies was determined using an addressable laser bead immunoassay (ALBIA). RESULTS: QTc prolongation was common in this SSc cohort (25%). In a univariate analysis, Ro antibodies, together or separately, were not associated with prolongation of the QTc interval [mean difference in QTc in anti-Ro antibody positive versus negative subjects was -2.2ms (p = 0.5748), in anti-Ro60/SS-A antibody positive versus negative subjects was 1.3ms (p = 0.8616), and in anti-Ro52/TRIM21 antibody positive versus negative subjects was -3.3ms (p = 0.4106)]. In a multivariate logistic regression analysis adjusting for possible confounders, there was no association between prolonged QTc and anti-Ro antibodies [odds ratio (OR) = 0.74, 95% confidence interval (CI): 0.45, 1.22], anti-Ro60/SS-A antibodies (OR = 1.57, 95% CI: 0.72, 3.41), and anti-Ro52/TRIM21 antibodies (OR = 0.76, 95% CI: 0.46, 1.26). However, in both univariate and multivariate analyses, QTc prolongation was associated with longer disease duration, greater disease severity, and the presence of anti-RNA polymerase III antibodies. CONCLUSIONS: QTc prolongation is common in SSc, although anti-Ro antibodies do not seem to be associated with it as is the case in systemic lupus erythematosus. The reasons for this difference as well as the cause of abnormalities in cardiac repolarization in SSc will require additional studies.

Clinical and serologic correlates of anti-PM/Scl antibodies in systemic sclerosis: a multicenter study of 763 patients.

OBJECTIVE: Anti-PM/Scl autoantibodies are found in polymyositis, dermatomyositis, systemic sclerosis (SSc), and systemic autoimmune disease overlap syndromes. PM-1α is a major epitope of the PM/Scl complex, and antibodies against PM-1α can be detected using a validated enzyme-linked immunosorbent assay (ELISA). This study was undertaken to determine the prevalence and identify the clinical correlates of anti-PM-1α antibodies in a large cohort of patients with SSc. METHODS: Serum samples were obtained from 763 patients with SSc enrolled in a multicenter Canadian cohort. The sera were analyzed by ELISA for the presence of antibodies against PM-1α. Associations between the presence of anti-PM-1α antibodies and demographic, clinical, and other serologic manifestations of SSc were investigated. RESULTS: Anti-PM-1α antibodies were present in 55 patients with SSc (7.2%), of whom almost 50% (26 of 55; 3.4% of the overall cohort) had no other SSc-specific antibodies, namely anticentromere, anti-topoisomerase I, and anti-RNA polymerase III. Features positively associated with the presence of anti-PM-1α antibodies included younger age at disease onset, skeletal muscle involvement, calcinosis, inflammatory arthritis, and overlap disease. Interstitial lung disease was less frequent and there were fewer gastrointestinal symptoms present in patients with anti-PM-1α antibodies compared to patients without these antibodies. CONCLUSION: Anti-PM-1α antibodies are relatively common in SSc and are associated with a distinct clinical phenotype, consistent with that described in association with other anti-PM/Scl autoantibodies. Although anti-PM-1α antibodies are not exclusive of other SSc-specific antibodies, they can be present in the absence thereof. Thus, anti-PM-1α antibodies may have considerable diagnostic and prognostic relevance in SSc.

The role of rheumatologists vis-à-vis assessment of traditional cardiovascular risk factors in rheumatoid arthritis.

This study was designed to estimate the burden of care that would be placed on rheumatologists to undertake cardiovascular (CV) risk assessment of traditional CV risk factors in their patients. This cross-sectional study was set in a rheumatology ambulatory clinic of a tertiary care, university hospital. Consecutive rheumatoid arthritis (RA) patients were recruited over 6 weeks and matched 1:1 on age and sex to patients with non-inflammatory problems who presented to the same clinic. CV risk was calculated using the Framingham Risk Score. We recruited 68 RA patients and 64 controls. The distribution of CV risk factors in RA patients and controls was similar. Ten-year Framingham CV risk scores based on traditional risk factors were moderate and similar in RA patients and controls (13.7 and 14.3%, respectively). Nevertheless, the proportion of RA patients with a history of coronary artery disease was more than twice that of controls (13 versus 5%, respectively). Approximately 20% of RA patients and controls did not have a primary care physician. In rheumatology practice, the problem of elevated CV risk due to traditional risk factors is not unique to RA patients. The burden for rheumatologists of undertaking CV risk assessment in their clinic could be considerable. Rheumatologists should manage inflammatory disease and health services should be improved to ensure the optimal management of traditional CV risk factors for all rheumatology patients.

The Canadian systemic sclerosis oral health study: orofacial manifestations and oral health-related quality of life in systemic sclerosis compared with the general population.

