PALO ALTO, California— Interleukin-6 blockade with tocilizumab (Actemra^®), when combined with conventional disease-modifying antirheumatic drugs (DMARDs), safely and effectively reduces articular and systemic symptoms in rheumatoid arthritis (RA) patients who have an inadequate response to conventional DMARDs alone. The results of this study, the Tocilizumab in Combination With Traditional DMARD therapy (TOWARD) trial, were reported in Arthritis & Rheumatism.¹

TNF-inhibitors have revolutionized RA treatment, but a significant proportion of RA patients have poor responses to these agents.

“Some patients may benefit from treatment with newer biologic agents with a different mechanism of action,” conclude the TOWARD researchers, led by Mark C. Genovese, MD, of Stanford University Medical Center in Palo Alto, California.

1200-patient RCT supports tocilizumab efficacy

Dr. Genovese et al randomized 1220 patients with active RA despite being on stable doses of DMARDs to receive 8 mg/kg of tocilizumab or placebo every 4 weeks for 24 weeks in addition to their DMARD dose. The results were striking: at week 24, 61% of patients in the tocilizumab group achieved an ACR20 response, compared with 25% of the participants randomized to receive placebo.

Patients in the tocilizumab arm were also more likely to achieve the study’s secondary end points including ACR50/70, DAS28, DAS28 remission responses (DAS28<2.6), EULAR responses, and systemic markers such as C-reactive protein (CRP) and hemoglobin levels.

Specifically, mean CRP levels decreased by -2.20 milligrams per deciliter of blood (mg/dL) in the tocilizumab arm versus -0.27 mg/dL in the placebo arm. The mean erythrocyte sedimentation rate (ESR) also decreased more significantly in patients treated with tocilizumab, compared with their counterparts who received placebo.

Questions remain about total cholesterol, liver ezyme elevations

Seventy-three percent of patients in the tocilizumab group had 1 or more adverse events (AEs), compared with 61% of patients in the control group. AEs that led to withdrawal from the study were infrequent in both groups. Serious AEs occurred in 6.7% of patients in the tocilizumab arm and 4.3% of patients in the control groups. Serious infections occurred in 2.7% of tocilizumab users and 1.9% of patients treated with placebo.

Liver enzyme elevations to >3-fold the upper limit of normal occurred in 4% of patients in the tocilizumab group and 1% of those in the control group. However, elevated total cholesterol levels were observed in 23% of the patients in the tocilizumab arm and 6% of patients taking placebo. Sixteen patients started lipid-lowering therapy during the study.

In addition, grade 3 neutropenia occurred in 3.7% of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported.

“The results show that treatment with the combination of tocilizumab plus DMARDs has a high likelihood of inducing a clinically relevant benefit in terms of ACR50 and ACR70 response rates and DAS28 remission responses,” the study authors conclude.

Translating research into practice

“The therapeutic responses are so dramatic, so good, so robust and so rapid that the drug looks like a TNF-inhibitor,“ said Herbert S.B. Baraf, MD, the medical director of the Center for Rheumatology and Bone Research and a practicing rheumatologist in Wheaton, Maryland. “Actemra may be a seconc line agent in RA, but it may become the first second line agent that rheumatologists turn to after TNF-blockade,” speculated Dr. Baraf, also a clinical professor of medicine at George Washington University Medical Center in Washington, D.C.


Reference

1. Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying anti-rheumatic drugs. Arthritis Rheum 2008;58:2968-2980.