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.
This is a preview of subscription content, log in to check access.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
There is no funding source.
This article does not contain any studies with human participants or animals performed by any of the authors.
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
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
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
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
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/keu1132CrossRefGoogle Scholar
Counsell C (1997) Formulating questions and locating primary studies for inclusion in systematic reviews. Ann Intern Med 127:380–387CrossRefPubMedGoogle Scholar
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
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
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/keq1123CrossRefGoogle Scholar
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
Blumenauer B, Judd M, Wells G et al (2002) Infliximab for the treatment of rheumatoid arthritis. Cochrane Database Syst Rev 3Google Scholar
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
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
Chang J, Girgis L (2007) Clinical use of anti-TNF-alpha biological agents—a guide for GPs. Aust Fam Physician 36:1035–1038PubMedGoogle Scholar
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/kep1239CrossRefGoogle Scholar
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.2008.098822CrossRefGoogle Scholar
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
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
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