Abstract
This review focuses on the genetic features of psoriatic arthritis (PsA) and their relationship to phenotypic heterogeneity in the disease, and addresses three questions: what do the recent studies on human leukocyte antigen (HLA) tell us about the genetic relationship between cutaneous psoriasis (PsO) and PsA – that is, is PsO a unitary phenotype; is PsA a genetically heterogeneous or homogeneous entity; and do the genetic factors implicated in determining susceptibility to PsA predict clinical phenotype? We first discuss the results from comparing the HLA typing of two PsO cohorts: one cohort providing the dermatologic perspective, consisting of patients with PsO without evidence of arthritic disease; and the second cohort providing the rheumatologic perspective, consisting of patients with PsA. We show that these two cohorts differ considerably in their predominant HLA alleles, indicating the heterogeneity of the overall PsO phenotype. Moreover, the genotype of patients in the PsA cohort was shown to be heterogeneous with significant elevations in the frequency of haplotypes containing HLA-B*08, HLA-C*06:02, HLA-B*27, HLA-B*38 and HLA-B*39. Because different genetic susceptibility genes imply different disease mechanisms, and possibly different clinical courses and therapeutic responses, we then review the evidence for a phenotypic difference among patients with PsA who have inherited different HLA alleles. We provide evidence that different alleles and, more importantly, different haplotypes implicated in determining PsA susceptibility are associated with different phenotypic characteristics that appear to be subphenotypes. The implication of these findings for the overall pathophysiologic mechanisms involved in PsA is discussed with specific reference to their bearing on the discussion of whether PsA is conceptualised as an autoimmune process or one that is based on entheseal responses.
Highlights
Introduction and concepts of pathogenesisPsoriatic arthritis (PsA) is a heterogeneous disease with diverse clinical and radiographic manifestations
Background findings Because the highly polymorphic major histocompatibility complex (MHC) genes have an important role in regulating immune responsiveness and because PsA was considered an immune-mediated disease, MHC genes were the first candidates to be examined for a role in determining susceptibility to the development of PsA, and this review focuses on the contribution of human leukocyte antigen (HLA) alleles
Propensity to develop severe psoriatic arthritis As an alternative approach to studying genotype–phenotype associations, we constructed a continuous variable severity score to order the cohort based on the presence of one or more of eight distinctive PsA phenotypic characteristics that we considered would denote a more severely involved patient, including enthesitis, symmetric or asymmetric sacroiliitis, dactylitis, joint deformity, joint erosion, joint fusion or osteolysis [2]
Summary
Data presented as mean ± standard deviation or n (%). DMARD, disease-modifying antirheumatic drug; PASI, Psoriasis Area Severity Index; PsA, psoriatic arthritis; TNFi, tumour necrosis factor inhibitor. aVariables used to construct the propensity score. T cells, which present antigen to molecules encoded by HLA class 1 alleles, were shown to predominate in PsA synovial fluid with a reversal of the CD4:CD8 ratio found in rheumatoid arthritis (RA) [6]. A more recent study demonstrated that PsA patients had upregulated IL-15 and MHC class I chain-related A (MICA) in their affected synovial tissues [11]. This unique inflammatory environment enabled natural killer cell activation and killing via NKG2D and cytosolic phospholipase cPLA2, suggesting a destructive role for natural killer cells when activated by environmental stress signals during the initiation of PsA. Increased susceptibility HLA-C*06:02:01 HLA-B*27:05:02 HLA-B*08:01 HLA-B*38:01 HLA-B*39:01
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