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Current Rheumatology Reports

, 21:43 | Cite as

Current Unmet Needs in Spondyloarthritis

  • Denis PoddubnyyEmail author
  • Joachim Sieper
Spondyloarthritis (M Khan, Section Editor)
  • 56 Downloads
Part of the following topical collections:
  1. Topical Collection on Spondyloarthritis

Abstract

Purpose of Review

There was a substantial progress in the field of spondyloarthritis (SpA) in terms of understanding disease mechanisms, early diagnosis, and improved treatment. Nonetheless, several unresolved questions and unmet needs do remain.

Recent Findings

Although the diagnostic delay in axial SpA is decreasing, it remains one of the longest in rheumatology. Application of referral strategies, as well as correct application and interpretation of imaging finding in the clinical context, is the main key to early diagnosis of axial SpA. Tumor necrosis factor (TNF) alpha and interleukin (IL)-17 represent currently two major treatment targets in SpA, while other promising targets such as IL-23 or IL-6 failed in clinical trials. There is an unmet need for strategy trials to optimize and to individualize treatment in SpA. The role of Janus kinases and their blockade in SpA is still to be explored. TNF blockade showed efficacy in peripheral SpA, and other targets (IL-17 and IL-23) should be investigated in clinical trials. Early, effective, and long-term suppression of inflammation is currently the best method to prevent structural damage progression in the spine in axial SpA, while specific effects of IL-17 blockade and of nonsteroidal anti-inflammatory drugs on new bone formation are still being investigated.

Summary

This review summarizes the recent advances in diagnosis and treatment of SpA and discusses the current unmet needs in the field.

Keywords

Spondyloarthritis Diagnosis Imaging Pathophysiology Treatment Radiographic progression Unmet needs 

Notes

Compliance with Ethical Standards

Conflict of Interest

Joachim Sieper reports grants and personal fees from Abbvie, Janssen, MSD, and Pfizer and personal fees from Lilly, Novartis, Roche, UCB, and Sun Pharma.

Denis Poddubnyy reports grants and personal fees from Abbvie, MSD, Novartis, and Pfizer, and personal fees from BMS, Lilly, Roche, UCB, and Celgene.

