Co-editors’ Messages

Among the issues that continue to intrigue me from our meeting in the Bahamas is the role of inflammation in producing alopecia of one type or another. The proinflammatory and inflammatory cascade of events are becoming ever more clearly understood. When such questions come to mind, it is satisfying as editor to recall articles in the Forum for reference: Marty Sawaya’s excellent review of her work on inflammasones,¹ an earlier article on strontium,² as well as other investigations such as that by Dr. Sadick and his study investigating an aspect of the “acquired immune response”: basement membranes of follicles being laden with antibodies.³ There seems to be a growing consensus that the “incidental” perifollicular inflammatory infiltrate may not be as incidental and insignificant as was thought for decades. Add to that intriguing questions regarding strontium’s anti-inflammatory properties and you’re in for a good ride of reflection and speculation.

Dr. Sawaya discusses the “innate immune reaction” (IIR) and especially the “inflammasome.” The inflammasome is formed from “pattern recognition receptors” that are on the membranes and in the cytoplasm of many cells including epidermal and dermal cell lines in the skin and its appendages. When activated by a specific “molecular pattern” from an invading pathogen, for instance, these recognition receptors oligomerize with other proteins to form the inflammasome, which in turn can activate both proinflammatory cytokines such as IL-1A, IL-1B, IL-6, and TNF-A as well as the part of the immune system that most of us are more familiar with that involves T and B lymphocytes further downstream and are part of what is called the “Adaptive Immune Response” (AIR).

Dr. Sawaya refers to an article by herself and Drs. Vaccari, Nusbaum, Bauman, and others wherein a protein that interacts with the inflammasome cascade, Caspase-1, is studied in balding scalp.⁴ Caspase-1 is recognized as an inducer of apoptosis and inflammation and they studied its levels as well as quantified androgen receptors in various in vivo and in vitro conditions involving the presence or absence of testosterone and finasteride. That androgen levels increase Caspase-1 levels and finasteride decreases them suggest the IIR (i.e., the inflammatory response) is perhaps the final common pathway for AGA.

Dr. Sadick’s article summarized a study he performed predominantly on women with AGA. He found IgM deposits continuously along the basement membrane of the dermal-epidermal junction in 64% of afflicted women with associated evidence of complement activation and found that those with this deposition responded better to a combination therapy that included beclomethasone and spironolactone. A non-specific perifollicular lymphocytic infiltrate was present and was perhaps more predominant in the positive group. One can speculate that his findings are compatible with and are a further downstream manifestation of the inflammatory reaction from the AIR and whose “upstream” progenitor, the IIR, is discussed by Dr. Sawaya.

A few years ago I wrote a summary of strontium² that is now marketed as an anti-itch formulation named TriCalm by a San Diego company, Cosmederm Bioscience. Strontium is a divalent cation just beneath Ca++ in the periodic table. It may replace Ca++ and hence affect the Ca++ cellular functions as the mechanism of action. As you can see by reading the review, strontium has strong anti-inflammatory properties via inhibiting the release of Substance P from the “nociceptor” Type C nerves, a non-myelenated nerve type that extends to the outermost layer of the epidermis. This has been termed “neurogenic inflammation” and their stimulation can release Substance P by depolarization exclusively within the terminal arborization of the nerve and needn’t go all the way to the dorsal root, much less upstream via the spino-thalamic tract, before returning with its message to release Substance P and its “neurogenic inflammation.” There is some evidence that strontium additionally acts even more directly on the pro-inflammatory proteins in addition to this function at the terminal synapse of the Type C nerve.⁵

Another pearl I took away from the Bahamas meeting was from Dr. Jeff Donovan when he said that he finds an itching or tender scalp to be a very useful complaint for detecting cicatricial alopecia. This is not surprising when you think of the inflammation driving the cicatricial alopecia and it begs the question of whether strontium and suppression of the IIR would help these conditions.

With strontium becoming ever better understood and the great work of Dr. Sawaya and her colleagues working to better understand the IIR, I can see intriguing ideas to pursue: Can we be comfortable (as we were with the perifollicular inflammatory infiltrate in AGA for decades) that seborrheic dermatitis and psoriasis, symptomatic chronic inflammatory states, are not contributing to hair loss? Perhaps even their inflammatory states that are below the threshold of producing symptoms are eroding our hair counts. Should scalp biopsies be done more often for routine male pattern balding to consider this, especially if the inflammatory pathogenesis of alopecia becomes more certain? And other questions arise: Will antagonists of the IIR, perhaps strontium or something similar, prove to be useful in reducing the induction of apoptosis in the post-transplant state?

Will antagonists of the IIR prove to be useful in treating any or even all forms of alopecia? One nice feature of writing an editorial instead of a quality investigation of science is that it only has to express an opinion and can be primarily based upon speculation! Whatever the truth, I’m becoming a believer that the answer is “yes” that many alopecias, and perhaps even the “Big One”—AGA—are related to this immune response… and just in time to save my teenage son’s hair from balding to the Stage VII of his two grandfathers! Many of these questions can be investigated fairly cheaply with the use of Hair Check, for example. I would appreciate a letter to the editor from anybody who can add to this line of thought. Let’s get started and enjoy the speculation that can abound in the emerging sophistication of our field!