Non-TNF Inhibitor Biologics: Expanding Opportunities for Rheumatoid Arthritis Control

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 75th Annual Meeting of the American College of Rheumatology

Chicago, Illinois / November 5-9, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Relative to disease-modifying antirheumatic drugs (DMARDs), biologics have offered a greater likelihood of a complete response in rheumatoid arthritis (RA). However, there is still a substantial proportion of patients who have an inadequate initial response—or poor sustained response—to TNF inhibitors. There are encouraging developments of agents that act on different molecular targets. In those with a poor response to a TNF inhibitor and intolerance to the most effective DMARDs, the need for alternative agents is even more urgent.

“Combination therapy with a biologic agent plus a traditional DMARD is a common approach for RA treatment, but there is a substantial number of patients in whom this is not an option,” reported Dr. Vivian Bykerk, Brigham and Women’s Hospital, Boston, Massachusetts. Principal investigator for 1 of 2 studies evaluating the interleukin-6 (IL-6) inhibitor tocilizumab as a monotherapy, Dr. Bykerk said the importance of demonstrating efficacy with a single biologic, relative to a biologic plus a DMARD, is that many patients are intolerant of or non-compliant on a DMARD.

A Potential for Monotherapy

A double-blind study was conducted in patients with moderate-to-severe RA despite a stable weekly dose of methotrexate (MTX). The goal was to evaluate change in progression of structural damage and quality of life when patients were randomized to continue on MTX with the addition of tocilizumab or to switch to placebo and receive tocilizumab monotherapy. Called the ACT-RAY study, all patients were started on tocilizumab (8 mg/kg every 4 weeks) but randomized to continue MTX or receive a placebo. At the end of 24 weeks, there was no statistical difference in the proportion of patients achieving a Disease Activity Score 28 (DAS28) <2.6 in those on tocilizumab monotherapy or who also received a DMARD (40.4% vs. 34.8%, respectively). There were also no significant differences in the ACR20 (71% vs. 72%) or ACR70 (25% vs. 26%) for the monotherapy and combination groups, respectively.

“We are seeing very high rates of efficacy with this agent as a monotherapy,” according to Dr. Maxime Dougados, Cochin Hospital, René Descartes University, Paris, France, who indicated that this has not been the pattern with other biologics. He suggested that the IL-6 inhibitor might be an appropriate option in patients intolerant of or non-compliant to MTX or other DMARDs.

The comparable effect of tocilizumab as monotherapy vs. with continued MTX was reflected by other measures of efficacy. Significantly, this included several radiologic measures, including the Genant-modified Sharp Score (GSS). There was no significant difference in the percentage of patients showing no progression on either GSS (58.7 vs. 65.3; P=0.09) or erosion score (64.9 vs. 68.6; P=0.33). According to Dr. Dougados, the rates of adverse events and serious adverse events were similar in the 2 groups with no deviations from the types and rates of adverse events reported previously.

Real-World ACT-SURE Results

In the phase IIIb ACT-SURE study presented by Dr. Bykerk, 1681 patients who had an inadequate response to a DMARD or TNF inhibitor were evaluated on the IL-6 inhibitor tocilizumab over 6 months. The eligibility for the study was intentionally designed to capture a real-world group of patients representative of typical practice. In this study, patients were treated with a dose of 8 mg/kg every 4 weeks alone or in combination with 1 or more DMARDs. Response rates were compared between those who did and did not receive combination therapy.

At the end of 24 weeks, tocilizumab provided high and similar rates of disease control whether used as a monotherapy or with a DMARD. DAS28 <2.6 was achieved in 49.8% of those on monotherapy and 57.9% of those on a combination regimen. For the monotherapy vs. the combination arms, respectively, the ACR20 scores were 66.9% in both groups, ACR70 in 23.8% vs. 26.8%, and CDAI remission in 20.0% vs. 18.5%. The reduction in the swollen joint count (-8.0 vs. -8.2) and tender joint count (-14.4 vs. -14.0) were also similar in the monotherapy and combination groups, respectively. The good and moderate EULAR responses combined were achieved in 82% and 83.6%, respectively. None of these differences approached statistical significance.

“ACT-SURE is the first study to demonstrate that tocilizumab is highly effective as monotherapy as well as combination therapy with DMARDs,” Dr. Bykerk told delegates.

Choosing a Biologic

Identifying where the growing array of biologics fit into clinical practice will be an important goal due to the potential for differences in both efficacy and safety. However, an analysis of relative efficacy with the first-generation biologics suggests that these agents are more similar than different. Here at the ACR, a study based on an analysis of the Arthritis Registry Monitoring Database (ARMD) and presented by Dr. Yusuf Yazici, Hospital for Joint Diseases, New York University, has been prospectively collecting data on all RA patients treated at New York University since 2005. The TNF inhibitors etanercept, adalimumab and infliximab along with the T-cell inhibitor abatacept produced response curves over time that were nearly parallel except for a modestly lower rate of response with infliximab.

“Those treated with abatacept had an increased likelihood of achieving a good response, but the statistical significance [P=0.05] was borderline,” Dr. Yazici reported. However, he explained that the difference was lost after adjusting for age and duration of disease. No other differences in unadjusted or adjusted analyses were observed between the treatment groups.

“With no difference in clinical outcomes or response time, most treatment decisions can be based on ease of use, safety data and long-term survival of biologic agents,” Dr. Yazici remarked, referring specifically to the first-generation agents assessed in this study.

Patient Participation Vital

One of the recurring themes in RA, largely made possible by the introduction of biologics, is the need to treat to target. Now formally endorsed by several guidelines, including those issued by EULAR, the concept involves predefining the level of control to produce sustained remission rather than treating symptomatic relapses alone. One of the issues is how to define targets. There is now a vast array of tools for measuring response to therapy with varying strengths and weaknesses.

“I do not think there is much disagreement any more about the need to treat to target, but I think there are a lot of differences in what people think are the best metrics. However, I am not sure there is just one best tool. It is more important to discuss with the patient where they want to go in relation to return of function and symptom control,” stated Dr. Norman Gaylis, Arthritis and Rheumatic Disease Associates, Miami, Florida.

According to Dr. Gaylis, the best tool is one that allows patients to monitor their own progress. “Not encouraging patients to participate in defining outcome is a mistake. It is important to compliance and it is important to the collaboration that allows goals to be met,” Dr. Gaylis told delegates.


The expansion of biologics beyond TNF inhibitors for the treatment of RA is providing new options for the substantial proportion of individuals who are not controlled on the first-generation targeted agents. The evidence that high rates of response can be achieved when newer biologics are employed to target alternative pathways of inflammation is important because it provides new opportunities to control disease. In that context, the evidence that an IL-6 inhibitor can provide similar degrees of RA control with or without a DMARD is an example of how newer agents can function in the broad spectrum of needs in disease management.

We Appreciate Your Feedback
Please take 30 seconds to help us better understand your educational needs.
Are you a healthcare professional practicing in Canada?
What type of healthcare professional best describes you?
Did you find this publication to be of educational value?
What is you preferred format for receiving and reading a report?
Would you like to have video available with the report?
Suggested future topics: