Which is the Ideal JAK Inhibitor for Alopecia Areata - Baricitinib, Tofacitinib, Ritlecitinib or Ifidancitinib - Revisiting the Immunomechanisms of the JAK Pathway

Abstract

Alopecia areata (AA) is an immune-mediated condition, clinically manifesting as non-cicatricial patches of alopecia. It is often a self-limiting condition; however, regrowth of hair can take a long period of time, resulting in significant psychological comorbidity. With the recent advances in pathomechanisms of AA, the therapeutic approach to the condition has become more specific, and targeted therapy with small molecules is probably the ideal intervention. Many therapies exist for AA, but none of the systemic agents were approved, until recently, when baricitinib (Janus kinase (JAK1 and JAK2 inhibitor) gained FDA approval for the treatment of adult patients with severe AA. JAK inhibitors (JAKibs) target the γc cytokine and interferon-gamma (IFN-γ) signaling pathway, which is critical to the immunopathogenesis of AA and thus can reverse the hair loss in AA. Although JAKibs are emerging as a promising treatment modality for AA, the ideal JAKib is not yet settled, as there is scant data on H-2-H (head-to-head) comparisons of JAK inhibitors in AA. Moreover, the response achieved with JAKibs is not sustained after treatment discontinuation, with many studies showing a high recurrence rate with tofacitinib and ruxolitinib post-treatment. Also, recent studies have hypothesized that JAK2, with its ubiquitous expression, can cause adverse effects, unlike JAK1, which is associated with multiple major cytokine receptor families and JAK3, which is exclusively associated with the γc cytokine receptor. Thus, JAK3ibs may be associated with a better side effect profile and, in conjunction with their specificity, may replace other JAKibs as the treatment of choice for AA. We herein discuss the role of the JAK/STAT (signal transducer and activator of transcription) pathway in AA, the intricacies of various JAKibs in the management of AA, and emphasize the need for studies on tissue JAK and cytokine expression before arriving at the ideal JAKibs for AA.

Keywords: Alopecia areata; IFN-γ; IL-15; JAK inhibitors; JAK/STAT; baricitinib; cyclosporine; deucravacitinib; hair cycling; ifidancitinib; methotrexate; ritlecitinib; tofacitinib.

Conflict of interest statement

There are no conflicts of interest.

Copyright: © 2023 Indian Dermatology Online Journal.

Figures

Figure 1

A depiction of role of JAK-STAT pathway, immune cells, and related cytokines in the immune-pathogenesis of alopecia areata. Specific targets of various JAKibs in alopecia areata are shown in the figure . The steps that predict AA, start with a loss of immune privilege leading to exposure of hair follicle antigens, which is followed by ingress of CD8+NKG2D+ T cell which interact with the follicular antigens through MHC class I The activated CD8+T cells then release IFN-γ which signals via JAK1 and JAK2 and releases IL 15 which mediates CD8+T cells induction. This is an autocrine loop that activates CD8+Tcells via JAK1 and JAK 3, to enhance the production of IFN-γ, amplifying the feedback loop. Apart from tofacitinib, specific JAK3 inhibitors including ritlecitinib and brepocitinib have been found to be effective and hold the potential of minimizing the side effects even though the efficacy may be similar. (APC: antigen presenting cells; TCR: T cell receptors; NKG2D: natural killer group 2D)

Figure 2

Schematic representation of the JAK/STAT pathway. Upon binding of cytokine to receptors, there is phosphorylation of JAK/STAT proteins and the pathway is activated. The dimerization and translocation of STAT into the nucleus result in signal transduction and expression of various inflammatory mediators

Figure 3

A diagrammatic depiction of the cytokine and Th cell interaction and the role of JAK/STAT. The interaction leads to activation of JAK/STAT pathway which releases cytokines that mediate various diseases. (GATA-3: GATA binding protein-3; FOX3P: forkhead box P3; IL: interleukin; PI3K: phosphoinositide 3-kinase; RORγT: retinoic acid-related orphan nuclear hormone receptor; T-bet: T-box containing protein; TGF-β: transforming growth factor β; TNF-α: tumor necrosis factor-α)