Comparing the frequency of isotretinoin-induced hair loss at <0.5-mg/kg/d versus ≥0.5-mg/kg/d dosing in acne patients: A systematic review

Over 1 million isotretinoin prescriptions are authorized in the United States per year. An insight into the frequency, dose dependency, timing, and reversibility of hair loss associated with isotretinoin treatment for acne vulgaris could help guide dosing regimens and patient counseling. The objective of this systematic review was to assess the frequency of hair loss in patients with acne vulgaris on <0.5 mg/kg/d daily doses of isotretinoin versus the frequency of hair loss in patients with acne vulgaris on ≥0.5 mg/kg/d daily doses of isotretinoin. An Embase and MEDLINE search was conducted on July 15, 2020, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The review focused on acne vulgaris patients. The treatment of acne vulgaris is the most common use of isotretinoin, and the population is typically younger and with fewer comorbidities. Twenty-two studies reported hair loss with oral isotretinoin treatment. A frequency analysis suggested that patients with acne vulgaris on <0.5 mg/kg/d of isotretinoin experienced hair loss at a frequency of 3.2% (n = 18/565) compared with those on ≥0.5 mg/kg/d, who experienced hair loss at a frequency of 5.7% (n = 192/3375). Inferential statistics were not possible. Physicians should consider counseling patients about the risk of telogen effluvium prior to drug initiation, as is commonly done for other side effects. The potential trend of increased hair loss frequency at a higher daily dosing warrants further investigation using higher-quality research.


INTRODUCTION
Acne vulgaris is a common disease that affects up to 80% of teenagers, [1][2][3][4][5] half of whom continue to experience acne in adulthood. 1,2,[5][6][7][8][9] The most clinically effective first-line therapy for nodular or inflammatory acne vulgaris is isotretinoin, with [1 million prescriptions per year in the United States. 5,10 Given the volume of patients on this medication, the side effects that occur at seemingly lower frequencies represent a large cohort of patients.
Although isotretinoin has a significant benefit and improves the quality of life, it has a broad side effect profile because of the expression of retinoic acid receptors throughout the body. 11 The most common side effects are related to dry skin and mucocutaneous membranes. 11 Hair loss in the form of telogen effluvium is a reported side effect of isotretinoin that can lead to treatment discontinuation. Although its mechanisms are unclear, retinoids are thought to arrest the onset of the anagen phase of the hair cycle and impair the anchoring of hair during the telogen phase, ultimately increasing hair shedding. 11,12 Current product monographs of commonly used isotretinoin formulations in North America (Clarus, Epuris, and Accutane) list hair loss as a rare side effect and warn that it may persist after treatment is completed. [13][14][15] The Clarus monograph reports that 13% of patients experience hair loss (presumably, these data are from pivotal clinical trials because other references are not provided) but does not describe the doses at which hair loss is observed. 13 In a recent review of postmarketing adverse events, hair loss was reported in 932 cases (9% of all dermatologic adverse events), 62.7% of which occurred in patients between 15 and 30 years of age. 16 With the exception of teratogenicity, the incidence and severity of side effects associated with isotretinoin are generally dependent on the dose and reversible with drug discontinuation. 11,17,18 In the past, a typical treatment regimen was started at 0.5 mg/kg/d and increased to 1.0 mg/kg/d to reach a cumulative dose of 120 to 150 mg/kg. [18][19][20] This approach was modified after studies demonstrated equal response rates and less adverse effects with lower cumulative doses. [21][22][23][24][25][26][27][28][29][30][31][32][33] This was contradicted by other studies that suggested that acne relapse rates are greater with lower cumulative doses. [34][35][36] The 2018 Global Alliance to Improve Outcomes in Acne reviewed the conflicting data and determined that to date, no high-quality clinical trials have defined a total cumulative dose that maintains remission. 37 The most recent recommendations indicate that the appropriate evidence-based approach is to continue treatment for over 2 months after complete acne resolution. [37][38][39][40] Dermatologists may adjust the isotretinoin dose throughout the course of the treatment to balance the response to therapy, with more common side effects such as dryness. However, it is currently unknown whether dose reduction is effective in managing isotretinoin-induced hair loss. The exact frequency and associated dose dependency of hair loss with the use of isotretinoin remain unclear. Therefore, the primary objective of this systematic review was to assess the frequency of hair loss in patients with acne vulgaris on daily oral doses of \0.5 mg/kg/d versus $0.5 mg/kg/d of isotretinoin. The goal was to assess whether there are sufficient data to provide evidence-based guidelines for dermatologists prescribing isotretinoin to patients with hair loss concerns, thus preventing the avoidance or discontinuation of this medication.

