Bedside to bench: defining the immunopathogenesis of psoriatic arthritis

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Abstract

Psoriatic arthritis (PsA) is an immune-mediated, systemic inflammatory disorder. PsA can present with heterogeneous clinical features. Advances in understanding the immunopathogenesis of PsA have helped to facilitate the development of agents targeting specific components of the dysregulated inflammatory and immune responses relevant to PsA. Interestingly, agents with distinct mechanisms of action have shown differential responses across the various disease domains of PsA, counter to what might have been expected from basic science investigations. Here, we review data utilizing various novel targeted therapies for PsA, focusing on biologic and targeted synthetic therapies. These data might support the idea of a ‘bedside to bench’ concept, whereby results from clinical trials of specific targeted therapies inform our understanding of the immunopathogenesis of PsA. For example, TNF inhibition confers substantial and comparable benefit for all domains of PsA, supporting the view that TNF is a central pro-inflammatory cytokine across diverse areas of disease involvement. On the other hand, inhibition of IL-12–IL-23, as compared with inhibition of TNF, has greater efficacy for psoriasis, comparable efficacy for peripheral arthritis, but was ineffective in studies of axial spondyloarthritis. Data from studies of agents with distinct mechanisms of action will help to further refine our understanding of the immunopathogenesis of PsA.

Key points

  • The development and introduction of novel targeted therapies has improved outcomes for patients with autoimmune systemic inflammatory diseases, including psoriatic arthritis (PsA).

  • Whereas some agents, such as TNF inhibitors, have been highly effective across many autoimmune diseases, and across domains of disease, other agents have had disparate impacts on various diseases and domains.

  • With a ‘bedside to bench’ approach to systemic autoimmune diseases, data from clinical trials targeting various immune mediators could further our understanding of the immunopathogenesis of PsA and other diseases.

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Fig. 1: Immunopathogenesis of PsA.
Fig. 2: Summary of immune target interactions in PsA.
Fig. 3: Summary of cytokine and non-cytokine targets in various chronic inflammatory diseases.
Fig. 4: Bedside to bench: towards precision medicine in PsA.

References

  1. 1.

    Ritchlin, C. T., Colbert, R. A. & Gladman, D. D. Psoriatic arthritis. N. Engl. J. Med. 376, 2095–2096 (2017).

  2. 2.

    Gladman, D. D., Antoni, C., Mease, P., Clegg, D. O. & Nash, P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann. Rheum. Dis. 64, ii14–ii17 (2005). Suppl 2.

  3. 3.

    Horreau, C. et al. Cardiovascular morbidity and mortality in psoriasis and psoriatic arthritis: a systematic literature review. J. Eur. Acad. Dermatol. Venereol. 27, Suppl 3,12–29 (2013).

  4. 4.

    Husni, M. E., Merola, J. F. & Davin, S. The psychosocial burden of psoriatic arthritis. Semin. Arthritis Rheum. 47, 351–360 (2017).

  5. 5.

    Veale, D. J. & Fearon, U. The pathogenesis of psoriatic arthritis. Lancet 391, 2273–2284 (2018).

  6. 6.

    Barnas, J. L. & Ritchlin, C. T. Etiology and pathogenesis of psoriatic arthritis. Rheum. Dis. Clin. North Am. 41, 643–663 (2015).

  7. 7.

    Cafaro, G. & McInnes, I. B. Psoriatic arthritis: tissue-directed inflammation? Clin. Rheumatol. 37, 859–868 (2018).

  8. 8.

    Boutet, M. A., Nerviani, A., Gallo Afflitto, G. & Pitzalis, C. Role of the IL-23/IL-17 axis in psoriasis and psoriatic arthritis: the clinical importance of its divergence in skin and joints. Int. J. Mol. Sci. 19, E530 (2018).

  9. 9.

    Millar, N. L., Murrell, G. A. & McInnes, I. B. Inflammatory mechanisms in tendinopathy — towards translation. Nat. Rev. Rheumatol. 13, 110–122 (2017).

  10. 10.