Human and Animal Rights and Informed Consent

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

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    •• Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet. 2017;390(10089):73–84.  https://doi.org/10.1016/S0140-6736(16)31591-4. A recent comprehensive review on spondyloarhtritis. CrossRefPubMedGoogle Scholar
  2. 2.
    Rudwaleit M, van der Heijde D, Landewe R, Listing J, Akkoc N, Brandt J, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis. 2009;68(6):777–83.  https://doi.org/10.1136/ard.2009.108233.CrossRefGoogle Scholar
  3. 3.
    Rudwaleit M, van der Heijde D, Landewe R, Akkoc N, Brandt J, Chou CT, et al. The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis. 2011;70(1):25–31.CrossRefGoogle Scholar
  4. 4.
    Feldtkeller E, Bruckel J, Khan MA. Scientific contributions of ankylosing spondylitis patient advocacy groups. Curr Opin Rheumatol. 2000;12(4):239–47.CrossRefGoogle Scholar
  5. 5.
    Rudwaleit M, van der Heijde D, Khan MA, Braun J, Sieper J. How to diagnose axial spondyloarthritis early. Ann Rheum Dis. 2004;63(5):535–43.CrossRefGoogle Scholar
  6. 6.
    • Redeker I, Callhoff J, Hoffmann F, Haibel H, Sieper J, Zink A, et al. Determinants of diagnostic delay in axial spondyloarthritis: an analysis based on linked claims and patient-reported survey data. Rheumatology (Oxford). 2019.  https://doi.org/10.1093/rheumatology/kez090. Recent data on diagnostic delay and factors associated with the delay.
  7. 7.
    • Poddubnyy D, van Tubergen A, Landewe R, Sieper J, van der Heijde D. Assessment of SpondyloArthritis international S. Development of an ASAS-endorsed recommendation for the early referral of patients with a suspicion of axial spondyloarthritis. Ann Rheum Dis. 2015;74(8):1483–7.  https://doi.org/10.1136/annrheumdis-2014-207151. The ASAS endorsed recommendation for early referral of patients with suspicion of axial spondyloarthritis. CrossRefPubMedGoogle Scholar
  8. 8.
    Lambert RG, Bakker PA, van der Heijde D, Weber U, Rudwaleit M, Hermann KA, et al. Defining active sacroiliitis on MRI for classification of axial spondyloarthritis: update by the ASAS MRI working group. Ann Rheum Dis. 2016;75(11):1958–63.  https://doi.org/10.1136/annrheumdis-2015-208642.CrossRefPubMedGoogle Scholar
  9. 9.
    de Winter J, de Hooge M, van de Sande M, de Jong H, van Hoeven L, de Koning A, 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. 2018;70(7):1042–8.  https://doi.org/10.1002/art.40475.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Weber U, Jurik AG, Zejden A, Larsen E, Jorgensen SH, Rufibach K, 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. 2018;70(5):736–45.  https://doi.org/10.1002/art.40429.CrossRefPubMedGoogle Scholar
  11. 11.
    Rudwaleit M, Feldtkeller E, Sieper J. Easy assessment of axial spondyloarthritis (early ankylosing spondylitis) at the bedside. Ann Rheum Dis. 2006;65(9):1251–2.  https://doi.org/10.1136/ard.2005.051045.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Cambre I, Gaublomme D, Burssens A, Jacques P, Schryvers N, De Muynck A, et al. Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis. Nat Commun. 2018;9(1):4613.  https://doi.org/10.1038/s41467-018-06933-4.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbst H, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum. 1995;38(4):499–505.CrossRefGoogle Scholar
  14. 14.
    Sieper J, Poddubnyy D. New evidence on the management of spondyloarthritis. Nat Rev Rheumatol. 2016;12(5):282–95.  https://doi.org/10.1038/nrrheum.2016.42.CrossRefPubMedGoogle Scholar
  15. 15.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8.  https://doi.org/10.1038/nature04753.CrossRefPubMedGoogle Scholar
  16. 16.
    Wellcome Trust Case Control C, Australo-Anglo-American Spondylitis C, Burton PR, Clayton DG, Cardon LR, Craddock N, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007;39(11):1329–37.  https://doi.org/10.1038/ng.2007.17.CrossRefGoogle Scholar
  17. 17.
    Poddubnyy D, Appel H, Sieper J. Investigation of involved tissue in axial spondyloarthritis—what have we learnt from immunohistochemical studies? Best Pract Res Clin Rheumatol. 2010;24(5):715–9.CrossRefGoogle Scholar
  18. 18.
    Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012;18(7):1069–76.  https://doi.org/10.1038/nm.2817.CrossRefPubMedGoogle Scholar
  19. 19.
    • Poddubnyy D, Sieper J. What is the best treatment target in axial spondyloarthritis: tumour necrosis factor alpha, interleukin 17, or both? Rheumatology (Oxford). 2017;57:1145–50.  https://doi.org/10.1093/rheumatology/kex361. An extensive discussion of possible ways of identification of the optimal treatment strategies in spondyloarthritis. CrossRefGoogle Scholar
  20. 20.
    Torgutalp M, Poddubnyy D. IL-17 inhibition in axial spondyloarthritis: current and future perspectives. Expert Opin Biol Ther. 2019;1–11.  https://doi.org/10.1080/14712598.2019.1605352.CrossRefGoogle Scholar
  21. 21.
