Meta-Analysis on Central Centrifugal Cicatricial Alopecia by Morgan Rameau

Introduction

Central Centrifugal Cicatricial Alopecia (CCCA) is a form of scarring hair loss that disproportionately affects black women. It is characterized by hair loss and scarring that begins at the crown of the head and gradually migrates outwards, resulting in permanent hair loss and visible scarring. It is also associated with symptoms such as itching, burning, and tenderness. Despite research efforts, understanding the exact biological mechanism that triggers CCCA remains elusive to scientists. Researchers have proposed many hypotheses for the cause of CCCA, including genetic mutations and scalp trauma due to hairstyling practices; though, none of these have been definitively proven. CCCA remains a poorly understood disease that negatively impacts the confidence and health of black women. While medical treatment is effective in stopping the continuation of hair loss, it cannot reverse existing damage. Thus, it is critical for us to enhance our understanding of the disease in order to increase early detection, reduce potential risk factors, and treat those affected. In this meta-analysis, we aim to analyze the existing research on CCCA’s disease mechanisms, possible causes, and current treatment options. Additionally, we will explore its impact on the quality of life for those affected.

Methods

This meta-analysis examines 13 clinical studies conducted between 2005 and 2022, all of which investigated patients with Central Centrifugal Cicatricial Alopecia (CCCA) and similar hair conditions. The studies included black, white, and middle eastern patients aged 14 to 78. It is also important to note that there is significant geographic diversity among the patients, which will allow for the effective analysis of cultural haircare practices as they relate to CCCA. These studies were sourced using reputable public research databases such as The National Institutes of Health (NIH) and the Journal of the American Academy of Dermatology (JAAD). Additionally, two interviews with licensed American dermatologists were virtually conducted to further supplement the information found in the research studies.

Results

Mechanisms

Understanding the underlying mechanism behind CCCA, which refers to the biological processes leading to the onset of a particular condition, is crucial for dermatologists and drug developers to effectively treat the condition by targeting the root cause of the disease. Such mechanisms include genetic mutations, hormonal imbalances, and inflammation.

Researchers at Wake Forest University used the similarities between CCCA and other scalp conditions to propose a potential mechanism. They suggest that a genetic predisposition can cause changes in your body’s proteins that inadvertently activates cells known as fibroblasts, which then cause a type of scarring known as fibrosis. While this has yet to be definitively proven, it is a potential mechanism that would explain the scarring of the follicles. Further research on the activation of fibroblasts in CCCA patients could support this hypothesis.

Potential Causes

Despite being a common and well-researched condition, scientists have yet to identify the exact cause of CCCA. However, there are many theories. Since CCCA almost exclusively affects a single population, many believe genetics plays a role in its development. Research has proven that CCCA can be inherited, but whether or not a particular gene impacts its development is still being studied. Two recent studies explored the relationship between CCCA development and a mutation of the peptidylarginine deiminase type III (PADI3) gene. The PADI3 gene is responsible for the production of an enzyme of the same name. The PADI3 enzyme is essential in modifying the proteins that form the hair shaft. In a study of 16 patients, 31% showed a missense mutation in the PADI3 gene. An additional 42 CCCA patients then had their genomes sequenced, which revealed that 21% of them also harbored a PADI3 mutation. Both of these results are statistically significant (P = 0.04) considering that PADI3 mutations are much less common among similar demographics who do not have CCCA. 

A similar study conducted in Germany sought to find the genetic makeup of people with a rare disease known as uncombable hair syndrome (UHS). UHS affects a wider range of people racially than CCCA does, providing a different perspective on the role of genes in hair diseases. This study found that 71% of patients with UHS possessed a PADI3 mutation. While UHS differs greatly from CCCA, this research further suggests that mutations of the PADI3 gene can have an impact on hair formation and health. While these results show an association, further research is necessary to prove causation.

Risk Factors

Identifying risk factors for CCCA is crucial for prevention and treatment. Knowing who is at a higher risk for developing CCCA, due to environmental factors or genetic factors, can help those at higher risk modify their habits in order to decrease them. The greatest risk factor for developing CCCA is race. Although large population-based studies are lacking, the current literature suggests that CCCA exclusively affects people of African descent. 

