The Th17 axis in psoriatic disease: pathogenetic and therapeutic implications

Abstract

Psoriasis and psoriatic arthritis represent two paradigmatic conditions characterized by chronic inflammation and possibly autoimmunity, despite the absence of known serum autoantibodies. The two diseases, albeit strongly correlated from clinical, genetic, and epidemiogical standpoints, manifest significant differences in terms of etiology and pathogenetic mechanisms. Nonetheless, Th17 cells appear crucial to both diseases, and IL23 is the cytokine involved in determining the fate of naive CD4+ cells to differentiate into a pathogenic phenotype. This basic experimental observation led to a clear understanding of the immune dysfunction causing psoriasis and psoriatic arthritis but, more importantly, also led to new therapeutic approaches. In recent years, monoclonal antibodies directed to IL12/IL23 (ustekinumab) or IL17 (secukinumab, ixekizumab, brodalumab) are being investigated or have proven to be beneficial for patients with psoriatic disease, thus further supporting the view that Th17 cells play a pivotal role in disease onset and perpetuation. These most recent reports indeed represent significant developments that may allow overcoming the TNFα pathway as the major therapeutic target in chronic inflammation.

Secukinumab: A New Treatment Option for Psoriatic Arthritis

“…The IL-17 pathway has been shown to play an important role in the pathology of PsA [18,31]. Inflammation in PsA is characterized by synovial tissue enriched by expression of IL-17A and IL-17RA [32].…”

“…Extensive evidence accrued with several agents across numerous clinical trials and registries shows that anti-TNF agents are efficacious in the treatment of PsA. However, a number of unmet needs remain; for example, some patients have an inadequate response to, or intolerance of anti-TNF agents, long-term therapy with these agents is associated with decreasing drug survival rates, and the increased risk of infection may be of concern to some patients [16][17][18].…”

T-Cell Abnormalities in Common Variable Immunodeficiency

“…Several studies have demonstrated that T H 17 cell counts and proportions increased in a variety of autoimmune diseases such as autoimmune hemolytic anemia and immune thrombocytopenia [52], rheumatoid arthritis [53], psoriasis [54], and lupus [55]. However, Barbosa et al [15] found no increase in the frequency of T H 17 cells in CVID patients with autoimmune manifestations, even when CVID patients were subdivided based on the type of autoimmune disorder, including organ-specific autoimmunity and autoimmune cytopenias.…”

Tipping Tumor Microenvironment against Drug Resistance

“…In consistent, some chemotherapeutic regimens were noticed to increase CAFs in colorectal TEM with over-expressing IL-17A to promote drug resistance [45]. Fortunately, therapeutic IL-17A antibodies such as ixekizumab have been clinically available to treat autoimmunitymediated disease [47], corroborating its human safety and pharmacological profiles. In this context, there is a good corollary to expand ixekizumab's clinical indications to circumvent the cancer drug resistant issue resulted from IL-17A-bearing stromal CAFs.…”