A glimpse into the future
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 . 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 . 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 .
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 . 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 . 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 . 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.
- Bergfeld, W. Oral presentation session S048, AAD Annual Meeting, February 16–20 2018.
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