Although race is the strongest indicator of developing CCCA, other factors impact how much hair is lost. A cross-sectional survey was conducted among 38 women with confirmed cases of CCCA. The women were grouped into two groups based on the severity of their disease: early-stage and advanced-stage. Their answers to the survey questions were compared to their disease severity to identify possible differences between early-stage and advanced-stage CCCA patients. The results showed a positive correlation between the duration of hair loss and the degree of hair loss (P = 0.003). This means that time is a significant risk factor in the severity of CCCA, suggesting that early detection and treatment can prevent hair loss. 

Similarly to the amount of time the disease has persisted, age is also a risk factor in CCCA. In a study at the University of Pennsylvania, researchers sought to examine the relationship between CCCA and age. Results showed that patients with CCCA had 25% fewer follicles per 4-mm punch than their younger counterparts. This further suggests that aging may affect the severity of the inflammation. However, young age has also been shown to be a risk factor. Because CCCA is most commonly found in middle-aged people, children are often misdiagnosed. While children do not necessarily show higher disease severity, this misdiagnosis allows the disease to persist longer without treatment, ultimately resulting in greater hair loss and scarring.

Haircare Practices

While the cause of CCCA is unknown, its development and severity are likely a combination of genetic and environmental factors. The most prominent environmental factor is hairstyling practices. Many styling practices, including tight braids and the use of chemical straighteners, can damage hair follicles over time and increase the severity of CCCA. In patients who wear natural hairstyles as opposed to heat- or chemically-straightened hairstyles, there is a higher likelihood of their condition improving after treatment. 

In addition to hairstyles, haircare practices also influence CCCA detection. A study by Tulane University showed that the best option for treating CCCA is early detection, which can involve seeing a regular hairstylist. In 21% of cases, a hairstylist was the first person to alert the patient that they may have a scalp condition that requires medical interference. 

To explore this further, we conducted interviews with dermatologists specializing in CCCA and other forms of alopecia in women of color. Dr. Susan Taylor at the University of Pennsylvania said, “Hairdressers and stylists should be trained on how to identify the problem.” Hairstylists are considered to be one of the critical first lines of defense in identifying people whose scalps may need medical attention. Additionally, dermatologist Dr. Cheri Frey of Howard University Hospital expressed a similar sentiment regarding the relationship between alopecia and hairstylists. “It’s hard to find a dermatologist, it’s even harder to find a black dermatologist… [we need to] bridge the gap between dermatologists and hairstylists.” Since CCCA mainly affects black women, having a black dermatologist can make the process more comfortable. A process by which stylists can refer their clients to local black dermatologists has the potential to improve early detection and outcomes.

Quality of Life

Hair loss can be detrimental to one’s confidence. The tenderness and inflammation experienced by CCCA patients further impact their quality of life. A study at the University of Pennsylvania examined the impact that CCCA had on the quality of life for those affected. The participants answered questions related to subjective symptoms, objective symptoms, relationships with others, and overall quality of life. The results showed a negative impact on quality of life using the Quality of Life Index (QLI), with suggestions for the patients to seek resources to assist in the psychosocial impacts of CCCA. 

Treatment Options

There are many effective treatment options currently available for patients with CCCA. Mild cases are often treated with topical steroids or corticosteroid injections in the scalp. However, once the disease has progressed to the point of scarring, there is little that can be done to revive the follicles. New treatments have emerged to potentially supplement the limits of the current treatment options.

Two studies examined the results of new CCCA treatments. The first examined the efficacy of a novel topical botanic solution containing key ingredients such as turmeric and fenugreek. Four African American women with treatment-refractory CCCA were treated with the topical solution, and some with its oral counterpart, for periods ranging from 8 weeks to 1 year. The results showed hair regrowth in all four patients within 8 weeks of use. 

The second study examined 30 adult African American women with CCCA and the efficacy of Clobetasol propionate 0.05% emollient foam in treating their conditions.  Safety and efficacy assessments were performed after 2, 6, 12, and 14 weeks of use. The results showed a substantial improvement in the tenderness and redness of the scalp. Scalp biopsies also revealed a reduction in inflammation. These are both promising treatments that have shown positive results in patients that were otherwise unable to be treated.

In speaking further with dermatologists, we gained insight into how alternate treatment options compare. Dr. Taylor said, “A scalp treatment, an oil treatment, a steam treatment, is not going to treat this.” CCCA is a medical condition that requires a professional analysis to find the best available treatment option. Currently, there is no research to prove the efficacy of any at-home treatments. It is important to understand this as well as the importance of seeing a dermatologist as early as possible to assist in successful treatment.

