Antiarrhythmic potential of anticytokine therapy in rheumatoid arthritis: tocilizumab reduces corrected QT interval by controlling systemic inflammation.

OBJECTIVE: Patients with rheumatoid arthritis (RA) are twice as likely to experience sudden cardiac death compared with individuals without RA. Although the underlying mechanisms of this have not been clarified, evidence points to the effects of systemic inflammation on ventricular repolarization. Accordingly, prolongation of the corrected QT (QTc) interval is more frequent in patients with RA compared with individuals without RA also correlating with C-reactive protein (CRP) and predicting all-cause mortality. Tocilizumab (TCZ) is an anti-interleukin-6 receptor antibody that potently inhibits inflammatory activation in RA, with rapid normalization of acute-phase reactant levels, including the CRP level. Therefore, we hypothesized that TCZ may normalize the QTc interval by dampening systemic inflammation, thus reducing the risk of arrhythmia in patients with RA. METHODS: Seventeen consecutive patients with active RA who were scheduled to receive TCZ once every 4 weeks underwent a clinical examination, electrocardiography, and blood sampling just before the first injection with TCZ and again after 3 months and 6 months of treatment. RESULTS: At baseline, 76% of patients displayed prolongation of the QTc interval (mean ± SD 452.3 ± 35.8 msec). TCZ treatment was associated with a rapid and significant reduction of the QTc interval to mean values <440 msec (up to 428.1 ± 34.3 msec). Throughout the study, QTc interval shortening correlated with decreases in both the CRP level, and more strongly, with circulating tumor necrosis factor α level. CONCLUSION: These data provide further evidence of the close link between the degree of systemic inflammation and QTc interval duration in RA and also suggest an anti-arrhythmic potential for TCZ treatment, which may have a beneficial impact on the mortality of these patients.

Efficacy and safety of rituximab with and without methotrexate in the treatment of rheumatoid arthritis patients: results from the GISEA register.

INTRODUCTION: Rituximab (RTX) is a monoclonal anti-CD20 antibody approved for the treatment of rheumatoid arthritis (RA) in association with methotrexate (MTX). OBJECTIVES: To evaluate the efficacy and safety of RTX-MTX combination therapy compared with RTX alone in the treatment of RA. METHODS: We analyzed data from a prospective cohort study, the Italian biologic register GISEA, to investigate the efficacy and safety of rituximab. Moreover, the adverse events (AE) and the causes of discontinuation therapy were analyzed. RESULTS: We identified 338 RA patients, 162 treated with RTX and 176 with RTX-MTX. After 52 and 104 weeks of therapy the disease activity score in 28 joints and the Health Assessment Questionnaire Score were available in 168 patients (78 with RTX-MTX and 60 with RTX alone), showing significant reduction without differences among the two groups. AE were reported in 142 patients (42%), for a total of 368 recorded side effects. The majority (90.5%) of AE were mild to moderate in severity. Comparable percentages of severe AE were reported in the 2 groups (9.9% for RTX alone and 9.3% for RTX+MTX). A poor disease control was observed in 14.2% and 13.5% of patients treated with RTX+MTX and RTX, respectively; while 12 patients (4.5% in RTX+MTX, and 2.5% in RTX group) suspended therapy for AE. CONCLUSIONS: RTX showed a good efficacy and safety profile in the real-life management of RA patients regardless of the association with MTX.

Anti-Ro/SSA-associated corrected QT interval prolongation in adults: the role of antibody level and specificity.

