Elsevier

The Lancet

Volume 391, Issue 10136, 2–8 June 2018, Pages 2273-2284
The Lancet

Series
The pathogenesis of psoriatic arthritis

https://doi.org/10.1016/S0140-6736(18)30830-4Get rights and content

Summary

Psoriatic arthritis is a chronic, immune-mediated, inflammatory arthropathy that presents with inflammation of the joints and entheses, including those of the axial skeleton, and is associated with increased mortality from cardiovascular disease. Diagnosis is primarily based on clinical phenotype because of the diversity of the associated features, which can include skin and nail disease, dactylitis, uveitis, and osteitis. Improved understanding of the pathogenesis of psoriatic arthritis has led to the development of effective biologics and small-molecular drugs targeting specific cytokines and signalling pathways, which can prevent disease progression and improve quality of life. However, at least 40% of patients with psoriatic arthritis have only a partial response or fail to respond to such treatments. Cytokine inhibitors, mainly those specific for tumour necrosis factor and, more recently, the interleukin 23–T-helper-17 cell pathway, have been highly successful in the treatment of disease manifestations in several different tissues, although targeting the interleukin 23–T-helper-17 cell pathway might be more effective in psoriasis than in arthritis. However, the precise mechanisms underlying the pathogenesis of psoriatic arthritis—which include genetics, environmental factors, and immune-mediated inflammation—are complex, and the relationship between disease of the joint and that of other domains is poorly understood. Improving our understanding of psoriatic arthritis pathogenesis could help to establish validated biomarkers for diagnosis, predict therapeutic response and remission, develop precision medicines, and predict which patients will respond to which therapy. We discuss advances in pathogenetic translational research that could inform these issues.

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

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.

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