Effect of Treatment With Low-Dose Metformin on Clinical Symptoms and Scalp Gene Expression Patterns in Patients With Central Centrifugal Cicatricial Alopecia

Metformin, traditionally used as an antidiabetic medication, has also demonstrated anti-inflammatory properties and enhancement of mitochondrial biogenesis and function. By modulating mitochondrial activity, metformin may reduce the production of free radicals and oxidative stress, ultimately enhancing cellular health. The association of oral metformin therapy with improved clinical outcomes in patients with central centrifugal cicatricial alopecia (CCCA) has been reported in the literature; however, it has not been thoroughly investigated.¹ This article by Bao et al aims to show the association of low-dose extended-release metformin treatment (500 mg; administered orally once daily) with clinical symptoms and scalp gene expression patterns in 12 patients with CCCA.

The significant findings included clinical improvement in 50% of the patients, with improvement in the central scalp alopecia photographic severity scale for the photographs published. Approximately 67% percent of the patients experienced improvement in symptoms, and approximately 17% experienced worsening symptoms. Of note, 1 patient experienced clinical regression 3 months after discontinuing metformin.

Of the 4 patients whose biopsy specimens were sent for gene expression profiling via RNA sequencing analysis, 3 were on monotherapy with low-dose metformin before and during the treatment period. The fourth patient received concomitant therapy with clobetasol 0.05% ointment, intralesional triamcinolone injections, and oral minoxidil. Clinical improvement in hair loss was noted in 1 patient in the monotherapy group as well as the patient receiving multitherapy. Additionally, baseline sequencing in both groups demonstrated similar levels of gene expression patterns. However, after metformin treatment, the differential gene expression between baseline lesional and metformin-treated lesional scalps was statistically significant. Specifically, MMP7, COL6A1, Th17, EMT, and dermcidin were downregulated, whereas keratin-associated proteins, AMPK, and Th22 were upregulated. This translates to a decrease in extracellular matrix remodeling and an increase in keratinization and hair cycling. However, the finding of Th22 upregulation requires further elucidation, as this marker is known to have both proinflammatory as well as anti-inflammatory effects.²

The authors state that, in patients with CCCA, hair growth may be promoted by "reversing" the fibrotic transcriptional signature with low-dose metformin. Although the results of this study are promising and demonstrate decreases in both inflammatory and fibrotic markers, the impact on extensively fibrosed hair follicles remains dubious. Areas of hair loss in CCCA (particularly the early stages) still have quiescent hair follicles which can be salvaged with anti-inflammatory therapy. This process is often referred to as "follicular rescue."³ Although metformin may improve the outcomes associated with these follicles, its reversal of fibrosis in severely fibrosed follicles requires further research. However, if low-dose metformin is utilized early in the course of CCCA, the decreased fibrotic changes may diminish the ultimate disease severity.

References

1. Onamusi T, Larrondo J, McMichael AJ. Clinical Factors and Hair Care Practices Influencing Outcomes in Central Centrifugal Cicatricial Alopecia. Arch Dermatol Res. 2023;315(8):2375–2381. https://link.springer.com/article/10.1007/s00403-023-02630-5
2. Jiang Q, Yang G, Xiao F, et al. Role of Th22 Cells in the Pathogenesis of Autoimmune Diseases. Front Immunol. 2021;12:688066. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.688066/full
3. Tan E, Martinka M, Ball N, et al. Primary Cicatricial Alopecias: Clinicopathology of 112 Cases. J Am Acad Dermatol. 2004;50(1):25–32. https://www.jaad.org/article/S0190-9622(03)02995-5/abstract