Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability in the Management of Autoimmune Diseases. A Systematic Review and Meta-Analysis

Abstract

Background

Tumor necrosis factor (TNF) inhibitors are a mainstay in the treatment of rheumatoid arthritis (RA), as well as in the management of spondyloarthritis (SpA) and inflammatory bowel diseases (IBD). Unfortunately, a portion of patients taking these drugs require escalating doses within the approved label to achieve response, while others lose response altogether. This may be due to the development of antibodies against TNFi agents.

Objectives

Our objective was to examine the immunogenicity of TNF inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab) in RA, SpA, and IBD, and to examine the potential effect of anti-drug antibodies (ADABs) on the loss of clinical response through a systematic literature review and meta-analysis.

Methods

We conducted a comprehensive literature search using three databases (PubMed, Web of Science, and the Cochrane library) to identify studies examining the immunogenicity of TNF inhibitors in autoimmune diseases between 1966 and 31 December 2013. Inclusion criteria required that studies be in English, be randomized controlled trials, observational studies, or case reports involving more than five patients, and that the patients be aged 18 years or older. Studies were excluded if they were strictly genetic with no clinical correlate, if the patients had concomitant cancer within 5 years of the study, or if the patients had a renal disease requiring dialysis. Double extraction was followed by a third extraction if needed. Consensus was reached by discussion when disagreements occurred. Random-effect models were generated for the meta-analysis of 68 studies to estimate the odds ratio (OR) of the ADAB effects on TNF inhibitor response. Regression analysis was used to compare among the drugs and diseases.

Results

A total of 68 studies (14,651 patients) matched the inclusion/exclusion criteria. Overall, the cumulative incidence of ADABs was 12.7 % [95 % confidence interval (CI) 9.5–16.7]. Of the patients using infliximab, 25.3 % (95 % CI 19.5–32.3) developed ADABs compared with 14.1 % (95 % CI 8.6–22.3) using adalimumab, 6.9 % (95 % CI 3.4–13.5) for certolizumab, 3.8 % (95 % CI 2.1–6.6) for golimumab, and 1.2 % (95 % CI 0.4–3.8) for etanercept. ADABs reduced the odds of clinical response by 67 % overall, although most of the data were derived from articles involving infliximab (nine) and adalimumab (eight). The summary effect for infliximab yielded an estimated OR (with ADABs vs. without) of 0.42 (95 % CI 0.30–0.58); the summary effect for adalimumab yielded an estimated OR (as above) of 0.13 (95 % CI 0.08–0.22); and the OR (as above) for golimumab was 0.42 (95 % CI 0.22–0.81). All figures were statistically significant. ADABS decreased response by 27 % in RA and 18 % in SpA, both of which were statistically significant. However, the effect of ADABS on response was not statistically significant for IBD when we only included the studies that reported the duration of exposure in the regression analysis. The use of concomitant immunosuppressives (methotrexate, 6-mercaptopurine, azathioprine, and others) reduced the odds of ADAB formation in all patients by 74 %. The OR for risk with immunosuppressives versus without was 0.26 (95 % CI 0.21–0.32).

Conclusion

ADABs developed in 13 % of patients. All five TNF inhibitors were associated with ADABs, but to varying degrees depending on the specific TNF inhibitor and the disease. ADABs are associated with reduced clinical response and an increased incidence of infusion reactions and injection site reactions. Concomitant use of immunosuppressives can reduce ADAB formation.

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Acknowledgments

Special thanks go to our librarian Lisa Federer, for without her tireless efforts and timely responses, this project would not be possible, and to Gabriel Valdivia, without whom this article could not have been completed.

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Correspondence to Sarah S. Thomas or Daniel E. Furst.

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Sarah Thomas, Nabeel Borazan, Nashla Barroso, Lewei Duan, Sara Taroumian, Benjamin Kretzmann, Ricardo Bardales, David Elashoff, and Sitaram Vangala have no conflicts to declare. Dr. Daniel Furst has received grant/research support from AbbVie, Actelion, Amgen, BMS, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, and UCB and is a consultant for AbbVie, Actelion, Amgen, BMS, Cytori, Janssen, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, and UCB; he is also on the speaker’s bureau (CME only) for AbbVie, Actelion, and UCB.

