Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

New insights into the pathogenesis and genetics of psoriatic arthritis

Abstract

Psoriasis vulgaris and psoriatic arthritis (PsA) are inter-related heritable diseases. Psoriatic skin is characterized by hyperproliferative, poorly differentiated keratinocytes and severe inflammation. Psoriatic joints are characterized by highly inflamed synovia and entheses with focal erosions of cartilage and bone. Genetic analyses have uncovered risk factors shared by both psoriasis and PsA. Predisposition to psoriasis and PsA arising from common variation is most strongly conferred by the HLA class I region. Other genetic risk factors implicate the interleukin (IL)-23 pathway and the induction and regulation of type 17 T-helper cells in the pathogenesis of both diseases. Secretion of cytokines, such as IL-22 and IL-17, could result in the hyperproliferative phenotype of keratinocytes and potentially synoviocytes, leading to a vicious cycle of cellular proliferation and inflammation in both the skin and joints. In synovial tissue, disease-related cytokines could also promote osteoclast formation, resulting in bone erosion. The next step will be to identify genetic risk factors specifically associated with PsA. Although therapies that target tumor necrosis factor are often highly successful in the treatment of both diseases, genetic findings are likely to lead to the development of treatments tailored to an individual's genetic profile.

Key Points

  • Multiple genes with low risk effects are involved in susceptibility to psoriasis vulgaris and psoriatic arthritis (PsA)

  • Newly uncovered genetic associations shared by psoriasis and PsA implicate components of the IL-23–TH17 pathway in both diseases

  • Given these genetic links, further evaluation of the pathogenic role of the IL-23–TH17 pathway in PsA is warranted

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Model of the relationship between skin and joint inflammation associated with psoriasis vulgaris and psoriatic arthritis.

Similar content being viewed by others

References

  1. Gelfand JM et al. (2005) The prevalence of psoriasis in African Americans: results from a population-based study. J Am Acad Dermatol 52: 23–26

    Article  PubMed  Google Scholar 

  2. Menter A et al. (2008) Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 58: 826–850

    Article  PubMed  Google Scholar 

  3. Zachariae H et al. (2002) Quality of life and prevalence of arthritis reported by 5,795 members of the Nordic Psoriasis Associations. Data from the Nordic Quality of Life Study. Acta Derm Venereol 82: 108–113

    Article  PubMed  Google Scholar 

  4. Tam LS et al. (2008) Cardiovascular risk profile of patients with psoriatic arthritis compared to controls—the role of inflammation. Rheumatology (Oxford) 47: 718–723

    Article  Google Scholar 

  5. Neimann AL et al. (2006) Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol 55: 829–835

    Article  PubMed  Google Scholar 

  6. Gladman DD et al. (2003) HLA is a candidate region for psoriatic arthritis: evidence for excessive HLA sharing in sibling pairs. Hum Immunol 64: 887–889

    Article  CAS  PubMed  Google Scholar 

  7. Bhalerao J and Bowcock AM (1998) The genetics of psoriasis: a complex disorder of the skin and immune system. Hum Mol Genet 7: 1537–1545

    Article  CAS  PubMed  Google Scholar 

  8. Myers A et al. (2005) Recurrence risk for psoriasis and psoriatic arthritis within sibships. Rheumatology (Oxford) 44: 773–776

    Article  CAS  Google Scholar 

  9. Rahman P and Elder JT (2005) Genetic epidemiology of psoriasis and psoriatic arthritis. Ann Rheum Dis 64 (Suppl 2): 37–39

    Google Scholar 

  10. Griffiths CE and Barker JN (2007) Pathogenesis and clinical features of psoriasis. Lancet 370: 263–271

    Article  CAS  PubMed  Google Scholar 

  11. Palazzi C et al. (2005) Hepatitis C virus infection in psoriatic arthritis. Arthritis Rheum 53: 223–225

    Article  PubMed  Google Scholar 

  12. Moll JM and Wright V (1973) Psoriatic arthritis. Semin Arthritis Rheum 3: 55–78

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  14. Gladman DD et al. (2005) Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 64 (Suppl 2): 14–17

    Google Scholar 

  15. Myers WA et al. (2006) Psoriasis and psoriatic arthritis: clinical features and disease mechanisms. Clin Dermatol 24: 438–447

