Biologic discontinuation studies: a systematic review of methods; comment on the article by Yoshida et al.
Yoshida et al present an overview of different designs and 'failure definitions' in biologic discontinuation studies in rheumatoid arthritis (RA). We feel it is a very important review, as the number of discontinuation studies is increasing and therefore awareness of the heterogeneity in these study designs as demonstrated in this review is essential. We have however a few comments. Firstly, one of the difficulties in interpreting discontinuation studies is that different protocols can be used, discontinuation protocol or dose tapering protocols, and that interpretation is sometimes not straightforward. This is exemplified by the misrepresentation of our study in the review. This study is a down-titration and discontinuation trial of infliximab in stable rheumatoid arthritis patients, in which we used a dose tapering protocol. We attempted to down-titrate infliximab until stop in all patients unless a flare occurred. In 16% of all 51 patients, infliximab could be discontinued. The review states however 0% in 12 patients. In 45% of the 51 patients the dose could be partially down- titrated and in 39% no down-titration was possible due to flare after the first down titration step. Additionally, we didn't have a variable follow up duration, as stated in the review article, but 1 year for all included patients. This error underscores the difficulty in interpreting different dose reduction study designs
A second remark we would like to make concerns the definition of 'failure' after biologic discontinuation. The authors found heterogeneity across studies with regard to definition of failure, with most of the included studies in this review using a version of a DAS28-based failure definition. We would like to point out a recently published paper in OMERACT cooperation in this journal, validating a DAS28-based flare criterion (delta DAS28>1.2 compared with baseline or delta DAS28>0.6 in case DAS28>3.2). Of note, this was also the flare definition used in our study, not delta DAS28-ESR>0.6 as mentioned in table 2. Use of this validated flare criterion could lead to better comparison of results between studies.
Finally, we would suggest to expand your search by using other databases (Embase, Cochrane Central Register of Controlled Trials, trial registries) and more search terms for discontinuation, as this should lead to a higher yield in studies. For example, the STRASS study  is not mentioned in this review, since it uses the term 'spacing'. This trial however does study tapering until discontinuation.
In conclusion, Yoshida et al. address and illustrate, very thoroughly, two important issues; differences in design and "failure definition" in biological discontinuation studies. The heterogeneity across current studies regarding these issues is demonstrated in a well-structured manner and we agree with Yoshida et al. that standardized, and also validated, definitions are important.
1. Yoshida K, Sung Y-k, Kavanaugh A, et al. Biologic discontinuation studies: a systematic review of methods. Ann Rheum Dis 2013.
2. Van der Maas A, Kievit W, van den Bemt BJF, et al. Down-titration and discontinuation of infliximab in rheumatoid arthritis patients with stable low disease activity and stable treatment: an observational cohort study. Ann Rheum Dis 2012;71:1849-54.
3. Van der Maas A, Lie E, Christensen R, et al. Construct and criterion validity of several proposed DAS28-based rheumatoid arthritis flare criteria: an OMERACT cohort validation study. Ann Rheum Dis 2012;0:1-6.
4. Fautrel B. Tapering TNF-Blockers in Established Rheumatoid Arthritis Patients in DAS28 Remission: Results of a DAS28-Driven Step-Down Strategy Randomized Controlled Trial [abstract]. Arthritis Rheum 2012;64 (Suppl):p4169-4170
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