Conclusion

In examining recent literature on Central Centrifugal Cicatricial Alopecia (CCCA), we further confirm what has been proven by research and what has yet to be proven. Despite the research, the exact cause of CCCA remains unknown. Current studies suggest a potential genetic predisposition, particularly mutations in the PADI3 gene, but more research is necessary to prove this. Environmental factors, such as hairstyling practices, also contribute to the development and severity of CCCA. What is known is that early detection and treatment are crucial in preventing hair loss and scarring in patients. It is imperative to raise awareness among hairstylists and dermatologists to identify those at higher risk of developing CCCA and provide early interventions. Further research is necessary to understand the complex interplay between genetic and environmental factors and to identify new treatment options to supplement the current treatment modalities.





References

  1. Basmanav FB, Cesarato N, Kumar S, et al. Assessment of the genetic spectrum of uncombable hair syndrome in a cohort of 107 individuals. JAMA Dermatology. 2022;158(11):1245. doi:10.1001/jamadermatol.2022.2319

  2. Callender V, Kazemi A, Young C, Chappell J, Sperling L. Safety and efficacy of Clobetasol propionate 0.05% emollient foam for the treatment of central centrifugal cicatricial alopecia. Journal of Drugs in Dermatology. 2020;19(7):719-724. doi:10.36849/jdd.2020.5201

  3. Dlova NC, Jordaan FH, Sarig O, Sprecher E. Autosomal dominant inheritance of central centrifugal cicatricial alopecia in black South Africans. Journal of the American Academy of Dermatology. 2014;70(4). doi:10.1016/j.jaad.2013.11.035

  4. Eginli AN, Dlova NC, McMichael A. Central centrifugal cicatricial alopecia in children: A case series and review of the literature. Pediatric Dermatology. 2016;34(2):133-137. doi:10.1111/pde.13046

  5. Malki L, Sarig O, Romano M-T, et al. Variant padi3 in central centrifugal cicatricial alopecia. New England Journal of Medicine. 2019;380(9):833-841. doi:10.1056/nejmoa1816614

  6. Maranga A, Roche FC, Alausa M, et al. Quality of life in patients with central centrifugal CICATRICIAL ALOPECIA: A preliminary study. British Journal of Dermatology. 2022;187(5):802-804. doi:10.1111/bjd.21710

  7. Onamusi T, Larrondo J, McMichael AJ. Clinical factors and hair care practices influencing outcomes in central centrifugal cicatricial alopecia. 2022. doi:10.21203/rs.3.rs-2394193/v1

  8. Roche FC, Fischer AS, Williams D, Ogunleye T, Seykora JT, Taylor SC. Central centrifugal cicatricial alopecia: Histologic progression correlates with advancing age. Journal of the American Academy of Dermatology. 2022;86(1):178-179. doi:10.1016/j.jaad.2021.01.028

  9. Subash J, Alexander T, Beamer V, McMichael A. A proposed mechanism for central centrifugal cicatricial alopecia. Experimental Dermatology. 2018;29(2):190-195. doi:10.1111/exd.13664

  10. Suchonwanit P, Hector CE, Bin Saif GA, McMichael AJ. Factors affecting the severity of central centrifugal cicatricial alopecia. International Journal of Dermatology. 2016;55(6). doi:10.1111/ijd.13061

  11. Uhlenhake EE, Mehregan DM. Prospective histologic examinations in patients who practice traumatic hairstyling. International Journal of Dermatology. 2013;52(12):1506-1512. doi:10.1111/j.1365-4632.2012.05621.x

  12. Umar S, Kan P, Carter MJ, Shitabata P. Treatment-refractory central centrifugal cicatricial alopecia responsive to a novel botanical treatment. Clinical, Cosmetic and Investigational Dermatology. 2022;Volume 15:609-619. doi:10.2147/ccid.s358618

  13. Veerabagu SA, Lauth MJ, Obayomi A, Correa M, Murina AT. Hair stylists as screeners for scarring hair loss within the African American Community: A cross‐sectional study. British Journal of Dermatology. 2021;184(4):769-770. doi:10.1111/bjd.19688

Ajia Minnis