    Article  PubMed  Google Scholar 

  16. McGonagle D (2005) Imaging the joint and enthesis: insights into pathogenesis of psoriatic arthritis. Ann Rheum Dis 64 (Suppl 2): 58–60

    Google Scholar 

  17. Nash P and Clegg DO (2005) Psoriatic arthritis therapy: NSAIDs and traditional DMARDs. Ann Rheum Dis 64 (Suppl 2): 74–77

    Google Scholar 

  18. Gottlieb A et al. (2008) Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol 58: 851–864

    Article  PubMed  Google Scholar 

  19. Warren RB and Griffiths CE (2008) Systemic therapies for psoriasis: methotrexate, retinoids, and cyclosporine. Clin Dermatol 26: 438–447

    Article  PubMed  Google Scholar 

  20. Chan ES and Cronstein BN (2002) Molecular action of methotrexate in inflammatory diseases. Arthritis Res 4: 266–273

    Article  PubMed Central  Google Scholar 

  21. Mease PJ (2006) 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

    Article  CAS  PubMed  Google Scholar 

  22. Dubertret L et al. (2006) Clinical experience acquired with the efalizumab (Raptiva) (CLEAR) trial in patients with moderate-to-severe plaque psoriasis: results from a phase III international randomized, placebo-controlled trial. Br J Dermatol 155: 170–181

    Article  CAS  PubMed  Google Scholar 

  23. Papp KA et al. (2007) Efalizumab for the treatment of psoriatic arthritis. J Cutan Med Surg 11: 57–66

    Article  CAS  PubMed  Google Scholar 

  24. Myers WA et al. (2006) New-onset, debilitating arthritis in psoriasis patients receiving efalizumab. J Dermatolog Treat 17: 353–354

    Article  CAS  PubMed  Google Scholar 

  25. Mease PJ and Antoni CE (2005) Psoriatic arthritis treatment: biological response modifiers. Ann Rheum Dis 64 (Suppl 2): 78–82

    Google Scholar 

  26. Fantuzzi F et al. (2008) Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis. Expert Opin Ther Targets 12: 1085–1096

    Article  CAS  PubMed  Google Scholar 

  27. Zaba LC et al. (2007) Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med 204: 3183–3194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Collamer AN et al. (2008) Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: a literature review and potential mechanisms of action. Arthritis Rheum 59: 996–1001

    Article  CAS  PubMed  Google Scholar 

  29. Leonardi CL et al. (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371: 1665–1674

    Article  CAS  PubMed  Google Scholar 

  30. Ritchlin C (2007) Psoriatic disease—from skin to bone. Nat Clin Pract Rheumatol 3: 698–706

    Article  CAS  PubMed  Google Scholar 

  31. Gladman DD et al. (1999) HLA-C locus alleles in patients with psoriatic arthritis (PsA). Hum Immunol 60: 259–261

    Article  CAS  PubMed  Google Scholar 

  32. Tsunemi Y et al. (2002) Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci 30: 161–166

    Article  CAS  PubMed  Google Scholar 

  33. Nair RP et al. (2006) Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am J Hum Genet 78: 827–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Helms C et al. (2005) Localization of PSORS1 to a haplotype block harboring HLA-C and distinct from corneodesmosin and HCR. Hum Genet 118: 466–476

    Article  CAS  PubMed  Google Scholar 

  35. Veal CD et al. (2002) Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus. Am J Hum Genet 71: 554–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Elder JT (2006) PSORS1: linking genetics and immunology. J Invest Dermatol 126: 1205–1206

    Article  CAS  PubMed  Google Scholar 

  37. Liu Y et al. (2008) A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet 4: e1000041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gladman DD and Farewell VT (2003) HLA studies in psoriatic arthritis: current situation and future needs. J Rheumatol 30: 4–6

    PubMed  Google Scholar 

  39. Korendowych E and McHugh N (2005) Genetic factors in psoriatic arthritis. Curr Rheumatol Rep 7: 306–312

    Article  CAS  PubMed  Google Scholar 

  40. Ho PY et al. (2007) HLA-Cw6 and HLA-DRB1*07 together are associated with less severe joint disease in psoriatic arthritis. Ann Rheum Dis 66: 807–811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Reich K et al. (2007) TNF polymorphisms in psoriasis: association of psoriatic arthritis with the promoter polymorphism TNF*-857 independent of the PSORS1 risk allele. Arthritis Rheum 56: 2056–2064