    Prinz, J. C. Human leukocyte antigen-class I alleles and the autoreactive T cell response in psoriasis pathogenesis. Front. Immunol. 9, 954 (2018).

  11. 11.

    Yago, T. et al. IL-23 and Th17 disease in inflammatory arthritis. J. Clin. Med. 6, pii: E81 https://doi.org/10.3390/jcm6090081 (2017).

  12. 12.

    Thorarensen, S. M. et al. Physical trauma recorded in primary care is associated with the onset of psoriatic arthritis among patients with psoriasis. Ann. Rheum. Dis. 76, 521–525 (2017).

  13. 13.

    Duffin, K. C. et al. Association between IL13 polymorphisms and psoriatic arthritis is modified by smoking. J. Invest. Dermatol. 129, 2777–2783 (2009).

  14. 14.

    Scher, J. U., Littman, D. R. & Abramson, S. B. Microbiome in inflammatory arthritis and human rheumatic diseases. Arthritis Rheumatol. 68, 35–45 (2016).

  15. 15.

    Gordon, K. B. et al. Efficacy of guselkumab in subpopulations of patients with moderate-to-severe plaque psoriasis: a pooled analysis of the phase III VOYAGE 1 and VOYAGE 2 studies. Br. J. Dermatol. 178, 132–139 (2018).

  16. 16.

    Deodhar, A. et al. Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study. Lancet 391, 2213–2224 (2018).

  17. 17.

    Baeten, D. 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. 77, 1295–1302 (2018).

  18. 18.

    Chatzantoni, K. & Mouzaki, A. Anti-TNF-α antibody therapies in autoimmune diseases. Curr. Top. Med. Chem. 6, 1707–1714 (2006).

  19. 19.

    Maini, R. et al. Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 354, 1932–1939 (1999).

  20. 20.

    Weinblatt, M. E. et al. Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 48, 35–45 (2003).

  21. 21.

    Keystone, E. C. et al. Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann. Rheum. Dis. 68, 789–796 (2009).

  22. 22.

    Moreland, L. W. et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann. Intern. Med. 130, 478–486 (1999).

  23. 23.

    Keystone, E. et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 58, 3319–3329 (2008).

  24. 24.

    Antoni, C. et al. Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann. Rheum. Dis. 64, 1150–1157 (2005).

  25. 25.

    Mease, P. J. Adalimumab: an anti-TNF agent for the treatment of psoriatic arthritis. Expert Opin. Biol. Ther. 5, 1491–1504 (2005).

  26. 26.

    Kavanaugh, A. et al. Golimumab, a new human tumor necrosis factor α antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: twenty-four-week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum. 60, 976–986 (2009).

  27. 27.

    Mease, P. J. et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA). Ann. Rheum. Dis. 73, 48–55 (2014).

  28. 28.

    Mease, P. J. et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum. 50, 2264–2272 (2004).

  29. 29.

    Li, W. Q., Han, J. L., Chan, A. T. & Qureshi, A. A. Psoriasis, psoriatic arthritis and increased risk of incident Crohn’s disease in US women. Ann. Rheum. Dis. 72, 1200–1205 (2013).

  30. 30.

    Makredes, M., Robinson, D. Jr., Bala, M. & Kimball, A. B. The burden of autoimmune disease: a comparison of prevalence ratios in patients with psoriatic arthritis and psoriasis. J. Am. Acad. Dermatol. 61, 405–410 (2009).

  31. 31.

    Egeberg, A., Thyssen, J. P., Burisch, J. & Colombel, J. F. Incidence and risk of inflammatory bowel disease in patients with psoriasis-a nationwide 20-year cohort study. J. Invest. Dermatol. 139, 316–323 (2019).

  32. 32.

    Rutgeerts, P. et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 353, 2462–2476 (2005).

  33. 33.

    Sandborn, W. J. et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 142, 257–265 e251-253 (2012).

  34. 34.

    Sandborn, W. J. et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology 146, 96–109 e101 (2014).

  35. 35.

    Ford, A. C. et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am. J. Gastroenterol. 106, 644–659 quiz 660 (2011).

  36. 36.

