Clinical Reviews in Allergy & Immunology

, Volume 54, Issue 2, pp 234–243 | Cite as

The Comparative Safety of TNF Inhibitors in Ankylosing Spondylitis—a Meta-Analysis Update of 14 Randomized Controlled Trials

  • Li-qiong Hou
  • Ga-xue Jiang
  • Yan-fei Chen
  • Xi-Mei Yang
  • Lei Meng
  • Miao Xue
  • Xiao-guang Liu
  • Xi-chao Chen
  • Xiao Li


TNF inhibitors have been used in ankylosing spondylitis (AS). The efficacy of TNF inhibitors was already evaluated by meta-analysis of randomized controlled trials (RCTs). However, the safety of TNF inhibitors is still unclear. Therefore, we aimed to evaluate and update the safety data from RCTs of TNF inhibitors in patients treated for AS. A systematic literature search was conducted from 1990 through May 31, 2016. All studies included were randomized, double-blind, controlled trials of patients with ankylosing spondylitis that evaluated adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab treatment. The overall serious adverse events, the risk of serious infection events, and the risk of malignancy and discontinuation rates were abstracted, and risk estimates were calculated by Peto odds ratios (ORs). Fourteen randomized controlled trials involving 2032 subjects receiving TNF inhibitors and 1030 subjects receiving placebo and/or traditional disease-modifying anti-rheumatic drugs (DMARDs) were included. The overall serious adverse events (OR, 1.34; 95% CI, 0.87–2.05), the risk of serious infection events (OR, 1.59; 95% CI, 0.63–4.01), the risk of malignancy (OR, 0.98; 95% CI, 0.25–3.85), and discontinuation due to adverse events (OR, 1.55; 95% CI, 0.95–2.54) in patients treated with TNF inhibitors as a group were not significantly different from those treated with placebo in the control group. TNF inhibitors were generally safe for treatment of ankylosing spondylitis. These data may help guide clinical comparative decision making in the management of AS.


Ankylosing spondylitis TNF inhibitors Safety Adverse events Meta-analysis 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


There is no funding source.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed Consent

Not applicable.


