Topical Pentoxifylline; Metformin Versus Betamethasone in the Treatment of Alopecia Areata.

Alopecia areata (AA) is a common tissue-specific autoimmune disease characterized by non-scaring hairloss.

Alopecia areata affects around 2.1% of the population at a point of their life. It affects both males and females without significant difference. Alopecia areata can occur at any age with a peak incidence in the twenties and thirties, however, the younger the attack, the more severe the course of the disease.

Alopecia areata is subdivided into 3 subgroups depending on the extent and site of hair loss; these are patchy alopecia areata, alopecia totalis and alopecia universalis. The most common presentation is patchy alopecia areata which presents as a rounded or oval patch(es) of hairloss.

Dermoscopy is a noninvasive tool which aids the diagnosis of alopecia areata. Characteristic dermoscopic features in AA include black dots (BDs), yellow dots (YDs), exclamation mark hairs (EHs), and broken hairs (BHs). BDs and EHs are the most specific findings in AA and correlate with disease activity, whereas YDs are seen in all the stages of the disease and correlate with disease severity.

The course of AA is unpredictable, with spontaneous remission during the first 6-12 months occurs in 30-50% of patients.

It has been hypothesized to be a T-cell mediated immune response disease through CD4+ and CD8+ that violate the immune privilege of the anagen hair follicle, leading to loss of the growing hair shaft (Islam et al., 2015). Studies regarding the pathogenesis of AA reveal an intricate complexity involving multiple factors including immunology, genetics, the environment, and potentially the microbiome.

Furthermore, it can be associated with other autoimmune diseases such as thyroid disease, diabetes mellitus type 2, vitiligo, systemic lupus erythematosus, psoriasis, inflammatory bowel disease and rheumatoid arthritis.

Alopecia areata has a major impact on patient's quality of life as it affects patient's self-esteem and his social relationships. Moreover, it was found to be associated with different psychiatric disorders such as depression and generalized anxiety disorder; which explains the need for early and appropriate treatment for alopecia areata.

There are many treatment modalities for AA including topical treatment, intralesional injections, systemic corticosteroids, systemic immunosuppressant like methotrexate or cyclosporine, excimer laser and photochemotherapy. Recently there's an emergence of new treatments for AA such as; Janus kinases signal transducer and activator of transcription proteins (JAK-STAT) inhibitors (baricitinib, ritlecitinib, deuruxolitinib, brepocitinib) as a promising new class of agents that can induce significant hair regrowth, phosphodiesterase-4 inhibitors (apremilast) and the biologics (dupilumab, secukinumab and aldesleukin) appear to have limited efficacy so far. However, there's no uniformly effective medication for this disease.

In the last few years, several topical agents were suggested as possible therapeutic options for patchy AA such as topical methotrexate and topical calcipotriol.

Topical corticosteroids are frequently used in treatment of patchy alopecia areata, potent and moderately potent steroids are the first line treatment in children and adults who can't tolerate intralesional steroid injection in patchy alopecia areata. However, they have a low success rate in treatment of alopecia totalis and universalis.

They have various formulations (foams, creams, lotions, ointment and solution) that can be used and have fewer side effects than systemic therapy.

Corticosteroids are known to have a strong inhibitory effect on activation of T-lymphocytes providing that AA is a T-cell mediated autoimmune response thus decreasing the inflammation around hair bulb region, allowing hair follicles to enter a normal hair cycle.

Side effects of topical formulations of corticosteroids include; folliculitis, that is the most common, post-inflammatory hyper/hypopigmentation, atrophy, and telangiectasia.

Pentoxifylline (PTX) is a methylxanthine derivative, which acts as a phosphodiesterase inhibitor and it is primarily used in microcirculatory disorders. Pentoxifylline also has an immunomodulatory effect through inhibition of several cytokines including TNF -α, IL-1, and IL-6 that play a role in inflammation. It has also been shown to suppress B cells, T cells, and neutrophils as well as decrease the expression of endothelial adhesion molecules.

Oral PTX has been used in dermatological disorders such as alopecia areata with beneficial effects. To the best of our knowledge there is no previous study reported the use of topical PTX in treatment of AA, however, there is only one study that used intralesional PTX in treatment of patchy AA. In this study intralesional PTX was tried both alone and in combination with intralesional triamcinolone acetonide (TRA) versus intralesional triamcinolone acetonide alone. This study found that the combined drug usage (TRA \& PTX) had the best results followed by PTX alone and then triamcinolone acetonide alone (72.0%, 60.0%, and 32.0%, respectively).

Metformin is commonly used as a first-line treatment for type 2 diabetes. It reduces glucose levels by improving peripheral tissues' sensitivity to insulin, decreasing the liver's gluconeogenesis and reducing intestinal glucose absorption. Recently, several studies reported the usefulness of metformin in treatment of different autoimmune disorders such as scleroderma and systemic lupus erythematosus due to its immunomodulatory actions, as a new deal of an old drug.

Metformin can modulate the immune system by increasing the cellular AMP-activated protein kinase (AMPK) enzyme that inhibits the Janus kinase/signal transducers and activators of transcription (JAK-STAT) and mammalian target of Rapamycin (mTOR) intracellular signaling pathways. Inhibition of the mTOR pathway prevents the proliferation and differentiation of T lymphocytes into cytotoxic T cells, which are the leading causes of hair follicle destruction in AA. It also promotes the proliferation of regulatory T cells (Tregs); that play a crucial role in maintaining the immune privilege of hair follicles as they produce transforming growth factor-1 (TGF-1) that contributes to maintaining immune privilege.

Inhibition of the JAK-STAT pathway by metformin prevents the production of cytokines, including interferon gamma (IFN-γ) and interleukin 17 (IL-17). The production of these cytokines is necessary to collapse the immune privilege status of the hair follicle. Moreover, metformin was found to enhance the proliferation and differentiation of hair follicle stem cells, aiding hair follicle regeneration.

Oral metformin has been used in different dermatological diseases such as hormonal acne, hidradenitis suppurativa (HS) and acanthosis nigricans in which it may act through improving hyperinsulinemia. Additionally, it was found effective when used topically in treatment of melasma with an equivalent effect to triple combination cream (TCC), and acne vulgaris.

Interestingly, topical metformin was reported to be successful in treating central centrifugal Cicatricial alopecia in a single case report.

Recently, Kokhabi et al., 2023 hypothesized that topical metformin may be effective in AA due to its anti-inflammatory and immunomodulatory actions, however, to the best of our knowledge, no clinical trials have been conducted yet and such a hypothesis still needs to be proven by future studies.