METHODS
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed for this systematic review. 41

Search strategy
Articles published between January 2005 and July 2020 were retrieved from Embase and MEDLINE electronic databases in Ovid on July 15, 2020 (Supplementary  File 1, available via Mendeley  at https://data.mendeley. com/datasets/hrhkctyppr/1). The titles, abstracts, and full texts of the retrieved articles were independently screened by 2 reviewers (Drs Lytvyn and McDonald), and a third reviewer (Dr Mufti) resolved any disagreements. The reference lists of the relevant articles were manually searched by 1 reviewer (Dr Lytvyn).

Inclusion criteria and study design
Original articles written in English were included if they involved the following: (1) human patients, (2) the use of isotretinoin to treat acne vulgaris, (3) hair loss outcomes, and (4) an observational or experimental study design.
Many of the available studies subdivided the data into doses of $0.5 mg/kg/d or those \0.5 mg/kg/ d. To extract these data and reference a clinically meaningful dose (the lower end of the recommended range), 18-20 a threshold value of 0.5 mg/kg/ d was maintained in this review.

Data abstraction
Two reviewers (Drs Lytvyn and McDonald) independently extracted data on study design, patient demographics and medical history, isotretinoin treatment (daily dose, cumulative dose, and duration), and reported hair loss. The isotretinoin doses reported in this systematic review were the target daily doses achieved and were maintained after titrating up the dose over a 1-to 2-month period. When possible, the isotretinoin dosing was converted to CAPSULE SUMMARY d There are limited published data on isotretinoin-induced hair loss. This systematic review compiles available data suggesting a frequency between 3.2% and 5.7%. Further studies are required for the analysis of dose dependency. d Physicians should consider discussing the possibility of telogen effluvium with patients.
daily weight-based dosing for a straightforward comparison.
If available, information for the following 3 outcomes was extracted: 1. The number of patients experiencing hair loss, reported as the percentage of all patients treated in the study. 2. Time to hair loss onset: time between the first isotretinoin dose and the first report of hair loss. 3. Reversibility of hair loss associated with isotretinoin.
Analysis A descriptive analysis was performed because of considerable heterogeneity in the reported data and study designs of the included articles. To illustrate the general trends, the overall frequency of hair loss was calculated for the 2 groups: patients taking \0.5 mg/kg/d versus those taking $0.5 mg/kg/d of oral isotretinoin.

Quality assessment
The quality of evidence was assessed independently in duplicate by 2 reviewers (Drs Lytvyn and McDonald) using the Oxford Centre for Evidence-Based Medicine, 2011, levels of evidence. 42

Study selection
The study focused on isotretinoin use in acne patients because this is the most common use of the drug and the patients are typically younger and with fewer comorbidities contributing to hair loss.

Evidence level
Of the 23 included studies, 16 were prospective trials, 3 were retrospective studies, and 3 were crosssectional studies (Table I). Most of the studies were considered to have a relatively high (1b) level of evidence as per the Centre for Evidence-Based Medicine scale. The method of hair loss measurement varied, with 17 studies presenting patient selfreported hair loss, 3 studies reporting hair loss following an inquiry by a dermatologist, and 2 prospective studies measuring hair loss using a video dermatoscope.

