A glimpse into the future

Alopecia areata (AA) is a chronic relapsing inflammatory disorder characterised by non-scarring hair loss on the scalp and/or body. As Prof. Wilma Bergfeld of the Cleveland Clinic indicated, in healthy subjects there is an immune privilege of the hair follicle [1]. A loss of this immune privilege leads to AA.

Genome-wide association studies implicated ligands for the Natural Killer Group 2D (NKG2D) receptor (a product of the KLRK1 gene) in disease pathogenesis [2]. In a murine model of AA, a type I cytotoxic pathway has been demonstrated as responsible for the disease state, with NKG2D-expressing CD8+ cytolytic T-lymphocytes necessary for the induction of the disease. Upregulation of IL-15 in the outer root sheath of the hair follicle activates cytolytic T-lymphocytes, which in turn produce Interferon (IFN)γ, leading to activation of the hair follicle and upregulation of IL-15, NKG2D ligands, and major histocompatibility complex (MHC) molecules, all of which target the hair follicle for attack [3].

A possible therapeutic approach is the restoration of this immune privilege by restoring the defective function of CD4+/CD25+ cells and by reducing CD8 T lymphocytes and IL-15. JAK 1/3 signalling mediates IL-15 activation of T-lymphocytes [4]. IL-15 is highly expressed in human and murine AA and drives CD8 killer activation. IFN γ is a second important player in the AA pathogenesis: it is produced by killer T cells and drives inflammation. JAK inhibitors block both IL-15 and IFNγ.

A breakthrough in AA therapy was a publication in 2014 where, in a patient with plaque psoriasis, the oral JAK-inhibitor tofacitinib reversed alopecia universalis [5]. An open trial where AA was treated with oral tofacitinib confirmed that the majority of patients experience a regrowth of hair independent of age, disease severity, and disease duration with only minimal side effects [6]. 47% of patients experience a regrowth of hair by 12 months. In addition, the JAK inhibitor also improves nail dystrophy that was reported in 23% of patients. This and other work has spawned so much interest that there are now many JAK inhibitors in the clinical development for AA.

1. Bergfeld, W. Oral presentation session S048, AAD Annual Meeting, February 16–20 2018.
2. Xing, L. et al. Nat Med 2014;20:1043–9.
3. Jabbari, A. et al. J Invest Dermatol 2013;12:1395.
4. Ghoreschi, K. et al. J Immunol. 2011;186: 4234–43
5. Craiglow, BG. & King, BA. J Invest Dermatol 2014;134:2988–90.
6. Ibrahim, O. et al. JAMA Dermatol 2017;153:600–02.



Posted on 20 December, 201828 March, 2024