    Article  CAS  PubMed  Google Scholar 

  42. Williams F et al. (2005) Activating killer cell immunoglobulin-like receptor gene KIR2DS1 is associated with psoriatic arthritis. Hum Immunol 66: 836–841

    Article  CAS  PubMed  Google Scholar 

  43. Nelson GW et al. (2004) Cutting edge: heterozygote advantage in autoimmune disease: hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis. J Immunol 173: 4273–4276

    Article  CAS  PubMed  Google Scholar 

  44. Boulet S et al. (2008) A combined genotype of KIR3DL1 high expressing alleles and HLA-B*57 is associated with a reduced risk of HIV infection. Aids 22: 1487–1491

    Article  CAS  PubMed  Google Scholar 

  45. Martin MP and Carrington M (2005) Immunogenetics of viral infections. Curr Opin Immunol 17: 510–516

    Article  CAS  PubMed  Google Scholar 

  46. Cargill M et al. (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80: 273–290

    Article  CAS  PubMed  Google Scholar 

  47. Huffmeier U et al. (2008) Genetic variants of the IL-23R pathway: association with psoriatic arthritis and psoriasis vulgaris, but no specific risk factor for arthritis. J Invest Dermatol [10.1038/jid.2008.233]

  48. Duerr RH et al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314: 1461–1463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Burton PR et al. (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39: 1329–1337

    Article  CAS  PubMed  Google Scholar 

  50. Nair RP et al.: Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat Genet (in press)

  51. Lee E et al. (2004) Increased expression of interleukin-23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 199: 125–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Szodoray P et al. (2007) Circulating cytokines in Norwegian patients with psoriatic arthritis determined by a multiplex cytokine array system. Rheumatology (Oxford) 46: 417–425

    Article  CAS  Google Scholar 

  53. McGeachy MJ and Cua DJ (2008) Th17 cell differentiation: the long and winding road. Immunity 28: 445–453

    Article  CAS  PubMed  Google Scholar 

  54. Awasthi A et al. (2008) Interplay between effector Th17 and regulatory T cells. J Clin Immunol 28: 660–670

    Article  CAS  PubMed  Google Scholar 

  55. Lowes MA et al. (2008) Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol 128: 1207–1211

    Article  CAS  PubMed  Google Scholar 

  56. Nograles K (2008) Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol 159: 1092–102

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Krueger JG and Bowcock A (2005) Psoriasis pathophysiology: current concepts of pathogenesis. Ann Rheum Dis 64 (Suppl 2): 30–36

    Google Scholar 

  58. Veale D et al. (1993) Reduced synovial membrane macrophage numbers, elam-1 expression, and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis. Arthritis Rheum 36: 893–900

    Article  CAS  PubMed  Google Scholar 

  59. Costello P et al. (1999) Predominance of CD8+ T lymphocytes in psoriatic arthritis. J Rheumatol 26: 1117–1124

    CAS  PubMed  Google Scholar 

  60. Colucci S et al. (2007) Lymphocytes and synovial fluid fibroblasts support osteoclastogenesis through RANKL, TNFalpha, and IL-7 in an in vitro model derived from human psoriatic arthritis. J Pathol 212: 47–55

    Article  CAS  PubMed  Google Scholar 

  61. Yago T et al. (2007) IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats. Arthritis Res Ther 9: R96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gottlieb A (2008) Phase 2 study of ustekinumab, a human IL-12/23 monoclonal antibody, in psoriatic arthritis: ACR criteria component score response through week 36 [abstract #1102]. Arthritis Rheum 58 (Suppl): S577

    Google Scholar 

  63. van Heel DA et al. (2007) A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 39: 827–829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Todd JA et al. (2007) Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 39: 857–864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhernakova A et al. (2007) Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases. Am J Hum Genet 81: 1284–1288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sawalha AH et al. (2008) Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus. Ann Rheum Dis 67: 458–461

    Article  CAS  PubMed  Google Scholar 

  67. Krueger JG et al. (2000) Successful in vivo blockade of CD25 (high-affinity interleukin 2 receptor) on T cells by administration of humanized anti-Tac antibody to patients with psoriasis. J Am Acad Dermatol 43: 448–458

    Article  CAS  PubMed  Google Scholar 

  68. Horwitz DA et al. (2003) The role of the combination of IL-2 and TGF-β or IL-10 in the generation and function of CD4+ CD25+ and CD8+ regulatory T cell subsets. J Leukoc Biol 74: 471–478

