Skip to main content
SpringerLink
Log in

Treatment of ankylosing spondylitis with TNF blockers: a meta-analysis

  • Review
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

Biological agents directed against tumor necrosis factor (TNF) represent therapeutic options for patients with ankylosing spondylitis with high disease activity despite use of non-steroidal anti-inflammatory drugs. To evaluate the efficacy and safety of the anti-TNF agents infliximab, etanercept, adalimumab, golimumab, and certolizumab for the treatment of ankylosing spondylitis, we performed a systematic review of randomized clinical trials on adult patients with ankylosing spondylitis using articles culled from the EMBASE, MEDLINE, Cochrane Controlled Trials Register and LILACS databases (September/2012), manual literature search, and the gray literature. Study selections and data collection were performed by two independent reviewers, with disagreements solved by a third reviewer. The following outcomes were evaluated: ASAS 20 response, disease activity, physical function, vertebral mobility, adverse events, and withdraws. The meta-analysis was performed using the Review Manager® 5.1 software by applying the random effects model. Eighteen studies were included in this review. No study of certolizumab was included. Patients treated with anti-TNF agents were more likely to display an ASAS 20 response after 12/14 weeks (RR 2.21; 95 % CI 1.91; 2.56) and 24 weeks (RR 2.68; 95 % CI 2.06; 3.48) compared with controls, which was also true for several other efficacy outcomes. Meta-analysis of safety outcomes and withdraws did not indicate statistically significant differences between treatment and control groups after 12 or 30 weeks. Adalimumab, infliximab, etanercept, and golimumab can effectively reduce the signs and symptoms of the axial component of ankylosing spondylitis. Safety outcomes deserve further study, especially with respect to long-term follow-ups.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Notes

  1. The GO-RAISE study presented the ASAS 20 response at week 24 only graphically and the exact value was unable to be obtained. We contacted the authors to get more information.

References

  1. Braun J, Sieper J (2007) Ankylosing spondylitis. Lancet 369:1379–1390

    Article  PubMed  Google Scholar 

  2. Gensler L (2011) Clinical features of ankylosing spondylitis. In: Hochberg MC, Silman AJ, Smolen JS et al (eds) Rheumatology (5th edn), pp 9–14

  3. Rudwaleit M (2011) Classification and epidemiology of spondyloarthrits. In: Hochberg MC, Silman AJ, Smolen JS et al (eds) Rheumatology (5th edn), pp 3–8

  4. Boonen A, Chorus A, Miedema H, Van Der Heijde D, Van Der Tempel H, Van Der Linden S (2001) Employment, work disability, and work days lost in patients with ankylosing spondylitis: a cross sectional study of Dutch patients. Ann Rheum Dis 60:353–358. doi:10.1136/ard.60.4.353

    Article  PubMed  CAS  Google Scholar 

  5. Boonen A (2006) A review of work-participation, cost-of-illness and cost-effectiveness studies in ankylosing spondylitis. Nat Clin Pract Rheumatol 2(10):546–553. doi:10.1038/ncprheum0297

    Article  PubMed  Google Scholar 

  6. Sieper J (2011) Management of ankylosing spondylitis. In: Hochberg MC, Silman AJ, Smolen JS et al (eds) Rheumatology (5th edn), pp 37–57

  7. Braun J, van den Berg R, Baraliakos X et al (2011) 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 70:896–904. doi:10.1136/ard.2011.151027

    Article  PubMed  CAS  Google Scholar 

  8. Escalas C, Trijau S, Dougados M (2010) Evaluation of the treatment effect of NSAIDs/TNF blockers according to different domains in ankylosing spondylitis: results of a meta-analysis. Rheumatology (Oxford) 49(7):1317–1325. doi:10.1093/rheumatology/keq078

    Article  CAS  Google Scholar 

  9. Green S, Higgins JPT, Alderson P et al (2011). In: Higgins JPT, Green S (eds) Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The cochrane collaboration. Available from www.cochrane-handbook.org

  10. Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6(7). doi:10.1136/bmj.b2700

  11. 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 27:361–368. doi:10.1002/art.1780270401

    Article  PubMed  Google Scholar 

  12. Sieper J (2011) Management of ankylosing spondylitis. Section 9 Spondyloarthropathies. In: Hochberg MC (ed) Rheumatology, 5th edn. Philadelphia, Elsevier

    Google Scholar 

  13. Woodroffe R, Yao GL, Meads C et al (2005) Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study. Health Technol Assess 9(21)

  14. Higgins JPT, Altman DG, Sterne JAC (2011) Chapter 8: assessing risk of bias in included studies. In: Higgins JPT, Green S (eds) Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The cochrane collaboration. Available from www.cochrane-handbook.org