Dose-dependent hair loss frequency with isotretinoin
Isotretinoin dose of \0.5 mg/kg/d. A total of 565 acne patients were treated with \0.5 mg/kg/d of isotretinoin therapy (mean age, 22.0 years; men, 63.7%; Table II). The mean weight-based dose was 0.24 mg/kg/d, and the patients were treated for an average of 4.4 months to reach a mean cumulative dose of 70.6 mg/kg. Of the 565 patients in this group, the average weight-based and cumulative doses were calculated for 302 patients. Twenty-nine patients were on a fixed dose of 20 mg every 2 days, and 234 patients were on a fixed dose of 20 mg/d. These patients were not represented in the frequency analysis. Although this would be considered lower dose, exact weight-based dosing could not be calculated.
Overall, hair loss was reported in 18 (3.2%) patients of all patients treated with \0.5-mg/kg/ d dosing (Table II).
Isotretinoin dose of $0.5 mg/kg/d. The group of acne patients treated with $0.5 mg/kg/ d of isotretinoin therapy comprised 3375 patients (mean age, 22.4 years; men, 60.7%; Table II). The mean weight-based dose was 0.59 mg/kg/d, and the patients were treated for an average of 6.5 months to reach a mean cumulative dose of 97.2 mg/kg. Of the 3375 patients, the average weight-based and cumulative doses were calculated for 3318 patients. The entire high-dose group was not represented because 57 patients were on an average fixed dose of 44.2 mg/d.
Overall, hair loss was reported in 192 (5.7%) patients of all patients treated with $0.5 mg/kg/ d of isotretinoin (Table II).

Time of hair loss onset with isotretinoin
The timing of hair loss onset during isotretinoin dose escalation has only been documented in 1 study to date. Demirseren et al 60 found that 20% of 300 patients experienced hair loss, with a median time of onset at 4 weeks and a wide range of 1 to 24 weeks.
Two prospective studies quantified hair loss with FotoFinder dermatoscope using TrichoScan Professional software. 11,56 The first study of 30 patients reported no significant change in the total hair count, hair density, or percentage of telogen hair within 3 months of 0.5-mg/kg/d isotretinoin treatment. 11 The second study treated 30 acne patients with higher isotretinoin doses (0.5-1 mg/kg/d) for a longer duration (4-7 months) and described a significant decrease in the total hair count, hair density, and percentage of anagen hair. 56 It is unclear whether it was the increased daily dosing or the higher cumulative dose with the longer treatment duration that contributed to the increased hair loss, but it does suggest that one of these factors contributed to telogen effluvium, especially when these data are compared with the first FotoFinder study described earlier.

Reversibility of hair loss with isotretinoin
Of the 22 studies reviewed, only 2 discussed the reversibility of hair loss. Brzezinski et al 61 described hair loss in 154 patients on isotretinoin and commented on its persistence after completing treatment; however, there were no data to support this comment, and the time frame as well as the number of patients affected were unclear. Conversely, a retrospective study by Gan et al 55 reported that hair loss was temporary in 33 patients who experienced hair loss on high-dose isotretinoin.

