Rheumatoid arthritis
Indirect Comparison of Tocilizumab and Other Biologic Agents in Patients with Rheumatoid Arthritis and Inadequate Response to Disease-Modifying Antirheumatic Drugs

https://doi.org/10.1016/j.semarthrit.2009.12.002Get rights and content

Objectives

To compare the patterns of American College of Rheumatology (ACR) response between tocilizumab and other biologic agents in patients with rheumatoid arthritis who have inadequate response to disease-modifying antirheumatic drugs (DMARD-IR).

Methods

Systematic literature review identified similarly designed double-blind, randomized, placebo-controlled trials over an 18-year period that investigated the effectiveness of abatacept (2), rituximab (2), and TNF-α inhibitors etanercept, infliximab, and adalimumab (11) in DMARD-IR patients; data from 3 placebo-controlled, phase 3 trials for tocilizumab, a newly developed IL-6 inhibitor, were included. The endpoint of interest was ACR20/50/70 response criteria at 24 to 30 weeks. Results were analyzed simultaneously using Bayesian mixed-treatment comparison techniques. Nonoverlapping ACR response rates (<ACR20, ACR20-50, ACR50-70, >ACR70) for each agent were compared among treatments to identify differences in ACR response pattern. Separate analyses of overlapping ACR20/50/70 responses were conducted to identify the source of any differences. Results were expressed as relative risk of ACR20/50/70 response and associated 95% credible interval (CrI).

Results

Patterns across nonoverlapping ACR response levels varied significantly across treatments. In subsequent analyses, the effectiveness of tocilizumab appeared to be comparable to that of other biologic agents for ACR20 and ACR50 responses but greater for ACR70. Specifically, tocilizumab had greater ACR70 responses than both TNF-α inhibitors (relative risk = 1.8; CrI = 1.2, 2.6) and abatacept (relative risk = 2.0; CrI = 1.3, 3.1).

Conclusions

Among DMARD-IR patients, tocilizumab shows a pattern of response that differs from that of other biologic agents. Post-hoc analyses suggest that the difference lies in a higher likelihood of ACR70 response with tocilizumab.

Section snippets

Identification of Eligible Studies and Data Extraction

A systematic literature search was performed to identify published results of RCTs that evaluated commonly used biologic agents licensed to treat patients with RA (adalimumab, etanercept, infliximab, abatacept, or rituximab). Anakinra, an IL-1 inhibitor, was excluded because of low frequency of use. MEDLINE and EMBASE databases were searched simultaneously using DataStar. Search terms included a combination of free-text and thesaurus terms relevant to RA agents. During the search period 1990

Identified Studies

The search strategy identified 714 potentially relevant studies. Of these, 650 studies did not meet inclusion criteria, primarily because they were not RCTs. After full text review and data extraction, 49 of the remaining 64 studies were excluded for reasons including absence of an ACR response measure, dose-ranging focus, and focus on a non–DMARD-IR population. Finally, after identifying 15 studies as candidates for inclusion, 3 studies of tocilizumab were added—2 in MTX-IR and 1 in DMARD-IR

Discussion

This meta-analysis suggests the efficacy of tocilizumab is at least as good as that of other biologics and may be even better. In particular, the overall response pattern of tocilizumab differed from that of other biologics: it was similar in ACR20/50 responses but better in ACR70 responses. Although this was an analysis of efficacy, it is important to note that both short-term safety data from the clinical studies and longer term data from the extension studies support a favorable benefit-risk

Acknowledgment

We thank Cathy R. Winter, PhD, of ApotheCom (Yardley, PA) for editorial assistance.

References (33)

  • M.C. Hochberg et al.

    Comparison of the efficacy of the tumour necrosis factor alpha blocking agents adalimumab, etanercept, and infliximab when added to methotrexate in patients with active rheumatoid arthritis

    Ann Rheum Dis

    (2003)
  • R.M. Nixon et al.

    Using mixed treatment comparisons and meta-regression to perform indirect comparisons to estimate the efficacy of biologic treatments in rheumatoid arthritis

    Stat Med

    (2007)
  • Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis: NICE Technology Appraisal Guidance 130

  • J.M. Bland et al.

    Bayesians and frequentists

    BMJ

    (1998)
  • J. Kremer et al.

    Safety and tolerability of tocilizumab in combination with methotrexate (MTX) in patients with rheumatoid arthritis and inadequate response to MTX: 1-year results of the LITHE study

    Ann Rheum Dis

    (2009)
  • M.C. Genovese et al.

    Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the Tocilizumab in Combination With Traditional Disease-Modifying Antirheumatic Drug Therapy Study

    Arthritis Rheum

    (2008)
  • Cited by (92)

    • Borrowing of strength from indirect evidence in 40 network meta-analyses

      2019, Journal of Clinical Epidemiology
      Citation Excerpt :

      Data sets that originally used extensions of the classical NMA model (e.g., models for competing-risk outcomes and evidence inconsistency) were excluded [38]. In addition, we excluded 5 NMAs that addressed similar questions and had overlapping studies [40–44]. Finally, we obtained 40 NMAs which evaluated a variety of conditions with important morbidity, including rheumatoid arthritis, stroke, cancer, chronic hepatitis B infection, depressive disorder, vertebral fractures, major cardiovascular events, etc.

    • Defining the optimal biological monotherapy in rheumatoid arthritis: A systematic review and meta-analysis of randomised trials

      2017, Seminars in Arthritis and Rheumatism
      Citation Excerpt :

      As biological agents have shown more favorable response in combination with csDMARD therapy (primarily MTX) [9] combination treatment strategies should be applied when possible [4]. As many RA patients might not adhere to their csDMARD prescription (e.g., intolerance), it is important to evaluate the benefit and harm associated with use of biological agents as monotherapy, and not only the traditional combination therapy strategies [10–12]. The objective of this study was to assess the efficacy and safety of the individual biological agents used in monotherapy in patients with RA to inform decision makers on the relative effectiveness of biological agents used in monotherapy for patients where csDMARD therapy is inappropriate.

    • Tofacitinib Versus Biologic Treatments in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Tumor Necrosis Factor Inhibitors: Results From a Network Meta-analysis

      2016, Clinical Therapeutics
      Citation Excerpt :

      Network meta-analyses are an accepted technique used to combine results of multiple RCTs, to allow treatment comparisons not directly made within trials. In recent years, several network meta-analyses of bDMARD treatments for RA have been published, including an analysis of TNFi-IR patients,22 and give comparable findings despite differences in methodology.22,35-40 However, when conducting network meta-analyses, randomization only holds within each trial, not across trials; therefore, only relative treatment effects can be assessed.

    View all citing articles on Scopus

    This study was funded by Hoffmann La-Roche.

    Neil Wintfeld and Adrian Kielhorn are employees of Hoffmann La-Roche. Gert J. D. Bergman and Jeroen P. Jansen are employees of Mapi Values. Mapi Values received fees to perform the analysis. Marc Hochberg is a consultant to or a member of an advisory board for Abbott, Amgen, Bristol-Myers Squibb, Hoffman La-Roche, and UCB, Inc. Maarten Boers is a consultant for GlaxoSmithKline, Sanofi, Genentech, Hoffmann La-Roche, MedImmune, Novartis, Schering-Plough, AstraZeneca, Nitec, NicOx, Savient, Combinatorx, Merck Serono, Augurex, and Mapi Values.

    View full text