  15. Landis JR, Koch GG (1977) The measurement of observer agreement for categorical data. Biometrics 33(1):159–174

    Article  PubMed  CAS  Google Scholar 

  16. Deeks JJ, Higgins JPT, Altman DG (2011) Chapter 9: analysing data and undertaking meta-analyses. In: Higgins JPT, Green S (eds) Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The cochrane collaboration. Available from www.cochrane-handbook.org

  17. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-ytter Y, Schünemann HJ (2008) GRADE: what is “quality of evidence” and why is it important to clinicians? BMJ 336:995–998. doi:10.1136/bmj.39490.551019.BE

    Article  PubMed  Google Scholar 

  18. Guyatt GH, Oxman AD, Vist GE et al (2008) GRADE: going from evidence to recommendations. BMJ 336:1049–1051. doi:10.1136/bmj.39493.646875.AE

    Article  PubMed  Google Scholar 

  19. 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(7):2136–2146

    Article  PubMed  Google Scholar 

  20. Davis JC Jr, Revicki D, van der Heijde DM et al (2007) Health-related quality of life outcomes in patients with active ankylosing spondylitis treated with adalimumab: results from a randomized controlled study. Arthritis Rheum 57(6):1050–1057. doi:10.1002/art.21913

    Article  PubMed  Google Scholar 

  21. Dougados M, Luo MP, Maksymowych WP et al (2008) Evaluation of the patient acceptable symptom state as an outcome measure in patients with ankylosing spondylitis: data from a randomized controlled trial. Arthritis Rheum 59(4):553–560. doi:10.1002/art.23527

    Article  PubMed  Google Scholar 

  22. Revicki DA, Luo MP, Wordsworth P et al (2008) Adalimumab reduces pain, fatigue, and stiffness in patients with ankylosing spondylitis: results from the adalimumab trial evaluating long-term safety and efficacy for ankylosing spondylitis (ATLAS). J Rheumatol 35(7):1346–1353 (Epub 2008 May 15). Erratum in: J Rheumatol. 2011 Apr; 38(4):788

    PubMed  CAS  Google Scholar 

  23. van der Heijde D, Schiff MH, Sieper J et al (2009) Adalimumab effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: long-term results from the ATLAS trial. Ann Rheum Dis 68(6):922–929. doi:10.1136/ard.2007.087270 (Epub 2008 Aug 13)

    Article  PubMed  Google Scholar 

  24. Maksymowych WP, Rahman P, Keystone E, Wong R, Inman R (2005) Efficacy of adalimumab in active ankylosing spondylitis (AS)—results of the Canadian AS study. Arthritis Rheum 52:505

    Google Scholar 

  25. Lambert RG, Salonen D, Rahman P et al (2007) Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 56(12):4005–4014. doi:10.1002/art.23044

    Article  PubMed  CAS  Google Scholar 

  26. Gorman JD, Sack KE, Davis JC Jr (2002) Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 346(18):1349–1356

    Article  PubMed  CAS  Google Scholar 

  27. Davis JC Jr, van der Heijde D, Braun J et al (2003) Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis. Arthritis Rheum 48(11):3230–3236. doi:10.1002/art.11325

    Article  PubMed  CAS  Google Scholar 

  28. 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(6):1667–1675. doi:10.1002/art.11017

    Article  PubMed  CAS  Google Scholar 

  29. 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 63(12):1594–1600. doi:10.1136/ard.2004.020875

    Article  PubMed  CAS  Google Scholar 

  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(12):1572–1577. doi:10.1136/ard.2006.056747

    Google Scholar 

  31. Braun J, McHugh N, Singh A, Wajdula JS, Sato R (2007) Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly. Rheumatology (Oxford) 46(6):999–1004. doi:10.1093/rheumatology/kem069

    Article  CAS  Google Scholar 

  32. 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(11):1926–1928. doi:10.1136/ard.2009.121327 Erratum in: Ann Rheum Dis. 2011 Aug; 70(8):1519

    Article  PubMed  CAS  Google Scholar 

  33. 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(5):799–804. doi:10.1136/ard.2010.139261. (Erratum in: Ann Rheum Dis. 2011 Jul; 70(7):1349)

    Article  PubMed  CAS  Google Scholar 

  34. Braun J, van der Horst-Bruinsma 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(6):1543–1551. doi:10.1002/art.30223

    Article  PubMed  CAS  Google Scholar 

  35. Braun J, Pavelka K, Ramos-Remus C et al (2012) Clinical efficacy of etanercept versus sulfasalazine in ankylosing spondylitis subjects with peripheral joint involvement. J Rheumatol 39(4):836–840. doi:10.1002/art.30223 (Epub 2012 Feb 15)

