Pathophysiological basis of systemic treatments in psoriasis

Abstract

Summary Over the past 15 years, the spectrum of systemic antipsoriatic treatments has dramatically expanded. Until the end of the last millennium, systemic therapy had been restricted to four oral agents: methotrexate, cyclosporine, acitretin, and fumaric acid esters. Today, there are additionally seven biologics and one new oral antipsoriatic drug, as well as the first available biosimilars. Six more biologics with novel target structures and at least four biosimilars are currently being developed (phase III). This progress has been based on new insights into the pathogenesis of psoriasis, in which tumor necrosis factor and especially Th17 immune responses with their associated cytokines interleukin 23 and 17 play a key role. The development of new‐generation biologics as well as immunomodulatory small molecules can be attributed to these pathophysiological findings. Phosphodiesterase 4 inhibitors, dimethyl fumarate, and Janus kinase inhibitors all interact with Th17 immune responses. Some of these drugs are in advanced clinical development and are also beneficial in psoriatic arthritis. Today, psoriasis and psoriatic arthritis therefore rank among the most readily treatable inflammatory autoimmune disorders. Dermatology is increasingly becoming a specialty of modern targeted immunotherapies.

Long‐term real‐life safety profile and effectiveness of fumaric acid esters in psoriasis patients: a single‐centre, retrospective, observational study

“…All of these patients were lymphopenic and had been receiving FAE therapy for prolonged periods. Only patients with prolonged uncontrolled lymphopenia during FAE therapy seem to be at higher risk for this very rare but serious side‐effect of FAEs . Additionally, fatal cases of West Nile encephalitis, generalized varicella zoster, and Kaposi sarcoma have been associated with FAEs .…”

“…In our total cohort, we did not observe any severe or opportunistic infections leading to treatment discontinuation. Eosinophilia is frequently observed within the first 3 months of FAE therapy and usually decreases to standard values with continued treatment, only rarely necessitating treatment discontinuation . Other frequent AEs among the three drug cohorts were hepatobiliary disorders (Table ).…”

“…It is therefore reasonable to assume that there might be an additive antipsoriatic effect of adding MTX, without any new or additional safety concerns . Transient and reversible hepatotoxicity was the most common limiting factor during combination therapy …”

Autoimmunity to heterogeneous nuclear ribonucleoprotein A1 in psoriatic patients and correlation with disease severity

“…The currently accepted model postulates that an unknown antigen or environmental trigger precipitates the activation of innate immune cells, with production of TNF‐α, IL‐1β and IL‐6. These cytokines then activate the adaptive immune response, namely Th17 and Th1 cells, generating a complex network of interactions between many different cell types, which ultimately leads to chronic inflammation and hyperproliferation of keratinocytes .…”

Ixekizumab for acrodermatitis continua

“…It is produced by T cells as well as other immune cells and leads to proliferation and activation of keratinocytes, which then attract and stimulate the infi ltrating immune cells such as neutrophils [ 26,27 ] Interleukin-17A antibodies such as secukinumab and ixekizumab have been used successfully in the treatment of psoriasis vulgaris [ 28 ] and generalized pustular psoriasis [ 29,30 ] . It is produced by T cells as well as other immune cells and leads to proliferation and activation of keratinocytes, which then attract and stimulate the infi ltrating immune cells such as neutrophils [ 26,27 ] Interleukin-17A antibodies such as secukinumab and ixekizumab have been used successfully in the treatment of psoriasis vulgaris [ 28 ] and generalized pustular psoriasis [ 29,30 ] .…”