Tocilizumab in rheumatoid arthritis: A meta-analysis of efficacy and selected clinical conundrums

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Abstract

Introduction

Tocilizumab (TCZ) is a biological agent used for the treatment of moderate to severe rheumatoid arthritis (RA). In the present systematic literature review and meta-analysis, we provide an update on the efficacy and safety of TCZ and our clinical comments for the treatment of RA.

Methods

We searched PubMed for randomized, double-blind, placebo-controlled clinical trials investigating the effects of TCZ on RA. The initial search included articles from 1966 to December 2011. The search was subsequently updated in April 2013. Studies had to report clinical efficacy using American College of Rheumatology (ACR) 20, 50, and 70 disease measures. The studies included participants who were 18 years of age and who met the ACR 1987 revised criteria for RA for 6 months or longer. Two reviewers independently abstracted the data, and disagreement was resolved by discussion with a third reviewer. Outcome measures were analyzed as odds ratio using the Mantel–Haenszel estimator under a random effects model to account for heterogeneity in intervention effects between trials. Descriptive statistics were used to compare adverse events.

Results

After reviewing and culling, 8 randomized, controlled, double-blind studies were included in the efficacy meta-analysis. TCZ 8 mg/kg was statistically favored over TCZ 4 mg/kg or placebo regarding ACR responses. Clinically significant adverse events that occurred with TCZ treatment included infections, lipid and liver function test abnormalities, and gastrointestinal side effects, all of which were more common with TCZ.

Conclusions

This meta-analysis supports the use of TCZ as an appropriate treatment for moderate to severe RA as monotherapy and combination therapy. Close monitoring for significant adverse events is required when treating patients with TCZ. Future long-term trials should focus further on safety of this agent.

Introduction

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder affecting approximately 0.5–1% of the population, with a higher prevalence in women [1]. Multiple, complex genetic factors act together with environmental stimuli to cause synovial inflammation, which results in joint damage and deformities [2], [3]. There is also significant organ involvement leading to anemia, fatigue, skin nodules, neuropathy, ocular disease, splenomegaly, vasculitis, and pleuropericarditis [4]. Overall, the disease decreases quality of life and may shorten life span.

The inflammation seen in RA is in part secondary to proinflammatory cytokines such as tumor necrosis factor alpha and Interleukins such as IL-1 and IL-6 [2]. IL-6 is a pleiotropic proinflammatory cytokine produced by synovial and endothelial cells in areas affected by T cells, B cells, lymphocytes, monocytes, and fibroblasts [5]. IL-6 has roles in T-cell activation, B-cell proliferation, and immunoglobulin secretion [6]. IL-6 is also a key mediator of both systemic and joint symptoms associated with RA. Furthermore, IL-6 is involved in hepatic acute phase protein synthesis and stimulation of hematopoietic precursor cell proliferation and differentiation [6]. An overproduction of the cytokine results in some of the common characteristics associated with RA and other autoimmune diseases [5].

Tocilizumab (TCZ), a recombinant humanized anti-human IL-6 receptor monoclonal antibody, provides an alternative to anti-TNF-α therapy [7]. TCZ was introduced in 2010 for the treatment of RA by the Chugai Pharmaceutical Co. Ltd [8]. It has been approved in the United States and Europe for use in patients with active moderate to severe disease but not for those with mild disease and also patients who have previously failed DMARDs [9]. TCZ binds to both membrane-bound and soluble IL-6 receptors and inhibits IL-6-mediated proinflammatory signaling [10] and, possibly, TH 17 function [11].

We conducted a systematic literature review and meta-analysis of TCZ randomized controlled studies to update and evaluate the evidence supporting the use of TCZ in RA and to examine selected adverse effects of TCZ. We incorporated these data into clinical opinions regarding the use of TCZ. The meta-analysis is used to support some of our opinions regarding the use of TCZ in RA.

Section snippets

Study selection

Two reviewers (G.N. and S.T.) independently searched PubMed from 1966 to December 2011 to identify relevant citations using the following Medical Subject Headings (MeSH) and text words: Rheumatoid Arthritis, IL-6 receptor inhibitor, myeloma receptor antibody (MRA), Actemra, tocilizumab, and clinical trials. The search was subsequently updated in April 2013. Studies were included if (1) they were randomized, placebo-controlled trials (RCTs) using TCZ compared to non-biologic DMARDs; (2)

Study characteristics

The initial search entailed all articles from 1966 to December 2011 and yielded 139 articles, of which, 133 were excluded. The search was updated in April 2013 and yielded 189 additional articles, of which, 188 were excluded. Fig. S1 in Appendix A shows the disposition of the articles. Manual review of the reference lists of the reviewed articles during the initial search yielded one additional article. The studies that qualified for inclusion in this meta-analysis are the following: Study of

Conclusion

The present meta-analysis and systematic review demonstrate that TCZ is efficacious for the treatment of moderate to severe RA in patients who have failed TNFi. It can also be used as monotherapy or in combination with MTX or other DMARDs. In regards to safety, multiple side effects have been studied in patients treated with TCZ. Clinically significant side effects include infections, serious infections, LFT abnormalities, lipid abnormalities (LDL and TC), GI side effects (including

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    D.E.F. has received research grants or been on advisory boards for Roche, Genentech, Brogen-Ldec, Abbott, Amgen, Centocare, UCB, and BMS.

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