The Risk of Systemic Diseases in Those with Psoriasis and Psoriatic Arthritis: From Mechanisms to Clinic

Abstract

Psoriasis and psoriatic arthritis (PsA) have been recently considered as chronic systemic inflammatory disorders. Over the past decades, enormous evidence indicates that patients with psoriasis and PsA have a higher risk of developing various comorbidities including cardiovascular disease, metabolic disease, cancers, infections, autoimmune disease, and psychiatric diseases. However, reported risks of some comorbidities in those with psoriasis and PsA are somewhat different according to the research design. Moreover, pathomechanisms underlying comorbidities of those with psoriasis and PsA remain poorly elucidated. The purpose of this review is to provide the most updated comprehensive view of the risk of systemic comorbidities in those with psoriasis and PsA. Molecular mechanisms associated with the development of various comorbidities in those with psoriasis and PsA are also reviewed based on recent laboratory and clinical investigations. Identifying the risk of systemic comorbidities and its associated pathomechanisms in those with psoriasis and PsA could provide a sufficient basis to use a multi-disciplinary approach for treating patients with psoriasis and PsA.

Keywords: autoimmune disease; cancer; cardiovascular disease; comorbidity; infection; metabolic syndrome; psoriasis; psoriatic arthritis; sleep disorder.

Figure 1

Psoriasis, psoriatic arthritis, and atherosclerosis have the common underlying pathomechanisms. In psoriatic plaque (left) and synovial cavity with psoriatic arthritis (right), myeloid dendritic cells (DC) stimulate naïve T-cells to differentiate into type 1 helper T (Th1) and type 17 helper T (Th17) cell subtypes. Th1 cells secrete tumor necrosis factor-α (TNF-α) and interferon gamma (IFN-γ), leading to keratinocyte and synovial fibroblast activation. Th17 cells secrete IL-17 and IL-22, which promote proliferation of keratinocytes and synovial fibroblasts and angiogenesis. Macrophages cooperates with Th1- and Th17-mediated inflammation by releasing monocyte chemoattractant protein (MCP-1), nitric oxide (NO), and vascular endothelial growth factor (VEGF), which further contribute to angiogenesis. Neutrophil-derived S100A8/A9 and IL-8 accelerates vascular inflammation. In atherosclerotic plaque (bottom), Th1 cells secrete TNF-α and IFN-γ, leading to endothelial activation and promote atherosclerosis. Leptin and resistin produced in adipose tissue enters into systemic circulation and promotes endothelial dysfunction, insulin resistance, and formation of atherosclerotic plaque. Recruitment of neutrophils on the plaque release neutrophil extracellular traps (NETs), which subsequently induces endothelial dysfunction and rupture of plaque. Macrophage-released MCP-1 synergistically promotes the formation of atherosclerotic plaque along with other pro-atherogenic cytokines in patients with psoriasis and psoriatic arthritis.

Figure 2

IL-6 and TNF-α-mediated inflammation: a possible link between psoriasis and accompanying psychiatric disorders. In psoriatic plaque (left), naïve T-cells to differentiate into type 17 helper T (Th17) cells under IL-6 and TNF-α-prone microenvironment. IL-6 and TNF-α stimulates Th17 cells proliferation and potentiates IL-17 mediated inflammation in psoriatic lesions. In systemic circulation (middle), elevated serum levels of IL-6, and TNF-α are commonly observed in psychiatric disorders such major depressive disorders. IL-6, and TNF-α are increased in the brain tissue (right) of patients who attempted suicide. The increased levels of serum IL-6, TNF-α, retinoic acid receptor-related orphan receptor gamma t (ROγt) and IL-17 are observed in patients with major depressive disorders, and these molecules appear to contribute to the development of both psoriasis and psychiatric comorbidities by passing through blood-brain barrier and influencing each other.