    Callhoff, J., Sieper, J., Weiss, A., Zink, A. & Listing, J. Efficacy of TNFα blockers in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann. Rheum. Dis. 74, 1241–1248 (2015).

  37. 37.

    Seyahi, E., Ozdogan, H., Celik, S., Ugurlu, S. & Yazici, H. Treatment options in colchicine resistant familial Mediterranean fever patients: thalidomide and etanercept as adjunctive agents. Clin. Exp. Rheumatol. 24, S99–S103 (2006).

  38. 38.

    Kearsley-Fleet, L. et al. Effectiveness and safety of TNF inhibitors in adults with juvenile idiopathic arthritis. RMD Open 2, e000273 (2016).

  39. 39.

    TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI analysis group. Neurology 53, 457–465 (1999).

  40. 40.

    McCoy, M. K. & Tansey, M. G. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J. Neuroinflammation 5, 45 (2008).

  41. 41.

    Kirkham, B. W., Kavanaugh, A. & Reich, K. Interleukin-17A: a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis. Immunology 141, 133–142 (2014).

  42. 42.

    Menon, B. et al. Interleukin-17+CD8+ T cells are enriched in the joints of patients with psoriatic arthritis and correlate with disease activity and joint damage progression. Arthritis Rheumatol. 66, 1272–1281 (2014).

  43. 43.

    Lin, A. M. et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J. Immunol. 187, 490–500 (2011).

  44. 44.

    Genovese, M. C. et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann. Rheum. Dis. 72, 863–869 (2013).

  45. 45.

    Fujino, S. et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70 (2003).

  46. 46.

    Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

  47. 47.

    Hall, A. O., Towne, J. E. & Plevy, S. E. Get the IL-17F outta here! Nat. Immunol. 19, 648–650 (2018).

  48. 48.

    Mease, P. J. et al. Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N. Engl. J. Med. 373, 1329–1339 (2015).

  49. 49.

    McInnes, I. B. et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 386, 1137–1146 (2015).

  50. 50.

    Mease, P. J. et al. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann. Rheum. Dis. 76, 79–87 (2017).

  51. 51.

    Nash, P. et al. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet 389, 2317–2327 (2017).

  52. 52.

    Baeten, D. et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 382, 1705–1713 (2013).

  53. 53.

    Mease, P. J. et al. Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N. Engl. J. Med. 370, 2295–2306 (2014).

  54. 54.

    Glatt, S. et al. Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation. Ann. Rheum. Dis. 77, 523–532 (2018).

  55. 55.

    Glatt, S. et al. First-in-human randomized study of bimekizumab, a humanized monoclonal antibody and selective dual inhibitor of IL-17A and IL-17F, in mild psoriasis. Br. J. Clin. Pharmacol. 83, 991–1001 (2017).

  56. 56.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02963506 (2018).

  57. 57.

    Vignali, D. A. & Kuchroo, V. K. IL-12 family cytokines: immunological playmakers. Nat. Immunol. 13, 722–728 (2012).

  58. 58.

    Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells. Nat. Med. 18, 1069–1076 (2012).

  59. 59.

    Fujita, H. Role of IL-22 in the pathogenesis of skin diseases. Nihon Rinsho Meneki Gakkai Kaishi 35, 168–175 (2012).

  60. 60.

    Hawkes, J. E., Chan, T. C. & Krueger, J. G. Psoriasis pathogenesis and the development of novel targeted immune therapies. J. Allergy Clin. Immunol. 140, 645–653 (2017).

  61. 61.

    Kavanaugh, A. et al. Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials. Ann. Rheum. Dis. 73, 1000–1006 (2014).

  62. 62.

    Kavanaugh, A. et al. Efficacy and safety of ustekinumab in psoriatic arthritis patients with peripheral arthritis and physician-reported spondylitis: post-hoc analyses from two phase III, multicentre, double-blind, placebo-controlled studies (PSUMMIT-1/PSUMMIT-2). Ann. Rheum. Dis. 75, 1984–1988 (2016).

  63. 63.

    Sandborn, W. J. et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N. Engl. J. Med. 367, 1519–1528 (2012).

  64. 64.

