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By Jan Bowers, Contributing Writer, May 1, 2022

A nearly $1.5 million windfall from a class action lawsuit is enabling intensive, multifaceted research of traditionally understudied aspects of hair disorders afflicting diverse populations and skin of color. Last year, the AAD received $1,459,000 as a result of a class action lawsuit against Wen by Chaz Dean, a line of hair and body care products targeted by tens of thousands of consumers who claimed that the brand’s cleansing conditioners were causing hair loss, hair breakage, balding, itching, and rash (Learn more at www.aad.org/dw/weekly/new-research-grant-focuses-on-understudied-hair-disorders). Although the Academy did not participate in the lawsuit, it received a portion of the $26 million settlement in the form of a cy pres award, which is the distribution of funds from a class action settlement to a charitable organization.

The AAD’s Wen Cy Pres Award Workgroup, tasked with developing and administering a grant program to award one-third of the funds, determined that the research should focus on hair loss and skin of color, with a particular emphasis on central centrifugal cicatricial alopecia (CCCA). The Hair Loss and Alopecia Initiative in Research (HAIR) Grant Program has now awarded seven grants to eight dermatologists (two are teaming up on one project).

“When this research opportunity became available, investigators jumped on the opportunity!  We received 26 applications in a very short period,” said Maria K. Hordinsky, MD, FAAD, professor and chair of the Department of Dermatology at the University of Minnesota. Dr. Hordinsky chairs the Wen Cy Pres Award Workgroup and led the committee that reviewed the HAIR Grant applications. Although applications on all aspects related to hair disorders were encouraged, “the highest number of applications focused on cicatricial alopecia,” she noted. All the award recipients will investigate CCCA or cicatricial disorders more broadly. “There was a lot of passion for this effort within our workgroup,” said Dr. Hordinsky. “Our goal was to get this program off the ground and move hair disease research forward It’s a big deal. Now we have the needed resources to support investigations that research a group of diseases that are primarily affecting patients with skin of color.”

DermWorld asked the HAIR Grant recipients to elaborate on their research plans.

Investigating the impact of hair washing on scalp cytokine expression in patients with CCCA

Crystal Aguh, MD, FAAD, associate professor, Department of Dermatology and director, Ethnic Skin Program, Johns Hopkins School of Medicine

DermWorld: Tell us why you chose to study this topic.

Dr. Aguh: CCCA is the most common form of scarring hair loss in Black women, but very little is known about its causes. Historically, much attention has been focused on hair styling practices as potential risk factors for development of this disease, but this emphasis may be misdirected as no one styling practice has been consistently linked to CCCA. Instead, due to the curly nature of average Black hair, shampooing occurs infrequently, and may play a more prominent role. The role of shampooing, which decreases scalp inflammation, has never been studied before in CCCA.

DermWorld: Tell us about your study, research design, and methodology.

Dr. Aguh: We will recruit Black women and divide them into four groups: Those with and without CCCA; within each of those two groups, those who wash frequently (approximately 30 times per year or greater) and those who wash infrequently (fewer than 12 times per year). We will conduct tape stripping to assess the levels of inflammation in the various groups to understand the impact of washing frequency.

DermWorld: What do you expect to find with your research?

Dr. Aguh: We suspect that less frequent washing is associated with higher levels of scalp inflammation and that in patients with CCCA, the type of inflammation is consistent with those seen in abnormal scarring disorders (Th2 inflammatory cytokines).

DermWorld: How will your research address gaps in hair disorder research?

Dr. Aguh: As eliminating inflammation is an important aspect of treatment for CCCA patients, as well as those with other forms of scarring alopecia, I am hopeful this study will identify a simple, yet effective intervention that patients can perform at home to slow disease progression.

Effect of mechanical intervention on the scalp microbiome: Setting the state for the future management of cicatricial alopecias

Ronda S. Farah, MD, FAAD, assistant professor, Department of Dermatology and cosmetic lead, University of Minnesota Health

DermWorld: Tell us why you chose to study this topic.

