The Molecular Pathophysiology of Psoriatic Arthritis—The Complex Interplay Between Genetic Predisposition, Epigenetics Factors, and the Microbiome

Abstract

Psoriasis is a symmetric autoimmune/inflammatory disease that primarily affects the skin. In a significant proportion of cases, it is accompanied by arthritis that can affect any joint, the spine, and/or include enthesitis. Psoriasis and psoriatic arthritis are multifactor disorders characterized by aberrant immune responses in genetically susceptible individuals in the presence of additional (environmental) factors, including changes in microbiota and/or epigenetic marks. Epigenetic changes can be heritable or acquired (e.g., through changes in diet/microbiota or as a response to therapeutics) and, together with genetic factors, contribute to disease expression. In psoriasis, epigenetic alterations are mainly related to cell proliferation, cytokine signaling and microbial tolerance. Understanding the complex interplay between heritable and acquired pathomechanistic factors contributing to the development and maintenance of psoriasis is crucial for the identification and validation of diagnostic and predictive biomarkers, and the introduction of individualized effective and tolerable new treatments. This review summarizes the current understanding of immune activation, genetic, and environmental factors that contribute to the pathogenesis of psoriatic arthritis. Particular focus is on the interactions between these factors to propose a multifactorial disease model.

Real-World Experience of Patient-Relevant Benefits and Treatment Satisfaction with Apremilast in Patients with Psoriasis: An Analysis of the APPRECIATE Study

“…Plaque psoriasis is a long-term immune-mediated inflammatory condition that requires ongoing routine clinical care and treatment to address high disease burden, impaired daily functioning, and reduced health-related quality of life (HRQoL) [1][2][3][4]. In this complex disease, interactions between genetic and environmental factors contribute to inflammation and clinical symptoms [5,6]. Pruritus due to psoriasis can be intense and is a major determinant of quality of life impairment [7,8].…”

DNA Methylation Patterns in CD8+ T Cells Discern Psoriasis From Psoriatic Arthritis and Correlate With Cutaneous Disease Activity

“…Measuring disease activity is a challenge in systemic autoimmune/inflammatory disease, including psoriasis ( Ballestar et al, 2020 ; Calle-Fabregat et al, 2020 ; Carvalho and Hedrich, 2021 ). Clinical scores, including PASI, are available but limited by their time-consuming and inter observer variability, especial in less experienced/specialized institutions ( Fink et al, 2018 ).…”

“…Multiple factors have been discussed, including genetic susceptibility, environmental triggers in combination with skin barrier disruption, and general immune dysfunction ( Ayala-Fontánez et al, 2016 ). Skin psoriasis and PsA are characterized by a pathological activation of the TNF/IL-23/IL-17 cytokine axis, contributing to an immunological imbalance favoring effector T cell differentiation and activation, as well as their accumulation in affected tissues ( Di Cesare et al, 2009 ; Hawkes et al, 2018 ; Carvalho and Hedrich, 2021 ). T cells play a pivotal role in disease pathogenesis at all stages, including breach of tolerance and the initiation of a pro-inflammatory phenotypes, the establishment of chronic inflammation, damage and amplification of self-reactivity, the maintenance of clinically established inflammatory tissue lesions, and “spreading” of inflammatory disease from initial sites (e.g., the skin) to secondary sites of inflammation (e.g., extra-cutaneous manifestations) ( Casciano et al, 2018 ).…”

“…It contributes to effector phenotypes and inflammatory cytokine expression in T cells from patients with various autoimmune/inflammatory conditions ( Brandt et al, 2018 ). In psoriasis, CD4 + , CD8 + as well as CD4 – CD8 – (double negative) T cells are involved in the molecular pathogenesis following their stimulation by (auto-)antigens ( Brandt et al, 2018 ; Carvalho and Hedrich, 2021 ).…”

Early Origins of Psoriatic Arthritis: Clinical, Genetic and Molecular Biomarkers of Progression From Psoriasis to Psoriatic Arthritis

“…The possible role of epigenetic factors which might identify Pso patients at risk of developing PsA has been nicely reviewed in 2 recent articles (18,19). There is early evidence for changes in methylation levels of some genes in patients with skin and joint disease and in patients with joint disease (20) with IL22 being proposed as a possible germ line risk factor for PsA.…”