European Journal of Clinical Pharmacology

, Volume 74, Issue 11, pp 1513–1521 | Cite as

Discontinuation of non-anti-TNF drugs for rheumatoid arthritis in interventional versus observational studies: a systematic review and meta-analysis

  • Fernanda S. Tonin
  • Laiza M. Steimbach
  • Leticia P. Leonart
  • Vinicius L. Ferreira
  • Helena H. Borba
  • Thais Piazza
  • Ariane G. Araújo
  • Fernando Fernandez-Llimos
  • Roberto Pontarolo
  • Astrid WiensEmail author
Pharmacoepidemiology and Prescription



Although randomized controlled trials (RCTs) are the gold standard for the assessment of clinical outcomes, long-term extension trials (LTEs) and observational cohorts may help generate evidence. Our goal was to compare the discontinuation rates of abatacept, rituximab, and tocilizumab in rheumatoid arthritis (RA) reported in different study designs.


A systematic review was conducted with searches in PubMed, Scopus, and the Cochrane Library, plus a manual search, for RCTs, LTEs, and observational cohorts reporting discontinuation rates by any of three causes (all-cause, inefficacy, adverse events). Meta-analyses with sensitivity analyses and meta-regressions were conducted.


Of the 111 studies included, 74 were RCTs (n = 55) or LTEs (n = 17) reporting data on abatacept (n = 33), rituximab (n = 10), and tocilizumab (n = 31) and 37 were observational cohort studies (abatacept = 11, rituximab = 8, tocilizumab = 18). The follow-up duration did not differ among the study designs. Discontinuation rates were similar among the drugs but varied among the study designs. Discontinuation rates were significantly higher in cohort studies than those in interventional studies for the three drugs. Sensitivity analyses could not identify patient characteristics associated with these differences. Meta-regression analyses demonstrated no correlation between study follow-up duration and discontinuation rates.


The discontinuation rates reported for non-anti-TNF drugs varied relative to the study design in which they were investigated. Regulatory agencies, price-setting entities, and evidence-gathering researchers should consider the effect of the real-life environment in their decisions and conclusions.


Rheumatoid arthritis Statistics and study design Evidence-based medicine Medication Adherence 


Author contributions

AW, RP, FFL, and FST designed the study and wrote the protocol. LMS, LPL, VLF, HHB, TP, and AGSA screened and abstracted publications. LMS, LPL, VLF, and HHB evaluated methodological quality. FST, AW, and FFL statistically analyzed data. FST and FFL wrote the manuscript, with editorial contributions from LMS, LPL, VLF, HHB, TP, AGSA, AW, and RP. All authors reviewed the manuscript for accuracy and scientific content.


This work was supported by Fellow of the Brazilian National Council of Scientific and Technological Research—CNPq (grant Universal 14/2014-442095/2014-7).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Fernanda S. Tonin
    • 1
  • Laiza M. Steimbach
    • 1
  • Leticia P. Leonart
    • 1
  • Vinicius L. Ferreira
    • 1
  • Helena H. Borba
    • 2
  • Thais Piazza
    • 1
  • Ariane G. Araújo
    • 1
  • Fernando Fernandez-Llimos
    • 3
  • Roberto Pontarolo
    • 2
  • Astrid Wiens
    • 2
    Email author
  1. 1.Universidade Federal do ParanáCuritibaBrazil
  2. 2.Department of PharmacyUniversidade Federal do ParanáCuritibaBrazil
  3. 3.Research Institute for Medicines (iMed.ULisboa), Department of Social Pharmacy, Faculty of PharmacyUniversidade de LisboaLisbonPortugal

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