OBJECTIVE: The aim of this study was to compare oral abnormalities and oral health-related quality of life (HRQoL) of patients with SSc with the general population. METHODS: SSc patients and healthy controls were enrolled in a multisite cross-sectional study. A standardized oral examination was performed. Oral HRQoL was measured with the Oral Health Impact Profile (OHIP). Multivariate regression analyses were performed to identify associations between SSc, oral abnormalities and oral HRQoL. RESULTS: We assessed 163 SSc patients and 231 controls. SSc patients had more decayed teeth (SSc 0.88, controls 0.59, P = 0.0465) and periodontal disease [number of teeth with pocket depth (PD) >3 mm or clinical attachment level (CAL) ≥5.5 mm; SSc 5.23, controls 2.94, P < 0.0001]. SSc patients produced less saliva (SSc 147.52 mg/min, controls 163.19 mg/min, P = 0.0259) and their interincisal distance was smaller (SSc 37.68 mm, controls 44.30 mm, P < 0.0001). SSc patients had significantly reduced oral HRQoL compared with controls (mean OHIP score: SSc 41.58, controls 26.67, P < 0.0001). Multivariate regression analyses confirmed that SSc was a significant independent predictor of missing teeth, periodontal disease, interincisal distance, saliva production and OHIP scores. CONCLUSION: Subjects with SSc have impaired oral health and oral HRQoL compared with the general population. These data can be used to develop targeted interventions to improve oral health and HRQoL in SSc.

Consensus opinion of a North American Working Group regarding the classification of digital ulcers in systemic sclerosis.

The objectives of this study were to develop a standard classification of digital ulcers (DUs) in systemic sclerosis (SSc) for use in observational or therapeutic studies and to assess the reliability of these definitions as well as of the measurement of ulcer area. Ten North American rheumatologists with expertise in SSc reviewed multiple photos of DUs, examined four SSc subjects with DUs, and came to a consensus on the definitions for digital, active, healed, and indeterminate ulcers. These ten raters then examined the right hand of ten SSc subjects twice and the left hand once to classify ulcers and to measure ulcer area. Weighted and Fleiss kappa were used to calculate intra- and interrater agreement on classification of ulcers, and intraclass correlation coefficient (ICC) was used to assess agreement on ulcer area. Because the traditional ICC calculations relied on a small number of ulcers, ICCs were recalculated using the results of linear mixed models to evaluate the variance components of observations on all the data. Intrarater kappa for classifying DU as not an ulcer/healed ulcer versus active/indeterminate ulcer was substantial (0.76), and interrater kappa was moderate (0.53). The ICC for ulcer area using the linear mixed models was moderate both for intrarater (0.57) and interrater (0.48) measurements. A consensus for the classification of DUs in SSc was developed, and after a training session, rheumatologists with expertise in SSc are able to reliably classify DUs and to measure ulcer area.

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.

Comparison of different measures of diffusing capacity for carbon monoxide (DLCO) in systemic sclerosis.

In systemic sclerosis (SSc), impaired diffusing capacity for carbon monoxide (DLCO) can indicate interstitial lung disease (ILD), pulmonary hypertension (PH), and/or other disease manifestations, including anemia. We undertook this study to compare the various measures of DLCO in the setting of a complex disease like SSc. We analyzed the pulmonary function tests of a cohort of SSc subjects, as a whole and among subjects with isolated PH and ILD separately. Associations were assessed using Spearman correlation coefficients, Student's t tests, and F tests by one-way ANOVA. P values <0.05 were considered statistically significant. This study included 225 subjects (mean age, 57 years; 88 % women; mean disease duration, 9.6 years; 32 % with diffuse disease, 44 % with ILD, and 17 % with PH). Mean percent predicted DLCO values were 75 % for DLCOsb and 83 % for DLCOrb. Adjustment for alveolar volume (VA) resulted in near normalization of both DLCOsb/VAsb (91 %) and DLCOrb/VArb (91 %). Subjects with ILD had significantly lower DLCOsb but not DLCOsb/VAsb, whereas those with PH had significantly lower DLCOsb and DLCOsb/VAsb. Among the various measures of DLCO, DLCOsb had the strongest and most consistent associations with clinical outcomes of interest. Adjusting for alveolar volume dampened the associations except with PH, with which DLCOsb/VAsb was more strongly associated than DLCOsb. Low DLCOsb is the most sensitive measure to detect abnormalities in gas exchange in SSc but reflects both parenchymal lung disease and pulmonary vascular disease. Low DLCOsb/VAsb is more specific for pulmonary vascular disease and should be the preferred measure of gas exchange in SSc.

Systemic sclerosis in Canada's North American Native population: assessment of clinical and serological manifestations.

OBJECTIVE: Certain North American Native (NAN) populations are known to have higher rates of systemic sclerosis (SSc) compared to non-NAN; however, little is known of the specific disease characteristics in this population in Canada. This study compares the clinical and serological manifestations of SSc in NAN and white patients. METHODS: This cross-sectional, multicenter study included subjects enrolled in the Canadian Scleroderma Research Group registry between September 2004 and June 2012. Subjects were evaluated with complete medical histories, physical examinations, and self-questionnaires. Ethnicity was defined by self-report. Disease characteristics were compared between NAN and white patients and multivariate analyses were performed to determine the independent association between ethnicity and various clinical manifestations. RESULTS: Of 1278 patients, 1038 (81%) were white, 71 (6%) were NAN, and 169 (13%) were classified as non-white/non-NAN. There were important differences between NAN and white subjects with SSc. In multivariate analysis adjusting for socioeconomic differences and smoking status, NAN ethnicity was an independent risk factor for the severity of Raynaud phenomenon and more gastrointestinal symptoms, and was associated with a nonsignificant increase in the presence of digital ulcers. CONCLUSION: NAN patients with SSc have a distinct clinical phenotype. Our study provides a strong rationale to pursue further research into genetic and environmental determinants of SSc.

Clinical correlates of CENP-A and CENP-B antibodies in a large cohort of patients with systemic sclerosis.

OBJECTIVE: To study the clinical phenotypes of centromeric proteins (CENP)-A- and CENP-B-positive patients with systemic sclerosis (SSc) and to compare them to anticentromere antibody (ACA)-positive and negative SSc patients. METHODS: Sera samples were collected from 802 patients with SSc enrolled in a multicenter cohort study. Antibodies to CENP-A and B were detected by ELISA, and ACA by indirect immunofluorescence. Associations with clinical and other serological manifestations of SSc were investigated. RESULTS: CENP-A antibodies were detected in 276 (34%), CENP-B in 286 (36%), and ACA in 279 (35%) patients. Patients having ACA, CENP-A, and/or CENP-B resembled each other and differed from the remainder of the cohort in the following respects: older chronologically and at disease onset; more commonly women; more likely to have limited disease and lower skin scores; less likely to have finger ulcers, digital tuft resorption, or finger contractures; more likely to have pulmonary hypertension; less likely to have interstitial lung disease, scleroderma renal crisis, inflammatory arthritis, and inflammatory myositis; and having lower overall disease severity. CENP-A and/or B status was predictive of the extent of skin involvement over time. Patients with limited disease who were CENP-A-negative at baseline were more likely to progress to diffuse disease compared to CENP-A-positive patients (OR 2.55, 95% CI 1.37, 4.85, p = 0.004). CONCLUSION: Clinical immunology laboratories are increasingly using high-throughput ELISA tests for CENP antibodies, with or without ACA detected by indirect immunofluorescence. The phenotype of CENP-A and/or B-positive patients is generally similar to that associated with ACA.

Clinical significance of antibodies to Ro52/TRIM21 in systemic sclerosis.

INTRODUCTION: Autoantibodies to Ro52 recently identified as TRIM21 are among the most common autoantibodies in systemic autoimmune rheumatic diseases, but their clinical association remains poorly understood. We undertook this study to determine the clinical and serologic associations of anti-Ro52/TRIM21 antibodies in patients with systemic sclerosis (SSc). METHODS: Detailed clinical data and sera from 963 patients with SSc enrolled in a multicenter cohort study were collected and entered into a central database. Antibodies to Ro52/TRIM21 and other autoantibodies were detected with an addressable laser-bead immunoassay and different enzyme-linked immunosorbent assay (ELISA) systems. Associations between anti-Ro52/TRIM21 antibodies and clinical and other serologic manifestations of SSc were investigated. RESULTS: Anti-Ro52/TRIM21 antibodies were present in 20% of SSc patients and overlapped with other main SSc-related antibodies, including anti-centromere (by immunofluorescence and centromere protein (CENP)-A and CENP-B ELISA), anti-topoisomerase I, anti-RNA polymerase III, and anti-Pm/Scl antibodies. Anti-Ro52/TRIM21 antibodies were strongly associated with interstitial lung disease (odds ratio (OR), 1.53; 95% confidence interval (CI), 1.11 to 2.12; P = 0.0091) and overlap syndrome (OR, 2.06; 95% CI, 1.01 to 4.19; P = 0.0059). CONCLUSIONS: Anti-Ro52/TRIM21 antibodies were the second most common autoantibodies in this SSc cohort. In SSc, anti-Ro52/TRIM21 antibodies may be a marker of interstitial lung disease and overlap syndrome.