Genetics and Pathogenesis of Psoriatic Arthritis

Genetics of PsA

Despite the long history of psoriatic arthritis (PsA), until recently, little had been known of its underlying genetics and pathogenesis. Without this knowledge, rational clinical management and drug development for this disease was limited.

PsA has a strong familial component; in Moll and Wright’s original series, the prevalence of PsA in first-degree relatives of probands was 5.5%. This actually corresponds to a much higher relative risk for PsA than for psoriasis. There are no published twin studies in PsA.

While these data suggest a high level of genetic influence on psoriasis and PsA, the correlations are not 100%. Additionally, no single gene has emerged to suggest a simple Mendelian inheritance pattern. Most now assume that the etiology of these diseases, like many others, is multifactoral, and that both complex genetics and environmental factors play a role in their pathogenesis.

The precise etiology of the joint disease in psoriasis, like the skin disease, remains uncertain, but, as noted, it is likely to be multifactoral. Genetic factors play a role, with a familial predisposition to PsA first noted in the studies of Moll and Wright. More recent data have shown that as many as 40% of patients with PsA have a first-degree relative with psoriasis or PsA, confirming the decision to include family history in the Classification of Psoriatic Arthritis (CASPAR) criteria. A number of different HLA loci have been associated with both the development of PsA and its progression. Interestingly, the genetic associations seen in psoriatic joint disease are not the same as those in skin disease.

As in psoriasis, genes within the MHC 1 region have been reported to be associated with PsA, although the magnitude of this association is not as strong. Another group of genes, known as the MHC class 1 related genes (MICA) have been implicated as candidate genes in PsA, as certain MICA alleles appear to be more specific for PsA than psoriasis. The TNF-alpha gene is located near the Class 1 HLA-B region, and TNF promoter polymorphisms have also been proposed to be important in PsA susceptibility. Figure 1-1 is a schematic illustration showing the location of a number of genes near the MHC I region that have been associated with psoriasis or PsA. The link between MHC Class II genes and PsA is not as strong. HLA-DR4 alleles, clearly linked to rheumatoid arthritis (RA), have been suggested in some studies to be linked to PsA, although this has not been widely replicated.

One of the important clinical elements of PsA is the distinction between peripheral and axial arthritis, and this distinction is reflected, to some extent, in genetic data. While the HLA-B27 locus has been associated with axial involvement, as in other axial spondyloarthropathies, other loci (HLA-B38, HLA-B39) have been reported to be associated with peripheral disease. The possibility that certain genetic factors may be associated with, or protective of, disease progression in PsA has been suggested, but there is, as yet, no consensus on which specific genes predict a worse prognosis.

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Pathogenesis of PsA

In contradistinction to the skin, there has been abundant experience in other inflammatory arthritides, such as rheumatoid arthritis (RA), to support the role of immune-mediated processes in the pathogenesis of psoriatic arthritis (PsA). Evidence implicates both innate and acquired immunity in the development of PsA. The common development of skin disease prior to the appearance of arthritis might suggest that pathogenic mechanisms originate in skin and then migrate to the synovium, although the evidence for this process has been limited. There is evidence for a limited T-cell receptor repertoire in both skin and joints, suggesting the possibility of an antigen-driven response, possibly due to the same antigen(s) in both locations.

While the clinical appearance of involved joints in PsA may appear similar to those in RA, there are characteristic features of the disease that have been felt to be more closely related to other spondyloarthropathies than to RA. This was demonstrated in a synovial biopsy study that found that biopsies from joints in ankylosing spondylitis (AS), PsA and undifferentiated spondyloarthopathy had greater numbers of neutrophils and CD163+ macrophages, along with fewer CD83+ dendritic cells than those from RA joints, while the RA biopsies had increased synovial lining layer hyperplasia and less vascularity than the biopsies from the spondyloarthropathy group. While, as noted above, there is evidence that both psoriasis and PsA are T cell-driven diseases, synovial T cell infiltration has been reported to be less pronounced in PsA than in RA.

Other authors, however, have suggested that there may be more similarities between the pathology in RA and PsA than there are differences. Synovial tissue from both RA and PsA expresses high levels of pro-inflammatory cytokines, including TNF-alpha and IL-6, supporting the cytokine-targeting approach that has proven to be so effective in both diseases. The IL-17 pathway appears to be active in psoriatic joints as well as in skin, as ustekinumab, secukinumab and ixekizumab, which downregulate this pathway, have been demonstrated to have activity in PsA.

One of the key pathologic distinctions between psoriatic skin and joint disease is the bone and cartilage destruction that occurs in the joints. There are abundant osteoclasts at the pannus–bone junction in PsA, with evidence that osteoclastogenesis is driven by increased expression of receptor activator of NF-kB ligand (RANKL) and decreased production of osteoprotegerin in this tissue. Cartilage degradation is likely mediated by matrix metalloproteinases that have been demonstrated in synovial and subsynovial tissue in PsA. Osteitis adjacent to involved joints is a commonly observed feature on imaging in PsA and other spondyloarthropathies, although little is known about the precise histopathology in these lesions.

Enthesitis is another unique clinical feature seen in PsA and other spondyloarthropathies. Again, little is known about the mechanisms of this manifestation, although some authors have hypothesized that the predilection for lower extremity involvement may indicate an etiologic role for tissue microtrauma. Local trauma has also been reported to foster the development of psoriatic synovitis.

Finally, the role of other environmental influences, such as infections, on the development of PsA, continues to be the subject of speculation. While a direct connection, such as that between streptococcal infection and guttate psoriasis, has not been observed, the partially restricted T-cell receptor repertoire observed in psoriatic synovial tissue has been suggested as evidence for an antigenic, possibly infectious, trigger. There has also been an interesting observation that patients infected with HIV can develop a particularly severe form of psoriasis and PsA. Psoriatic disease has been noted to worsen with progressive loss of CD4+ T cells and may improve with HIV therapy that restores circulating CD4 cell counts.