Systematic review of tumor necrosis factor inhibitor discontinuation studies in rheumatoid arthritis

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.

Keywords: anti–tumor necrosis factor discontinuation; rheumatoid arthritis; rheumatoid arthritis remission.

Figure 1

Flow chart of literature search for articles regarding anti-tumor necrosis factor discontinuation in patients with rheumatoid arthritis within PubMed through June 2013

Figure 2

Mean (A) disease activity score in 28 joints and (B) simplified disease activity index among patients treated with either etanercept 50 mg weekly, 25 mg weekly or placebo, each of them on background methotrexate Legend Figure 2: Patients from the modified intention-to-treat population in the double-blind period included. Last-observation-carried-forward analysis. Bars show 95% CIs. *50 mg etanercept plus methotrexate versus placebo plus methotrexate p<0·0001. †25 mg etanercept plus methotrexate versus placebo plus methotrexate p<0·0001.

Figure 3

Time to loss of efficacy (i.e. persistent LDA) among patients treated with either etanercept 50 mg weekly, 25 mg weekly or placebo, each of them on background methotrexate Legend Figure 3: Patients in this analysis were randomized after achieving disease activity score in 28 joints with erythrocyte sedimentation rate of ≤ 3.2 at week 36 of treatment with methotrexate and 50 mg or 25 mg of etanercept. Crosses indicate censoring.