Inhibition of T-cell activity in alopecia areata: recent developments and new directions

Abstract

Alopecia areata (AA) is an autoimmune disease that has a complex underlying immunopathogenesis characterized by nonscarring hair loss ranging from small bald patches to complete loss of scalp, face, and/or body hair. Although the etiopathogenesis of AA has not yet been fully characterized, immune privilege collapse at the hair follicle (HF) followed by T-cell receptor recognition of exposed HF autoantigens by autoreactive cytotoxic CD8+ T cells is now understood to play a central role. Few treatment options are available, with the Janus kinase (JAK) 1/2 inhibitor baricitinib (2022) and the selective JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor ritlecitinib (2023) being the only US Food and Drug Administration–approved systemic medications thus far for severe AA. Several other treatments are used off-label with limited efficacy and/or suboptimal safety and tolerability. With an increased understanding of the T-cell–mediated autoimmune and inflammatory pathogenesis of AA, additional therapeutic pathways beyond JAK inhibition are currently under investigation for the development of AA therapies. This narrative review presents a detailed overview about the role of T cells and T-cell–signaling pathways in the pathogenesis of AA, with a focus on those pathways targeted by drugs in clinical development for the treatment of AA. A detailed summary of new drugs targeting these pathways with expert commentary on future directions for AA drug development and the importance of targeting multiple T-cell–signaling pathways is also provided in this review.

Deciphering the Complex Immunopathogenesis of Alopecia Areata

“…Both baricitinib and ritlecitinib are approved for the treatment of severe AA in adults, while ritlecitinib is also safe to treat severe AA in adolescents. Several JAK inhibitors with various profiles of selectivity toward JAK isoforms, such as deuruxolitinib, jaktinib, ivarmacitinib, KL130008, and deucravacitinib, are under investigation for the treatment of several immunoinflammatory diseases, including AA [ 133 ]. Other traditional systemic medications used in AA include glucocorticoids, cyclosporine, methotrexate, and other anti-inflammatory drugs or contact immunotherapy for immunomodulation [ 134 ].…”

“…With an increased understanding of AA’s T-cell-mediated autoimmune and inflammatory pathogenesis, additional therapeutic pathways controlling T-cell recruitment in HF and upstream cytokine signaling are being explored to develop AA therapies. Other T-cell-related targets of interest for future treatment development include Tregs, immune tolerance, and the microbiome [ 133 ].…”

“…Given the complex multifactorial nature of the signaling pathways underlying the immune-mediated attack on HF in AA, there is a requisite for developing therapies that target multiple distinct signaling pathways. By using dual-targeted therapies, we could overcome the ceiling effect of current therapies, such as immune escape and drug resistance [ 133 , 134 ].…”

Pathogenesis of Alopecia Areata and Vitiligo: Commonalities and Differences

“…Although the complex pathophysiology of AA is not fully understood, cumulative evidence from AA mouse models and human AA skin and blood samples indicates that key players in AA pathogenesis include immune privilege collapse [13], activated interferon-γ (IFN-γ) signaling pathways, and activated pathways involved in the cytotoxic cluster of differentiation (CD)8+ T lymphocytes [14][15][16][17][18][19].…”

Alopecia areata: Time for position statement to include new systemic therapeutic advances

“…This frustration has been rooted for the past decades by the absence of effective systemic treatments 1 . However, times are changing, and recent advances in understanding the immune mechanisms of the disease have led to the development and approval of new systemic treatments, revolutionizing the approach to managing AA 2 …”