Psoriatic Arthritis: Pathogenesis and Targeted Therapies

Abstract

Psoriatic arthritis (PsA), a heterogeneous chronic inflammatory immune-mediated disease characterized by musculoskeletal inflammation (arthritis, enthesitis, spondylitis, and dactylitis), generally occurs in patients with psoriasis. PsA is also associated with uveitis and inflammatory bowel disease (Crohn’s disease and ulcerative colitis). To capture these manifestations as well as the associated comorbidities, and to recognize their underlining common pathogenesis, the name of psoriatic disease was coined. The pathogenesis of PsA is complex and multifaceted, with an interplay of genetic predisposition, triggering environmental factors, and activation of the innate and adaptive immune system, although autoinflammation has also been implicated. Research has identified several immune-inflammatory pathways defined by cytokines (IL-23/IL-17, TNF), leading to the development of efficacious therapeutic targets. However, heterogeneous responses to these drugs occur in different patients and in the different tissues involved, resulting in a challenge to the global management of the disease. Therefore, more translational research is necessary in order to identify new targets and improve current disease outcomes. Hopefully, this may become a reality through the integration of different omics technologies that allow better understanding of the relevant cellular and molecular players of the different tissues and manifestations of the disease. In this narrative review, we aim to provide an updated overview of the pathophysiology, including the latest findings from multiomics studies, and to describe current targeted therapies.

Genetic and Epigenetic Mechanisms of Psoriasis

“…Moreover, the HLA-B*08.01 allele has been linked to asymmetric sacroiliitis, peripheral arthritis, ankylosis and increased join damage, and HLA-B*27 with symmetric sacroiliitis, dactylitis, and enthesitis [60]. On the other hand, polymorphisms in IL23R, TNFAIP3, PTPN22 (tyrosine-protein phosphatase non-receptor type 22), IL12B, RUNX1 (CD8-lymphocyte activation and differentiation), IL13, KIR (killer-cell immunoglobulin-like receptor), and MAGI1 genes have shown association with psoriatic arthritis [10,58]. Also, variants in the ADAMTS9 gene, involved in the cartilage extracellular matrix, are found to be associated with psoriatic arthritis [58].…”

Inflammatory Cytokines in Psoriatic Arthritis: Understanding Pathogenesis and Implications for Treatment

“…Ustekinumab effectively inhibits the differentiation of Th1 and Th17 cells. Phase 3 clinical trials (PSUMMIT trials 1 and 2) showed that this drug effectively treats skin manifestations, peripheral arthritis, enthesitis, and dactylitis in both TNFi-experienced and TNFi-naïve patients with PsA [15]. The use of ustekinumab resulted in a higher rate of achieving the primary outcome, defined as an ACR20 response at week 24, compared to the placebo group [97].…”

“…Neither of the IL-23 inhibitors has met the primary endpoint to be a considered as a treatment option for axSpA [15]. However, a post hoc analysis indicated potential efficacy of guselkumab in treating axial involvement in PsA [111].…”

“…Apremilast, an orally administered small molecule that functions as a PDE4 inhibitor, obtained FDA approval in 2014 for the management of PsA. Inhibition of PDE4 elevates intracellular cyclic AMP levels, which subsequently reduces the synthesis of pro-inflammatory cytokines and enhances the production of anti-inflammatory cytokines such as IL-10 [15]. The efficacy of apremilast in PsA has been shown in the PALACE trials [62,[126][127][128].…”

The Effect of JAK Inhibitors on Patient-Reported Outcomes in Psoriatic Arthritis

“…The aetiology and pathophysiology of PsA are not fully understood, but they are thought to involve a complex interplay of genetic and environmental factors that trigger an abnormal immune and inflammatory response. 5 Several genes have been associated with PsA susceptibility and severity, such as HLA-B27, IL23R. 6 Environmental factors that may influence PsA development and progression include infections, trauma, stress, smoking, and alcohol consumption.…”