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Pathophysiology


genetic susceptibility to PsO and PsA, the pathogenic role that these genes play in the development of PsA remains unclear. The canonical function of the class I HLA molecule is to present antigen to CD8+ T cells, but these cells are dispensable in the human HLA-B27-transgenic rat model of spondyloarthritis. The hypothesis of the unfolded protein response, which induces production of IL-23 in the endoplasmic reticulum, has been proposed to explain the indirect role of HLA-B27 in the pathogenesis of spondyloarthritis. As trauma and overload in enthesis have been associated with PsA onset, probably through stimulation of TLR and activation of the innate immune response, the case for an auto-inflammatory component of PsA has emerged.24


Several


studies have demonstrated that synovial innate immune cells (CD163+ macrophages, neutrophils and mast cells) are relevant in PsA pathogenesis, as they were sensitive to change after effective therapy. Although human studies and clinical trials support the relevance of TNF-alpha and the IL-17/IL-23 axis in the pathophysiology of PsA, it remains unclear which cells are the source of IL-17 (isoforms A and F) and what is the relationship between TNF and IL-17/ IL-23 cytokines; these pathways are probably partially complementary, as suggested by the worse response of TNF-insufficient responders to ustekinumab.25


In contrast to the findings


of increased CD4+IL-17+ or CD8+ IL-17+ T cells in peripheral blood or synovial fluid in PsA, few CD3+IL-17+ T cells are detected in synovium, whereas the cells with the highest content of IL-17 belong to the innate immune system. The pathophysiological relationship between joint and skin manifestations in PsA is a relatively unexplored area of research. There is no convincing hypothesis that explains why only approximately 20–30% of PsO patients develop PsA. The pathophysiology of PsO is better-defined than that of PsA and the autoimmune component is clear, with an important role of presentation of known antigens to T cells by dendritic cells. Better responses in PsO than in PsA with IL-17 and IL-12/IL-23 inhibitors clearly support a greater role of these molecules in the pathophysiology of PsO than in PsA.26


14


Although, as expected, there is a clear overlap in the genetic susceptibility to PsO and PsA, an important missing genetic component remains to be identified and this, together with insights


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on the role of the microbioma in the pathogenesis of PsO and PsA, may clarify the relationship between the different manifestations of psoriatic disease in the near future.27 l


References 1. Winchester R et al. HLA associations reveal genetic heterogeneity in psoriatic artritis and in the psoriasis phenotype. Arthritis Rheum 2102;64:1134–44.


2. Haroon M et al. Certain class I HLA alleles and haplotypes implicated in susceptibility play a role in determining specific features of the psoriatic arthritis phenotype. Ann Rheum Dis 2014; doi:10.1136/annrheumdis-2014-205461 [Epub ahead of print].


3. O'Rielly DD et al. Genetics of susceptibility and treatment response in psoriatic arthritis. Nat Rev Rheumatol 2011;7:718–32.


4. Pollock RA et al. Gene expression differences between psoriasis patients with and without inflammatory arthritis. J Invest Dermatol 2014;doi: 10.1038/jid.2014.414.


5. Kruithof E et al. Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis Res Ther 2005;7:R569–80.


6. Reece RJ et al. Distinct vascular patterns of early synovitis in psoriatic, reactive, and rheumatoid arthritis. Arthritis Rheum 1999;42:1481–4.


7. Cañete JD et al. Antiangiogenic effects of anti-tumor necrosis factor alpha therapy with infliximab in psoriatic arthritis. Arthritis Rheum 2004;50:1636–41.


8. Goedkoop AY et al. Deactivation of endothelium and reduction in angiogenesis in psoriatic skin and synovium by low dose infliximab therapy in combination with stable methotrexate therapy: a prospective single-centre study. Arthritis Res Ther 2004;6:R326–34.


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


10. Kruithof E et al. Identification of synovial biomarkers of response to experimental treatment in early-phase clinical trials in spondylarthritis. Arthritis Rheum 2006;54: 1795–804.


11. Lin AM et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol 2011;187:490–500.


12. Ritchlin CT et al. Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest 2003;111:821–31.


13. Adamopoulos IE et al. IL-17A gene transfer induces bone loss and epidermal hyperplasia associated with psoriatic arthritis. Ann Rheum Dis doi:10.1136/annrheumdis-2013-204782 [Epub ahead of print].


14. Sherlock JP et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells. Nat Med 2012;18:1069–76.


15. Russell CB et al. Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti-IL-17 receptor monoclonal antibody. J Immunol 2014;192; 3828–36.


16. Celis R et al. Synovial cytokine expression in psoriatic arthritis and associations with lymphoid neogenesis and clinical features. Arthritis Res Ther 2012;14(2):R93.


17. Leipe J et al. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum 2010;62:2876–85.


18. 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 2014;66:1272–81.


19. Mease P. Psoriatic arthritis and spondyloarthritis assessment and management update. Curr Opin Rheumatol 2013;25:287–96.


20. 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 2014;73:1000–6.


21. Mease PJ et al. Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med 2014;370:2295–306.


22. Kavanaugh A et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis 2014;73(6):1020–6.


23. Schafer PH et al. Novel systemic drugs for psoriasis: mechanism of action for apremilast, a specific inhibitor of PDE4. J Am Acad Dermatol 2013;68:1041–2.


24. Hreggvidsdottir HS et al. Inflammatory pathways in spondyloarthritis. Mol Immunol 2014;57:28–37.


25. Ritchlin C et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis 2014;73:990–9.


26. Lynde CW et al. Interleukin 17A: toward a new understanding of psoriasis pathogenesis. J Am Acad Dermatol 2014;71:141–50.


27. Castelino M et al. The bacterial skin microbiome in psoriatic arthritis, an unexplored link in pathogenesis: challenges and opportunities offered by recent technological advances. Rheumatology (Oxford) 2014;53:777–84.


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