In a new study published in the JAMA Dermatology, Dr. Aguh's research team studied the potential of metformin, a widely used antidiabetic drug, as a novel targeted therapy for Central Centrifugal Cicatricial Alopecia (CCCA) and other cicatricial alopecias. Cicatricial or scarring alopecias are a group of chronic inflammatory hair disorders characterized by permanent hair loss due to the destruction of hair follicles and their replacement with fibrous scar tissue. These conditions not only affect physical appearance but also significantly impair the quality of life of those affected.
Among the various forms of cicatricial alopecia, CCCA is the most common, predominantly affecting Black women. Interestingly, CCCA has been linked to an increased risk of systemic comorbidities, particularly type 2 diabetes mellitus (T2DM).
Current treatments for CCCA focus on inflammation but do not address fibrosis and scarring leading to permanent hair loss. Gene expression profiling shows similarities with other scarring disorders, highlighting the need for interventions targeting and reversing fibrosis. Metformin enhances insulin sensitivity via AMPK, showing antifibrotic effects by inhibiting TGFβ signaling, collagen production, and the angiotensin II pathway. Its approval for T2DM makes it a promising candidate for repurposing in cicatricial alopecia treatment.
The manuscript presents a retrospective case series involving 12 patients with treatment-refractory CCCA, who were administered low-dose oral metformin (500 mg daily). These patients had not responded to conventional therapies, and their clinical symptoms had either stagnated or worsened. Following metformin treatment, eight of the 12 patients experienced noticeable improvements in symptoms such as scalp pain, pruritus, inflammation, and resistance. Six patients showed clinical evidence of hair regrowth after at least six months of treatment, with one patient experiencing a relapse three months after discontinuing metformin.
To understand the impact of metformin at the molecular level, bulk RNA sequencing was performed on scalp biopsies taken from four patients before and after metformin treatment. The analysis revealed significant changes in gene expression, with 34 genes upregulated and eight genes downregulated post-treatment. Notably, pathways related to keratinization, epidermis development, and the hair cycle were upregulated, while those associated with scarring and fibrosis were downregulated. These findings suggest that metformin may reverse the pathological fibrosis observed in CCCA, promoting hair regrowth and improving clinical outcomes.
The study also highlighted the potential anti-inflammatory effects of metformin, particularly through the suppression of the Th17 inflammatory pathway. This is significant because Th17 cells and their associated cytokines, such as IL-17, have been implicated in the pathogenesis of other skin diseases. By inhibiting these inflammatory processes, metformin may offer a dual benefit in treating both the fibrotic and inflammatory components of CCCA.
Larger, prospective, randomized clinical trials are necessary to validate these results and establish metformin's efficacy and optimal dosing in treating cicatricial alopecias. However, this study lays important groundwork, suggesting that metformin, beyond its role in diabetes management, could be a valuable tool in combating the devastating effects of CCCA and potentially other fibrosing hair disorders.
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