  1. 1.
    Senabre JM, Santos C, Santos G et al (2013) Long-term safety and efficacy of etanercept in the treatment of ankylosing spondylitis. Patient Prefer Adherence 10:961–972CrossRefGoogle Scholar
  2. 2.
    Wu D, Guo YY, Xu NN et al (2015) Efficacy of anti-tumor necrosis factor therapy for extra-articular manifestations in patients with ankylosing spondylitis: a meta-analysis. BMC Musculoskelet Disord 10:2016–2019Google Scholar
  3. 3.
    Machado MA, Barbosa MM, Almeida AM et al (2013) Treatment of ankylosing spondylitis with TNF blockers: a meta-analysis. Rheumatol Int 33:2199–2213. doi: 10.1007/s00296-00013-02772-00296 CrossRefPubMedGoogle Scholar
  4. 4.
    Liu W, Wu YH, Zhang L et al (2016) Efficacy and safety of TNF-alpha inhibitors for active ankylosing spondylitis patients: multiple treatment comparisons in a network meta-analysis. Sci Rep 10:32768CrossRefGoogle Scholar
  5. 5.
    Inman RD, Davis JC, Heijde D et al (2008) Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo- controlled, phase III trial. Arthritis Rheum 10:3402–3412CrossRefGoogle Scholar
  6. 6.
    Dougados M, Braun J, Szanto S et al (2011) Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: results of a randomised double-blind placebo-controlled study (SPINE). Ann Rheum Dis 70:799–804. doi: 10.1136/ard.2010.1392617 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bao C, Huang F, Khan MA et al (2014) Safety and efficacy of golimumab in Chinese patients with active ankylosing spondylitis: 1-year results of a multicentre, randomized, double-blind, placebo-controlled phase III trial. Rheumatology (Oxford) 53:1654–1663. doi: 10.1093/rheumatology/keu1132 CrossRefGoogle Scholar
  8. 8.
    Counsell C (1997) Formulating questions and locating primary studies for inclusion in systematic reviews. Ann Intern Med 127:380–387CrossRefPubMedGoogle Scholar
  9. 9.
    van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 27:361–368CrossRefPubMedGoogle Scholar
  10. 10.
    Benucci M, Saviola G, Baiardi P et al (2011) Efficacy and safety of leflunomide or methotrexate plus subcutaneous tumour necrosis factor-alpha blocking agents in rheumatoid arthritis. Int J Immunopathol Pharmacol 24:269–274CrossRefPubMedGoogle Scholar
  11. 11.
    Billiau AD, Loop M, Le P et al (2010) Etanercept improves linear growth and bone mass acquisition in MTX-resistant polyarticular-course juvenile idiopathic arthritis. Rheumatology (Oxford) 49:1550–1558. doi: 10.1093/rheumatology/keq1123 CrossRefGoogle Scholar
  12. 12.
    Bliddal H, Terslev L, Qvistgaard E et al (2006) A randomized, controlled study of a single intra-articular injection of etanercept or glucocorticosteroids in patients with rheumatoid arthritis. Scand J Rheumatol 35:341–345CrossRefPubMedGoogle Scholar
  13. 13.
    Blumenauer B, Judd M, Wells G et al (2002) Infliximab for the treatment of rheumatoid arthritis. Cochrane Database Syst Rev 3Google Scholar
  14. 14.
    Boesen M, Boesen L, Jensen KE et al (2008) Clinical outcome and imaging changes after intraarticular (IA) application of etanercept or methylprednisolone in rheumatoid arthritis: magnetic resonance imaging and ultrasound-Doppler show no effect of IA injections in the wrist after 4 weeks. J Rheumatol 35:584–591PubMedGoogle Scholar
  15. 15.
    Breedveld FC, Emery P, Keystone E et al (2004) Infliximab in active early rheumatoid arthritis. Ann Rheum Dis 63:149–155CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Breedveld FC, Han C, Bala M et al (2004) Association between baseline radiographic damage and improvement in physical function after treatment of patients with rheumatoid arthritis. Ann Rheum Dis 64:52–55CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Chang J, Girgis L (2007) Clinical use of anti-TNF-alpha biological agents—a guide for GPs. Aust Fam Physician 36:1035–1038PubMedGoogle Scholar
  18. 18.
    Anis A, Zhang W, Emery P et al (2009) The effect of etanercept on work productivity in patients with early active rheumatoid arthritis: results from the COMET study. Rheumatology (Oxford) 48:1283–1289. doi: 10.1093/rheumatology/kep1239 CrossRefGoogle Scholar
  19. 19.
    Deeks JJ, Higgins J, Altman DG (2008) Analysing data and undertaking meta-analyses. Cochrane Handbook for Systematic Reviews of Interventions, Cochrane Book Series, pp 243–296Google Scholar
  20. 20.
    Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558CrossRefPubMedGoogle Scholar
  22. 22.
    Wallace BC, Schmid CH, Lau J et al (2009) Meta-analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Res Methodol 10:2080Google Scholar
  23. 23.