    Feagan, B. G. et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N. Engl. J. Med. 375, 1946–1960 (2016).

  65. 65.

    McInnes, I. B. 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 382, 780–789 (2013).

  66. 66.

    Araujo, E. G. 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. 48, 632–637 (2019).

  67. 67.

    Ibler, E. & Gordon, K. B. IL-23 inhibitors for moderate-to-severe psoriasis. Semin. Cutan. Med. Surg. 37, 158–162 (2018).

  68. 68.

    Fotiadou, C., Lazaridou, E., Sotiriou, E. & Ioannides, D. Targeting IL-23 in psoriasis: current perspectives. Psoriasis 8, 1–5 (2018).

  69. 69.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01094093 (2017).

  70. 70.

    Reich, K. et al. Efficacy and safety of mirikizumab (LY3074828) in the treatment of moderate-to-severe plaque psoriasis: results from a randomized phase II study. Br. J. Dermatol. 181, 88–95 (2019).

  71. 71.

    Mease P. J. et al. Efficacy and safety of risankizumab, a selective IL-23p19 inhibitor, in patients with active psoriatic arthritis over 24 weeks: results from a phase 2 trial [OP0307]. Ann. Rheum. Dis. 77, 200–201 (2018).

  72. 72.

    Langley, R. G. et al. FRI0445 Tildrakizumab treatment improved measures of psoriatic arthritis in adults with chronic plaque psoriasis. Ann. Rheum. Dis. 75, 596–597, (2016).

  73. 73.

    Feagan, B. G. et al. Risankizumab in patients with moderate to severe Crohn’s disease: an open-label extension study. Lancet Gastroenterol. Hepatol. 3, 671–680 (2018).

  74. 74.

    Sands, B. E. et al. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn’s disease: a phase 2a study. Gastroenterology 153, 77–86.e6 (2017).

  75. 75.

    Sandborn, W. J. et al. Efficacy and safety of anti-interleukin-23 therapy with mirikizumab (LY3074828) in patients with moderate-to-severe ulcerative colitis in a phase 2 study [abstract 882]. Gastroenterology 154 (Suppl.), S-1360–S-1361 (2018).

  76. 76.

    Kim, W. et al. The role of IL-12 in inflammatory activity of patients with rheumatoid arthritis (RA). Clin. Exp. Immunol. 119, 175–181 (2000).

  77. 77.

    Zaky, D. S. & El-Nahrery, E. M. Role of interleukin-23 as a biomarker in rheumatoid arthritis patients and its correlation with disease activity. Int. Immunopharmacol. 31, 105–108 (2016).

  78. 78.

    Smolen, J. S. et al. A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate. Ann. Rheum. Dis. 76, 831–839 (2017).

  79. 79.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02407223 (2019).

  80. 80.

    Merola, J. F., Espinoza, L. R. & Fleischmann, R. Distinguishing rheumatoid arthritis from psoriatic arthritis. RMD Open 4, e000656 (2018).

  81. 81.

    Przepiera-Bedzak, H., Fischer, K. & Brzosko, M. Serum IL-6 and IL-23 levels and their correlation with angiogenic cytokines and disease activity in ankylosing spondylitis, psoriatic arthritis, and SAPHO syndrome. Mediators Inflamm. 2015, 785705 (2015).

  82. 82.

    Tesmer, L. A., Lundy, S. K., Sarkar, S. & Fox, D. A. Th17 cells in human disease. Immunol. Rev. 223, 87–113 (2008).

  83. 83.

    Mease, P. J. et al. The efficacy and safety of clazakizumab, an anti-interleukin-6 monoclonal antibody, in a phase IIb study of adults with active psoriatic arthritis. Arthritis Rheumatol. 68, 2163–2173 (2016).

  84. 84.

    Sieper, J., Porter-Brown, B., Thompson, L., Harari, O. & Dougados, M. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann. Rheum. Dis. 73, 95–100 (2014).

  85. 85.

    Sieper, J. et al. Sarilumab for the treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann. Rheum. Dis. 74, 1051–1057 (2015).

  86. 86.

    Smolen, J. S. et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371, 987–997 (2008).