    •• van der Heijde D, Ramiro S, Landewe R, Baraliakos X, Van den Bosch F, Sepriano A, et al. 2016 Update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6):978–91.  https://doi.org/10.1136/annrheumdis-2016-210770. The current set of management recommendations in for axial spondyloarthritis. CrossRefPubMedGoogle Scholar
  22. 22.
    Sieper J, Deodhar A, Marzo-Ortega H, Aelion JA, Blanco R, Jui-Cheng T, et al. Secukinumab efficacy in anti-TNF-naive and anti-TNF-experienced subjects with active ankylosing spondylitis: results from the MEASURE 2 Study. Ann Rheum Dis. 2017;76(3):571–92.  https://doi.org/10.1136/annrheumdis-2016-210023.CrossRefPubMedGoogle Scholar
  23. 23.
    Deodhar A, Poddubnyy D, Pacheco-Tena C, Salvarani C, Lespessailles E, Rahman P, et al. Efficacy and safety of ixekizumab in the treatment of radiographic axial spondyloarthritis: sixteen-week results from a phase III randomized, double-blind, placebo-controlled trial in patients with prior inadequate response to or intolerance of tumor necrosis factor inhibitors. Arthritis Rheumatol. 2019;71(4):599–611.  https://doi.org/10.1002/art.40753.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Deodhar A, Gensler LS, Sieper J, Clark M, Calderon C, Wang Y, et al. Three multicenter, randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of ustekinumab in axial spondyloarthritis. Arthritis Rheumatol. 2019;71(2):258–70.  https://doi.org/10.1002/art.40728.CrossRefPubMedGoogle Scholar
  25. 25.
    Baeten D, Ostergaard M, Wei JC, Sieper J, Jarvinen P, Tam LS, et al. Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study. Ann Rheum Dis. 2018;77(9):1295–302.  https://doi.org/10.1136/annrheumdis-2018-213328.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Noack M, Ndongo-Thiam N, Miossec P. Role of podoplanin in the high interleukin-17A secretion resulting from interactions between activated lymphocytes and psoriatic skin-derived mesenchymal cells. Clin Exp Immunol. 2016;186(1):64–74.  https://doi.org/10.1111/cei.12830.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Noordenbos T, Blijdorp I, Chen S, Stap J, Mul E, Canete JD, et al. Human mast cells capture, store, and release bioactive, exogenous IL-17A. J Leukoc Biol. 2016;100(3):453–62.  https://doi.org/10.1189/jlb.3HI1215-542R.CrossRefPubMedGoogle Scholar
  28. 28.
    Tamassia N, Arruda-Silva F, Calzetti F, Lonardi S, Gasperini S, Gardiman E, et al. A reappraisal on the potential ability of human neutrophils to express and produce IL-17 family members in vitro: failure to reproducibly detect it. Front Immunol. 2018;9:795.  https://doi.org/10.3389/fimmu.2018.00795.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    • Lee JS, Tato CM, Joyce-Shaikh B, Gulen MF, Cayatte C, Chen Y, et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity. 2015;43(4):727–38.  https://doi.org/10.1016/j.immuni.2015.09.003. A study providing evidence for IL-23 independent production of IL-17. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mangan PR, Su LJ, Jenny V, Tatum AL, Picarillo C, Skala S, et al. Dual inhibition of interleukin-23 and interleukin-17 offers superior efficacy in mouse models of autoimmunity. J Pharmacol Exp Ther. 2015;354(2):152–65.  https://doi.org/10.1124/jpet.115.224246.CrossRefPubMedGoogle Scholar
  31. 31.
    McInnes IB, Kavanaugh A, Gottlieb AB, Puig L, Rahman P, Ritchlin C, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013;382(9894):780–9.  https://doi.org/10.1016/S0140-6736(13)60594-2.CrossRefPubMedGoogle Scholar
  32. 32.
    Araujo EG, Englbrecht M, Hoepken S, Finzel S, Kampylafka E, Kleyer A, et al. Effects of ustekinumab versus tumor necrosis factor inhibition on enthesitis: results from the enthesial clearance in psoriatic arthritis (ECLIPSA) study. Semin Arthritis Rheum. 2019;48(4):632–7.  https://doi.org/10.1016/j.semarthrit.2018.05.011.CrossRefPubMedGoogle Scholar
  33. 33.
    Paramarta JE, De Rycke L, Heijda TF, Ambarus CA, Vos K, Dinant HJ, et al. Efficacy and safety of adalimumab for the treatment of peripheral arthritis in spondyloarthritis patients without ankylosing spondylitis or psoriatic arthritis. Ann Rheum Dis. 2013;72(11):1793–9.  https://doi.org/10.1136/annrheumdis-2012-202245.CrossRefPubMedGoogle Scholar
  34. 34.
    Carron P, Varkas G, Cypers H, Van Praet L, Elewaut D, Van den Bosch F, et al. Anti-TNF-induced remission in very early peripheral spondyloarthritis: the CRESPA study. Ann Rheum Dis. 2017;76(8):1389–95.  https://doi.org/10.1136/annrheumdis-2016-210775.CrossRefPubMedGoogle Scholar
  35. 35.
    Mease P, Sieper J, Van den Bosch F, Rahman P, Karunaratne PM, Pangan AL. Randomized controlled trial of adalimumab in patients with nonpsoriatic peripheral spondyloarthritis. Arthritis Rheumatol. 2015;67(4):914–23.  https://doi.org/10.1002/art.39008.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Schwartz DM, Bonelli M, Gadina M, O'Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 2016;12(1):25–36.  https://doi.org/10.1038/nrrheum.2015.167.CrossRefPubMedGoogle Scholar
  37. 37.
