Niall Jones

A comparison of the frequency of antibodies to cyclic citrullinated peptides using a third generation anti-CCP assay (CCP3) in systemic sclerosis, primary biliary cirrhosis and rheumatoid arthritis

The objective was to investigate the frequency of anti-cyclic citrullinated peptides (CCP) antibodies in systemic sclerosis (SSc) and primary biliary cirrhosis (PBC), utilizing a new “third generation” anti-CCP ELISA (anti-CCP3) kit and a conventional anti-CCP2 assay. Patients with PBC, SSc, RA, and normal controls were included in the study. Serum samples were screened for autoantibodies by indirect immunofluorescence (IIF), antibodies to CCP by a second- and third-generation ELISA, antibodies to “scleroderma” antigens (CENP B, Scl-70, PM/Scl and fibrillarin—Scl-34) by a line immunoassay (LIA), and IgM RF by ELISA. The frequency of anti-CCP2 antibodies in SSc and PBC samples was 14.8% (11/74) and 6.2% (5/80), respectively, and the frequency of anti-CCP3 antibodies in SSc was 13.5% (10/74) and in PBC was 3.7% (3/80). By comparison, in the RA group the frequency of anti-CCP3 and anti-CCP2 antibodies was 79.1% (38/48) and 77% (37/48), respectively. Anti-CCP3 ELISA had a sensitivity, specificity, and positive and negative likelihood ratios (LR) of 79% (95% confidence interval [CI] = 64–89%), 93% (95% CI = 88–96%), 11.8 (95% CI = 6.8–20.3), and 0.22 (95% CI = 0.12–0.38), respectively. By comparison, the anti-CCP2 assay had a sensitivity, specificity, and positive and negative LRs of 77% (95% CI = 62–87), 90% (95% CI = 85–94), 8.3 (95% CI = 5.2–13.2), and 0.25 (95% CI = 0.15–0.42), respectively. In patients with SSc, there was an association of anti-CCP2 antibodies with the presence of arthritis, but there was no association of anti-CCP2 or anti-CCP3 with anti-CENP B, anti-Scl 70, or RF. This study confirmed the high specificity and sensitivity of both anti-CCP assays for the diagnosis of RA. The presence of anti-CCP antibodies in SSc was only correlated with the presence of arthritis.

Spontaneous tendon ruptures in patients on chronic dialysis

Large tendon rupture is a rare catastrophic occurrence in dialysis patients. Pathogenesis of this has been variably thought to be due to malnutrition, insufficient dialysis, amyloidosis, chronic acidosis, or hyperparathyroidism. We investigated contributory causes and timing of this complication in 44 dialysis patients (42 hemodialysis and two peritoneal dialysis patients). Five cases were our own; the other 39 were reported in the literature during the last two decades. Data were compared with a hospital database of 916 patients. The patients who experienced tendon ruptures had been on dialysis longer (mean duration, 7.6 years v 4.0 years; P = 0.001), were younger (mean age, 39.7 years v 48.4 years; P = 0.0001), had much higher parathyroid hormone levels (1,802 pg/mL v 202 pg/mL; P = 0.0001), had a higher phosphate level (6.8 mg/dL v 5.9 mg/dL; P = 0.001), had a slightly higher calcium level (9.2 mg/dL v 8.8 mg/dL; P = 0.038), and had a higher alkaline phosphatase level (649 IU/L v 109 IU/L; P = 0.0001) than control patients. Patients with tendon ruptures had no evidence of malnutrition (albumin 3.7 g/dL v 3.8 g/dL; P = 0.237) and had the same acidosis (bicarbonate 22.2 mEq/L v 22.0 mEq/L; P = 0.180). The time on dialysis to rupture was inversely related to the patients age (r = 0.47, P = 0.004). Most patients had evidence of years of poorly controlled hyperparathyroidism with high and increasing levels of parathyroid hormone and alkaline phosphatase. Previous steroid use was also much more common in patients with tendon ruptures, as was radiographic evidence of osteitis fibrosa. The disease led to long hospitalization and prolonged morbidity, with mobility limitations in several patients. Spontaneous large tendon rupture in patients is secondary to hyperparathyroidism; is more common in young patients, particularly if exposed to corticosteroids; leads to long-lasting morbidity; and should be preventable by better supervision and treatment of hyperparathyroidism.