    Braun J, Brandt J, Listing J et al (2002) Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 359:1187–1193CrossRefPubMedGoogle Scholar
  24. 24.
    Gorman JD, Sack KE, Davis JC et al (2002) Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 346:1349–1356CrossRefPubMedGoogle Scholar
  25. 25.
    Davis JC, Van Der Heijde D, Braun J et al (2003) Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 48:3230–3236CrossRefPubMedGoogle Scholar
  26. 26.
    van der Heijde D, Dijkmans B, Geusens P et al (2005) Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum 52:582–591CrossRefPubMedGoogle Scholar
  27. 27.
    Calin A, Dijkmans BA, Emery P et al (2004) Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis 2063:1594–2600CrossRefGoogle Scholar
  28. 28.
    Marzo H, McGonagle D, Jarrett S et al (2005) Infliximab in combination with methotrexate in active ankylosing spondylitis: a clinical and imaging study. Ann Rheum Dis 64:1568–1575CrossRefGoogle Scholar
  29. 29.
    van der Heijde D, Kivitz A, Schiff MH et al (2006) Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 54:2136–2146CrossRefPubMedGoogle Scholar
  30. 30.
    van der Heijde D, Da Silva JC, Dougados M et al (2006) Etanercept 50 mg once weekly is as effective as 25 mg twice weekly in patients with ankylosing spondylitis. Ann Rheum Dis 65:1572–1577CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Barkham N, Coates LC, Keen H et al (2010) Double-blind placebo-controlled trial of etanercept in the prevention of work disability in ankylosing spondylitis. Ann Rheum Dis 69:1926–1928. doi: 10.1136/ard.2009.121327 CrossRefPubMedGoogle Scholar
  32. 32.
    Huang F, Gu J, Zhu P et al (2014) Efficacy and safety of adalimumab in Chinese adults with active ankylosing spondylitis: results of a randomised, controlled trial. Ann Rheum Dis 73:587–594. doi: 10.1136/annrheumdis-2012-202533 CrossRefPubMedGoogle Scholar
  33. 33.
    Braun J, van der Horst IE, Huang F et al (2011) Clinical efficacy and safety of etanercept versus sulfasalazine in patients with ankylosing spondylitis: a randomized, double-blind trial. Arthritis Rheum 63:1543–1551CrossRefPubMedGoogle Scholar
  34. 34.
    Brandt J, Khariouzov A, Listing J et al (2003) Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis. Arthritis Rheum 48:1667–1675CrossRefPubMedGoogle Scholar
  35. 35.
    Brandt J, Listing J, Sieper J et al (2004) Development and preselection of criteria for short term improvement after anti-TNF alpha treatment in ankylosing spondylitis. Ann Rheum Dis 63:1438–1344CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Dijkmans B, Emery P, Hakala M et al (2009) Etanercept in the longterm treatment of patients with ankylosing spondylitis. J Rheumatol 36:1256–1264. doi: 10.3899/jrheum.081033 CrossRefPubMedGoogle Scholar
  37. 37.
    Inman RD, Maksymowych WP (2010) A double-blind, placebo-controlled trial of low dose infliximab in ankylosing spondylitis. J Rheumatol (37):1203–1210. doi: 10.3899/jrheum.091042
  38. 38.
    Fouque A, Jette L, Combescure C et al (2010) Serious infections in patients with ankylosing spondylitis with and without TNF blockers: a systematic review and meta-analysis of randomised placebo-controlled trials. Ann Rheum Dis 69:1756–1761. doi: 10.1136/ard.2008.098822 CrossRefGoogle Scholar
  39. 39.
    Baeten D, Kruithof E, Van den Bosch F et al (2003) Systematic safety follow up in a cohort of 107 patients with spondyloarthropathy treated with infliximab: a new perspective on the role of host defence in the pathogenesis of the disease? Ann Rheum Dis 62:829–834CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Askling J, Fored CM, Brandt L et al (2005) Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis 64:1421–1426CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Burmester GR, Mease P, Dijkmans BA et al (2009) Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases. Ann Rheum Dis 68:1863–1869. doi: 10.1136/ard.2008.102103 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Nannini C, Cantini F, Niccoli L et al (2009) Single-center series and systematic review of randomized controlled trials of malignancies in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis receiving anti-tumor necrosis factor alpha therapy: is there a need for more comprehensive screening procedures? Arthritis Rheum 61:801–812CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of RheumatologyThe First Hospital of Lanzhou UniversityLanzhouChina
  2. 2.Department of CardiologyThe First Hospital of Lanzhou UniversityLanzhouChina
  3. 3.Department of Evidence-Based Medicine CenterThe First Hospital of Lanzhou UniversityLanzhouChina

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