Dr. Farah: Scalp health and care may be important for hair disease. Hydradermabrasion is a form of dermabrasion that utilizes a solution along with suction to abrade the skin. We wanted to assess the effect of standardized scalp care utilizing hydradermabrasion on the scalp microbiome. We also hope to characterize the microbiome of healthy scalp, thereby providing a baseline for future scalp disease research.

DermWorld: Tell us about your study, research design, and methodology.

Dr. Farah: This is a prospective four-week study. Adult subjects with healthy scalp will be treated weekly with hydradermabrasion. We will study their scalp health and their microbiome changes.

DermWorld: What do you expect to find with your research?

Dr. Farah: We expect to document the changes in the scalp microbiome and scalp health. We might also find that scalp health improves. This may include a decrease in redness, scale, or other symptoms such as itchiness.

DermWorld: How will your research address gaps in hair disorder research?

Dr. Farah: This research will build a foundation for understanding hydradermabrasion and how it impacts scalp health. This technology can then be applied to scalp disease and hair loss.

Mast cells in central centrifugal cicatricial alopecia

Lynne J. Goldberg, MD, FAAD, professor of dermatology and pathology & laboratory medicine, Boston University School of Medicine, and director, Hair Clinic, Boston Medical Center

DermWorld: Tell us why you chose to study this topic.

Dr. Goldberg: Little is known about the role of mast cells in cicatricial alopecia, including CCCA. As a dermatologist and dermatopathologist with a longstanding interest in hair disorders who practices in an urban setting, I am in a unique position to study CCCA under the microscope.

DermWorld: Tell us about your study, research design, and methodology.

Dr. Goldberg: I plan to look for the presence of mast cells in biopsies of CCCA, comparing two different staining techniques. I will then quantify mast cell number and location and correlate their presence with clinical and other histopathologic parameters.

DermWorld: What do you expect to find with your research?

Dr. Goldberg: This is an exploratory study. I hypothesize that mast cells will be identified in CCCA biopsies that contain inflammation. If so, it will be interesting to see if their presence correlates with disease duration, severity, and patient symptoms.

DermWorld: How will your research address gaps in hair disorder research?

Dr. Goldberg: Findings could potentially have pathogenetic and therapeutic implications for CCCA. In addition, they could be applicable to lymphocytic scarring alopecias in general.

Establishment of a preclinical model for human PCA using the asebia mouse

Jin Yong Kim, MD, PhD, FAAD, postdoctoral research scientist, Columbia University Irving Medical Center

DermWorld: Tell us why you chose to study this topic.

Dr. Kim: Primary cicatricial alopecias (PCAs) are heterogeneous disorders characterized by the destruction of hair follicle (HF) structures, leading to permanent hair loss in patients. However, the underlying pathogenesis and treatment options are poorly understood due to the lack of research models.

DermWorld: Tell us about your study, research design, and methodology.

Dr. Kim: The asebia mouse, which harbors mutations in the stearoyl-CoA desaturase 1 (Scd1) gene, was previously proposed as a model for PCA. However, the pathogenic mechanisms underlying permanent hair loss in Scd1−/− mice are largely unknown. In our preliminary studies, we found that intraepithelial CD207+ Langerhans cells (LCs) were significantly increased primarily within the HF isthmus and infundibulum, suggesting that Scd1−/− mice share immunologic features with human CCCA. Moreover, we found that topical treatment with a liver X receptor (LXR) agonist showed a promising efficacy on the attenuation of progressive hair loss.

DermWorld: What do you expect to find with your research?

Dr. Kim: We will determine the single-cell transcriptional landscape of epithelial and immune cells in Scd1−/− mice before and after LXR agonist treatment. We will determine whether intraepithelial CD207+ LCs are the primary pathogenic driver in hair loss using anti-CD207 depletion antibodies in Scd1−/− mice. Lastly, we will investigate lipid profile changes in Scd1−/− HF epithelium by LXR agonist treatment for the further clinical evaluation of LXR agonists in the treatment of PCAs.

DermWorld: How will your research address gaps in hair disorder research?

Dr. Kim: A major obstacle for developing treatment options for PCA is the lack of a research model. Given that human PCAs are driven by lymphocytic and/or neutrophilic infiltrate surrounding HFs, we characterized the immunologic features and found a massive increase of intraepithelial LCs underlying hair loss in Scd1−/− mice, which was attenuated by LXR agonist treatment. In this study, we will develop a novel therapeutic option, LXR agonist, for the treatment of PCA patients.

