Long-Term Efficacy of Tumor Necrosis Factor Inhibitors for the Treatment of Methotrexate-Naïve Rheumatoid Arthritis: Systematic Literature Review and Meta-Analysis

  • László GulácsiEmail author
  • Zsombor Zrubka
  • Valentin Brodszky
  • Fanni Rencz
  • Rieke Alten
  • Zoltán Szekanecz
  • Márta Péntek
Original Research



Synthesis of evidence on the long-term use of first-line biologic therapy in patients with early rheumatoid arthritis (RA) is required. We compared the efficacy of up to 5 years’ treatment with first-line tumor necrosis factor inhibitors (TNFis) versus other treatment strategies in this population.


Previous systematic reviews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) involving treatment of methotrexate-naïve RA patients with first-line TNFis. Literature was synthesized qualitatively, and a meta-analysis conducted to evaluate American College of Rheumatology (ACR) responses, clinical remission defined by any standard measure, and Health Assessment Questionnaire Disability Index (HAQ) at Years 2 and/or 5.


Ten RCTs involving 4306 patients [first-line TNFi, n = 2234; other treatment strategies (control), n = 2072] were included in the meta-analysis. Three studies were double-blind for the first 2 years, while seven were partly/completely open label during this period. Five studies reported data at Year 5; all were open label at this time point. At Year 2, ACR50 response, ACR70 response and remission rates were significantly improved with first-line TNFi versus control in double-blind RCTs [log-odds ratio (OR) 0.32 [95% confidence interval (CI) 0.02, 0.62; p = 0.035], log-OR 0.48 (95% CI 0.20, 0.77; p = 0.001), and log-OR 0.44 (95% CI 0.13, 0.74; p = 0.005), respectively], but not in open-label studies. No significant between-group differences were observed in mean HAQ at Year 2 in double-blind or open-label RCTs or in ACR response or remission outcomes at Year 5.


In double-blind studies, 2-year efficacy outcomes were significantly improved with first-line TNFi versus other treatment strategies in patients with MTX-naïve RA. No significant differences in these outcomes were observed when data from open-label RCTs were considered on their own. Further data on the efficacy of TNFi therapy over ≥ 2 years in patients with methotrexate-naïve RA are required.

Plain Language Summary

Plain language summary available for this article.


Biologic Disease-modifying antirheumatic drug Early Efficacy First line Meta-analysis Methotrexate-naïve Systematic review Tumor necrosis factor inhibitor 




The authors received no funding for the analyses reported here. The article processing charges were funded by Celltrion Healthcare Co., Ltd (Incheon, Republic of Korea).

At the time of publication of the current article, the authors are performing additional work related to the analyses reported here; funding for this work will be provided by Celltrion Healthcare Co., Ltd.


All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the article to be published.

Medical Writing, Editorial, and Other Assistance

Medical writing support for this article (including copyediting and fact checking) was provided to the authors by Rick Flemming, PhD CMPP and Emma Evans, PhD CMPP at Aspire Scientific Limited (Bollington, UK) and was funded by Celltrion Healthcare Co., Ltd.


László Gulácsi has received consultancy and lecturing fees from Astellas, BMS, Celltrion, Egis Pharmaceuticals, GSK, Hikma, Hospira, Lilly Hungaria Ltd, MSD Hungary, Pfizer, Roche, Sandoz and UCB. Zsombor Zrubka used to be a full-time employee of Egis Pharmaceuticals, Janssen Cilag, Sandoz and Pfizer. Valentin Brodszky has received grants and personal fees from Celltrion, Egis Pharmaceuticals, Pfizer and Sager Pharma. Fanni Rencz has received consultancy fees from Celltrion and Hospira. Rieke Alten has received honoraria from Celltrion. Zoltán Szekanecz has received consultancy and lecturing fees from AbbVie, Amgen, BMS, Lilly, MSD, Novartis, Pfizer, Roche and UCB. Márta Péntek has received grants and personal fees from Celltrion, Egis Pharmaceuticals, Merck, Pfizer and Sager Pharma.

Compliance with Ethics Guidelines

This article does not contain any new studies with human or animal subjects performed by any of the authors.

Data Availability

All data used in this systematic review and meta-analysis are available in the published sources.

Supplementary material

12325_2018_869_MOESM1_ESM.docx (3.1 mb)
Supplementary material 1 (DOCX 3153 kb)


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Copyright information

© Springer Healthcare Ltd., part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Health EconomicsCorvinus University of BudapestBudapestHungary
  2. 2.Doctoral School of Business and ManagementCorvinus University of BudapestBudapestHungary
  3. 3.Rheumatology Research Center, Schlosspark-Klinik ChariteUniversity Medicine BerlinBerlinGermany
  4. 4.Division of Rheumatology, Department of Medicine, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  5. 5.Department of RheumatologyFlór Ferenc County HospitalKistarcsaHungary

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