Rheumatology-Rhumatologie

Pro-inflammatory cytokines are directly implicated in the pathogenesis of Rheumatoid arthritis (RA). Variable clinical response to cytokine targeted therapies as TNFalpha and IL-6, strongly highlights the heterogeneity of inflammatory process in RA.

Results

We found higher and significant levels of TNFalpha, IL-6 and IL-15Ralpha but not of IL-15 in RA compared with the OA group. Additionally, a high inter-individual variability in the levels of these 4 cytokines was observed in RA, although we identified 4 patients’ subgroups by cluster analysis of cytokines concentration in SF. We also found a positive correlation between IL-15Ralpha-IL-6 and IL-15Ralpha-IL-15, but not for other pairs of cytokines in RA. In addition we found correlation between the value of IL-15Ralpha in SF and disease activity score, DAS28.

Conclusions

In our current work we found a high inter-individual variability in the levels of TNFalpha, IL-6, IL-15 and IL-15Ralpha in SF of RA patients and were identified four principal clusters of cytokines concentration in SF, suggesting the importance of identifying disease subset of patients for personalized treatment. Finally, we found a correlation between IL-15Ralpha-IL-6, IL-15Ralpha-IL-15, but we did not find any correlation between other pairs of studied cytokines in SF.

Abstract

Objectives To evaluate safety and efficacy of weekly (qw) and every other week (q2w) dosing of sarilumab, a fully human anti-interleukin 6 receptor α (anti-IL-6Rα) monoclonal antibody, for moderate-to-severe rheumatoid arthritis (RA).

Methods In this dose-ranging study, patients (n=306) with active RA, despite methotrexate, were randomly assigned to placebo or one of five subcutaneous doses/regimens of sarilumab: 100 mg q2w, 150 mg q2w, 100 mg qw, 200 mg q2w, 150 mg qw for 12 weeks, plus methotrexate. The primary end point was ACR20 at Week 12. Secondary endpoints included ACR50, ACR70, Disease Activity Score in 28 joints (C reactive protein). Safety, pharmacokinetics, pharmacodynamics and efficacy in population subgroups were assessed.

Results The proportion of patients achieving an ACR20 response compared with placebo was significantly higher for sarilumab 150 mg qw (72.0% vs 46.2%, multiplicity adjusted p=0.0203). Higher ACR20 responses were also attained with 150 mg q2w (67%; unadjusted (nominal) p=0.0363) and 200 mg q2w (65%; unadjusted p=0.0426) versus placebo. Sarilumab ≥150 mg q2w reduced C reactive protein, which did not return to baseline between dosing intervals. Infections were the most common adverse event; none were serious. Changes in laboratory values (neutropenia, transaminases and lipids) were consistent with reports with other IL-6Rα inhibitors.

Conclusions Sarilumab improved signs and symptoms of RA over 12 weeks in patients with moderate-to-severe RA with a safety profile similar to reports with other IL-6 inhibitors. Sarilumab 150 mg and sarilumab 200 mg q2w had the most favourable efficacy, safety and dosing convenience and are being further evaluated in Phase III.

The safety and efficacy profiles in clinical trials of olokizumab, sarilumab and sirukumab are similar and are consistent with those observed in RA patients treated with tocilizumab. Furthermore, the clinical efficacy of these IL-6 inhibitors is similar to that of TNF inhibitors in patients with MTX-IR and TNF-IR. Screening of biomarkers or genetics in each RA patient, for instance, baseline serum levels of TNF and/or soluble IL-6R, may help to predict the efficacy of each drug and to select patients for cytokine-oriented targeted therapies.33 However, better strategies are warranted for selecting and identifying appropriate patients earlier once bDMARDs targeting IL-6 are launched in the near future. We also need to determine whether there are important differences between the many IL-6 inhibitors and which are suitable for particular patients, otherwise companies may waste time and money in development.

An evaluation of risk factors for major adverse #cardiovascular events during #tocilizumab therapy http://t.co/EymLTiXiv1 #rheum

Objective. To explore associations of baseline and on-treatment lipid levels, inflammation, and rheumatoid arthritis (RA) disease activity with risk for major adverse cardiovascular events (MACE) in tocilizumab-treated RA patients.

Methods. In retrospective post hoc analyses, data were pooled from 3986 adults with moderate to severe RA administered ≥1 dose of tocilizumab 4 or 8 mg/kg intravenously every 4 weeks in randomized controlled trials and extension studies. Cox proportional hazards modeling was used to evaluate associations among baseline characteristics and posttreatment initiation variables (week 24) and change from baseline to week 24 disease activity and laboratory values, with risk for future MACE during extended follow-up.

Results. There were 50 independently adjudicated cases of MACE during 14,683 patient-years (PY) of follow-up (0.34 MACE/100 PY). At baseline, age, history of cardiac disorders, disease activity score using 28 joints (DAS28), and total cholesterol/high-density lipoprotein ratio were independently (P<0.05 for all) associated with MACE in multivariable models. On treatment, higher DAS28 scores and swollen and tender joint counts at week 24 were associated with future MACE. In separate models, greater reductions in DAS28 score and joint counts from baseline to week 24 were inversely associated with future MACE; changes in lipid parameters were not statistically significantly associated with risk for MACE.

Conclusion. As in the general population, an association was observed between baseline total cholesterol/high-density lipoprotein ratio and increased risk for MACE. Risk for on-treatment MACE, however, was found to be associated with control of disease activity but not lipid changes. Larger studies are needed to confirm these findings. © 2014 American College of Rheumatology.

Abstract

Objectives The safety and efficacy of sirukumab, an anti-interleukin-6 (IL-6) monoclonal antibody, were evaluated in a 2-part, placebo-controlled phase II study of patients with active rheumatoid arthritis (RA) despite methotrexate therapy.

Methods In Part A (proof-of-concept), 36 patients were randomised to placebo or sirukumab 100 mg every 2 weeks (q2w) through week 10, with crossover treatment during weeks 12–22. In Part B (dose finding), 151 patients were randomised to sirukumab (100 mg q2w, 100 mg q4w, 50 mg q4w, or 25 mg q4w) through week 24, or placebo through week 10 with crossover to sirukumab 100 mg q2w (weeks 12–24). The proportion of patients with an American College of Rheumatology 50 (ACR50) response and the change from baseline in the 28-joint count disease activity score using C-reactive protein (DAS28-CRP) were determined. Safety was evaluated through week 38 in both parts.

Results The primary endpoint (ACR50 at week 12 in Part B) was achieved only with sirukumab 100 mg q2w versus placebo (26.7% vs 3.3%; p=0.026). Greater improvements in mean DAS28-CRP at week 12 were observed with sirukumab 100 mg q2w versus placebo in Parts A (2.1 vs 0.6, p<0.001) and B (2.2 vs 1.1; p<0.001). The incidence of adverse events (AEs) was similar for sirukumab-treated and placebo-treated patients through week 12 in Part A (70.6% and 63.2%, respectively) and B (67.8% and 66.7%, respectively). Infections were the most common type of AE; one death occurred (Part B, sirukumab 100 mg q2w, brain aneurysm).

Conclusions Sirukumab-treated patients experienced improvements in the signs/symptoms of RA. Safety results through 38 weeks were consistent with other IL-6 inhibitors.

Trial registration number NCT00718718.