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  • Review Article
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Developments in therapies for spondyloarthritis

Nature Reviews Rheumatology volume 8, pages 280–287 (2012)Cite this article

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Abstract

First-line therapy for spondyloarthritis (SpA) has not yet altered in the wake of new classification criteria; NSAIDs and physical therapy are recommended. Anti-TNF agents can be used when NSAIDs fail, but their efficacy has potentially been limited in previous trials by inclusion criteria requiring the presence of established, active disease. Now, not only patients with axial SpA (axSpA) with radiographic signs of sacroiliitis (that is, with ankylosing spondylitis), but also patients in whom structural damage is not—yet—visible radiographically (non-radiographic axSpA) can be included in trials of therapy for axSpA. TNF blockers, it seems already, are at least similarly effective in patients with non-radiographic axSpA as in those with established AS. Short symptom duration and a positive C-reactive protein test at baseline are currently the best predictors for a good response to TNF-blocking agents. Biologic agents besides anti-TNF therapies have so far failed in the treatment of axSpA. New bone formation seems currently to be best prevented by NSAIDs, not by TNF blockers. Whether earlier effective treatment of bony inflammation with anti-TNF therapy will be able to prevent ossification at a later stage has yet to be determined. New classification criteria for peripheral SpA will also allow treatment trials to be conducted more systematically than has previously been possible in this subgroup of patients.

Key Points

  • The term axial spondyloarthritis (axSpA) now includes patients with ankylosing spondylitis (radiographically visible sacroiliitis with or without syndesmophytes) as well as non-radiographic axSpA

  • Responses to TNF-blockers are similar between patients with non-radiographic and radiographic axSpA

  • Short symptom duration and elevated C-reactive protein levels are the best predictors for a good response to anti-TNF therapy

  • Antibiotic treatment might be an interesting treatment option in a subgroup of patients with peripheral spondyloarthritis

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References

  1. van Tubergen, A. & Weber, U. Diagnosis and classification in spondyloarthritis: identifying a chameleon. Nat. Rev. Rheumatol. http://dx.doi.org/10.1038/nrrheum.2012.33.

  2. Rudwaleit, M. & Sieper, J. Referral strategies for an early diagnosis of axial spondyloarthritis. Nat. Rev. Rheumatol. http://dx.doi.org/10.1038/nrrheum.2012.39.

  3. Tse, S. M. L. & Laxer, R. M. New advances in juvenile spondyloarthritis. Nat. Rev. Rheumatol. http://dx.doi.org/10.1038/nrrheum.2012.37.

  4. Rudwaleit, M. et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann. Rheum. Dis. 68, 777–783 (2009).

    Article  CAS  Google Scholar 

  5. Rudwaleit, M. et al. The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann. Rheum. Dis. 70, 25–31 (2011).

    Article  CAS  Google Scholar 

  6. Taylor, W. et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 54, 2665–2673 (2006).

    Article  Google Scholar 

  7. Braun, J. et al. 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann. Rheum. Dis. 70, 896–904 (2011).

    Article  CAS  Google Scholar 

  8. Zochling, J. et al. ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann. Rheum. Dis. 65, 442–452 (2006).

    Article  CAS  Google Scholar 

  9. Braun, J. et al. International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis. Ann. Rheum. Dis. 62, 817–824 (2003).

    Article  CAS  Google Scholar 

  10. Braun, J. et al. First update of the international ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis. Ann. Rheum. Dis. 65, 316–320 (2006).

    Article  CAS  Google Scholar 

  11. van der Heijde, D. et al. 2010 Update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis. Ann. Rheum. Dis. 70, 905–908 (2011).

    Article  Google Scholar 

  12. van der Linden, S., Valkenburg, H. A. & Cats, A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 27, 361–368 (1984).

    Article  CAS  Google Scholar 

  13. Sieper, J. & Rudwaleit, M. How early should ankylosing spondylitis be treated with tumour necrosis factor blockers? Ann. Rheum. Dis. 64 (Suppl. 4), iv61–iv64 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. van der Heijde, D. et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 54, 2136–2146 (2006).

    Article  CAS  Google Scholar 

  15. Haibel, H. et al. Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo-controlled trial followed by an open-label extension up to week fifty-two. Arthritis Rheum. 58, 1981–1991 (2008).

    Article  CAS  Google Scholar 

  16. Barkham, N. et al. Clinical and imaging efficacy of infliximab in HLA-B27-Positive patients with magnetic resonance imaging-determined early sacroiliitis. Arthritis Rheum. 60, 946–954 (2009).

    Article  CAS  Google Scholar 

  17. Song, I. H. et al. Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48-week randomised controlled trial. Ann. Rheum. Dis. 70, 590–596 (2011).

