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Review
. 2009 Feb;5(2):83-91.
doi: 10.1038/ncprheum0987.

New insights into the pathogenesis and genetics of psoriatic arthritis

Kristine E Nograles  1 , Richard D Brasington, Anne M Bowcock
Affiliations
Review

New insights into the pathogenesis and genetics of psoriatic arthritis

Kristine E Nograles et al. Nat Clin Pract Rheumatol. 2009 Feb.

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.

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Figures

Figure 1
Figure 1. Model of the relationship between skin and joint inflammation
Genes with variants (box) contributing to psoriasis and/or psoriatic arthritis susceptibility. While infiltrating leukocytes and their cytokine products are currently better characterized in the skin than in the inflamed joint, they may be similar in both sites. Leukocytes and cytokines originating in the skin may play a direct or indirect role in the development of arthritis. Alternatively, they may originate in the synovium in a similar manner to their development in the skin. Gene variants (blue boxes) that predispose to psoriasis influence pro-inflammatory pathways, notably the Th1 and Th17 pathways. Model of cytokine networks in psoriasis adapted from Lowes, MA et al, 2007. The role of the 5q31 region harboring IL4/IL13 is speculative at this stage. HBD (beta defensin) is upregulated in keratinocytes as a result of stimulation by IL20 and other cytokines. An increase in the number of copies of gene family members is also associated with psoriasis.
Figure 1
Figure 1. Model of the relationship between skin and joint inflammation
Genes with variants (box) contributing to psoriasis and/or psoriatic arthritis susceptibility. While infiltrating leukocytes and their cytokine products are currently better characterized in the skin than in the inflamed joint, they may be similar in both sites. Leukocytes and cytokines originating in the skin may play a direct or indirect role in the development of arthritis. Alternatively, they may originate in the synovium in a similar manner to their development in the skin. Gene variants (blue boxes) that predispose to psoriasis influence pro-inflammatory pathways, notably the Th1 and Th17 pathways. Model of cytokine networks in psoriasis adapted from Lowes, MA et al, 2007. The role of the 5q31 region harboring IL4/IL13 is speculative at this stage. HBD (beta defensin) is upregulated in keratinocytes as a result of stimulation by IL20 and other cytokines. An increase in the number of copies of gene family members is also associated with psoriasis.
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