    Article  PubMed  Google Scholar 

  36. Braun J, Brandt J, Listing J et al (2002) Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 359(9313):1187–1193. doi:10.1016/S0140-6736(02)08215-6

    Article  PubMed  CAS  Google Scholar 

  37. 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(2):582–591. doi:10.1002/art.24001

    Article  PubMed  Google Scholar 

  38. van der Heijde D, Han C, DeVlam K et al (2006) Infliximab improves productivity and reduces workday loss in patients with ankylosing spondylitis: results from a randomized, placebo-controlled trial. Arthritis Rheum 55(4):569–574. doi:10.1002/art.22097

    Google Scholar 

  39. Braun J, Landewé R, Hermann KG et al (2006) Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: results of a multicenter, randomized, double-blind, placebo-controlled magnetic resonance imaging study. Arthritis Rheum 54(5):1646–1652. doi:10.1002/art.21790

    Article  PubMed  CAS  Google Scholar 

  40. Barkham N, Keen HI, Coates LC et al (2009) Clinical and imaging efficacy of infliximab in HLA-B27-Positive patients with magnetic resonance imaging-determined early sacroiliitis. Arthritis Rheum 60(4):946–954. doi:10.1002/art.24408 Erratum in: Arthritis Rheum. 2010 Oct; 62(10):3005

    Article  PubMed  CAS  Google Scholar 

  41. Inman RD, Maksymowych WP (2010) CANDLE study group. A double-blind, placebo-controlled trial of low dose infliximab in ankylosing spondylitis. J Rheumatol 37(6):1203–1210. doi:10.3899/jrheum.091042 (Epub 2010 Mar 15)

    Article  PubMed  Google Scholar 

  42. Maksymowych WP, Salonen D, Inman RD, Rahman P, Lambert RG (2010) CANDLE study group. Low-dose infliximab (3 mg/kg) significantly reduces spinal inflammation on magnetic resonance imaging in patients with ankylosing spondylitis: a randomized placebo-controlled study. J Rheumatol 37(8):1728–1734. doi:10.3899/jrheum.091043 (Epub 2010 May 1)

    Article  PubMed  CAS  Google Scholar 

  43. Marzo-Ortega 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(11):1568–1575. doi:10.1136/ard.2004.022582 (Epub 2005 Apr 13)

    Article  PubMed  CAS  Google Scholar 

  44. Inman RD, Davis JC Jr, Heijde Dv 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 58(11):3402–3412

    Article  PubMed  CAS  Google Scholar 

  45. Giardina AR, Ferrante A, Ciccia F et al (2010) A 2-year comparative open label randomized study of efficacy and safety of etanercept and infliximab in patients with ankylosing spondylitis. Rheumatol Int 30:1437–1440. doi:10.1007/s00296-009-1157-3 (Epub 2009 Oct 23)

    Article  PubMed  Google Scholar 

  46. EU Clinical Trials Register. Prevention of the progression of very early symptoms into ankylosing spondylitis: a placebo controlled trial with etanercept. https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-015515-40. Accessed 11 Jan 2013

  47. EU Clinical Trials Register. Estudio piloto randomizado, doble ciego, multicéntrico a 12 semanas para evaluar el efecto de etanercept 100 mg y 50 mg semanales en sujetos con espondilitis anquilosante. https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-002349-35. Accessed 11 Jan 2013

  48. EU Clinical Trials Register. A multicentre, double-blind, placebo-controlled, randomised study of etanercept in the treatment of adult patients with active, severe and advanced axial ankylosing spondylitis. https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-002748-27. Accessed 11 Jan 2013

  49. McLeod C, Bagust A, Boland A, et al (2007) Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation. Health Technol Assess 11(28)

  50. Montilla Salas J, Muñoz Gomáriz E, Collantes E (2007) Meta-analysis of efficacy of anti-TNF alpha therapy in ankylosing spondylitis patients. Reumatol Clin 3(5):204–212. doi:10.1016/S1699-258X(07)73688-4 (Epub 2008 Dec 29)

    Article  PubMed  Google Scholar 

  51. Fouque-Aubert A, Jette-Paulin L, Combescure C, Basch A, Tebib J, Gossec L (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(10):1756–1761. doi:10.1136/ard.2008.098822 (Epub 2009 Jul 28)

    Article  PubMed  CAS  Google Scholar 

  52. Baraliakos X, van den Berg R, Braun J, van der Heijde D (2012) Update of the literature review on treatment with biologics as a basis for the first update of the ASAS/EULAR management recommendations of ankylosing spondylitis. Rheumatology (Oxford) 51(8):1378–1387