    Article  CAS  Google Scholar 

  18. Certolizumab pegol in subjects with active axial spondyloarthritis. ClinicalTrials.gov [online], (2012).

  19. Study comparing etanercept (ETN) against a placebo for etanercept on a background nonsteroidal anti inflammatory drug (NSAIDs) in the treatment of early spondyloarthritis (SpA) patients who do not have X-ray structural changes (AS EARLY). ClinicalTrials.gov [online], (2012).

  20. Effect of golimumab in participants with active axial spondyloarthritis (P07642) (GO-AHEAD). ClinicalTrials.gov [online], (2012).

  21. Sieper, J. et al. Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis—results of the phase 3 study [abstract 2486A]. Arthritis Rheum. 63 (Suppl.), S970–S971 (2011).

    Google Scholar 

  22. Baraliakos, X. et al. Persistent clinical efficacy and safety of infliximab in ankylosing spondylitis after 8 years—early clinical response predicts long-term outcome. Rheumatology (Oxford) 50, 1690–1699 (2011).

    Article  CAS  Google Scholar 

  23. Martin-Mola, E. et al. Sustained efficacy and safety, including patient-reported outcomes, with etanercept treatment over 5 years in patients with ankylosing spondylitis. Clin. Exp. Rheumatol. 28, 238–245 (2010).

    CAS  PubMed  Google Scholar 

  24. Sieper, J. et al. Early response to adalimumab predicts long-term remission through 5 years of treatment in patients with ankylosing spondylitis. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2011-200358.

  25. Sieper, J. et al. Persistent reduction of spinal inflammation as assessed by magnetic resonance imaging in patients with ankylosing spondylitis after 2 yrs of treatment with the anti-tumour necrosis factor agent infliximab. Rheumatology (Oxford) 44, 1525–1530 (2005).

    Article  CAS  Google Scholar 

  26. Braun, J. et al. Golimumab reduces spinal inflammation in ankylosing spondylitis: MRI results of the randomised, placebo- controlled GO-RAISE study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2011-200308

  27. Rudwaleit, M., Listing, J., Brandt, J., Braun, J. & Sieper, J. Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor α blockers in ankylosing spondylitis. Ann. Rheum. Dis. 63, 665–670 (2004).

    Article  CAS  Google Scholar 

  28. Rudwaleit, M. et al. Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis. J. Rheumatol. 36, 801–808 (2009).

    Article  CAS  Google Scholar 

  29. Vastesaeger, N. et al. Predicting the outcome of ankylosing spondylitis therapy. Ann. Rheum. Dis. 70, 973–981 (2011).

    Article  Google Scholar 

  30. Rudwaleit, M. et al. MRI in predicting a major clinical response to anti-tumour necrosis factor treatment in ankylosing spondylitis. Ann. Rheum. Dis. 67, 1276–1281 (2008).

    Article  CAS  Google Scholar 

  31. de Vries, M. K. et al. Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation. Ann. Rheum. Dis. 66, 1252–1254 (2007).

    Article  CAS  Google Scholar 

  32. de Vries, M. K. et al. Decreased clinical response to adalimumab in ankylosing spondylitis is associated with antibody formation. Ann. Rheum. Dis. 68, 1787–1788 (2009).

    Article  CAS  Google Scholar 

  33. Baert, F. et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N. Engl. J. Med. 348, 601–608 (2003).

    Article  CAS  Google Scholar 

  34. Breban, M. et al. Maintenance of infliximab treatment in ankylosing spondylitis: results of a one-year randomized controlled trial comparing systematic versus on-demand treatment. Arthritis Rheum. 58, 88–97 (2008).

    Article  CAS  Google Scholar 

  35. Li, E. K. et al. Short-term efficacy of combination methotrexate and infliximab in patients with ankylosing spondylitis: a clinical and magnetic resonance imaging correlation. Rheumatology (Oxford) 47, 1358–1363 (2008).

    Article  CAS  Google Scholar 

  36. Mulleman, D. et al. Infliximab in ankylosing spondylitis: alone or in combination with methotrexate? A pharmacokinetic comparative study. Arthritis Res. Ther. 13, R82 (2011).

    Article  CAS  Google Scholar 

  37. Rudwaleit, M., Van den Bosch, F., Kron, M., Kary, S. & Kupper, H. Effectiveness and safety of adalimumab in patients with ankylosing spondylitis or psoriatic arthritis and history of anti-tumor necrosis factor therapy. Arthritis Res. Ther. 12, R117 (2010).

    Article  Google Scholar 

  38. Lie, E. et al. Effectiveness of switching between TNF inhibitors in ankylosing spondylitis: data from the NOR-DMARD register. Ann. Rheum. Dis. 70, 157–163 (2011).

