Dear Editor:
Although advances in molecular biology have led clinicians to develop new treatments for alopecia areata (AA), it remains a difficult disease to treat due to its unpredictable course1. Superficial cryotherapy (SC) using liquid nitrogen or other cryogens has been used as an alternative treatment in patients with recalcitrant AA2. Despite several studies reporting positive results3,4, the efficacy of SC in treating AA remains unestablished. Therefore, we conducted a systematic review to evaluate the efficacy of SC for AA treatment.
In accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis reporting guidelines, we conducted a comprehensive literature search of the PubMed, Embase, and Web of Science databases for research published before August 2022 (Supplementary Fig. 1). The search terms used were “alopecia,” “hair loss,” “baldness,” “cryo-,” and “nitrog-.” As all the studies arbitrarily defined the degree of hair regrowth, we standardized and categorized the degree of hair regrowth based on the criteria used in each study into major hair regrowth (≥75% regrowth), minor hair regrowth (25%~74% regrowth), and minimal hair regrowth (<25% regrowth, including vellus hair regrowth) groups to enable objective assessment of hair regrowth rate. If regrowth could not be clearly classified according to this scale, we assumed even distribution within each range and assigned the number of patients accordingly. Quality assessment was conducted using a modified version of the Newcastle–Ottawa Scale, and articles with adequate quality (score≥5) were included. We evaluated the rates of adverse events (AEs) and recurrence after SC. All estimates were computed using the R statistical software (4.1.1; R Foundation for Statistical Computing).
Of the 570 studies screened, 12 were included in the analysis (Table 1, Supplementary Materials). Most of the included studies did not compare the SC-treated group with controls, but rather with other treatment-modality groups. In summary, the proportions of individuals with major and minor hair regrowth were 26.2% and 37.8% respectively. We further searched the literature within the retrieved studies to evaluate the efficacy of SC in combination with other treatment modalities in treating AA (Table 2). Although a small number, two studies reported combination therapy to be more efficacious in treating AA.
Table 1. Characteristics and main findings of the included studies.
| Authors (year) | Country | Study design | Follow up | The degree of hair regrowth (%) | Total | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Aslam et al. (2022) | Pakistan | Descriptive case series | 6 months | >50 | ≤50 | |||||
| 26 (27.4) | 69 (72.6) | 95 (100) | ||||||||
| El Sayed et al. (2022) | Egypt | Prospective comparative study (SC vs. intralesional steroid injection, comparing patches within a single subject) | 4 months | >75 | 50~75 | 20~50 | 0~20 | |||
| 2 (10.0) | 3 (15.0) | 11 (55.0) | 4 (20.0) | 20 (100) | ||||||
| Nouh et al. (2022) | Egypt | Cross-sectional study (SC vs. fractional CO2 laser) | 3 months | ≥75 | 51~75 | 26~50 | 11~25 | <10 | ||
| 13 (32.5) | 10 (25.0) | 10 (25.0) | 7 (17.5) | 0 (0.0) | 40 (100) | |||||
| Sardana et al. (2022) | India | Prospective comparative study (SC vs. intralesional steroid injection) | 3 months | 90~100 | 60~90 | 30~60 | 0~30 | |||
| 9 (18.0) | 18 (36.0) | 14 (28.0) | 9 (18.0) | 50 (100) | ||||||
| Aboeldahab et al. (2021) | Egypt | Prospective randomized single-blinded trial (SC* vs. microneedling) | 3 months | ≥75 | 51~75 | 50 | ||||
| 15 (37.5) | 6 (15) | 19 (47.5) | 40 (100) | |||||||
| Abdel Motaleb et al. (2020) | Egypt | Randomized trial (Comparisons of different freezing times: group A, 3~5 sec; group B, 8~10 sec; group C, 13~15 sec) | 1 month after the last treatment | >75 | 51~75 | 26~50 | ≤25 | |||
| A | 7 (30.4) | 8 (34.8) | 5 (21.7) | 3 (13.0) | 23 (100) | |||||
| B | 11 (44.0) | 8 (32.0) | 3 (12.0) | 3 (12.0) | 25 (100) | |||||