Investigation of genetic study of the genetic mutations in CCCA in a large cohort of Black women across the United States

Amy McMichael, MD, FAAD, professor and chair, Department of Dermatology, Wake Forest University Health Sciences, and Yolanda M. Lenzy, MD, Lenzy Dermatology, Chicopee, Massachusetts

DermWorld: Tell us why you chose to study this topic.

Drs. McMichael and Lenzy: CCCA is a chronic progressive scarring alopecia causing potentially devastating psychosocial consequences and permanent hair loss. Women with this diagnosis often have severe itch, tenderness, or pain in the scalp accompanying the hair loss. CCCA is likely the most common form of scarring alopecia in Black women. Due to the scarring nature of the condition, there is little that can be done for patients when they present to the dermatologist for treatment. Despite the condition being first described in the literature over 50 years ago, in 1968, fewer than 200 articles on this topic have been published, making it one of the greatest areas of unmet needs in dermatology and hair loss research.

DermWorld: Tell us about your study, research design, and methodology.

Drs. McMichael and Lenzy: In previous research published in 2019 (McMichael, Sprecher, Dlova) in the New England Journal of Medicine (doi:  10.1056/NEJMoa1816614) using Next Generation Sequencing (NGS), pathogenic variants of the PADI3 gene were identified in 24% of CCCA patients. NGS is increasingly used to identify the genetic basis of complex traits, given the profound limitations of genome-wide association studies-based approaches for reasons well detailed in Nature Reviews Genetics (2010;11:415-25) and as initially exemplified in Science (2009; 324:387–9). Although a large number of cases (albeit less than for GWAS studies) is usually still needed for NGS-based genetic studies, pre-selection of population-specific coding variants in functionally relevant loci is expected to significantly lower the number of cases needed to identify causative genes as shown in the NEJM paper.

The current study will utilize a large-scale study of Black women called the Black Women’s Health Study (BWHS), on which Dr. Lenzy has collaborated and published research on CCCA in this population. Launched in 1995, the BWHS is a follow-up study of the general health of 59,000 African American women. There are no larger database studies that incorporate women of African descent with genetic information included. In previous studies of CCCA in this population for the 2015/2016 follow-up cycle, participants who completed the main 2015/2016 questionnaire were invited to fill out a web questionnaire about hair loss. Each woman in the study has been asked to provide a sputum sample and a blood sample. DNA samples (either sputum or blood and sputum) from the BWHS and data for women who answered the hair questionnaire and for whom appropriate samples were collected will be provided for analysis by our research colleagues in Israel: Drs. Eli Sprecher and Ofer Sarig at the Tel Aviv Sourasky Genomic Center. The hope is to utilize this large database to identify more genetic determinants of CCCA in this population.

DermWorld: What do you expect to find with your research?

Drs. McMichael and Lenzy: The main outcome measure in this study is to identify the common genes and genetic expression patterns in CCCA patients relative to their age and potential other illness — since this study has other disease data points. We will be analyzing a large sample of DNA for genetic sequencing using NGS for potential refinement of a genetic polymorphism that will potentially lead to deeper understanding of the pathogenesis or to potential treatment options.

DermWorld: How will your research address gaps in hair disorder research?

Drs. McMichael and Lenzy: As we further refine the genetic determinants of CCCA, we can broaden the search among other dermatology practices across the U.S., using even larger cohorts. These findings can then be correlated with histologic findings and outcomes to predict the likelihood of development and progression of disease as well as potential response to treatment. Ultimately, it would be our goal to determine a viable treatment for CCCA based on our genetic findings.

Identification of biomarkers for central centrifugal cicatricial alopecia

John T. Seykora, MD, PhD, FAAD, professor of dermatology, Perelman School of Medicine, University of Pennsylvania

DermWorld: Tell us why you chose to study this topic.

Dr. Seykora: Research into the biological mechanisms of CCCA represents an understudied area on a disease that exerts a strong negative impact primarily on African American women and disadvantaged groups. There is a major unmet medical need to learn more about this disease.