    Article  CAS  PubMed  Google Scholar 

  69. Parrish-Novak J et al. (2002) Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. J Leukoc Biol 72: 856–863

    CAS  PubMed  Google Scholar 

  70. Wei L et al. (2007) IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 282: 34605–34610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhou L et al. (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8: 967–974

    Article  CAS  PubMed  Google Scholar 

  72. Zhou L et al. (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORγt function. Nature 453: 236–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Koenen HJ et al. (2008) Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 112: 2340–2352

    Article  CAS  PubMed  Google Scholar 

  74. Zaiss MM et al. (2007) TREG cells suppress osteoclast formation: a new link between the immune system and bone. Arthritis Rheum 56: 4104–4112

    Article  CAS  PubMed  Google Scholar 

  75. Cookson W (2004) The immunogenetics of asthma and eczema: a new focus on the epithelium. Nat Rev Immunol 4: 978–988

    Article  CAS  PubMed  Google Scholar 

  76. Li Y et al. (2008) The 5q31 variants associated with psoriasis and Crohn's disease are distinct. Hum Mol Genet 17: 2978–2985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ho P et al. (2005) Evidence for common genetic control in pathways of inflammation for Crohn's disease and psoriatic arthritis. Arthritis Rheum 52: 3596–3602

    Article  CAS  PubMed  Google Scholar 

  78. Finnegan A et al. (1999) Proteoglycan (aggrecan)-induced arthritis in BALB/c mice is a Th1-type disease regulated by Th2 cytokines. J Immunol 163: 5383–5390

    CAS  PubMed  Google Scholar 

  79. Albanesi C et al. (2007) IL-4 and IL-13 negatively regulate TNF-alpha- and IFN-gamma-induced beta-defensin expression through STAT-6, suppressor of cytokine signaling (SOCS)-1, and SOCS-3. J Immunol 179: 984–992

    Article  CAS  PubMed  Google Scholar 

  80. Skapenko A et al. (2005) The IL-4 receptor alpha-chain-binding cytokines, IL-4 and IL-13, induce forkhead box P3-expressing CD25+CD4+ regulatory T cells from CD25CD4+ precursors. J Immunol 175: 6107–6116

    Article  CAS  PubMed  Google Scholar 

  81. Musone SL et al. (2008) Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet 40: 1062–1064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Thomson W et al. (2007) Rheumatoid arthritis association at 6q23. Nat Genet 39: 1431–1433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Plenge RM et al. (2007) Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 39: 1477–1482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Rahman P et al. (2006) Association between the interleukin-1 family gene cluster and psoriatic arthritis. Arthritis Rheum 54: 2321–2325

    Article  CAS  PubMed  Google Scholar 

  85. Athanasou NA et al. (1991) Use of monoclonal antibodies to recognise osteoclasts in routinely processed bone biopsy specimens. J Clin Pathol 44: 664–666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang F et al. (2006) Prominent production of IL-20 by CD68+/CD11c+ myeloid-derived cells in psoriasis: Gene regulation and cellular effects. J Invest Dermatol 126: 1590–1609

    Article  CAS  PubMed  Google Scholar 

  87. Nakae S et al. (2007) Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17. J Leukoc Biol 81: 1258–1268

    Article  CAS  PubMed  Google Scholar 

  88. Barrett JC et al. (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40: 955–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Martin MP et al. (2002) Cutting edge: susceptibility to psoriatic arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles. J Immunol 169: 2818–2822

    Article  CAS  PubMed  Google Scholar 

  90. International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437: 1299–1320

Download references

Acknowledgements

Supported in part by an NIH grant (AMB) and the Clinical Scholars Program at The Rockefeller University (KEN). We thank Drs James Krueger and Michelle Lowes for critical comments on the Review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anne M Bowcock.

Ethics declarations

Competing interests

RD Brasington has received research support from Abbott, Centocor and Wyeth, and speakers' honoraria from Abbott and Centocor for work in relation to therapeutics for rheumatoid arthritis. The other authors declared no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nograles, K., Brasington, R. & Bowcock, A. New insights into the pathogenesis and genetics of psoriatic arthritis. Nat Rev Rheumatol 5, 83–91 (2009). https://doi.org/10.1038/ncprheum0987

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncprheum0987

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing