Systematic Review of Tumor Necrosis Factor Inhibitor Discontinuation Studies in Rheumatoid Arthritis
Introduction
The combination of anti–tumor necrosis factor agents (anti-TNFs) (adalimumab [ADA], certolizumab, etanercept [ETA], golimumab, and infliximab) and nonbiologic disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX) in patients with rheumatoid arthritis (RA) who have an inadequate or incomplete response to MTX has been shown to be efficacious in preventing progression of structural damage and functional deterioration.1, 2, 3, 4 Despite the efficacy of these biologic therapies for RA, their high cost5 and safety issues (serious infections, malignancy, and other adverse events)6, 7, 8, 9, 10, 11 are among the concerns associated with prolonged use that may motivate physicians and patients to consider discontinuing anti-TNF therapy for RA patients who have been in sustained low disease activity (LDA) or remission. Given that the prevalence of RA is ~1.0% in the United States,12 peak onset is when patients are in their 40s, and that anti-TNFs may cost up to ~$18,000 per year,5 there is an enormous expense associated with long-term continuation of such therapy. For many RA patients receiving the current paradigm of care, lifelong treatment might be required.
Questions surrounding when, how, and in whom to discontinue anti-TNF therapy were within the top 3 most important scientific gaps that needed to be answered in RA, as decided at a 2010 national consensus conference sponsored by the American College of Rheumatology (ACR).13 The objective of the present article was to conduct a systematic review of the available literature on discontinuation of anti-TNF therapy in RA patients and the associated features of study designs, including eligibility criteria, outcome definitions, and outcomes of discontinuation.
Section snippets
Materials And Methods
Relevant studies were selected as part of this systematic review for patients with RA from July 1999 through June 2013. The authors conducted 11 separate searches within PubMed that consisted of the following word combinations: “discontinuation of anti-TNF in rheumatoid arthritis”; “discontinuation of adalimumab and rheumatoid arthritis”; “discontinuation of infliximab and rheumatoid arthritis”; “discontinuation of golimumab and rheumatoid arthritis”; “discontinuation of etanercept and
Results
The initial search strategy retrieved 270 unique articles, which, after exclusion of articles that did not meet inclusion criteria, yielded 29 potentially relevant studies (Figure 1). After hand- reviewing these articles, 9 relevant full-text studies were included in the systematic review regarding discontinuation of anti-TNFs in patients with RA. Of these, 6 evaluated the proportion of patients at the end of the observation time that remained in LDA or remission, and 3 evaluated the durability
Discussion
The present systematic review summarized the published literature that investigated the inclusion criteria, outcome definitions, and results of anti-TNF cessation in patients with RA who were in either LDA or clinical remission. The majority of these studies consisted of long-term extension clinical trials of efficacy studies of anti-TNF biologic agents for RA patients who were anti-TNF naive or, in some instances, DMARD and biologic naive. There were several other observational studies that
Conclusions
Discontinuation of anti-TNFs in patients with RA without increasing disease activity seems possible, especially among patients with earlier RA treated with more aggressive combination treatment. There is a subgroup of patients with established RA who can successfully discontinue therapy, but at present, specific predictors for this population do not exist. Reassuringly for future studies, among patients who discontinued anti-TNF therapy and who had an increase in their disease activity, 70% to
Conflicts of Interest
Dr. Curtis is supported by the Agency for Healthcare Research & Quality (R01 HS018517). The authors have indicated that they have no other conflicts of interest regarding the content of this article.
Acknowledgments
Dr. Navarro-Millan was responsible for the literature search, data interpretation and writing. Dr. Sattui was responsible for the literature search. Dr. Curtis was responsible for the data interpretation and writing.
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