INTRODUCTION
Alopecia areata (AA) is an autoimmune hair loss disorder arising due to loss of hair follicle immune privilege.1 Increased antigen presentation at the bulb of the hair follicle leads to recruitment of various immune cells including CD8+ cytotoxic T cells and natural killer (NK) cells. The subsequent release of numerous inflammatory mediators causes hair follicle destruction and further antigen presentation, thus feeding a perpetuating cycle resulting in clinical hair loss. Treatments for AA target the inflammatory aspect of the disease, such that prevention of further inflammatory destruction allows for the restoration of the hair follicle immune privilege and therefore cessation of the destructive autoimmune cycle. These treatments have traditionally included local and systemic corticosteroids, immunomodulatory agents (ie, janus kinase [JAK] inhibitors, calcineurin inhibitors, anthralin, etc.), and excimer laser.2 However, no treatment modality is curative and relapse rates remain high. The purpose of this narrative review is to examine localized cryotherapy as a low-tech therapeutic option for patients with AA and compare its efficacy with that of other local treatments, including intralesional steroids as the current standard of care.3
Steroid and Other Therapeutics for Alopecia Areata
Traditional therapies for AA have been aimed at treating active disease and reducing relapse. Time of active disease correlates with probability of relapse with rates of ~13%, ~65%, and ~100% for patients with <6 months, 6 to 12 months, and >12 months active disease, respectively.4
Topical steroids are also mainstay treatments for AA. Tosti et al found that treatment with topical clobetasol propionate 0.05% ointment under occlusion nightly for 6 days a week for 6 months yielded hair regrowth in 8 of 28 (30%) patients.7 However, only 5 of 28 (17.8%) patients had long-term benefits without relapse.
Steroid and Other Therapeutics for Alopecia Areata
Traditional therapies for AA have been aimed at treating active disease and reducing relapse. Time of active disease correlates with probability of relapse with rates of ~13%, ~65%, and ~100% for patients with <6 months, 6 to 12 months, and >12 months active disease, respectively.4
First-line therapy for localized AA remains intralesional corticosteroid injection with triamcinolone acetonide.5 A meta-analysis found 81% and 77% of subjects having hair regrowth following injections of 5 mg/mL and 10 mg/mL of triamcinolone acetonide, respectively.6 Subjects were treated every 3 weeks or monthly intervals, for either 6 weeks (1 study), 12 weeks (4 studies), or 6 months (2 studies). The main adverse effect was skin atrophy, seen in 20% of patients treated with a higher concentration of 10 mg/mL.6
Topical steroids are also mainstay treatments for AA. Tosti et al found that treatment with topical clobetasol propionate 0.05% ointment under occlusion nightly for 6 days a week for 6 months yielded hair regrowth in 8 of 28 (30%) patients.7 However, only 5 of 28 (17.8%) patients had long-term benefits without relapse.
Other studies have shown that topical desoximetasone 0.25% cream showed promising results with some cases of complete hair regrowth.5 Relapse rates following cessation of topical treatment were found to vary between 37% and 63%.
Other agents have been investigated for the treatment of AA but remain uncommonly used for various reasons. Calcineurin inhibitors have been investigated for the treatment of AA. Both tacrolimus and pimecrolimus showed promising results as topical agents when used in animal models, but these results failed to translate in clinical trials involving patients with AA.8
Similar results were observed in trials investigating anthralin, a hydroxyanthrone anthracene derivative. Despite successful results in animal models, the drug failed to achieve acceptable results in patients with AA.8 The JAK inhibitor baricitinib has only been recently approved for the treatment of AA by the US Food and Drug Administration. It has shown great efficacy, with 32.6% of patients with moderate to severe AA who were treated with 4 mg of Baricitinib once daily achieving at least 80% scalp hair coverage at week 36, as compared with 3% of patients in the placebo arm.9 Nevertheless, safety and adverse effects remain a major concern with the use of baricitinib and the drug comes with a boxed warning for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis.10 Thus, there remains a great need for other effective treatment modalities for AA.
