Experimental Pharmacological Management of Psoriasis

Abstract

Psoriasis is a chronic, relapsing, immune-mediated systemic disease. Its pathogenesis is complex and not fully understood yet. Genetic and epigenetic factors interact with molecular pathways involving TNF-α, IL-23/IL-17 axis, and peculiar cytokines, as IL-36 or phosphodiesterase 4. This review discusses the mechanisms involved in the development of the disease, as well as the therapeutic options proposed following the investigation of the inflammatory psoriatic pathways. We performed a comprehensive search using the words "psoriasis" and the newest molecules currently under investigation and approval. From these data, a new scenario in psoriasis is occurring to personalize the therapies - especially systemic ones and those using small molecules - and avoid topical and injectable drugs. We reported the newest therapeutic opportunities, including the inhibitors of Janus kinase/tyrosine kinase 2, phosphodiesterase-4 and IL-36 receptor. Today, more than 20 molecules are under investigation for the treatment of cutaneous psoriasis. Most of them are constituted by small molecules or biologic therapies. This underlines how psoriasis needs systemic therapies, due to its complex pathogenesis and multisystemic involvement.

Keywords: IL-36 receptors inhibitors; janus kinase inhibitors; phosphodiesterase 4 inhibitors; psoriasis; tyrosine kinase 2 inhibitors.

Figure 1

(A) Clinical manifestation of palmar psoriasis. (B) Clinical manifestation of sacral psoriasis. (C) Clinical manifestation of nail psoriasis. All the three clinical images report the difficult-to-treat areas, recognized as unmet needs by patients and physician. (D) Histopathological features of plaque psoriasis. The classic epidermal psoriasiform hyperplasia is associated with hyperparakeratosis and loss of granular layer. Collections of neutrophils are observed in the upper stratum spinosum (spongiosiform pustules of Kogoj). In the dermis, thin capillary vessels reach almost the top of the dermal papillae and are surrounded by a chronic lymphocytic infiltrate with sparse neutrophils (Haematoxylin-eosin. Original magnification: 100x). (E) Histopathological features of genital psoriasis. The classic features observed in plaque psoriasis are attenuated in the genital area. The epidermal hyperplasia is associated with less extensive hyperparakeratosis, which is accompanied by mounds of neutrophils in the stratum corneum (Munro’s microabscesses). In the chorion, thin capillary vessels are surrounded by a chronic lymphocytic infiltrate, with sparse neutrophils (Haematoxylin-eosin. Original magnification: 200x).

Figure 2

Summary of drugs under investigation or with preliminary efficacy in psoriasis disease (red), and drugs with no data reporting efficacy (orange). A) The JAK inhibitor blocks the JAK-STAT pathway signaling in Th17 cells. Specifically, deucravacitinib inhibits TYK2. B) Tapinarof, an AhR agonist, reduces IL-17 and IL-22 in both Th17 cells and keratinocytes. C) Spesolimab and imsidolimab inhibit IL-36R. D) Imo-8400 inhibits TLR-7/8/9. E) BAY1834345, ND2110 and ND2158 inhibit IRAK4. F) Piclidenoson inhibits A3AR in keratinocytes. G) Ponesimod, a selective S1PR1 agonist, induces sequestration of lymphocytes into lymph nodes and decreases peripheral lymphocyte counts and tracking of lymphocytes to peripheral tissues. H) Namilumab has not shown efficacy in psoriasis. J) PDE4 inhibitors act on lymphocytes. K) Among RORγt, just ABVV-157 and AUR-101 have shown efficacy in psoriasis. L) KD025, a ROCK2 inhibitor, reduces IL-17 secretion in Th17 cells.