  87. 87.

    De Benedetti, F. et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2385–2395 (2012).

  88. 88.

    Fujikawa, K. et al. Interleukin-6 targeting therapy in familial Mediterranean fever. Clin. Exp. Rheumatol. 31, 150–151 (2013).

  89. 89.

    Ravindran, J. S. et al. Interleukin 1α, interleukin 1β and interleukin 1 receptor gene polymorphisms in psoriatic arthritis. Rheumatology 43, 22–26 (2004).

  90. 90.

    Mertens, M. & Singh, J. A. Anakinra for rheumatoid arthritis. Cochrane Database Syst. Rev., CD005121, https://doi.org/10.1002/14651858.CD005121.pub3 (2009).

  91. 91.

    Singh, J. A. et al. A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ 181, 787–796 (2009).

  92. 92.

    Dayer, J. M. & Bresnihan, B. Targeting interleukin-1 in the treatment of rheumatoid arthritis. Arthritis Rheum. 46, 574–578 (2002).

  93. 93.

    Dayer, J. M. Interleukin 1 or tumor necrosis factor-alpha: which is the real target in rheumatoid arthritis? J. Rheumatol. Suppl. 65, 10–15 (2002).

  94. 94.

    Gibbs, A. et al. Anakinra (Kineret) in psoriasis and psoriatic arthritis: a single-center, open-label, pilot study. Arthritis Res. Ther. 7, 68 (2005).

  95. 95.

    Gul, A. et al. Efficacy and safety of canakinumab in adolescents and adults with colchicine-resistant familial Mediterranean fever. Arthritis Res. Ther. 17, 243 (2015).

  96. 96.

    De Benedetti, F. et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N. Engl. J. Med. 378, 1908–1919 (2018).

  97. 97.

    Hashkes, P. J. et al. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann. Intern. Med. 157, 533–541 (2012).

  98. 98.

    Ben-Zvi, I. et al. Anakinra for colchicine-resistant familial Mediterranean fever: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 69, 854–862 (2017).

  99. 99.

    O’Shea, J. J. et al. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu. Rev. Med. 66, 311–328 (2015).

  100. 100.

    Winthrop, K. L. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat. Rev. Rheumatol. 13, 320 (2017).

  101. 101.

    Mease, P. et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N. Engl. J. Med. 377, 1537–1550 (2017).

  102. 102.

    Kuo, C. M., Tung, T. H., Wang, S. H. & Chi, C. C. Efficacy and safety of tofacitinib for moderate-to-severe plaque psoriasis: a systematic review and meta-analysis of randomized controlled trials. J. Eur. Acad. Dermatol. Venereol. 32, 355–362 (2018).

  103. 103.

    Sandborn, W. J. et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 376, 1723–1736 (2017).

  104. 104.

    van Vollenhoven, R. F. et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N. Engl. J. Med. 367, 508–519 (2012).

  105. 105.

    van der Heijde, D. et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 65, 559–570 (2013).

  106. 106.

    Fleischmann, R. et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N. Engl. J. Med. 367, 495–507 (2012).

  107. 107.

    Gladman, D. et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF Inhibitors. N. Engl. J. Med. 377, 1525–1536 (2017).

  108. 108.

    Tanaka, Y., Maeshima, K. & Yamaoka, K. In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis. Ann. Rheum. Dis. 71, i70–i74 (2012).

  109. 109.

    Fleischmann, R. et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 64, 617–629 (2012).

  110. 110.

    Hutmacher, M. M. et al. Evaluating dosage optimality for tofacitinib, an oral Janus kinase inhibitor, in plaque psoriasis, and the influence of body weight. CPT Pharmacomet. Syst. Pharmacol. 6, 322–330 (2017).

  111. 111.

    Panes, J. et al. Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two phase IIb randomised placebo-controlled trials. Gut 66, 1049–1059 (2017).

  112. 112.

    van der Heijde, D. et al. Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study. Ann. Rheum. Dis. 76, 1340–1347 (2017).

  113. 113.

    van der Heijde, D. 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 392, 2378–2387 (2018).

  114. 114.

