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.

Keywords: JAK inhibitors; biological therapy; cytokines; immune cells; multiomics; pathogenesis; psoriatic arthritis; single-cell RNA sequencing; synovial fibroblasts; tissue heterogeneity.

Figure 1

Pathological processes in psoriatic disease (PsD). Predisposing genetic background, infections, obesity, or biomechanical factors act as triggers and precipitate disease onset by activating DC macrophages which present antigens through type major histocompatibility complex (MHC) I to T cells (mainly CD8), through Toll-like receptor (TLR) type 2. This favors the local release of cytokines by triggering the innate and adaptive immune response. IL-12 and IFNα stimulate the Th1 response, which releases TNFα and IFN-γ. IL-23, TGFß, IL-6, and IL-1b activate the Th17 response in the presence of IL23, leading to the release of IL17 (mainly A isoform), IL22, IL26, and CCL20. Moreover, regulating and deactivating the inflammatory cascade requires the response mediated by Treg cells through IL-2 and TGFß. These released cytokines interact with their transmembrane receptors, promoting the release of more cytokines and attracting endothelial cells, macrophages, fibroblasts, keratinocytes, dendritic cells, epithelial cells, chondrocytes, osteoclasts, and osteoblasts. Activation of the immune system leads to synovitis, enthesitis, erosions, and lesions in the articular cartilage and skin. DAMPS (Damage-associated molecular pattern), PAMPs (Pathogen-associated molecular patterns), DC (dendritic cells), MΦ (Macrophages), CD8 (CD8 T lymphocyte), CD4 (CD4 T lymphocyte), Th1 (T helper 1 cells), Th17 (T helper 17 cells), Treg (T regulatory), FLS (synovial fibroblast).

Figure 2

Targeted therapies. Mechanism of action of the latest approved or in-development molecules for the treatment of PsA. Interleukin 17 (IL-17) and isoforms IL-17A/F/E and IL17 receptor (IL-17R); janus kinase 1, 2, 3 (JAK1, JAK2, JAK3) and tyrosine kinase 2 (TYK2).

Figure 3

Multiomics technologies. The use of omic methods can be applied in DNA, RNA, proteins, lipids, and metabolites, among others, allowing expansion of knowledge of immune-mediated diseases to approach personalized medicine. NGS: next generation sequencing; SNP: single nucleotide polymorphisms; CNV: cellular number variations; GWAS: DNA copy number analysis; genome-wide association; scRNA-Seq: single-cell RNA Sequencing; IMC: imaging mass cytometry; qRT-PCR: quantitative reverse transcription PCR; ChIP: chromatin immunoprecipitation ; ncRNAs: histone modification and non-coding RNAs; RT-PCR: reverse transcription polymerase chain; CyTOF: single-cell with mass cytometry; MALDI-MSI: matrix-assisted laser desorption ionization mass spectrometry imaging.