Ritlecitinib

Alopecia areata is an autoimmune disorder that causes hair loss mainly in the scalp but also on the face and other areas. In normal conditions, hair follicles are immune-privileged sites characterized by the presence of well-suppressed natural killer cells. However, disruptions to this system can lead to the loss of immune privilege and cause alopecia areata. Genome-wide association studies have linked the overexpression of UL16-binding protein 3 (ULBP3), a protein that binds to natural killer cell receptors, to the pathogenesis of alopecia areata. The overexpression of ULBP3 promotes the attack of cytotoxic cluster of differentiation 8-positive (CD8+) NK group 2D-positive (NKG2D+) T cells to hair follicles, leading to hair follicle dystrophy. CD8+ NKG2D+ T cells promote the inflammation of hair follicles through interferon-γ (IFN-γ) and interleukin-15 (IL-15) signaling pathways, which consequently activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) molecular pathways. Therefore, JAK inhibitors have been proposed for the treatment of alopecia areata.

Ritlecitinib inhibits Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family in an irreversible manner by blocking the adenosine triphosphate (ATP) binding site. In vitro, ritlecitinib inhibits cytokine-induced STAT phosphorylation mediated by JAK3-dependent receptors and the signaling of immune receptors dependent on TEC kinase family members. Although it is possible that JAK inhibitors, such as ritlecitinib, inhibit the inflammatory pathways activated in alopecia areata, the precise mechanism of action has not been fully elucidated.