A number sign (#) is used with this entry because of evidence that susceptibility to psoriatic arthritis is determined by multiple genes as demonstrated by the strong association between psoriasis/psoriatic arthritis and HLA-Cw*0602 (see HLA-C, 142840) on chromosome 6p21 and between psoriatic arthritis and sequence variants of the TNFA (191160) and LTA (153440) genes.

Psoriasis (177900) is a chronic inflammatory skin disease that may have an autoimmune basis. The disorder has a strong but complex genetic basis, with a concordance rate of 50 to 70% among monozygotic twins. Psoriatic arthritis affects more than 10% of patients with psoriasis and, in most cases, there is an association between the severity of the arthritis and the skin involvement (Gudjonsson et al., 2002).

Psoriatic arthritis is somewhat more common in HLA-Cw6-negative patients than in Cw6-positive ones (Gudjonsson et al., 2002). The association of psoriatic arthritis with HLA-Cw*0602 is less profound than the association of psoriasis and HLA-Cw*0602 and is most evident in patients with psoriatic arthritis with early onset of arthritis (Enerback et al., 1997; Gladman et al., 1999).

In Iceland, Karason et al. (2003) identified 178 patients with psoriatic arthritis out of 906 patients (about 20%) who were included in a genetic study of psoriasis. Using a comprehensive genealogy database, they were able to connect 100 of these into 39 families. They genotyped the patients using a framework marker set of 1,000 microsatellite markers, with an average density of 3 cM, and performed multipoint, affected-only, allele-sharing linkage analysis. On the basis of the initial results, they genotyped more markers for the most prominent loci. Linkage with a lod score of 2.17 was observed on 16q. The linkage analysis, conditioned on paternal transmission to affected individuals, gave a lod score of 4.19, whereas a lod score of only 1.03 was observed when conditioned for maternal transmission. The data indicated that a gene on 16q may be involved in paternal transmission of psoriatic arthritis.

In studies of psoriatic arthritis in Newfoundland, Rahman et al. (2003) found a strong association between 3 independent variants in the NOD2/CARD15 gene.

In blood samples from patients with psoriatic arthritis, Ritchlin et al. (2003) observed a marked increase in osteoclast precursors compared to those from healthy controls. Peripheral blood mononuclear cells from patients readily formed osteoclasts in vitro and spontaneously secreted higher levels of TNF-alpha than did those from healthy controls. In vivo, osteoclast precursor frequency declined substantially in patients following treatment with anti-TNF agents. Immunohistochemical analysis of subchondral bone and synovium revealed TNFRSF11A (603499)-positive perivascular mononuclear cells and osteoclasts in patient specimens. TNFSF11 (602642) expression was dramatically upregulated in the synovial lining layer, whereas TNFRSF11B (602643) immunostaining was restricted to the endothelium. Ritchlin et al. (2003) suggested a model for the pathogenesis of the aggressive bone erosions seen in psoriatic arthritis: osteoclast precursors arise from TNF-alpha-activated peripheral bone marrow cells that migrate to the inflamed synovium and subchondral bone, where they are exposed to unopposed TNFSF11 and TNF-alpha, resulting in osteoclastogenesis at the erosion front and in subchondral bone, which results in a bidirectional assault on psoriatic bone.

In a study of 147 patients with psoriatic arthritis and 389 controls, Balding et al. (2003) found that the TNF-alpha -308G-A (191160.0004) and TNF-beta +252A-G (153440.0002) polymorphisms were significantly associated with age at psoriasis onset and with the presence and progression of joint erosions in psoriatic arthritis. The authors suggested that TNF gene polymorphisms may be useful prognostic markers in psoriatic arthritis.

By SNP analysis, Giardina et al. (2006) excluded linkage to the PSORS2 locus (602723) on chromosome 17q25 in 245 Italian patients with psoriatic arthritis.

Huffmeier et al. (2009) analyzed 4 variants in the IL12B (161561) and IL23R (607562) genes in 748 patients with psoriatic arthritis, 1,114 patients with psoriasis, and 937 controls. Variations in both genes had previously been associated with psoriasis; see PSORS7 (605606) and PSORS11 (612599). In the study, the strongest associations in both disease groups were found with IL12B variants rs3212227 and rs6887695 (p values ranging between 2.10 x 10(-5) and 9.67 x 10(-7) with corresponding odds ratios of 1.43 to 1.50). The IL12B risk haplotype also showed an association in both groups (p value on the order of 10(-6)). The effect for rs11209026 in the IL23R gene was slightly weaker for psoriasis (p = 2.42 x 10(-6)) and psoriatic arthritis (p = 0.002). The findings confirmed previous studies that variants in the IL12B and IL23R genes are susceptibility factors for psoriasis, and extended the findings to psoriatic arthritis.