Putting the pieces together

By Allison Evans, Assistant Managing Editor, August 1, 2024

Most dermatologists have likely encountered patients with a scarring alopecia like frontal fibrosing alopecia (FFA) or central centrifugal cicatricial alopecia (CCCA). Each of those patients likely wants to know what caused their hair loss. Was it the daily use of sunscreen lotion on the face? Was it hair care practices? Genetics? Unfortunately, there isn’t a completely satisfying answer yet; however, growing research on FFA and CCCA have pushed researchers in the right direction — ever-closer to being able to provide much-needed answers to patients. Researchers are beginning to piece together more about these traditionally understudied scarring alopecias.

Dermatologist experts in scarring alopecias discuss where we are in our understanding of what may be causing CCCA and FFA.

Central centrifugal cicatricial alopecia

CCCA is the most common scarring alopecia among African American women. CCCA has been associated with hot combing and traumatic hair styling for years; however, studies fail to confirm these as the sole etiologic factor.

Environmental factors

“What we know about the environmental impact of hair care practices on CCCA is very little,” said Amy McMichael, MD, FAAD, professor in the Department of Dermatology at Wake Forest School of Medicine. “Recent research on CCCA supports the idea that there are several contributing factors, including variants in gene expression, hair grooming practices that increase fragility of the hair fiber, and associations with other systemic conditions.”

“As hair-styling practices have changed, the focus shifted from hot combs to chemical relaxers to hair extensions,” said Crystal Aguh, MD, FAAD, in a previous DermWorld article. “It’s only in the last five to 10 years that we’ve really seen an effort to understand the pathogenesis of this disease.”

“Contrary to historical belief, we’re now seeing that women are developing CCCA without having practiced any harmful styling practices,” Dr. Aguh added. “Although research and understanding of the disease is still very much in its infancy.”

“In terms of hair care practices as a causal etiology, there are contradictory studies out there. When we looked at risk factors for people with CCCA who improve, it seems like having natural hair, or not doing a lot to their hair, did seem to be associated with more stable or improved disease,” Dr. McMichael added.

“Most would agree that there isn’t any strong evidence that hairstyling methods alone cause CCCA,” said Temitayo Ogunleye, MD, FAAD, associate professor of Clinical Dermatology at Penn Medicine. “When I talk to my patients, I generally tell them that they are genetically susceptible to this condition, and some hair care practices may contribute to its worsening. So that’s why we recommend certain types of modifications for certain hairstyle practices.”

Genetics

In 2019, a study published in the New England Journal of Medicine identified a variant in the PADI3 gene in 31% of CCCA patients. PADI3 encodes peptidyl arginine deiminase, type III (PADI3), an enzyme that post-translationally modifies other proteins that are essential to hair shaft formation.

“While the PADI3 gene may play a part in CCCA, it’s much more likely that genetic variants in multiple genes related to hair shaft formation play a role,” Dr. Ogunleye said. “These genes may make the patients more susceptible to hair shaft fragility.”

Dr. McMichael, a co-author on the NEJM study, believes that there is probably a genetic predisposition to CCCA. “We did research alongside dermatogeneticists that showed a predisposition to having a genetic polymorphism — a change in PADI3.” Decreased expression, diminished activity, or misfolding of PADI3 is likely to exert a deleterious effect on hair shaft formation and hair follicle development, which may underlie the disease phenotype seen in CCCA, Dr. McMichael and colleagues wrote in the study.

“You likely have to have that underlying genetic predisposition, and if you have a patient who also engages in hair care practices that pull or cause tension, then that may trigger the disease in a patient with a genetic predisposition. We know that people can have those hair styles all day long and never get CCCA, so clearly there is more than hair styling practices at work,” Dr. McMichael said.

A 2022 study published in Clinical and Experimental Dermatology found that clinically extensive and severe disease showed different gene expression patterns than focal and limited disease.“ There’s probably more than one genetic polymorphism that may put people at risk for CCCA, but only a few have been discovered to date,” Dr. McMichael said.