    van der Heijde D, Deodhar A, Wei JC, Drescher E, Fleishaker D, Hendrikx T, et al. Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study. Ann Rheum Dis. 2017;76(8):1340–7.  https://doi.org/10.1136/annrheumdis-2016-210322.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    van der Heijde D, Baraliakos X, Gensler LS, Maksymowych WP, Tseluyko V, Nadashkevich O, et al. Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial. Lancet. 2018;392:2378–87.  https://doi.org/10.1016/s0140-6736(18)32463-2.CrossRefPubMedGoogle Scholar
  39. 39.
    •• Poddubnyy D, Sieper J. Mechanism of new bone formation in axial spondyloarthritis. Curr Rheumatol Rep. 2017;19(9):55.  https://doi.org/10.1007/s11926-017-0681-5. A comprehensive review on the topic of structural damage progression in axial spondyloarthritis. CrossRefPubMedGoogle Scholar
  40. 40.
    van der Heijde D, Landewe R, Baraliakos X, Houben H, van Tubergen A, Williamson P, et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum. 2008;58(10):3063–70.  https://doi.org/10.1002/art.23901.CrossRefPubMedGoogle Scholar
  41. 41.
    van der Heijde D, Landewe R, Einstein S, Ory P, Vosse D, Ni L, et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum. 2008;58(5):1324–31.  https://doi.org/10.1002/art.23471.CrossRefPubMedGoogle Scholar
  42. 42.
    van der Heijde D, Salonen D, Weissman BN, Landewe R, Maksymowych WP, Kupper H, 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. 2009;11(4):R127.  https://doi.org/10.1186/ar2794.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    van der Heijde D, Baraliakos X, Hermann KA, Landewe RBM, Machado PM, Maksymowych WP, et al. Limited radiographic progression and sustained reductions in MRI inflammation in patients with axial spondyloarthritis: 4-year imaging outcomes from the RAPID-axSpA phase III randomised trial. Ann Rheum Dis. 2018;77(5):699–705.  https://doi.org/10.1136/annrheumdis-2017-212377.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Maas F, Arends S, Wink FR, Bos R, Bootsma H, Brouwer E, et al. Ankylosing spondylitis patients at risk of poor radiographic outcome show diminishing spinal radiographic progression during long-term treatment with TNF-alpha inhibitors. PLoS One. 2017;12(6):e0177231.  https://doi.org/10.1371/journal.pone.0177231.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    • Molnar C, Scherer A, Baraliakos X, de Hooge M, Micheroli R, Exer P, et al. TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort. Ann Rheum Dis. 2018;77(1):63–9.  https://doi.org/10.1136/annrheumdis-2017-211544. A recent study indicating an association between the depth of inflammation suppression and inhibition of radiographic spinal progression. CrossRefPubMedGoogle Scholar
  46. 46.
    Haroon N, Inman RD, Learch TJ, Weisman MH, Lee M, Rahbar MH, et al. The impact of tumor necrosis factor alpha inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum. 2013;65(10):2645–54.  https://doi.org/10.1002/art.38070.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    •• Smolen JS, Schols M, Braun J, Dougados M, FitzGerald O, Gladman DD, et al. Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force. Ann Rheum Dis. 2018;77(1):3–17.  https://doi.org/10.1136/annrheumdis-2017-211734. The current treat-to-target recommendations for spondyloarthritis. CrossRefPubMedGoogle Scholar
  48. 48.
    •• Gravallese EM, Schett G. Effects of the IL-23-IL-17 pathway on bone in spondyloarthritis. Nat Rev Rheumatol. 2018;14(11):631–40.  https://doi.org/10.1038/s41584-018-0091-8. Summary of the recent data on the effect of IL-23/IL-17 on bone. CrossRefPubMedGoogle Scholar
  49. 49.
    Braun J, Baraliakos X, Deodhar A, Poddubnyy D, Emery P, Delicha EM, et al. Secukinumab shows sustained efficacy and low structural progression in ankylosing spondylitis: 4-year results from the MEASURE 1 study. Rheumatology (Oxford). 2018;58:859–68.  https://doi.org/10.1093/rheumatology/key375.CrossRefGoogle Scholar
  50. 50.
    Wanders A, Heijde D, Landewe R, Behier JM, Calin A, Olivieri I, et al. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum. 2005;52(6):1756–65.CrossRefGoogle Scholar
  51. 51.
    Sieper J, Listing J, Poddubnyy D, Song IH, Hermann KG, Callhoff J, et al. Effect of continuous versus on-demand treatment of ankylosing spondylitis with diclofenac over 2 years on radiographic progression of the spine: results from a randomised multicentre trial (ENRADAS). Ann Rheum Dis. 2016;75(8):1438–43.  https://doi.org/10.1136/annrheumdis-2015-207897.CrossRefPubMedGoogle Scholar
  52. 52.
    Proft F, Muche B, Listing J, Rios-Rodriguez V, Sieper J, Poddubnyy D. Study protocol: COmparison of the effect of treatment with Nonsteroidal anti-inflammatory drugs added to anti-tumour necrosis factor a therapy versus anti-tumour necrosis factor a therapy alone on progression of StrUctural damage in the spine over two years in patients with ankyLosing spondylitis (CONSUL)—an open-label randomized controlled multicenter trial. BMJ Open. 2017;7(6):e014591.  https://doi.org/10.1136/bmjopen-2016-014591.CrossRefPubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Gastroenterology, Infectious Diseases, and Rheumatology, Campus Benjamin FranklinCharité—Universitätsmedizin BerlinBerlinGermany
  2. 2.Epidemiology UnitGerman Rheumatism Research CentreBerlinGermany

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