OBJECTIVE: Recent evidence suggests that anti-Ro/SSA antibodies, strongly associated with the development of congenital heart block, may also be arrhythmogenic for the adult heart. In fact, anti-Ro/SSA-positive patients with connective tissue disease (CTD) frequently display corrected QT (QTc) prolongation associated with an increase in ventricular arrhythmias. However, QTc prolongation prevalence markedly differs throughout the studies (10-60%), but the reason why is not yet clear. The aim of this study was to evaluate whether anti-Ro/SSA-associated QTc prolongation in adult patients with CTD is related to antibody level and specificity. METHODS: Forty-nine adult patients with CTD underwent a resting 12-lead electrocardiogram recording to measure QTc interval, and a venous withdrawal to determine anti-Ro/SSA antibody level and specificity (anti-Ro/SSA 52 kd and anti-Ro/SSA 60 kd) by immunoenzymatic methods and Western blotting. RESULTS: In our population, a direct correlation was demonstrated between anti-Ro/SSA 52-kd level and QTc duration (r = 0.38, P = 0.007), patients with a prolonged QTc had higher levels of anti-Ro/SSA 52 kd with respect to those with a normal QTc (P = 0.003), and patients with a moderate to high level (≥50 units/ml) of anti-Ro/SSA 52 kd showed a longer QTc interval (P = 0.008) and a higher QTc prolongation prevalence (P = 0.008) than those with a low positive/negative level (<50 units/ml). On the contrary, no association was found between QTc and anti-Ro/SSA 60-kd level. CONCLUSION: In anti-Ro/SSA-positive adult patients with CTD, the occurrence of QTc prolongation seems strictly dependent on the anti-Ro/SSA 52-kd level. This finding, possibly explaining the different QTc prolongation prevalence reported, strengthens the hypothesis that an extremely specific autoimmune cross-reaction is responsible for the anti-Ro/SSA-dependent interference on ventricular repolarization.

Prevalence of anti-histone antibodies, their clinical significance and correlation with other autoantibodies in a cohort of Italian scleroderma patients.

PURPOSE: The aim of our study was to determine the prevalence, clinical significance of antibodies to individual histone components and to evaluate their correlation with other autoantibody specificities in a cohort of Italian SSc patients. Some authors, demonstrated high prevalence of anti-histone antibodies in Italian SSc patients, associated with cardiac and renal involvement, suggesting a prognostic value of these autoantibodies; however, these data need to be confirmed. METHODS: Serum from 112 adult SSc patients, classified as diffuse (dc) and limited cutaneous (lc) SSc subsets were analyzed for autoantibodies by indirect immunofluorescence, fluoroenzyme immunoassay and enzyme immunoassay. RESULTS: AHA were found in 13 patients (11.6%), nine with lcSSc and four with dcSSc. Among them, five patients were anti-Scl70+ and four were anti-CENP B+. The presence of AHA was not associated with multi-organ involvement or with diffuse subset, as already described. Anti-Scl70 was detected in 43% of patients, anti-CENP B in 32% and anti-RNA polymerase III in 7.1%. We confirmed the association between anti-Scl70 antibodies and pulmonary fibrosis (OR 15.75, p < 0.0001). CONCLUSION: In our experience, the very low prevalence of AHA in Italian SSc patients and the lack of association with clinical manifestations suggest that this test is of little clinical use; however, it would be worthwhile extending the study to a larger population of patients.

Anti-cofactor autoantibodies in systemic lupus erythematosus: prevalence, clinical and HLA class II associations.

The aim of our study was to evaluate the clinical and HLA-class II allele associations of some anti-cofactor antibodies in a homogeneous group of European patients with SLE. One hundred thirty-six patients with SLE, fulfilling four or more of the ACR 1997 revised criteria for the classification of the disease, coming from 7 European countries, were enrolled consecutively. Anti-prothrombin (anti-PT), anti-annexin V (anti-AnnV), anti-protein C (anti-Cprot) and anti-protein S (anti-Sprot) were determined by using commercial ELISA kits. Molecular typing of HLA-DRB1, DRB3, DRB4, DRB5, DQA1, DQB1 and DPB1 loci was performed by using PCR-SSOP method, carried out using digoxygenin (DIG) labeled probes. The prevalence of anti-AnnV, anti-PT, anti-Cprot and anti-Sprot was 19%, 10.4%, 4.4% and 8.1%, respectively. Twenty-seven % of anti-AnnV positive patients reported migraine vs 5.5% of anti-AnnV negatives (p = 0.003, but p not significant, odds ratio (OR) = 6.4, 95% confidence interval (CI) = 2-21). Anti-PT, anti-AnnV and anti-Sprot were positively associated with some HLA alleles, but pc was not significant. In this study we have shown that some HLA alleles carry the risk to produce antibodies against phospholipid-binding proteins, but these association need confirmation in other studies, because they have never been reported and appear to be weak associations.