| C | 10 (47.6) | 6 (28.6) | 3 (14.3) | 2 (9.5) | 21 (100) | |||||
| Sayed et al. (2020) | Egypt | Randomized controlled trial (SC vs. topical psoralen and UVA) | 3 months | >75 | 51~75 | 26~50 | 0~25 | |||
| 9 (33.3) | 8 (29.6) | 3 (11.1) | 7 (25.9) | 27 (100) | ||||||
| Jun et al. (2017) | Korea | Retrospective cohort study | 3 months | ≥60 | <60 | Vellus only | 0 | |||
| 79 (22.4) | 136 (38.5) | 85 (24.1) | 53 (15.0) | 353 (100) | ||||||
| Zawar et al. (2016) | India | Case series | 2-week intervals until the 16th week | ≥75 | 51~75 | 26~50 | 11~25 | <10 | 10 (100) | |
| 5 (50.0) | 3 (30.0) | 1 (10.0) | 1 (10.0) | 0 (0.0) | ||||||
| Amirnia et al. (2015) | Iran | Descriptive, comparative study (SC vs. intralesional steroid injection) | 3, 6, 9, and 12 weeks | 90~100 | 60~90 | 30~60 | 0~30 | |||
| 28 (23.3) | 40 (33.3) | 0 (0.0) | 52 (43.3) | 120 (100) | ||||||
| Mohammad et al. (2013) | Iran | Cross-sectional, non-randomized study† | >75 | 50~75 | 25~50 | 1~25 | 0 | |||
| 4 weeks | 0 (0.0) | 9 (20.5) | 12 (27.3) | 6 (13.6) | 17 (38.6) | 44 (100) | ||||
| 8 weeks | 2 (4.5) | 15 (34.1) | 8 (18.2) | 4 (9.1) | 15 (34.1) | 44 (100) | ||||
| Lei et al. (1991) | USA | Case-control study (SC vs. control [custom-prepared lotion]) | 4 weeks | >60 | ≤60 | |||||
| 70 (97.2) | 2 (2.8) | 72 (100) | ||||||||
SC: superficial cryotherapy, UVA: ultraviolet A. *SC was performed using dimethyl ether and propane mixture. †SC was performed using CO2 contact cryogun.
Table 2. Summary of hair regrowth in alopecia areata treated using superficial cryotherapy in combination with other treatment modalities.
| Authors (year) | Country | Study design | Combination therapy | Participants (n) | Follow-up | Relation to clinical efficacy |
|---|---|---|---|---|---|---|
| Lee and Lee (2021) | Korea | Retrospective cohort study | SC+TC vs. SC+TC+AH (fexofenadine [180 mg/day for adults and 30 mg/day for pediatric patients] and ebastine [10 mg/day for adults]) | 121 vs. 24 | 79 months | Cumulative incidence analysis showed a significant increase in major hair regrowth (60% reduction in SALT score) in the SC+TC+AH group (p=0.045). |
| Choe et al. (2017) | Korea | Prospective, split-face comparative study | SC+DPCP vs. DPCP On each eyebrow of a single patient, DPCP was treated in the scalp | 20 | 5 months | Hair density (hair count/cm2) was significantly increased in the SC-treated eyebrows at 5 months of treatment (p<0.01); hair thickness was increased in the SC-treated eyebrows (p<0.01) |
| Morita et al. (2002) | Japan | Case series | SADBE+SC* and/or Ca and/or Ce | 17 | Up to 21 months | Five patients (29.4%) showed hair regrowth with SADBE+SC*+Ca+ Ce combination therapy, three (17.6%) showed regrowth with SADBE monotherapy, and one patient (5.9%) revealed regrowth with SADBE+SC*+Ce combination therapy |
SC: superficial cryotherapy, TC: topical corticosteroid, AH: antihistamines, DPCP: diphenylcyclopropenone, SADBE: squaric acid dibutylester, Ca: carpronium chloride, Ce: cepharantin. *Superficial cryotherapy was performed using topical dry ice.
Commonly reported AEs included pain, erythema, vesiculation, and pigmentary changes. However, all AEs were well tolerated and managed, and no participant withdrew because of an AE (Supplementary Table 1). The proportion of patients with recurrence varied between studies (4.55%~21.7%), although the data available were limited.
Since the utility of SC in treating AA was first reported by Huang et al.3, only a few studies have reported that SC exhibits satisfactory efficacy in treating AA. Several underlying mechanisms have been proposed, including significant local vasodilation following initial vasoconstriction leading to local edema, inflammation, and improved microcirculation5. Associations with diminished T-cell and monocyte activation and decreased interleukin (IL)-17, IL-1β, and IL-23 levels have also been reported, which indicates immune rebalancing6,7.
Overall, SC in treating AA appears to be effective. The proportion of patients with more than 25% of hair regrowth was 64.0%, though some recurrent cases were reported. Combination therapy including SC may escalate treatment efficacy. SC seems to be particularly effective for treating eyebrow lesions. Our previous study8 and two case reports9,10 reported that hair regrowth was without significant adverse effects after SC for AA patches in the eyebrows. As AA is a chronic, relapsing disease that requires long-term treatment1, topical or intralesional corticosteroid use inevitably causes adverse effects, such as telangiectasia, purpura, and skin atrophy. Furthermore, exposure of the eyes to topical immunotherapy could be hazardous. Therefore, SC can be considered as a safe and effective therapy for eyebrow lesions, provided the eyes are adequately protected.
Although we could not directly compare patients who received SC with controls due to the lack of well-structured studies, we found that SC is considerably effective for hair regrowth and can lead to considerable hair regrowth in patients with recalcitrant AA. Our study has several limitations. Few studies were included in the analysis, and few reported the recurrence rate, which could have been used to determine the long-term efficacy of SC. Moreover, publication bias, i.e., reporting of only effective cases, may be present, due to small number of included studies and participants. Nonetheless, our study is the first comprehensive and systematic review of SC for treating AA.
In conclusion, SC can be an effective alternative treatment for recalcitrant AA and is associated with minimal adverse effects. SC can be used to treat eyebrow lesions. Furthermore, large-scale studies should be conducted to evaluate the underlying mechanisms and assess the clinical efficacy and support our findings.
Footnotes
CONFLICTS OF INTEREST: The authors have nothing to disclose.
FUNDING SOURCE: None.
SUPPLEMENTARY MATERIALS
Supplementary data can be found via http://anndermatol.org/src/sm/ad-22-095-s001.pdf.
The rate of adverse events (AEs) and recurrence for superficial cryotherapy
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart showing the literature search and study selection processes.
References
- 1.Strazzulla LC, Wang EHC, Avila L, Lo Sicco K, Brinster N, Christiano AM, et al. Alopecia areata: an appraisal of new treatment approaches and overview of current therapies. J Am Acad Dermatol. 2018;78:15–24. doi: 10.1016/j.jaad.2017.04.1142. [DOI] [PubMed] [Google Scholar]
- 2.Lee S, Lee WS. Management of alopecia areata: updates and algorithmic approach. J Dermatol. 2017;44:1199–1211. doi: 10.1111/1346-8138.13933. [DOI] [PubMed] [Google Scholar]
- 3.Huang P, Huang S, Wei G. One-hundred twenty three cases of alopecia areata treated with liquid nitrogen cryotherapy. J Clin Dermatol. 1986;15:269 [Google Scholar]
- 4.Abdel Motaleb AA, Sayed DS. Different freezing time of superficial liquid nitrogen cryotherapy in treatment of recalcitrant alopecia areata: randomized clinical trial. Dermatol Ther. 2020;33:e13640. doi: 10.1111/dth.13640. [DOI] [PubMed] [Google Scholar]
- 5.Pimentel CB, Moraes AM, Cintra ML. Angiogenic effects of cryosurgery with liquid nitrogen on the normal skin of rats, through morphometric study. An Bras Dermatol. 2014;89:410–413. doi: 10.1590/abd1806-4841.20142249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Atanaskova Mesinkovska N. Emerging unconventional therapies for alopecia areata. J Investig Dermatol Symp Proc. 2018;19:S32–S33. doi: 10.1016/j.jisp.2017.10.012. [DOI] [PubMed] [Google Scholar]
- 7.Lindsay A, Othman MI, Prebble H, Davies S, Gieseg SP. Repetitive cryotherapy attenuates the in vitro and in vivo mononuclear cell activation response. Exp Physiol. 2016;101:851–865. doi: 10.1113/EP085795. [DOI] [PubMed] [Google Scholar]
- 8.Choe SJ, Lee WS. Efficacy of superficial cryotherapy on the eyebrows of patients with alopecia universalis also treated with contact immunotherapy on the scalp: a prospective, split-face comparative study. Int J Dermatol. 2017;56:184–189. doi: 10.1111/ijd.13533. [DOI] [PubMed] [Google Scholar]
- 9.Jeon SY, Ahn BK, Lee S, Lee WS. Superficial cryotherapy of alopecia areata in eyebrows. Korean J Dermatol. 2004;42:1024–1027. [Google Scholar]
- 10.Lee SJ, Kim JY, Hann SK. Two cases of alopecia areata on eyebrow treated by superficial cryotherapy. Korean J Dermatol. 2003;41:1079–1081. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
The rate of adverse events (AEs) and recurrence for superficial cryotherapy
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart showing the literature search and study selection processes.