“There is also data that indicate autosomal dominant inheritance of CCCA in Black South Africans,” Dr. McMichael pointed out. Fourteen index African families with 31 immediate family members participated in the initial screening. All patients displayed histologic features typical for CCCA. Familial analysis suggested an autosomal dominant mode of inheritance with hair-grooming habits influencing disease expression.

Association with systemic disease

More recent literature has explored the possible connection between CCCA and systemic diseases. One study reported a statistically significant increase in the prevalence of diabetes mellitus type 2 among patients with CCCA, suggesting that CCCA may be a marker of metabolic dysregulation. Dr. McMichael notes that there are many contradicting studies about whether this association exists.

There have also been recent connections of CCCA to systemic fibrosis. A Hopkins study of 447 women with a medical history of CCCA were identified, 62 of whom had uterine leiomyomas. On the other hand, a 2021 article published in JID Innovations showed no evidence of causational or linked mechanobiology that accounts for the increased prevalence of leiomyomas in patients with CCCA.

There is at least one study looking at upregulation of fibroproliferative genes in CCCA biopsies compared to biopsies of unaffected scalp. However, according to Dr. Ogunleye, “It’s a question of: Are they upregulated because of the fibrosis or did the upregulation cause the fibrosis. It’s a chicken versus egg situation — it’s unclear whether fibrosis is the primary pathway to disease or whether (and what) environmental factors may trigger the fibrosis.”

While the impact of using chemical relaxers is still up in the air, Dr. McMichael noted, it is more than likely not a cause of CCCA. “However, hair styles with high tension plus a genetic predisposition is really the story.”

The historical nomenclature for CCCA, such as ‘hot comb alopecia,’ has created a bias when thinking about the etiology of the disease. “It has made it seem like the primary etiologic factor was hair care practices and there was a lot of blaming of patients when there really is no evidence that supports this theory,” Dr. Ogunleye said.

“When we are talking with our patients with CCCA, we have to make sure that there is actual treatment recommended and not just behavior modifications. The patient should also know that it’s not their fault. It’s not something that they did, and it’s more likely a genetic susceptibility that puts them at a higher risk to be more sensitive to certain types of hair care practices,” she said.

Frontal fibrosing alopecia

Frontal fibrosing alopecia (FFA) is a scarring alopecia with progressive recession of the frontotemporal hairline, eyebrow and body hair loss, development of flesh-colored facial papules and, in some cases, involvement of the posterior hair line. FFA was initially thought to only affect postmenopausal women, but now has been described in premenopausal women and adult men. FFA was first described in 1994 by Kossard in a series of six cases in postmenopausal white women.

“FFA has been increasing in incidence in the past 10 years in most areas of the world, including the Americas and Europe. However, it is uncommon in some countries, such us India, Saudi Arabia, and China. We think environmental factors including cosmetic ingredients might be a reason, but we still don’t know the culprit,” said Antonella Tosti, MD, FAAD, the Fredric Brandt Endowed Professor of Dermatology and Cutaneous Surgery at the University of Miami’s Miller School of Medicine.

The cause of FFA is unknown, however hypotheses include decreased estrogen levels, allergic contact dermatitis, environmental factors, and genetic factors.

Sunscreen products

Although many different factors have been considered as contributors to the development of FFA, the increasing incidence has sparked speculation over possible environmental triggers — most notably facial sunscreen use.

According to a study published in the Archives of Dermatological Research, a meta-analysis strongly suggests that leave-on facial products, facial sunscreen, and moisturizer are associated with FFA. There was no significant relationship found with hair products or treatments.

“Titanium nanoparticles and oxybenzone might be implicated according to some studies,” Dr. Tosti said. “My group detected titanium inside the hair taken from the hairline of patients and controls, and a group from Israel recently showed that the content is considerably higher in patients than in controls. Also, oxybenzone is known to be a possible endocrine disruptor.”

The potential role of sunscreen in the pathogenesis of FFA gained further traction after a retrospective questionnaire study reported higher recalled rates of sunscreen use among patients with FFA compared with healthy controls. According to a JAAD article, the hypothesis is attractive for a few reasons: (1) the popularization of sunscreen-containing beauty products fits temporally with the increasing incidence of FFA, (2) FFA was first reported in Australia, coinciding with a sunscreen use campaign launched in the 1980s, and (3) the distribution of FFA roughly corresponds with the area of facial sunscreen application.

