Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor

Abstract

Background: Tocilizumab (TCZ), a humanized anti-interleukin-6 receptor monoclonal antibody, represents a new treatment strategy for patients with rheumatoid arthritis (RA) and is currently approved in the United States for RA patients who have failed to improve with at least one anti-tumor necrosis factor therapy.

Objective: The goal of this study was to summarize the efficacy and safety profile of TCZ.

Methods: A systematic literature review was conducted to identify English-language articles within PubMed and the Cochrane Library from January 1989 to August 2011 reporting results from Phase III TCZ double-blind, randomized controlled trials (RCTs), noncontrolled clinical trials, and open-label extensions with a duration ≥6 months. Study outcomes had to include at least one of the following: American College of Rheumatology (ACR) 20, 50, or 70 response rates; tender/swollen joint count; Health Assessment Questionnaire-Disability Index; radiographic outcomes and drug persistence. Phase II RCTs were included only if they contained relevant information not available in Phase III RCTs. Relevant studies were selected to evaluate TCZ's pharmacokinetics and pharmacodynamics.

Results: Ten published clinical trials (7 Phase III, 3 Phase II) for TCZ were retrieved (7833 articles initially identified) from PubMed and 31 from the Cochrane library. Compared with methotrexate (MTX) monotherapy, TCZ 8 mg/kg IV monotherapy had higher rates of ACR20 (P < 0.001), ACR50 (P = 0.002), and ACR70 (P < 0.001) scores at week 24. TCZ 8 mg/kg IV plus oral MTX had a higher ACR20 response rate than oral MTX plus placebo in patients with RA who failed to respond to MTX or anti-tumor necrosis factor therapy (P < 0.001). Patients receiving TCZ 8 mg/kg had less radiographic progression on the Genant-modified Sharp score (85% had no progression) than the control group (67% had no progression) (P < 0.001). The rate of serious infections was 4.7 events/100 patient-years of exposure in the TCZ groups. A greater frequency of neutropenia, thrombocytopenia, hyperlipidemia, and transaminitis was observed with TCZ compared with placebo.

Conclusion: The short-term efficacy and safety profile of TCZ is promising. Additional long-term safety data are needed to better characterize the risk-benefit profile of this agent.

Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Figures

Figure 1

Flow chart of literature search for biologic agents from January 1989 through August 2011 within PubMed and the Cochrane Library. RCT randomized controlled trials; CCT = controlled clinical trials. CHARISMA = Chugai Humanized Anti-Human Recombinant Interleukin-6 Monoclonal Antibody; SAMURAI = Study of Active Controlled Monotherapy Used for Rheumatoid Arthritis, an IL-6 Inhibitor; TOWARD = Tocilizumab in Combination With Traditional DMARD Therapy; OPTION Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders; RADIATE = Research on Actemra Determining efficacy after Anti-TNF failurEs; STREAM = Safety and Efficacy of Tocilizumab, an anti-IL-6 receptor monoclonal antibody, in Monotherapy, in Patients With Rheumatoid Arthritis; SATORI = Study of Active Controlled TCZ Monotherapy for RA Patients with and Inadequate Response to Methotrexate; AMBITION = Actemra Versus Methotrexate Double-Blind Investigative Trial in Monotherapy; LITHE = Tocilizumab Safety and the Prevention of Structural Joint Damage. *All the 8 included studies from Cochrane library were part of the 10 included studies from the PubMed search, leading to a total of 10 unique studies included in our review.

Figure 2

Tocilizumab (TCZ) response rate compared with methotrexate (MTX) at 24 weeks in patients who were treated previously with MTX. The ACR response is defined by a decrease of ≥ 20%, 50%, or 70% in a formula that includes tender and swollen joint counts, the patient's and the physician's global assessments of disease activity, patient's assessment of pain, HAQ-DI score, and acute-phase reactants (CRP or ESR). ACR = American College of Rheumatology; ITT = intention-to-treat. *P29

Figure 3

American College of Rheumatology (ACR) response rates with tocilizumab (TCZ) in patients at 24 weeks at 4 and 8 mg/kg plus disease-modifying antirheumatic drugs (DMARD) in the LITHE (Tocilizumab Safety and the Prevention of Structural Joint Damage), OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders), and TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) trials. The ACR response is defined by a decrease of ≥ 20%, 50%, or 70% in a formula that includes tender and swollen joint counts, the patient's and the physician's global assessments of disease activity, patient's assessment of pain, HAQ-DI score, and acute-phase reactants(CRP or ESR). *P 27,28,31,39

Figure 4

Efficacy and response rate of tocilizumab in patients exhibiting incomplete response (IR) to anti.tumor necrosis factor (TNF) therapy. *P < 0.001 and †P= 0.001 versus methotrexate (MTX) plus placebo. NS = not statistically significant versus MTX plus placebo. ACR = American College of Rheumatology; RADIATE = Research on Actemra Determining efficacy after Anti-TNF failurEs. The ACR response is defined by a decrease of ≥20%, 50%, or70% in a formula that includes tender and swollen joint counts, the patient's and the physician's global assessments of disease activity, patient's assessment of pain, HAQ-DI score, and acute-phase reactants (CRP or ESR).