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Pathophysiology


Pathophysiology of psoriatic arthritis


Phenotypic diversity makes it difficult to study the pathophysiology of PsA but, despite this, key advances in recent years have paved the way for new therapeutic targets and targeted therapies for this chronic inflammatory disease


Juan D Cañete MD PhD Arthritis Unit, Rheumatology Department Hospital Clínic, Barcelona, Spain


Psoriatic arthritis (PsA) is a clinically heterogeneous inflammatory musculoskeletal disease associated with skin psoriasis (PsO), with various clinical patterns involving all, or a combination, of the peripheral joints, axial skeleton, enthesis, tendons, eyes or gut. Skin manifestations precede PsA in approximately 80% of patients, but in 10–15%, PsA presents before psoriasis or they occur almost simultaneously. Clinical patterns usually change during the disease evolution, and bone erosion and neoformation coincide in the same patient. This phenotypic diversity makes it difficult to study the pathophysiology of PsA. Nevertheless, key advances in recent years have paved the way for new therapeutic targets. Here, we review the pathophysiology of PsA and its relationship with PsO, taking into account fresh insights derived from the effects of new targeted therapies.


Genetic clues 12


PsA is a chronic immune-mediated inflammatory disease, the result of a strong genetic component interacting with environmental agents. Genetic and genomic studies have confirmed the close association between class I human leukocyte antigen (HLA) and PsA. HLA-Cw*062 is the main genetic determinant of susceptibility to PsO and PsA and is closely associated with the


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One study found that different HLA susceptibility genes were associated with particular clinical features that defined the PsA phenotype of a given patient. Additive interactions between HLA alleles with differing susceptibility have defined the propensity for a more severe or milder musculoskeletal phenotype.2


Genome-wide association


studies have identified several susceptibility genes related to various pathogenic pathways relevant to PsO and PsA: nuclear factor kB (NFkB) pathway (REL, TRAF3IP2, TNIP1), genes to IL-17/ IL-23 pathway (IL-23R, TRAF3IP2), CD8+ T cells (RUNX3, HLA-C) and Th1 (IL12B) responses.3


With the exception of


HLA-B alleles, there is no clear difference between susceptibility genes for PsA and PsO. However, a recent study with whole blood gene expression profiling suggests that innate immunity may be important in the pathogenesis of PsA, via toll-like receptors (TLR) signalling and NFkB,4 consistent with evidence implicating environmental triggers of the innate immune system, such as infections or tissue damage in the development of PsA in PsO patients


Lessons learned from synovial immunopathology


Synovial tissue (ST), one of the most important targets of PsA, is easy and safe


phenotype of more severe skin involvement in late occurring PsA. HLA-B alleles, specifically HLA-B*27, B*38, B*39 and B*08, are associated with the predominant musculoskeletal phenotype that is related in time with psoriasis onset.1


to obtain, in contrast with other tissues involved in spondylitis, enthesitis and dactylitis. Although cellular infiltrate in PsA is similar to that in rheumatoid arthritis (RA), that is, sharing the presence of follicular aggregates (organisation of T and B cells as germinal centres), plasma cells, CD68+ macrophages and synovial fibroblasts, the two types of synovitis have structural and


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