Non-TNF Drugs an Option for Patients With Unresponsive RA

Jennifer Garcia

September 22, 2016

Patients with rheumatoid arthritis (RA) who have an inadequate response to a first-line anti-tumor necrosis factor (TNF) drug may experience a better response with non-TNF-targeted drugs than with another anti-TNF medication, according to a new study published in the September 20 issue of JAMA.

Although approximately 50% of patients with insufficient response to an anti-TNF agent responded to a second anti-TNF agent, "[t]he proportion of [European League Against Rheumatism (EULAR)] response at week 24, the primary end point of the study, was greater among those treated with a non–TNF-targeted biologic than those treated with a second anti-TNF biologic," write Jacques-Eric Gottenberg, MD, PhD, from the Université de Strasbourg, France, and colleagues.

Between December 2009 and August 2012, the researchers enrolled 300 adults with RA who had a disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) of 3.2 or higher and who had experienced an insufficient response to anti-TNF therapy, according to their physician. The study excluded patients who had been previously treated with two or more anti-TNF agents or with non-TNF-targeted agents.

The researchers randomly assigned patients to receive either a second anti-TNF agent (ie, adalimumab, certolizumab, etanercept, or infliximab) or a non-TNF biologic (ie, abatacept, rituximab, or tocilizumab). The choice of biologic was at the discretion of the treating physician, and treatment was administered for 12 months unless discontinuation resulting from inefficacy, adverse events, or patient choice was necessary.

Dr Gottenberg and colleagues defined a good response as a decrease of more than 1.2 points in the DAS28-ESR, whereas a moderate response was defined as a decrease of more than 0.6 points. Secondary endpoints included EULAR response at weeks 12 and 52; DAS28-ESR at weeks 12, 24, and 52; mean oral corticosteroid use at weeks 24 and 52; and a health assessment questionnaire (HAQ) at weeks 2, 24, and 52.

Overall, 69% (101/146) in the non-TNF group and 52% (76/146) in the second anti-TNF group achieved a good or moderate EULAR response by week 24 (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.27 - 3.37; P = .004). The DAS28-ESR was lower in the patients who received non-TNF therapy than in the group that received the second anti-TNF therapy (mean difference adjusted for baseline differences, −0.43; 95% CI, −0.72 to −0.14; P = .004).

Also, disease activity was lower among patients in the non-TNF group (45% vs 28% at week 24 [OR, 2.09; 95% CI, 1.27 to 3.43; P = .004] and 41% vs 23% at week 52 [OR, 2.26; 95% CI, 1.33 - 3.86; P = .003]). Further, the researchers found a nonsignificant mean difference of −0.04 (95% CI, −0.15 to 0.07; P = .44) in the HAQ at week 24.

The authors acknowledge that the lack of a standardized treatment regimen or exclusion of certain agents (eg, golimumab and anakinra) are limitations of the study. They also note that approximately 40% of patients in each group were not being treated concurrently with methotrexate, an agent known to improve the efficacy of most biologics. However, these limitations "actually enhance the clinical relevance of the study in common practice, since one third of patients in 'real life' do not receive concomitant methotrexate, as evidenced in registries of biologics all over the world," Dr Gottenberg told Medscape Medical News.

"Likewise, clinicians are looking for guidance for a strategy (non-TNF targeted biologics or anti-TNF) rather than for the choice of the second-line agent itself. Therefore, the present study has a great external validity for common practice," he noted.

Evidence Is Promising, but More Work Is Needed

"The trial contributes helpful evidence to managing patients who have had an inadequate response to a prior TNF biologic," Jeffrey Curtis, MD, MPH, from the University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology, told Medscape Medical News. Dr Curtis was not involved in the study.

"However, despite the trial achieving its primary outcome, the absolute mean differences in the change in the DAS28-ESR (−0.43 units) or the HAQ (−0.04 units) between the two treatment strategies at 24 weeks is quite small," Dr Curtis noted.

"The caution is that on average, patients won't be able to detect differences this small; they are below the thresholds established for a minimally important difference in the DAS28-ESR and the HAQ", said Dr Curtis.

Funding for this study was provided by the French Ministry of Health. Dr Gottenberg and several coauthors reported receiving grant support, personal fees, or other financial or nonfinancial relationships with one or more of the following companies: AbbVie, Pfizer, Roche, Bristol-Myers Squibb, Merck, Sharp, and Dohme, UCB, GlaxoSmithKline, Novartis, Roche Chugai, Amgen, Nordic Pharma, and Hospira, Menarini, SOBI, Janssen, Celgene, and Actelion. Dr Curtis has consulting relationships with Amgen, UCB, BMS, Pfizer, and Janssen.

JAMA. 2016;316:1172-1180. Abstract

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