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Improving the design of RCTs in non-radiographic axial spondyloarthritis

Nature Reviews Rheumatology volume 18, pages 481–489 (2022)Cite this article

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Abstract

Concerns have been raised that randomized placebo-controlled trials (RCTs) in non-radiographic axial spondyloarthritis (nr-axSpA) might be failing to identify patients that best show differences in clinical response rates between those receiving active drug and those receiving placebo therapies; in addition, some studies might even be showing spurious differences in responses to TNF and IL-17 inhibitor therapies. In particular, the most recent phase III RCTs in nr-axSpA have reported variable and generally lower response rates than observed in phase III trials of patients with ankylosing spondylitis and in trials conducted a decade ago in patients with early axSpA who were selected on the basis of axial inflammation evident on MRI scans. We argue that these observations at least partly reflect an RCT design that does not take full advantage of MRI to select patients who are responsive to therapy because the current MRI-based inclusion criteria cannot identify patients with axSpA with sufficient specificity. We propose that future studies should be designed using revised patient inclusion criteria based on expanded MRI evaluation and the application of data-driven definitions of a positive MRI for inflammatory and structural lesions typical of axSpA reported in an international multicentre analysis of MRI scans from the Assessment of SpondyloArthritis International Society (ASAS) classification cohort.

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Fig. 1: ASAS classification criteria for axial spondyloarthritis14.
Fig. 2: ASAS40 responses in RCTs of ankylosing spondylitis and non-radiographic axial spondyloarthritis.
Fig. 3: Proposed pathway to patient eligibility for participation in an RCT of nr-axSpA.

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References

  1. Anderson, J. J. et al. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum. 43, 22–29 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Wang, R. et al. Predicting probability of response to tumor necrosis factor inhibitors for individual patients with ankylosing spondylitis. JAMA Netw. Open 5, e222312 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Theander, E. et al. Early psoriatic arthritis: short symptom duration, male gender and preserved physical functioning at presentation predict favourable outcome at 5-year follow-up. Results from the Swedish Early Psoriatic Arthritis Register (SwePsA). Ann. Rheum. Dis. 73, 407–413 (2014).

    Article  PubMed  Google Scholar 

  4. FDA. Rheumatoid Arthritis: Developing Drug Products for Treatment. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/rheumatoid-arthritis-developing-drug-products-treatment (2013).

  5. European Medicines Agency. Guideline on clinical investigation of medicinal products for the treatment of rheumatoid arthritis. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-treatment-rheumatoid-arthritis_en.pdf (2018).

  6. European Medicines Agency. Guideline on clinical investigation of medicinal products for the treatment of psoriatic arthritis. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-treatment-psoriatic-arthritis_en.pdf (2007).

  7. Monti, S. et al. Rheumatoid arthritis treatment: the earlier the better to prevent joint damage. RMD Open. 1, e000057 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Maksymowych, W. P. Controversies in conventional radiography in spondyloarthritis. Best. Pract. Res. Clin. Rheumatol. 26, 839–852 (2012).

    Article  PubMed  Google Scholar 

  9. Christiansen, A. A. et al. Limited reliability of radiographic assessment of sacroiliac joints in patients with suspected early spondyloarthritis. J. Rheumatol. 44, 70–77 (2017).

    Article  PubMed  Google Scholar 

  10. van den Berg, R. et al. Agreement between clinical practice and trained central reading in reading of sacroiliac joints on plain pelvic radiographs. Results from the DESIR cohort. Arthritis Rheumatol. 66, 2403–2411 (2014).

    Article  PubMed  Google Scholar 

  11. Rudwaleit, M. et al. The challenge of diagnosis and classification in early ankylosing spondylitis: do we need new criteria? Arthritis Rheum. 52, 1000–1008 (2005).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  13. Rudwaleit, M. et al. The early disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception Cohort. Arthritis Rheum. 60, 712–727 (2009).

    Article  CAS  Google Scholar 

  14. 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  PubMed  Google Scholar 

  15. 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  PubMed  Google Scholar 

  16. Lambert, R. G. W. et al. Defining active sacroiliitis on MRI for classification of axial spondyloarthritis: update by the ASAS MRI working group. Ann. Rheum. Dis. 75, 1958–1963 (2016).

    Article  PubMed  Google Scholar 

  17. Poddubnyy, D. Radiographic evaluation of sacroiliac joints in axial spondyloarthritis–still worth performing? J. Rheumatol. 44, 1–3 (2017).

    Article  PubMed  Google Scholar 

  18. van Tubergen, A. et al. Radiographic assessment of sacroiliitis by radiologists and rheumatologists: does training improve quality? Ann. Rheum. Dis. 62, 519–525 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bennett, P. H. & Burch, T. A. (eds) Population Studies of the Rheumatic Diseases. 456–457 (Excerpta Medica Foundation, 1968).