DISCUSSION
A summary of the available data suggested that patients on \0.5 mg/kg/d of isotretinoin    Lytvyn et al 133   54 Prospective study (   experienced hair loss at a frequency of 3.2% versus those on $0.5 mg/kg/d, who experienced hair loss at a frequency of 5.7%. Inferential statistics comparing the groups was not possible because of the heterogeneity of the data. Hair loss onset and prognosis Drug-induced telogen hair loss has previously been reported to start after 12 weeks of therapy. 63 The drug prematurely transitions the follicles from the anagen phase to the telogen phase, which has a duration of 3 months prior to shedding. 64,65 Data on hair loss with isotretinoin dose escalation are lacking and have only been documented in a small cohort of patients, with a median time of onset at 4 weeks. 60 It is unclear whether the duration of treatment or the cumulative isotretinoin dose plays a significant role in the timing of hair loss onset, but contrasting results of 2 similar prospective studies using FotoFinder trichoscopy at doses of 0.5 and $0.5 mg/kg suggested that higher doses for longer periods ([4 months) result in higher rates of telogen effluvium.
The reversibility and extent of hair regrowth are important to consider because patients may view permanent hair thinning as a barrier to therapy. Although the product monographs of isotretinoin formulations (Clarus, Epuris, and Accutane) warn that hair loss may persist after treatment is completed, there is no definitive evidence to support this prognosis. 55,61 Impact on clinical practice Hair loss has been described as a rare side effect of isotretinoin in product monographs and in the literature. [13][14][15] This systematic review demonstrated a 3.2% to 5.7% frequency of hair loss, which is comparable with the frequency of the side effect of dry eyes (5.7% frequency). 61 This highlights the importance of counseling and monitoring for hair loss during isotretinoin treatment. The most up-todate recommendations for isotretinoin therapy suggest that the patient should remain clear of acne for 1 to 2 months prior to discontinuing the treatment in order to reduce recurrence rates. 5,37,39 These suggestions are based on a systematic literature review by Tan et al, 39 which showed that daily and cumulative doses did not influence the relapse rates as long as the treatment was continued for [2 months after acne resolution. Therefore, in patients concerned about hair loss, dermatologists may consider prescribing lower daily isotretinoin doses over a longer period of time to reach the same goal prior to discontinuation. This approach has been successful, with other reported side effects.  56 Rademaker et al, 18 Demirseren et al, 60 Alshammari et al, 62  Although data specific to hair loss have not been reported, previous studies have shown that low daily doses in the range of 0.10 to 0.40 mg/kg can be efficacious while reducing the risk of mucocutaneous side effects. 23,29,43 Intermittent dosing may also represent an alternative treatment, especially for mild-to-moderate acne. Daily isotretinoin for 1 week every 4 weeks over a duration of 6 months was shown to be an effective treatment for mild-tomoderate acne and resulted in minimal side effects. 66,67 For patients with more severe acne, there were fewer side effects when isotretinoin was prescribed for either the first 10 days of each month for 6 months (a cumulative dose of 25 mg/kg) or each day in the first month and the first 10 days of each subsequent month for 5 months (a cumulative dose of 49 mg/kg) at 0.5 mg/kg/d. 49 If hair thinning is a serious concern and a potential barrier to the systemic management of acne vulgaris, one of these low-dose regimens might be an alternative approach, although definitive data for hair loss are lacking.

Study limitations
There are limitations resulting from the available data in the literature. Because of the study design, heterogeneity, and large difference in the number of patients between the groups, a statistical analysis comparing the\0.5-mg/kg/d and $0.5-mg/kg/d isotretinoin groups was not possible. Most of the included studies were not randomized and, thus, limited the comparison of adverse effects between the isotretinoin doses. Moreover, there were not enough data available to make comparisons of hair loss with isotretinoin use in men versus that with isotretinoin use in women. Similarly, data on confounding variables, such as iron deficiency anemia, were not available. Despite the large volume of literature on isotretinoin, there are a limited number of studies that assessed hair loss (n = 22 , Fig 1), of which only 6 studies reported hair loss outcomes in patients using \0.5 mg/kg/d. Furthermore, the majority of the outcomes were patient-reported and, thus, prone to subjectivity. Although the studies that reported hair loss had a lower mean proportional cumulative dose (70.6-97.6 mg/kg, Table II) compared with the frequently targeted cumulative dose of 120 to 150 mg/kg, newer recommendations suggest that maintained clearance is a more important therapeutic target than cumulative dose. 19,20,37 The relationship between cumulative dose and hair loss could not be elucidated from the data available.
Despite these limitations, this systematic review comprehensively summarized the literature to date, identified the gaps in the literature, and demonstrated evidence for the frequency of isotretinoin-induced hair loss (up to 5.7%). Given the volume of patients with acne on isotretinoin in North America, dose reduction could be further explored as an alternative to discontinuation for patients experiencing hair loss. A high-quality prospective study is required to formally assess the dose dependency and impact of a cumulative dose.

CONCLUSION
Physician knowledge of the frequency, timing, dose dependency, and reversibility of hair loss with isotretinoin treatment is limited because of the lack of discussion in the literature. This systematic review analyzed the data available and suggested that \0.5-mg/kg/day isotretinoin dosing results in hair loss at a frequency of 3.2%, whereas $0.5-mg/kg/day isotretinoin dosing demonstrates hair loss at a frequency of 5.7%. This frequency is not dissimilar to many of the side effects commonly discussed with patients and impacts a large patient population because of the frequency of isotretinoin prescription. 10 The role of dose reduction in hair loss frequency is important to establish because it would allow patients with acne and distressing levels of hair loss to still receive effective therapy.