MATERIALS AND METHODS
Literature Search
A literature search in September 2022 was performed using the PubMed, EMBASE, and MEDLINE databases. Clinical studies that assess the use of liquid nitrogen cryotherapy with or without intralesional steroid for the treatment of alopecia areata were included. The databases were searched using different combinations of the following keywords: cryotherapy, alopecia areata, hair loss, intralesional steroid, and combined therapy. Roughly 1800 results were found and examined for relevance. Studies were chosen based on good clinical design and pertinence to the topic of interest. Of the 1800 published articles, 25 were selected for possible inclusion in this review. After reviewing the types of cryotherapy and the method of administration, the authors chose to omit 17 of the studies due to differences in type of cryotherapy administered. Eight studies were chosen to include in this review, some examined only cryotherapy for the treatment of AA, while others compared superficial cryotherapy with intralesional steroid, and some examined both superficial cryotherapy with intralesional steroid injection.
Cryotherapy for Alopecia Areata
Cryotherapy is an existing treatment used for a variety of dermatological conditions such as verruca vulgaris and basal cell carcinoma mainly due to its destructive property.11 However, cryotherapy also exhibits immunomodulatory properties. In vivo studies revealed cryotherapy to reduce IL-17 release by T lymphocytes and to reduce T cell activation through reduced IL-1β/IL-23.12,13 A hypothermic microenvironment also leads to decreased lymphocyte proliferation, cytotoxic CD8+ T cell function, and expression of interferon-gamma (IFN-y) and IL-2.14 Furthermore, Lei et al postulated that superficial cryotherapy could induce reactive vasodilation after the immediate initial vasoconstrictive response and improve microcirculation in hair follicles leading to increased hair growth.15 The immunomodulatory and vascular effects of cryotherapy have made it an attractive low-cost and safe potential therapeutic modality for AA. Outcomes of clinical studies focused on cryotherapy for AA are reviewed next (Table 1).
Efficacy of Cryotherapy Monotherapy for Alopecia Areata
Jun et al performed a retrospective review of 353 subjects with AA treated with superficial cryotherapy consisting of liquid nitrogen sprayed on patches of AA 3 to 4 times each session every 2 weeks for 3 months.16 Seventy-nine (~23%) subjects had 60% terminal hair regrowth and 136 subjects (~39%) had <60%of regrowth in alopecic lesions. When stratifying by affected scalp surface area, subjects with 25% to 50% scalp involvement demonstrated greater response (82.0%) compared with subjects with more severe disease involving >=50% of the scalp with 17.0% being responders. With respect to adverse effects, only 18 (5.1%) of all treated subjects reported adverse effects consisting of mild pain, pruritis, or swelling. All symptoms resolved within 48 hours after treatment without intervention.
Zawar et al examined the efficacy of cryotherapy with liquid nitrogen in 11 subjects with recalcitrant AA.17 Recalcitrant AA was defined as lack of therapeutic benefit with various treatment modalities over 6 months. Subjects were treated every 2 weeks for a maximum of 8 weeks and followed for 2 months after their last cryotherapy treatment. Each subject was treated with dual freeze and thaw cycles of 15s each. A total of 10 subjects completed the study and all exhibited some degree of regrowth. 50% demonstrated excellent response (defined as greater than 75% regrowth of terminal hairs) while 30% of patients reported a satisfactory response (defined as 51–75% regrowth of terminal hairs). Only 1 subject reported a poor response with less than 25% regrowth. Adverse effects, which included erythema and edema, were minimal and self-limited.
The efficacy of superficial cryotherapy with liquid nitrogen was also evaluated by Abdel-Majed et al in 17 participants with recalcitrant AA.18 Participants underwent weekly cryotherapy once a week for 6 weeks. Each lesion was sprayed for 2 to 3 seconds and thawed for 3 to 5 seconds, followed by another cycle with the same parameters. Thirteen lesions (65.0% of lesions) responded to treatment with at least 25% of terminal
