Elsevier

Clinical Therapeutics

Volume 35, Issue 11, November 2013, Pages 1850-1861.e1
Clinical Therapeutics

Systematic Review of Tumor Necrosis Factor Inhibitor Discontinuation Studies in Rheumatoid Arthritis

https://doi.org/10.1016/j.clinthera.2013.09.015Get rights and content

Abstract

Background

Anti–tumor necrosis factor agents (anti-TNFs) have changed the course of rheumatoid arthritis (RA) for more than a decade. Use of these medications often results in remission, or at least low disease activity (LDA), but at a substantial cost. It has been postulated that discontinuation of these medications among patients with RA in remission or LDA may be possible without an associated increase in RA disease activity.

Objective

The goal of this systematic literature review was to summarize published articles regarding discontinuation of anti-TNFs in patients with RA.

Methods

A systematic literature review was conducted to identify English-language articles indexed in PubMed from July 1999 through June 2013 reporting results regarding anti-TNF discontinuation in patients with RA. Study designs included observational longitudinal studies and clinical trials. Outcomes had to include 1 of the following: time to flare after anti-TNF discontinuation, failure to remain in remission, or proportion of patients in LDA or remission at the end of the study.

Results

Ten studies examined discontinuation of anti-TNF therapies in RA. Inclusion criteria varied significantly across studies in terms of disease activity status (remission or LDA) and duration of this disease status (1 year or 1 month) before discontinuation being attempted. Results from larger studies (eg, >100 patients) suggest that the proportion of patients who discontinued anti-TNF and did not have an increase in disease activity ranged from 24% to 81%. In 3 studies that evaluated durability of LDA or remission after anti-TNF discontinuation, the mean time to relapse varied from 15 weeks to 17 months. In studies that analyzed radiographic data, once therapies were reinitiated after an increase in disease activity was detected, patients generally did not experience progression in structural damage.

Conclusions

Discontinuation of anti-TNF therapy is achievable for many RA patients who start in clinical remission or LDA. However, heterogeneous inclusion criteria and highly variable outcome definitions across studies make it difficult to efficiently summarize the literature on this topic or to conduct a meta-analysis. There is a lack of evidence regarding how to best predict which patients have the greatest likelihood of continuing to do well after discontinuation of anti-TNF therapy.

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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