    Mease, P. et al. Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active psoriatic arthritis (EQUATOR): results from a randomised, placebo-controlled, phase 2 trial. Lancet 392, 2367–2377 (2018).

  115. 115.

    Smolen, J. S. et al. Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON). Ann. Rheum. Dis. 76, 694–700 (2017).

  116. 116.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03104374 (2019).

  117. 117.

    Papp, K. et al. Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis. N. Engl. J. Med. 379, 1313–1321 (2018).

  118. 118.

    Pucci, E. et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD007621.pub2 (2011).

  119. 119.

    Guagnozzi, D. & Caprilli, R. Natalizumab in the treatment of Crohn’s disease. Biologics 2, 275–284 (2008).

  120. 120.

    Feagan, B. G. et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 369, 699–710 (2013).

  121. 121.

    Sandborn, W. J. et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N. Engl. J. Med. 369, 711–721 (2013).

  122. 122.

    Papp, K. A., Caro, I., Leung, H. M., Garovoy, M. & Mease, P. J. Efalizumab for the treatment of psoriatic arthritis. J. Cutan. Med. Surg. 11, 57–66 (2007).

  123. 123.

    Boehncke, W. H. Efalizumab in the treatment of psoriasis. Biologics 1, 301–309 (2007).

  124. 124.

    Mease, P. J. & Reich, K. Alefacept in Psoriatic Arthritis Study Group. Alefacept with methotrexate for treatment of psoriatic arthritis: open-label extension of a randomized, double-blind, placebo-controlled study. J. Am. Acad. Dermatol. 60, 402–411 (2009).

  125. 125.

    Kavanaugh, A. F. et al. A phase I/II open label study of the safety and efficacy of an anti-ICAM-1 (intercellular adhesion molecule-1; CD54) monoclonal antibody in early rheumatoid arthritis. J. Rheumatol. 23, 1338–1344 (1996).

  126. 126.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00083759 (2016)

  127. 127.

    Mosli, M. H. & Feagan, B. G. Vedolizumab for Crohn’s disease. Expert Opin. Biol. Ther. 13, 455–463 (2013).

  128. 128.

    Varkas, G. et al. An induction or flare of arthritis and/or sacroiliitis by vedolizumab in inflammatory bowel disease: a case series. Ann. Rheum. Dis. 76, 878–881 (2017).

  129. 129.

    Garcia-Vicuna, R. & Brown, M. A. Vedolizumab for inflammatory bowel disease: a two-edge sword in the gut-joint/enthesis axis. Rheumatology 58, 937–939 (2019).

  130. 130.

    Paccou, J. et al. OP0029 Clinical effect of vedolizumab on articular manifestations in patients with spondyloarthritis associated with inflammatory bowel disease. Ann. Rheum. Dis. 77, 64–65 (2018).

  131. 131.

    Orlando, A. et al. Clinical benefit of vedolizumab on articular manifestations in patients with active spondyloarthritis associated with inflammatory bowel disease. Ann. Rheum. Dis. 76, e31 (2017).

  132. 132.

    Mease, P. J., Gladman, D. D. & Keystone, E. C. Alefacept in Psoriatic Arthritis Study Group. Alefacept in combination with methotrexate for the treatment of psoriatic arthritis: results of a randomized, double-blind, placebo-controlled study. Arthritis Rheum. 54, 1638–1645 (2006).

  133. 133.

    Ellis, C. N. & Krueger, G. G. Alefacept Clinical Study Group. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N. Engl. J. Med. 345, 248–255 (2001).

  134. 134.

    Malizia, G. et al. Expression of leukocyte adhesion molecules by mucosal mononuclear phagocytes in inflammatory bowel disease. Gastroenterology 100, 150–159 (1991).

  135. 135.

    Davies, M. E., Sharma, H. & Pigott, R. ICAM-1 expression on chondrocytes in rheumatoid arthritis: induction by synovial cytokines. Mediators Inflamm. 1, 71–74 (1992).

  136. 136.

    Wang, L., Ding, Y., Guo, X. & Zhao, Q. Role and mechanism of vascular cell adhesion molecule-1 in the development of rheumatoid arthritis. Exp. Ther. Med. 10, 1229–1233 (2015).

