Psoriasis is a common disease (affects ~ 2% whites); and up to 10% of these patients have associated inflammatory arthritis [psoriatic arthritis (PsA), including spondyloarthropathy (SpA)], which may, in up to 15% of patients, precede the onset or diagnosis of psoriasis. There are no internationally agreed criteria for the diagnosis of (PsA); it has been broadly defined by Moll and Wright as an “inflammatory arthritis associated with psoriasis, which is usually negative for rheumatoid factor”. More precise criteria and a large case-control study comparing patients with PsA with controls without arthritis (despite having had psoriasis for >10 years), properly matched for age, race, gender, geographical area, and for the subtypes of psoriasis/arthritis are needed. It would be advisable to have another control group with inflammatory arthritis without psoriasis.
The sibling recurrence risk (lamda s value) is estimated to be roughly 4 for psoriasis. Self-reported positive family histories for psoriasis among PsA patients have been observed in up to 40% and for PsA in 10%, but the familial aggregation does not follow a simple Mendelian trait. Psoriasis and PsA have not only clinical but also genetic heterogeneity, and multiple susceptibility alleles at different loci may produce the same phenotype, resulting in clinical misclassification of the disease type. There are, as yet unknown, genetic and environmental interactions, and also different combinations of susceptibility genes may predispose to different patterns of psoriasis and PsA (variable disease expression), and not everyone with such genes will develop the disease (variable penetrance). Psoriasis is associated with HLA allele Cw*0602, MICA allele 5.1, corneodesmosin allele 5 (CD*5), OTF3 beta, and HCR (pg8); they are all located on chromosome at the 6p21 region. Associations with chromosomes 17q25, 4q32–35 and 1q (S100A7) have also been reported. Similar studies of affected sib-pair families with PsA are also needed.
Activated T lymphocytes and dendritic cells mediate the disease, but the antigen (s) responsible are not known. Although CD4+ T cells may help initiate the skin lesions, CD8+ T cells that produce type 1 cytokines (IFN-gamma) are responsible for the persistence of the lesions. This may explain the paradox observed in HIV infected patients in whom psoriasis (and PsA/reactive arthritis) can worsen dramatically even as CD4+ T-cell counts fall. In PsA patients a predominantly TH1 cytokine response is observed (increased IL2, TNF-beta, and IFN-gamma), but there is also an increased IL-10 response. It has recently been proposed, based on MRI studies, that PsA is enthesis based disease, and that it is distinct from RA, where synovitis is the primary pathological feature. Local treatment of psoriasis with psoralens plus ultraviolet A radiation (PUVA) often results in long-standing remissions by greatly reducing the number of activated T cells in psoriatic skin due to induction of T-cell apoptosis. Methotrexate, and DAB389-interleukin-2 preferentially induce apoptosis of activated T cells in skin and other sites. On the other hand, cyclosporine A and topical corticosteroids only inhibits the production of cytokines; and psoriasis often recurs soon after the cessation of this treatment. Likewise, TNF-alpha blockade therapy has been found to be very effective in treating patients with severe psoriasis and PsA (including SpA), but the benefit is relatively short-lived after the therapy is discontinued. Administration of CTLA4Ig fusion protein (that blockades the B7-CD28/CD152 pathway of T cell costimulation) has produced a marked improvement of psoriasis in a phase I trial.
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