Office capillaroscopy in systemic sclerosis

The aims of this study are to assess the reliability of two office techniques, the ophthalmoscope and the Dermlite® dermatoscope, and to detect nailfold capillaroscopy abnormalities in systemic sclerosis (SSc). Two separate studies were performed. In the first, the nailfolds of two fingers on one hand of 13 SSc patients and two normals were examined by four rheumatologists using an ophthalmoscope. In the second, the nailfolds of the two fingers of each hand of six SSc patients and two normals were examined by six rheumatologists with a Dermlite® dermatoscope. Widefield capillary microscopy was performed by one observer in the ophthalmoscope study to assess validity. The examiners determined the presence or absence of dilated loops, giant capillary loops, and/or avascular areas on each digit. The kappa coefficient was calculated to demonstrate agreement. With the ophtalmoscope, the inter-observer kappa coefficients were 0.43, 0.54, and 0.19; the average intra-observer agreements were 0.61, 0.56, and 0.31; and the ophthalmoscope–microscope agreement were 0.63, 0.52, and <0.1 for dilated capillaries, giant capillaries, and avascular areas, respectively. With the dermatoscope, the kappa values for inter-observer reliability were 0.63, 0.40, and 0.20; and intra-observer reliability was 0.71, 0.55, and 0.40 for dilated capillaries, giant capillaries, and avascular areas, respectively. The ophthalmoscope and the dermatoscope provide moderate to substantial reliability to detect the presence of giant and dilated capillaries but poor inter-observer agreement for avascular areas. The ophthalmoscope is valid when compared to the microscope for detecting giant or dilated capillaries. We conclude that these techniques are useful office tools to detect capillary abnormalities in SSc.

Targeting tumour necrosis factor alleviates signs and symptoms of inflammatory osteoarthritis of the knee

IntroductionInflammation associated with synovial expression of TNFα is a recognised feature of osteoarthritis (OA), although no studies have yet reported beneficial effects of anti-TNFα therapy on clinical manifestations of inflammation in OA.MethodsWe conducted an open-label evaluation of adalimumab over 12 weeks in 20 patients with OA of the knee and evidence of effusion clinically. Inclusion criteria included daily knee pain for the month preceding study enrolment and a summed pain score of 125 to 400 mm visual analogue scale on the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain subscale. The primary outcome was the Osteoarthritis Research Society International/Outcome Measures in Rheumatology Clinical Trials (OARSI/OMERACT) response criterion at week 12. Secondary outcomes included the WOMAC pain score 20% and 50% improvement, WOMAC stiffness and function scores, patient and physician global visual analogue scale, as well as target joint swelling.ResultsTreatment was well tolerated and completed by 17 patients with withdrawals unrelated to lack of efficacy or adverse events. By intention to treat, an OARSI/OMERACT response was recorded in 14 (70%) patients. WOMAC pain 20% and 50% responses were recorded in 14 (70%) patients and eight (40%) patients, respectively. Significant improvement was observed in mean WOMAC pain, stiffness, function, physician and patient global, as well as target joint swelling at 12 weeks (P < 0.0001 for all). After treatment discontinuation, 16 patients were available for assessment at 22 weeks and OARSI/OMERACT response compared with baseline was still evident in 10 (50%) patients.ConclusionTargeting TNFα may be of therapeutic benefit in OA and requires further evaluation in controlled trials.Trial registrationClinicalTrials.gov: NCT00686439.

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.

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.

Anti-Fibrillarin Antibody in African American Patients with Systemic Sclerosis: Immunogenetics, Clinical Features, and Survival Analysis

Objective. Anti-U3-RNP, or anti-fibrillarin antibodies (AFA), are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. We examined the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc. Methods. Overall, 278 AA patients with SSc and 328 unaffected AA controls were enrolled from 3 North American cohorts. Clinical features, autoantibody profile, and HLA class II genotyping were determined. To compare clinical manifestations, relevant clinical features were adjusted for disease duration. Cox proportional hazards regression was used to determine the effect of AFA on survival. Results. Fifty (18.5%) AA patients had AFA. After Bonferroni correction, HLA-DRB1*08:04 was associated with AFA, compared to unaffected AA controls (OR 11.5, p < 0.0001) and AFA-negative SSc patients (OR 5.2, p = 0.0002). AFA-positive AA patients had younger age of disease onset, higher frequency of digital ulcers, diarrhea, pericarditis, higher Medsger perivascular and lower Medsger lung severity indices (p = 0.004, p = 0.014, p = 0.019, p = 0.092, p = 0.006, and p = 0.016, respectively). After adjustment for age at enrollment, AFA-positive patients did not have different survival compared to patients without AFA (p = 0.493). Conclusion. Our findings demonstrate strong association between AFA and HLA-DRB1*08:04 allele in AA patients with SSc. AA SSc patients with AFA had younger age of onset, higher frequency of digital ulcers, pericarditis and severe lower gastrointestinal involvement, but less severe lung involvement compared to AA patients without AFA. Presence of AFA did not change survival.

The relationship of dyspnoea to function and quality of life in systemic sclerosis

Aim: Up to 50% of patients with systemic sclerosis (SSc) have complaints of dyspnoea. We evaluated the independent contributions of dyspnoea to function and health related quality of life (HRQoL) in SSc and also assessed the contributions of pulmonary hypertension, measured by the pulmonary artery systolic pressure (PASP), and interstitial lung disease, measured by the forced vital capacity (FVC), to dyspnoea. Methods: We assessed dyspnoea, PASP, FVC, function and HRQoL in a cohort of unselected patients with SSc. Multiple linear regression was used to assess the independent contributions of dyspnoea, PASP and FVC to function and HRQoL, after controlling for possible confounding variables. Results: A total of 194 patients with mean disease duration of 11.6 years were studied. Dyspnoea was a significant independent predictor of function and HRQoL. A model including age, gender, disease duration, disease severity and dyspnoea explained 33.3%, 10.6%, 39.2% and 29.4% of the variance of the Stanford Health Assessment Questionnaire, the Short-Form 36 (SF-36) mental component summary score, the SF-36 physical component summary score and the World Health Organization Disability Assessment Schedule II. PASP and FVC were significant independent predictors of dyspnoea but only 21.9% of the variance in dyspnoea was explained by age, gender, disease duration, FVC and PASP. The FVC was a significant independent predictor of function and HRQoL. Conclusion: In an unselected population of SSc patients, dyspnoea is a very important contributor to function and HRQoL. Interstitial lung disease, as measured by the FVC, contributes significantly to the sense of dyspnoea, function and HRQoL in SSc. Pulmonary hypertension, assessed echocardiographically by the PASP, predicts the degree of dyspnoea but not function and HRQoL in SSc.

Antinuclear antibody-negative systemic sclerosis.

OBJECTIVE To examine the demographic and clinical characteristics of systemic sclerosis (SSc) patients without antinuclear antibodies (ANA) compared to ANA-positive patients. METHODS SSc patients enrolled in the Scleroderma Family Registry and DNA Repository were included. Relevant demographic and clinical data were entered by participating sites or obtained by chart review. ANA and SSc-related antibodies were determined in all investigated patients using commercially available kits at our laboratories. RESULTS This study included 3249 patients, of whom 208 (6.4%) were ANA negative. The proportion of male patients was higher in the ANA-negative group (OR = 1.65; p = 0.008). ANA-negative patients experienced less vasculopathic manifestations of SSc. The percent predicted diffusing capacity of carbon monoxide (DLCO) was higher in ANA-negative patients (p = 0.03). Pulmonary arterial hypertension (PAH) per right heart catheterization was less common in the ANA-negative group (OR = 0.28; p = 0.03). Furthermore, patients with negative ANA had a lower prevalence of telangiectasias and digital ulcers/pits (OR = 0.59, p = 0.03 and OR = 0.38, p = 0.01, respectively). Although diffuse cutaneous involvement was more common, the modified Rodnan Skin Score (mRSS) was lower in the ANA-negative group (2.4 points lower, p = 0.05). Furthermore, they experienced more malabsorption (p = 0.05). There was no difference in the frequency of pulmonary fibrosis or scleroderma renal crisis. All-cause mortality was not different between the 2 groups (p = 0.28). CONCLUSIONS In conclusion, the results of this study suggest that SSc patients who are ANA negative constitute a distinct subset of SSc with less vasculopathy (less PAH, digital ulcers, and fewer telangiectasias), a greater proportion of males, and possibly, more frequent lower gastrointestinal involvement.

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.