  137. 137.

    Gladman, D. D. et al. Therapeutic benefit of apremilast on enthesitis and dactylitis in patients with psoriatic arthritis: a pooled analysis of the PALACE 1-3 studies. RMD Open 4, e000669 (2018).

  138. 138.

    Kavanaugh, A. et al. Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J. Rheumatol. 42, 479–488 (2015).

  139. 139.

    Genovese, M. C. et al. Apremilast in patients with active rheumatoid arthritis: a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheumatol. 67, 1703–1710 (2015).

  140. 140.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01583374 (2019).

  141. 141.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02289417 (2019)

  142. 142.

    Moreland, L., Bate, G. & Kirkpatrick, P. Abatacept. Nat. Rev. Drug Discov. 5, 185–186 (2006).

  143. 143.

    Maxwell, L. J. & Singh, J. A. Abatacept for rheumatoid arthritis: a Cochrane systematic review. J. Rheumatol. 37, 234–245 (2010).

  144. 144.

    Mease, P. J. et al. Efficacy and safety of abatacept, a T-cell modulator, in a randomised, double-blind, placebo-controlled, phase III study in psoriatic arthritis. Ann. Rheum. Dis. 76, 1550–1558 (2017).

  145. 145.

    Edwards, J. C. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004).

  146. 146.

    Cohen, S. B. et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 54, 2793–2806 (2006).

  147. 147.

    Memon, A. B. et al. Long-term safety of rituximab induced peripheral B-cell depletion in autoimmune neurological diseases. PLoS One 13, e0190425 (2018).

  148. 148.

    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).

  149. 149.

    Jimenez-Boj, E. et al. Rituximab in psoriatic arthritis: an exploratory evaluation. Ann. Rheum. Dis. 71, 1868–1871 (2012).

  150. 150.

    Jung, N. et al. An open-label pilot study of the efficacy and safety of anakinra in patients with psoriatic arthritis refractory to or intolerant of methotrexate (MTX). Clin. Rheumatol. 29, 1169–1173 (2010).

  151. 151.

    Veale, D., Rogers, S. & Fitzgerald, O. Immunolocalization of adhesion molecules in psoriatic arthritis, psoriatic and normal skin. Br. J. Dermatol. 132, 32–38 (1995).

  152. 152.

    Riccieri, V. et al. Adhesion molecule expression in the synovial membrane of psoriatic arthritis. Ann. Rheum. Dis. 61, 569–570 (2002).

  153. 153.

    Riccieri, V. et al. [Immunohistochemical analysis of the expression of main adhesion molecules and tumor necrosis factors in the synovial membrane of psoriatic arthritis]. Reumatismo 55, 164–170 (2003).

  154. 154.

    Diani, M., Altomare, G. & Reali, E. T cell responses in psoriasis and psoriatic arthritis. Autoimmun. Rev. 14, 286–292 (2015).

  155. 155.

    Celis, R. et al. Synovial cytokine expression in psoriatic arthritis and associations with lymphoid neogenesis and clinical features. Arthritis Res. Ther. 14, R93 (2012).

  156. 156.

    Zhu, J., Yamane, H. & Paul, W. E. Differentiation of effector CD4 T cell populations*. Annu. Rev. Immunol. 28, 445–489 (2010).

  157. 157.

    Szentpetery, A. et al. Abatacept reduces synovial regulatory T-cell expression in patients with psoriatic arthritis. Arthritis Res. Ther. 19, 158 (2017).

  158. 158.

    Ciccia, F. et al. Interleukin-9 and T helper type 9 cells in rheumatic diseases. Clin. Exp. Immunol. 185, 125–132 (2016).

  159. 159.

    Mitra, A., Raychaudhuri, S. K. & Raychaudhuri, S. P. Functional role of IL-22 in psoriatic arthritis. Arthritis Res. Ther. 14, R65 (2012).

  160. 160.

    Soare, A. et al. Cutting edge: Homeostasis of innate lymphoid cells is imbalanced in psoriatic arthritis. J. Immunol. 200, 1249–1254 (2018).