  20. Tuite, M. J. Sacroiliac joint imaging. Semin. Musculoskelet. Radiol. 12, 72–82 (2008).

    Article  PubMed  Google Scholar 

  21. van den Berg, R. et al. Classification of axial SpA based on positive imaging (radiographs and/or MRI of the sacroiliac joints) by local rheumatologists or radiologists versus central trained readers in the DESIR cohort. Ann. Rheum. Dis. 74, 2016–2021 (2015).

    Article  PubMed  CAS  Google Scholar 

  22. Maksymowych, W. P. et al. MRI lesions in the sacroiliac joints of patients with spondyloarthritis: an update of definitions and validation by the ASAS MRI working group. Ann. Rheum. Dis. 78, 1550–1558 (2019).

    Article  PubMed  Google Scholar 

  23. Deodhar, A. et al. The concept of axial spondyloarthritis: joint statement of the spondyloarthritis research and treatment network and the Assessment of SpondyloArthritis international Society in response to the US Food and Drug Administration’s comments and concerns. Arthritis Rheumatol. 66, 2649–2656 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Sieper, J. et al. The Assessment of Spondyloarthritis International Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann. Rheum. Dis. 68, ii1–ii44 (2009).

    Article  PubMed  Google Scholar 

  25. Haibel, H. et al. Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis. Arthritis Rheumatol. 58, 1981–1991 (2008).

    Article  CAS  Google Scholar 

  26. 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 randomized controlled trial. Ann. Rheum. Dis. 70, 590–596 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. 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  PubMed  Google Scholar 

  28. Sieper, J. et al. Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann. Rheum. Dis. 72, 815–822 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. van der Heijde, D. et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis. Arthritis Rheumatol. 54, 2136–2146 (2006).

    Article  CAS  Google Scholar 

  30. Sieper, J. et al. Impact of time since diagnosis, age, and number of prior non-steroidal anti-in!ammatory drugs on response to adalimumab in patients with ankylosing spondylitis. Arthritis Rheumatol. 68, 735 (2016).

    Google Scholar 

  31. Song, I. H. et al. Similar response rates in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis after 1 year of treatment with etanercept: results from the ESTHER trial. Ann. Rheum. Dis. 72, 823–825 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Maksymowych, W. P. et al. Clinical and MRI responses to etanercept in early non-radiographic axial spondyloarthritis: 48-week results from the EMBARK study. Ann. Rheum. Dis. 75, 1328–1335 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. van der Heijde, D. et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum. 52, 582–591 (2005).

    Article  PubMed  CAS  Google Scholar 

  34. Sieper, J. et al. A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis. Ann. Rheum. Dis. 67, 2702–2712 (2015).

    CAS  Google Scholar 

  35. Landewé, R. et al. Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled phase 3 study. Ann. Rheum. Dis. 73, 39–47 (2014).

    Article  PubMed  CAS  Google Scholar 

  36. Deodhar, A. et al. A fifty-two-week, randomized, placebo-controlled trial of certolizumab pegol in nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 71, 1101–1111 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Inman, R. D. et al. Efficacy and safety of Golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum. 58, 3402–3412 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Deodhar, A. et al. Improvement of signs and symptoms of nonradiographic axial spondyloarthritis in patients treated with secukinumab: primary results of a randomized, placebo-controlled phase III study. Arthritis Rheumatol. 73, 110–120 (2021).

    Article  CAS  PubMed  Google Scholar 

  39. Deodhar, A. et al. Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial. Lancet 395, 53–64 (2020).

    Article  CAS  PubMed  Google Scholar 

  40. Baeten, D. et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N. Engl. J. Med. 373, 2534–2548 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. van der Heijde, D. et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet 392, 2441–2451 (2018).

    Article  PubMed  Google Scholar 

  42. Maksymowych, W. P. et al. Predictors of long-term clinical response in patients with non-radiographic axial spondyloarthritis receiving certolizumab pegol. Arthritis Res. Ther. 23, 274 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. de Winter, J. J. et al. Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a metaanalysis. Arthritis Res. Ther. 18, 196 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  44. van Hoeven, L. et al. Identifying axial spondyloarthritis in Dutch primary care patients, ages 20–45 years, with chronic low back pain. Arthritis Care. Res. 66, 446–453 (2014).

    Article  Google Scholar 

  45. Porter, D. et al. Classification criteria: time for a rethink? Ann. Rheum. Dis. 79, 1264–1266 (2020).

    Article  PubMed  Google Scholar 

  46. De Winter, J. et al. Magnetic resonance imaging of the sacroiliac joints indicating sacroiliitis according to the Assessment of SpondyloArthritis International Society definition in healthy individuals, runners, and women with postpartum back pain. Arthritis Rheumatol. 70, 1042–1048 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Weber, U. et al. Frequency and anatomic distribution of magnetic resonance imaging features in the sacroiliac joints of young athletes: exploring “background noise” toward a data-driven definition of sacroiliitis in early spondyloarthritis. Arthritis Rheumatol. 70, 736–745 (2018).

    Article  PubMed  Google Scholar 

  48. Varkas, G. et al. Effect of mechanical stress on magnetic resonance imaging of the sacroiliac joints: assessment of military recruits by magnetic resonance imaging study. Rheumatology 57, 508–513 (2018).

    Article  PubMed  Google Scholar 

  49. Dougados, M. et al. Symptomatic efficacy of etanercept and its effects on objective signs of inflammation in early nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 66, 2091–2102 (2016).

    Article  CAS  Google Scholar 

  50. Maksymowych, W. P. et al. Data-driven definitions for active and structural MRI lesions in the sacroiliac joint in spondyloarthritis and their predictive utility. Rheumatology 60, 4778–4789 (2021).

    Article  PubMed  Google Scholar 

  51. Seven, S. et al. Magnetic resonance imaging of lesions in the sacroiliac joints for differentiation of patients with axial spondyloarthritis from control subjects with or without pelvic or buttock pain: a prospective, cross-sectional study of 204 participants. Arthritis Rheumatol. 71, 2034–2046 (2019).

    Article  PubMed  Google Scholar 

  52. Latourte, A. et al. Imaging findings suggestive of axial spondyloarthritis in diffuse idiopathic skeletal hyperostosis. Arthritis Care Res. 70, 145–152 (2018).

    Article  Google Scholar 

  53. de Hooge, M. et al. Patients with chronic back pain of short duration from the SPACE cohort: which MRI structural lesions in the sacroiliac joints and inflammatory and structural lesions in the spine are most specific for axial spondyloarthritis? Ann. Rheum. Dis. 75, 1308–1314 (2016).

    Article  PubMed  CAS  Google Scholar 

  54. Maksymowych, W. P. et al. Spondyloarthritis Research Consortium of Canada magnetic resonance imaging index for assessment of sacroiliac joint inflammation in ankylosing spondylitis. Arthritis Rheum. 53, 703–709 (2005).

    Article  PubMed  Google Scholar 

  55. Maksymowych, W. P. et al. Development and preliminary validation of the spondyloarthritis research Consortium of Canada magnetic resonance imaging sacroiliac joint structural score. J. Rheumatol. 42, 79–86 (2015).

    Article  PubMed  Google Scholar 

  56. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03993847 (2021).

  57. van Tubergen, A. The changing clinical picture and epidemiology of spondyloarthritis. Nat. Rev. Rheumatol. 11, 110–118 (2015).

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Medicine, University of Alberta, Edmonton, Canada

    Walter P. Maksymowych

  2. CARE Arthritis, Edmonton, Canada

    Walter P. Maksymowych

  3. Department of Radiology and Diagnostic Imaging, University of Alberta, Edmonton, Canada; Medical Imaging Consultants, Edmonton, Canada

    Robert G. W. Lambert

  4. Rocky Mountain Regional Veterans Affairs Medical Center and University of Colorado Division of Rheumatology, Aurora, CO, USA

    Liron Caplan

  5. Ghent University, Ghent, Belgium and Rheumatology Department, Ghent University Hospital, Ghent, Belgium

    Filip E. van den Bosch

  6. Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark

    Mikkel Østergaard

  7. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Mikkel Østergaard

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Contributions

W.P.M. researched data for this article and wrote this article. All authors provided a substantial contribution to the discussion of content and were involved in the review/editing of the manuscript before submission.

Corresponding author

Correspondence to Walter P. Maksymowych.

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Competing interests

W.P.M. is Chief Medical Officer of CARE Arthritis Limited, has acted as a paid consultant/participated in advisory boards for AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer and UCB; received research and/or educational grants from AbbVie, Novartis, Pfizer and UCB; received speaker fees from AbbVie, Janssen, Novartis, Pfizer and UCB; and is a member of the ASAS-MRI Working Group. R.G.W.L. has consulted for AbbVie, CARE Arthritis, Parexel, Pfizer and UCB; and is a member of the ASAS-MRI Working Group. F.v.d.B. has received consultancy fees and/or speaker fees from AbbVie, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer and UCB Pharma. M.Ø. has received grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Merck and Novartis; has worked as a paid consultant for AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, CARE Arthritis, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB; and received speaker fees from AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Orion, Pfizer, Roche, Sandoz, Sanofi and UCB, and is a member of the ASAS-MRI Working Group. L.C. declares no competing interests.

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Nature Reviews Rheumatology thanks Uta Kiltz, who co-reviewed with Sabina Gall; Nurullah Akkoc; Philip Robinson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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ASAS-MRI imaging electronic Case Report Form: https://www.carearthritis.com/mriportal/mrimagine/index/

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Maksymowych, W.P., Lambert, R.G.W., Caplan, L. et al. Improving the design of RCTs in non-radiographic axial spondyloarthritis. Nat Rev Rheumatol 18, 481–489 (2022). https://doi.org/10.1038/s41584-022-00789-1

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