A Fresh Look at Alopecia Areata

At the European Academy of Dermatology and Venereology 2022 Congress in Milan, Italy, Ralf Paus, MD, research professor of dermatology at the University of Miami Miller School of Medicine in Miami, Florida, presented a fresh look at alopecia areata (AA) with an in-depth discussion of targeted cells and therapy treatments.

“We all know alopecia areata (AA) as an autoimmune hair loss disorder. One of the first messages and the most important message I want to send today is not every case of AA you see in front of you is a classic autoimmune disease. That forces us to think into other directions as well. What is definitely true and remains true is that AA hair loss pattern always indicates and requires that hair follicle immune privilege has collapsed (HCIP). You cannot get the disease without collapse of hair follicle immune privilege,” said Paus.

There will be no lasting hair regrowth if the hair follicle does not manage to restore its immune privilege after therapy has been discontinued. Whatever therapy is chosen, besides regrowing hair shafts, dermatologists must also restore hair follicle immune privilege, or the patient will be stuck on therapy forever.

Janus kinase (JAK) inhibitors are a gold standard in AA management and regrow hair effectively in the majority of patients, but not all. Expert dermatologists still do not understand why there is a difference among some AA patients. The main problem, besides concern over long-term adverse effects, is after years of treatment with JAK inhibitors, the disease relapses quickly after therapy is discontinued. That suggests that JAK inhibitors actually fail to restore hair follicle immune privilege.

What is hair follicle immune privilege (HFIP)? The hair follicle has 2 compartments, a distal one which is not immune privileged and hidradenitis suppurative develops from this part of the hair follicle. Then, there is a proximal compartment where invisible immunological water is shed. In human AA, the key immune privileged guardians that support AA are interlueken-10 (IL-10), TFB1/2, VIP-R, IGF-1, cortisol, inhibitory NKT cells, and perifollicular regulatory T cells. Around normal hair follicles, mast cells are immunoinhibitory in their profile.

All of this changes in AA. Below the immunological water shed, the follicle begins to express high amounts of MHC class 1 and 2. The levels of immunoinhibitory privileged guardians go down and the mast cells become proinflammatory.

AA is also a hair follicle cycling disorder. Only anagen hair follicles are being attacked, and primarily the hair follicles that make pigment (anagen iii-vi). Then, an inflammatory infiltrate (which patients must have in order to develop AA) moves in on the anagen hair follicles and kicks them into catagen. In order to get hair shaft shedding, the follicle needs to become damaged. The key cytokine that has long been established in driving this process is IFN-γ.The key cells secreting IFN-γ are CD8 T cells, and several other NKG2D+ cells.

“We need to step out of the idea that AA is one single disease. What we really see when we have an AA patient, which is easy to diagnose, is a stereotypic hair loss response pattern to a specific kind of inflammatory hair follicle damage. Even the healthiest of anagen hair follicles will show when the following things happen, and this is irrespective of genetic predisposition, only if and when the physiological hair follicle immune privilege collapses during anagen. This also attracts an inflammatory infiltrate that secretes so much IFN-γ and possibly interleuken-18, that major hair follicle dystrophy and premature catagen are induced,” said Paus.

Paus concludes his presentation by listing his “personal drug wish-list" for improved future AA management. Some of the drugs include topically effective JAK inhibitors that do not target IL-10R, IL-15 & prolactin-R signaling, topical hair follicle-targeting tacrolimus, TYK2 antagonists, and systemic substance P receptor antagonists.

Disclosure:

Paus is the founder and CEO of Monasterium Laboratory in Munster, Germany, and CUTANEON – Skin & Hair Innovations in Hamburg, Germany, Paus is also a consultant for Pfizer, Leo Pharma, Bristol Myers Squibb, Giuliani, and Alieron et al.

Reference:

1. R. Paus. A fresh look at alopecia areata. Latest news in hair and nail disorders. Presented at the European Academy of Dermatology and Venereology 31st Annual Congress. August 7-10, 2022; Milan, Italy.