We searched PubMed using the terms “psoriatic”, “arthritis”, “pathogenesis”, “genetics”, and “inflammatory synovitis”. The search included all articles published in the English language until March 16, 2018. We prioritised original articles specific to psoriatic arthritis.
SeriesThe pathogenesis of psoriatic arthritis
Introduction
Psoriatic arthritis is a common inflammatory disease of the peripheral and axial skeleton. Psoriatic disease in general remains poorly defined because of its varied clinical features, which include enthesitis, dactylitis, nail dystrophy, uveitis, and osteitis, in addition to associated comorbidities such as obesity, metabolic syndrome, and cardiovascular disease. Many studies of psoriatic arthritis have focused on the skin and joints; however, in the past 10 years, important advances have concentrated on the entheses—although in which tissue the disease begins probably varies between individuals. The importance of associated comorbidities and their effects on mortality has also been recognised.1 In this Series paper, we focus on gene–environment interactions, immune-mediated mechanisms in the synovial tissue and entheses, and how these factors could form the basis of new treatment strategies.
Synovial membrane inflammation, characterised by increased vascularisation and immune cell infiltration, is a key feature of psoriatic arthritis.2, 3, 4 The infiltrating immune cells release proinflammatory mediators that activate fibroblast-like synoviocytes, which then invade adjacent cartilage and bone. Activation of monocytic progenitor cells to form osteoclasts further mediates bone resorption, resulting in joint deformity and loss of function.5 Synovial inflammation and bone erosion are important features with respect to diagnosis and treatment, as radiographic changes occur within 2 years of disease onset in up to 47% of patients.6
Enthesitis—inflammation of the connective tissue between tendon or ligament and bone—is a common feature of psoriatic arthritis. MRI studies suggest that enthesitis, evidenced by bone marrow or soft tissue inflammation, precedes clinical joint involvement, although this notion remains controversial.7 The pathology of an entheseal lesion, in which mechanical stress is hypothesised to be a trigger, can differ from that of the skin and the synovial joint.8 Dactylitis—inflammation of an entire digit—is also common and is a useful diagnostic feature.9 Ultrasound scanning suggests that dactylitis is indicative of both joint synovitis and tenosynovitis, whereas MRI studies suggest that it represents enthesitis.9, 10 Arthritis of the distal interphalangeal joint is associated with inflammation of the nail bed, which might also represent enthesitis, as the nail bed and interphalangeal joint share common tendinous insertions.11
Section snippets
Genetic and environmental factors
Psoriatic arthritis is characterised by complex genotypes, a detailed account of which is beyond the scope of this Series paper. In brief, genome-wide association studies and studies of heritability and HLA alleles have provided substantial evidence that psoriatic arthritis has a genetic component that is stronger than and distinct from that of psoriasis.12 Twin and family studies of psoriatic arthritis in European populations have reported greater concordance in monozygotic twins (80–100%)
Synovial pathology and cellular infiltrates
Synovial angiogenesis—the formation of new blood vessels—facilitates leucocyte migration from the peripheral blood, which results in persistent infiltration of immune cells into the inflamed joint. In psoriatic arthritis, activated immune cells release cytokines that drive inflammation (table 2). Fibroblast-like synoviocytes show an abnormal phenotype characterised by increased proliferation and invasiveness, transforming the synovial membrane into a tumour-like pannus capable of destroying
Angiogenesis
Espinoza and colleagues were the first to identify vascular changes—characterised by endothelial cell swelling and inflammatory cell infiltration—in the psoriatic synovium.34 Notably, there are increased blood vessels in the synovial lining layer in psoriatic arthritis, in contrast to the thickened, avascular synovial lining seen in rheumatoid arthritis.35 The most striking difference in psoriatic arthritis is the macroscopic vascular pattern, characterised by elongated, tortuous, dilated
Dendritic cells
Dendritic cells activate the adaptive immune response through antigen presentation and cytokine secretion to generate distinct subsets of T cells.59 The ratio of myeloid dendritic cells to plasmacytoid dendritic cells is significantly increased in the synovial fluid in psoriatic arthritis, indicating a predominance of an immature phenotype among these dendritic cells, which remain responsive to Toll-like receptor ligands.60, 61 This immature phenotype might further perpetuate disease by
Adaptive immune cells: T cells and B cells
Lymphocytes are the most frequent immune infiltrates in psoriatic arthritis. Lymphoid aggregates of T cells and B cells have been found in the psoriatic arthritis synovium, and the absence of these aggregates is associated with disease remission.86 Larger aggregates are suggested to be associated with increased disease activity.87 The role of B cells in the pathogenesis of psoriatic arthritis is unclear; they might be involved in antigen presentation, co-stimulation of T cells, or synthesis of
Synovial fibroblasts
The lining layer of the synovium consists of resident macrophages and fibroblast-like synoviocytes, which are fundamental to disease progression and actively drive joint destruction.119 Fibroblast-like synoviocytes are characterised by increased proliferation, resistance to apoptosis, anchorage independence, increased invasiveness, and the production of proinflammatory cytokines and matrix-degrading enzymes.119, 120, 121, 122, 123 Furthermore, cadherin 11, a key protein involved the
Structural changes: cartilage, bone, and entheses
The inflammatory synovium primarily causes damage to the cartilage and bone as a result of synovial tissue invasion and release of powerful matrix-degrading enzymes (figure 2). The production of matrix metalloproteinases and other enzymes by fibroblast-like synoviocytes results in the breakdown of collagen, proteoglycans, and gelatins, which facilitates the invasion of fibroblast-like synoviocytes and endothelial cells.42 Fibrillation of the cartilage surface develops, and chondrocytes undergo
Conclusion
Psoriatic arthritis is a complex manifestation of a disease characterised by diverse clinical phenotypes involving the joints, skin, nails, entheses, and other tissues. The genetic factors associated with arthritis and with skin disease have become more clearly defined, and appear to be quite distinct from one another. The evidence for gene–environment interactions in the pathogenesis of the disease has identified possible modifiable risk factors, including smoking, trauma, and infection.
Search strategy and selection criteria
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