    Article  CAS  Google Scholar 

  53. Pérez-Sola MJ, Torre-Cisneros J, Pérez-Zafrilla B et al (2011) Infections in patients treated with tumor necrosis factor antagonists: incidence, etiology and mortality in the BIOBADASER registry. Med Clin (Barc). 137(12):533–540. doi:10.1016/j.medcli.2010.11.032 (Epub 2011 Apr 22)

    Article  PubMed  Google Scholar 

  54. Gómez-Reino JJ, Carmona L, Descalzo MA (2007) Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection. Arthritis Rheum 57(5):756–761. doi:10.1002/art.22768

    Article  PubMed  Google Scholar 

  55. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev, Issue 2. Art. No.: CD008794. doi:10.1002/14651858.CD008794.pub2

  56. Migliore A, Broccoli S, Bizzi E, Laganà B (2012) Indirect comparison of the effects of anti-TNF biological agents in patients with ankylosing spondylitis by means of a mixed treatment comparison performed on efficacy data from published randomised, controlled trials. J Med Econ 15(3):473–480. doi:10(3111/13696998).2012.660255 (Epub 2012 Feb 16)

    Article  PubMed  CAS  Google Scholar 

  57. Li EK, Griffith JF, Lee VW et al (2008) Short-term efficacy of combination methotrexate and infliximab in patients with ankylosing spondylitis: a clinical and magnetic resonance imaging correlation. Rheumatology (Oxford) 47(9):1358–1363. doi:10.1093/rheumatology/ken207 (Epub 2008 Jun 23). Erratum in: Rheumatology (Oxford). 2010 Jul; 49(7):1423

    Article  CAS  Google Scholar 

  58. Chen J, Liu C, Lin J. Methotrexate for ankylosing spondylitis. Cochrane Database Syst Rev 2006, Issue 4. Art. No.: CD004524. doi:10.1002/14651858.CD004524.pub3

  59. Chen J, Liu C (2006) Is sulfasalazine effective in ankylosing spondylitis? A systematic review of randomized controlled trials. J Rheumatol 33(4):722–731

    PubMed  CAS  Google Scholar 

  60. Bero L, Oostvogel F, Bacchetti P, Lee K (2007) Factors associated with findings of published trials of drug–drug comparisons: why some statins appear more efficacious than others. PLoS Med. 4(6):e184. doi:10.1371/journal.pmed.0040184

    Article  PubMed  Google Scholar 

  61. Lexchin J, Bero LA, Djulbegovic B, Clark O (2003) Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 326:1167. doi:10.1136/bmj.326.7400.1167

    Article  PubMed  Google Scholar 

  62. Kjaergard LL, Als-Nielsen B (2002) Association between competing interests and authors’conclusions: epidemiological study of randomised clinical trials published in the BMJ. BMJ 325:249. doi:10.1136/bmj.325.7358.249

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

Adriana Maria Kakehasi claims to have received an educational grant from Abbott. The other authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. College of Medicine, Federal University of Minas Gerais, Rua Daniel de Carvalho 1551 Apt 301 Gutierrez, Belo Horizonte, Minas Gerais, 30441-152, Brazil

    Marina Amaral de Ávila Machado

  2. René Rachou Research Center, Oswaldo Cruz Foundation (FIOCRUZ), Av. Augusto de Lima 1715 Barro Preto, Belo Horizonte, Minas Gerais, 30190-002, Brazil

    Mariana Michel Barbosa

  3. Faculty of Medical Sciences of Minas Gerais, Alameda Ezequiel Dias, 275, Belo Horizonte, Minas Gerais, 30130-110, Brazil

    Alessandra Maciel Almeida

  4. College of Pharmacy, Federal University of Minas Gerais, Av. Presidente Antônio Carlos, 6627 Campus Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Vânia Eloisa de Araújo & Francisco de Assis Acurcio

  5. College of Medicine, Federal University of Minas Gerais, Av. Prof. Alfredo Balena, 190, Belo Horizonte, Minas Gerais, 30130-100, Brazil

    Adriana Maria Kakehasi, Eli Iola Gurgel Andrade & Mariangela Leal Cherchiglia

Authors
  1. Marina Amaral de Ávila Machado
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariana Michel Barbosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessandra Maciel Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vânia Eloisa de Araújo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Adriana Maria Kakehasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eli Iola Gurgel Andrade
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mariangela Leal Cherchiglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francisco de Assis Acurcio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marina Amaral de Ávila Machado.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 31 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Machado, M.A.Á., Barbosa, M.M., Almeida, A.M. et al. Treatment of ankylosing spondylitis with TNF blockers: a meta-analysis. Rheumatol Int 33, 2199–2213 (2013). https://doi.org/10.1007/s00296-013-2772-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-013-2772-6

Keywords

Search

Navigation