“But to date, there is no proven causality. I think most dermatologists who manage FFA patients encourage use of sunscreens with zinc since it has been around for ages, and avoidance of chemical sunscreens. Unfortunately at this time, there’s no slam-dunk research that says there’s a direct correlation,” said Maria Hordinsky, MD, FAAD, RW Goltz Professor in the Department of Dermatology at the University of Minnesota.

In a retrospective, case-control study of 30 men with FFA compared with control patients (with androgenetic alopecia, alopecia areata, or unrelated skin disorders), there was no statistical difference in the use of these products between the two groups.

Genetics

“A genetic study showed that patients with FFA have a mutation in a gene that is important for estrogen catabolism and for metabolism of xenobiotics. So, both environmental factors and genetics can be involved,” Dr. Tosti added.

“There are reported cases of two or more family members having FFA; however, this is not a disease that you commonly see in multiple generations,” Dr. Hordinsky said. “There is likely a genetic predisposition to this disease, but it’s not crystal clear.”

Another study supports the genetic etiology theory by demonstrating that a higher percentage (66%) of FFA patients have both a personal history and a first-degree family history of autoimmune disease. Additionally, hypothyroidism due to autoimmune thyroiditis is associated with up to 30% of patients with FFA. These theories support the idea that the manifestation of the disease within families can be attributed to a shared environmental trigger that may be exacerbated by genetic susceptibility.

Allergic contact dermatitis

Allergic contact dermatitis is another facet when it comes to understanding the etiology of FFA. In addition to sunscreen, fragrances — linalool in particular — have also been suggested as a possible cause of FFA.

“There’s research from Harvard where investigators, under the leadership of Dr. Maryanne Senna, are studying how a particular chemical interacts with the bulge or the stem cell region of the hair follicle causing injury and development of FFA,” Dr. Hordinsky said. “Also, if the patient already has FFA and they’re applying chemicals to their scalp that they might be allergic to, this will just continue to drive the inflammatory process.”

In a multicenter study on FFA, cobalt chloride hexahydrate — a metal found in various products including facial skin care products — was the most frequent allergen detected.

Another study showed the most common relevant allergens included gallates (26%), linalool (19%), and fragrance mixes (19%). All of these allergens are commonly found in cosmetics, creams, lotions, and hair care products.

“If a patient is receiving treatment and they’re doing well with treatment, then typically this treatment plan is continued,” Dr. Hordinsky said. “But if a patient has all the right tools and they’re still not getting better, then there’s something else driving the process, and that’s when we recommend getting allergy testing done. There are articles in the literature showing subjective and objective improvement when the allergen is removed,” she added.

Hormones

“FFA was first described in postmenopausal women, so it was thought that hormones do play a role in the etiology of the condition. The fact that the condition is diagnosed in men and premenopausal women, however, make it harder to determine its real role,” Dr. Tosti explained.

One study that examined this hypothesis was conducted by Bernárdez et al on premenopausal women diagnosed with FFA with a median age of 42.5 years. After analyzing the laboratory results, they determined that only 9% of these 43 premenopausal patients had analytic alterations suggestive of perimenopause, while the remaining 39 (91%) had the sex hormone profiles expected of fertile women. It was concluded that serum sex hormone levels may not be directly linked to the pathophysiology of FFA, as they are not consistently altered in premenopausal FFA patients.

“As of now, it does predominantly affect postmenopausal women. Hormones are probably playing a role, but there’s not one thing right now that we can identify that is implicated in the cause of FFA. In studies from Spain, a good percentage of patients respond to antiandrogens like dutasteride and finasteride, but not everybody,” Dr. Hordinsky added.

“Many physicians think that FFA is just a variant of lichen planopilaris,” said Dr. Hordinsky. “The two diseases can coexist, but FFA is a distinct entity.” In fact, Dr. Hordinsky, along with her colleagues, including Dr. McMichael, worked to get ICD-10 codes approved for FFA, which should be released in October.

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