    Article  CAS  Google Scholar 

  39. Haibel, H., Rudwaleit, M., Listing, J. & Sieper, J. Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann. Rheum. Dis. 64, 296–298 (2005).

    Article  CAS  Google Scholar 

  40. Song, I. H. et al. Different response to rituximab in tumor necrosis factor blocker-naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed: a twenty-four-week clinical trial. Arthritis Rheum. 62, 1290–1297 (2010).

    Article  CAS  Google Scholar 

  41. Song, I. H. et al. Treatment of active ankylosing spondylitis with abatacept: an open-label, 24-week pilot study. Ann. Rheum. Dis. 70, 1108–1110 (2011).

    Article  CAS  Google Scholar 

  42. Lekpa, F. K. et al. Lack of efficacy of abatacept in axial spondylarthropathies refractory to tumor-necrosis-factor inhibition. Joint Bone Spine 79, 47–50 (2012).

    Article  CAS  Google Scholar 

  43. A study of RoActemra/Actemra (tocilizumab) in patients with ankylosing spondylitis who have failed treatment with NSAIDs. ClinicalTrials.gov [online], (2011).

  44. A study of RoActemra/Actemra (tocilizumab) in patients with ankylosing spondylitis who have had an inadequate response to previous TNF antagonist therapy. ClinicalTrials.gov [online], (2011).

  45. Appel, H. et al. Analysis of IL-17+ cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the TH17-mediated adaptive immune response. Arthritis Res. Ther. 13, R95 (2011).

    Article  CAS  Google Scholar 

  46. Griffiths, C. E. et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N. Engl. J. Med. 362, 118–128 (2010).

    Article  CAS  Google Scholar 

  47. Hueber, W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. 2, 52ra72 (2010).

    Article  Google Scholar 

  48. Baeten, D. et al. The anti-IL-17A monoclonal antibody secukinumab (AIN457) showed good safety and efficacy in the treatment of active ankylosing spondylitis. Ann. Rheum. Dis. 70 (Suppl. 3), 127 (2011).

    Google Scholar 

  49. Ustekinumab for the treatment of patients with active ankylosing spondylitis (TOPAS). ClinicalTrials.gov [online], (2011).

  50. Landewe, R., Dougados, M., Mielants, H., van der Tempel, H. & van der Heijde, D. Physical function in ankylosing spondylitis is independently determined by both disease activity and radiographic damage of the spine. Ann. Rheum. Dis. 68, 863–867 (2009).

    Article  CAS  Google Scholar 

  51. Wanders, A. et al. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum. 52, 1756–1765 (2005).

    Article  CAS  Google Scholar 

  52. Boersma, J. W. Retardation of ossification of the lumbar vertebral column in ankylosing spondylitis by means of phenylbutazone. Scand. J. Rheumatol. 5, 60–64 (1976).

    CAS  PubMed  Google Scholar 

  53. Poddubnyy, D. et al. Effect of non-steroidal anti-inflammatory drugs on radiographic progression in patients with axial spondyloartrhitis: results from the German Spondyloarthritis Inception Cohort. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2011-201252

  54. Dougados, M. et al. ASAS recommendations for collecting, analysing and reporting NSAID intake in clinical trials/epidemiological studies in axial spondyloarthritis. Ann. Rheum. Dis. 70, 249–251 (2011).

    Article  CAS  Google Scholar 

  55. Blackwell, K. A., Raisz, L. G. & Pilbeam, C. C. Prostaglandins in bone: bad cop, good cop? Trends Endocrinol. Metab. 21, 294–301 (2010).

    Article  CAS  Google Scholar 

  56. van der Heijde, D. et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum. 58, 3063–3070 (2008).

    Article  Google Scholar 

  57. van der Heijde, D. et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum. 58, 1324–1331 (2008).

    Article  CAS  Google Scholar 

  58. van der Heijde, D. et al. Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Res. Ther. 11, R127 (2009).

    Article  Google Scholar 

  59. Rudwaleit, M. et al. Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis: a consensual approach by the ASAS/OMERACT MRI group. Ann. Rheum. Dis. 68, 1520–1527 (2009).

    Article  CAS  Google Scholar 

  60. Song, I. H. et al. Relationship between active inflammatory lesions in the spine and sacroiliac joints and new development of chronic lesions on whole-body MRI in early axial spondyloarthritis: results of the ESTHER trial at week 48. Ann. Rheum. Dis. 70, 1257–1263 (2011).

    Article  Google Scholar 

  61. Chiowchanwisawakit, P., Lambert, R. G., Conner-Spady, B. & Maksymowych, W. P. Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis. Arthritis Rheum. 63, 2215–2225 (2011).