  161. 161.

    Dunphy, S. & Gardiner, C. M. NK cells and psoriasis. J. Biomed. Biotechnol. 2011, 248317 (2011).

  162. 162.

    Chiba, A. et al. Mucosal-associated invariant T cells promote inflammation and exacerbate disease in murine models of arthritis. Arthritis Rheum. 64, 153–161 (2012).

  163. 163.

    Teunissen, M. B. M. et al. The IL-17A-producing CD8+ T-cell population in psoriatic lesional skin comprises mucosa-associated invariant T cells and conventional T cells. J. Invest. Dermatol. 134, 2898–2907 (2014).

  164. 164.

    Jongbloed, S. L. et al. Enumeration and phenotypical analysis of distinct dendritic cell subsets in psoriatic arthritis and rheumatoid arthritis. Arthritis Res. Ther. 8, R15 (2006).

  165. 165.

    Lande, R. et al. Characterization and recruitment of plasmacytoid dendritic cells in synovial fluid and tissue of patients with chronic inflammatory arthritis. J. Immunol. 173, 2815–2824 (2004).

  166. 166.

    Wenink, M. H. et al. Impaired dendritic cell proinflammatory cytokine production in psoriatic arthritis. Arthritis Rheum. 63, 3313–3322 (2011).

  167. 167.

    Danning, C. L. et al. Macrophage-derived cytokine and nuclear factor κB p65 expression in synovial membrane and skin of patients with psoriatic arthritis. Arthritis Rheum. 43, 1244–1256 (2000).

  168. 168.

    Vandooren, B. et al. Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis. Arthritis Rheum. 60, 966–975 (2009).

  169. 169.

    Arango Duque, G. & Descoteaux, A. Macrophage cytokines: involvement in immunity and infectious diseases. Front. Immunol. 5, 491 (2014).

  170. 170.

    Noordenbos, T. et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum. 64, 99–109 (2012).

  171. 171.

    Veale, D. J. et al. The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis. Rheumatology 58, 197–205 (2019).

  172. 172.

    Li, H., Zuo, J. & Tang, W. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front. Pharmacol. 9, 1048 (2018).

  173. 173.

    Ospelt, C. Synovial fibroblasts in 2017. RMD Open 3, e000471 (2017).

  174. 174.

    Espinoza, L. R. et al. Fibroblast function in psoriatic arthritis. II. Increased expression of beta platelet derived growth factor receptors and increased production of growth factor and cytokines. J. Rheumatol. 21, 1507–1511 (1994).

  175. 175.

    Goldring, M. B. & Berenbaum, F. The regulation of chondrocyte function by proinflammatory mediators: prostaglandins and nitric oxide. Clin. Orthop. Relat. Res., S37-S46, https://doi.org/10.1097/01.blo.0000144484.69656.e4 (2004).

  176. 176.

    Burrage, P. S., Mix, K. S. & Brinckerhoff, C. E. Matrix metalloproteinases: role in arthritis. Front. Biosci. 11, 529–543 (2006).

  177. 177.

    Lin, E. A. & Liu, C. J. The role of ADAMTSs in arthritis. Protein Cell 1, 33–47 (2010).

  178. 178.

    Rahimi, H. & Ritchlin, C. T. Altered bone biology in psoriatic arthritis. Curr. Rheumatol. Rep. 14, 349–357 (2012).

  179. 179.

    Mensah, K. A., Schwarz, E. M. & Ritchlin, C. T. Altered bone remodeling in psoriatic arthritis. Curr. Rheumatol. Rep. 10, 311–317 (2008).

  180. 180.

    Coury, F., Peyruchaud, O. & Machuca-Gayet, I. Osteoimmunology of bone loss in inflammatory rheumatic diseases. Front. Immunol. 10, 679 (2019).

  181. 181.

    Delaisse, J. M. et al. Matrix metalloproteinases (MMP) and cathepsin K contribute differently to osteoclastic activities. Microsc. Res. Tech. 61, 504–513 (2003).

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Correspondence to Arthur Kavanaugh.

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