DermWorld: Tell us about your study, research design, and methodology.

Dr. Seykora: Our research study design will be to identify biomarkers of CCCA by performing a subtractive RNA sequencing analysis on CCCA- affected vs. CCCA-unaffected vs. control follicles isolated from patient biopsies. In this way, we will be able to identify genes only expressed in CCCA-affected follicles. Our control follicles are terminal anagen follicles obtained from age-matched androgenetic alopecia biopsies. To enhance precision, we will use laser-capture microdissection to isolate CCCA-affected and CCCA-unaffected follicles, and control follicles from tissue sections.

DermWorld: What do you expect to find with your research?

Dr. Seykora: By applying this experimental approach to CCCA and androgenetic alopecia biopsies, we will identify novel biomarkers associated with the disease. These novel biomarkers represent potential therapeutic targets that may be evaluated in clinical trials.

DermWorld: How will your research address gaps in hair disorder research?

Dr. Seykora: There is a major unmet medical need to identify targetable biomarkers of CCCA. Identification of such biomarkers will help dermatologists design novel clinical trials targeting the function of these biomarkers, with the goal of identifying new therapies for CCCA.

The genetic basis of central centrifugal cicatricial alopecia

Susan C. Taylor, MD, FAAD, professor and director of diversity, Department of Dermatology, Perelman School of Medicine, University of Pennsylvania

DermWorld: Tell us why you chose to study this topic.

Dr. Taylor: The genetic basis of CCCA remains understudied and represents an important health disparity. My work has focused on advancing clinical knowledge and addressing gaps in research and education regarding skin of color populations. I strive to invigorate an ongoing national dialogue about skin of color-related issues within the specialty of dermatology.

DermWorld: Tell us about your study, research design, and methodology.

Dr. Taylor: Blood samples for genetic analysis will be obtained from 350 patients from my database, active clinic patients, as well as patients from the Penn Medicine BioBank (PMBB) with a diagnosis of CCCA. In addition, patients with a diagnosis of CCCA who participated in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study — a study investigating the genetic architecture of Primary Open-Angle Glaucoma in the African American Philadelphia population — will be included. Three hundred and fifty unrelated controls will be identified from genotyped PMBB subjects, my non-CCCA patients, and review of the electronic medical record through IRB protocol: 834059.

For aim two of the genetic analysis, we will identify a set of candidate SNPs/genes associated with CCCA by genetic association analysis comparing cases to controls, using linear mixed models for per-SNP association testing (GCTA) and SNP set models for per-gene association (SKAT).

DermWorld: What do you expect to find with your research?

Dr. Taylor: There are candidate genes that have been identified that may influence hair structure in the Khoesan population from Africa who are ancestral to all human populations including African Americans. The Khoesan population has tightly coiled hair that is linked to the predilection for CCCA. Given these associations, we hypothesize that these genes may play a role in the risk for CCCA. We propose genetic studies of African and African American CCCA patients and matched controls to identify new disease loci. Once a complete genetic profile is identified, clinicians will have the ability to predict who will be affected by the disorder, institute preventative strategies, and identify effective therapies.

DermWorld: How will your research address gaps in hair disorder research?

Dr. Taylor: CCCA is a disease that reflects ethnic disparities in dermatologic care and research. A SCOPUS search revealed 157 CCCA citations from 1998 through 2020, as compared to 5,265 alopecia areata citations during the same time period. Furthermore, there are no randomized controlled trials and hence no evidence-based treatments for CCCA. It is known that CCCA is a devastating and non-reversible form of scarring alopecia that negatively impacts quality of life. In a study of 50 South African women with CCCA, the disease impacted self-image (56.3%) as well as relationships and interaction with others (34.8%) (Aguh et al., 2018). Current treatment options for CCCA are anecdotal, are directed at limiting further hair loss by eliminating follicular inflammation, and do not impact existing disease. Anti-inflammatory agents including oral antibiotics, topical and intralesional corticosteroids, and immunosuppressive agents are currently utilized for treatment. Data do not exist to predict who will develop CCCA, and this gap in medical knowledge leaves the population of women of African descent vulnerable to the onset and progression of this devastating form of hair loss.

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