title: Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype.
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.
authors.affiliation: Department of Rheumatology, St Vincent's University Hospital, Elm Park, Dublin, 4, Ireland. oliver.fitzgerald@ucd.ie.
authors.forename: Oliver
authors.initials: O
authors.lastname: FitzGerald
authors.affiliation: Department of Rheumatology, St Vincent's University Hospital, Elm Park, Dublin, 4, Ireland. mharoon301@hotmail.com.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Haroon
authors.affiliation: Rheumatology Division, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York City, NY, 10032, USA. jtg2122@columbia.edu.
authors.forename: Jon T
authors.initials: JT
authors.lastname: Giles
authors.affiliation: Rheumatology Division, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York City, NY, 10032, USA. rjw8@columbia.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Winchester
mesh_terms: D000328:Adult; D000483:Alleles; D015535:Arthritis, Psoriatic / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D012720:Severity of Illness Index
chemical_list: D006680:HLA Antigens