    Article  Google Scholar 

  62. Sieper, J., Appel, H., Braun, J. & Rudwaleit, M. Critical appraisal of assessment of structural damage in ankylosing spondylitis: implications for treatment outcomes. Arthritis Rheum. 58, 649–656 (2008).

    Article  Google Scholar 

  63. Appel, H., Rudwaleit, M. & Sieper, J. Relevance of osteoproliferation as an outcome parameter in ankylosing spondylitis. Nat. Clin. Pract. Rheumatol. 4, 578–579 (2008).

    Article  Google Scholar 

  64. Maksymowych, W. P. et al. Inflammatory lesions of the spine on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis: evidence of a relationship between inflammation and new bone formation. Arthritis Rheum. 60, 93–102 (2009).

    Article  Google Scholar 

  65. Dougados, M. et al. Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum. 38, 618–627 (1995).

    Article  CAS  Google Scholar 

  66. Clegg, D. O. et al. Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. A Department of Veterans Affairs cooperative study. Arthritis Rheum. 39, 2004–2012 (1996).

    Article  CAS  Google Scholar 

  67. Braun, J. et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 359, 1187–1193 (2002).

    Article  CAS  Google Scholar 

  68. Rudwaleit, M. et al. Effectiveness of adalimumab in treating patients with ankylosing spondylitis associated with enthesitis and peripheral arthritis. Arthritis Res. Ther. 12, R43 (2010).

    Article  Google Scholar 

  69. Dougados, M. et al. A randomised, multicentre, double-blind, placebo-controlled trial of etanercept in adults with refractory heel enthesitis in spondyloarthritis: the HEEL trial. Ann. Rheum. Dis. 69, 1430–1435 (2010).

    Article  CAS  Google Scholar 

  70. Gossec, L. et al. European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. Ann. Rheum. Dis. 71, 4–12 (2012).

    Article  CAS  Google Scholar 

  71. Sieper, J. et al. No benefit of long-term ciprofloxacin treatment in patients with reactive arthritis and undifferentiated oligoarthritis: a three-month, multicenter, double-blind, randomized, placebo-controlled study. Arthritis Rheum. 42, 1386–1396 (1999).

    Article  CAS  Google Scholar 

  72. Kvien, T. K. Three month treatment of reactive arthritis with azithromycin: a EULAR double blind, placebo controlled study. Ann. Rheum. Dis. 63, 1113–1119 (2004).

    Article  CAS  Google Scholar 

  73. Lauhio, A., Leirisalo-Repo, M., Lahdevirta, J., Saikku, P. & Repo, H. Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheum. 34, 6–14 (1991).

    Article  CAS  Google Scholar 

  74. Carter, J. D. et al. Chlamydiae as etiologic agents in chronic undifferentiated spondyloarthritis. Arthritis Rheum. 60, 1311–1316 (2009).

    Article  Google Scholar 

  75. Carter, J. D. et al. Combination antibiotics as a treatment for chronic Chlamydia-induced reactive arthritis: a double-blind, placebo-controlled, prospective trial. Arthritis Rheum. 62, 1298–1307 (2010).

    Article  CAS  Google Scholar 

  76. Braun, J., Baraliakos, X., Listing, J. & Sieper, J. Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept. Arthritis Rheum. 52, 2447–2451 (2005).

    Article  CAS  Google Scholar 

  77. Rudwaleit, M. et al. Adalimumab effectively reduces the rate of anterior uveitis flares in patients with active ankylosing spondylitis: results of a prospective open-label study. Ann. Rheum. Dis. 68, 696–701 (2009).

    Article  CAS  Google Scholar 

  78. Sieper, J. et al. Analysis of uveitis rates across all etanercept ankylosing spondylitis clinical trials. Ann. Rheum. Dis. 69, 226–229 (2010).

    Article  CAS  Google Scholar 

  79. Wendling, D. et al. New onset of uveitis during anti-tumor necrosis factor treatment for rheumatic diseases. Semin. Arthritis Rheum. 41, 503–510 (2011).

    Article  Google Scholar 

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  1. Department of Medicine, Rheumatology, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    Joachim Sieper

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J. Sieper has worked as a consultant for Abbott, Merck, Pfizer, Roche and UCB, has been a member of a speakers bureau for Abbott, Merck, Pfizer and UCB, and has received grant or research support from Abbott, Bristol-Myers Squibb, Merck, Pfizer and Roche.

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Sieper, J. Developments in therapies for spondyloarthritis. Nat Rev Rheumatol 8, 280–287 (2012). https://doi.org/10.1038/nrrheum.2012.40

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