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S. S Thomas and N. Borazan contributed equally to this work.

Appendices

Appendix 1

(“Arthritis, Rheumatoid”[MeSH Terms] OR (Rheumatoid [all fields] AND arthriti* [all fields]) OR “caplan syndrome” [all fields] OR (“felty syndrome” [all fields] OR “felty’s syndrome” [all fields]) OR (“adult” [all fields] AND (“still disease” [all fields] OR “still’s disease” [all fields])) OR “Crohn Disease”[MeSH Terms] OR (crohn [all fields] OR crohn’s [all fields]) OR ((colitis [all fields] OR enteritis [all fields] OR ileitis [all fields]) AND (regional [all fields] OR granulomatous [all fields])) OR ((regional [all fields] OR terminal [all fields]) AND ileitis [all fields]) OR (“Spondylitis, Ankylosing”[Mesh] OR “ankylosing spondylitis” [all fields] OR “Bechterew Disease” [all fields] OR “Marie Struempell Disease” [all fields] OR “Marie Strumpell Disease” [all fields]) OR (“Arthritis, Psoriatic”[Mesh] OR “psoriatic arthritis”[all fields] OR (psoriasis [all fields] AND arthritis [all fields])) OR (“Colitis, Ulcerative”[Mesh] OR (ulcerative [all fields] AND colitis [all fields]))) AND ((cimzia [all fields] OR certolizumabpegol [all fields] OR cdp870[All Fields] OR certolizumabpegol [Supplementary Concept]) OR (enbrel [all fields] OR etanercept [all fields] OR TNFR-Fc fusion protein [All Fields] OR TNFR-Fc fusion protein [Supplementary Concept]) OR (humira [all fields] OR adalimumab [all fields] OR adalimumab [Supplementary Concept]) OR (remicade [all fields] OR infliximab [all fields] OR infliximab [Supplementary Concept] OR mab ca2 [All Fields] OR monoclonal antibody ca2[All Fields]) OR (simponi [all fields] OR golimumab [all fields] OR golimumab [Supplementary Concept] OR cnto-148[All Fields])) AND (immunogenic* [all fields] OR “antibody formation” [all fields] OR Antibody Formation [MeSH terms] OR “response failure” [all fields] OR bioavailability OR biological availability OR “Biological Availability”[MeSH Terms] OR “drug tolerance”[all fields] OR Drug Tolerance [MeSH Terms] OR “treatment outcome” [all fields] OR Treatment Outcome [MeSH Terms]) AND ((“Randomized Controlled Trial” [ptyp] OR “Controlled Clinical Trial” [ptyp] OR “Multicenter Study” [ptyp] OR “randomized”[tiab] OR “randomised”[tiab] OR “placebo”[tiab] OR “randomly”[tiab] OR “trial”[tiab] OR “randomized controlled trials as topic”[MeSH Terms]OR “random allocation”[MeSH Terms] OR “double-blind method”[MeSH Terms] OR “double-blind”[text word] OR “single-blind method”[MeSH Terms] OR “single-blind” [text word] NOT (“Meta-Analysis” [ptyp]OR “Review” [ptyp] OR “Letter” [ptyp] OR “Editorial” [ptyp])) AND (“1966/01/01”[PDat] : “2012/12/1”[PDat] AND English[lang]) NOT (animals[mh] NOT human[mh])).

Appendix 2: Quality Assessment Tool for Quantitative Studies

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Thomas, S.S., Borazan, N., Barroso, N. et al. Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability in the Management of Autoimmune Diseases. A Systematic Review and Meta-Analysis. BioDrugs 29, 241–258 (2015). https://doi.org/10.1007/s40259-015-0134-5

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Keywords

  • Rheumatoid Arthritis
  • Inflammatory Bowel Disease
  • Infliximab
  • Etanercept
  • Adalimumab