Weekly Azathioprine Pulse versus Betamethasone Oral Mini-Pulse in the Treatment of Moderate-to-Severe Alopecia Areata.

BACKGROUND: Corticosteroids are the most common agents used in the treatment of alopecia areata (AA), however, their long-term use is associated with severe side effects. Therefore, other immunosuppressive agents have been tried and azathioprine appears to be an effective and promising alternative.
OBJECTIVE: The main objective of this study was to compare the efficacy of 300 mg once weekly azathioprine pulse (WAP) and 5 mg betamethasone on 2 consecutive days every week in the management of AA.
MATERIALS AND METHODS: In this open-label, randomized comparative study, 50 patients of AA with >10% scalp area involvement were treated with either 300 mg WAP or 5 mg betamethasone on 2 consecutive days every week for 4 months or till complete scalp hair regrowth and followed up for next 5 months. Primary efficacy parameters were average percentage scalp hair regrowth and change in average Severity of Alopecia Tool (SALT) score at 4 months.
RESULTS: Twenty patients in WAP group and 21 patients in betamethasone group completed the study. The median percent scalp hair regrowth and the median change in SALT score was 44.52 and 9.5 in WAP group compared to 71.43 and 14 in betamethasone group at 4-month, respectively, which were statistically similar in two groups, however, side effects were significantly higher in betamethasone group. On further follow-up at 9 months, 10 (50%) patients in WAP group and 13 (62%) patients in betamethasone group achieved complete hair regrowth. Lack of control group was a limitation of our study.
CONCLUSION: WAP and betamethasone therapy, both appear to be effective in the treatment of AA. However, betamethasone caused several side effects; therefore, WAP can be used as a better alternative to corticosteroids in AA.

Introduction

Alopecia areata (AA) is a recurrent noncicatricial, autoimmune, chronic inflammatory patchy hair loss on the scalp and/or body.[1] Oral corticosteroids have shown high efficacy in moderate-to-severe disease, however, their long-term use results in serious side effects. Azathioprine has been shown to be efficacious in the treatment of this disease.[2]

Pulse regimens of immunosuppressive agents have been used in various immune-mediated dermatological conditions such as lichen planus, vitiligo, and parthenium dermatitis, with good results, favorable side effect profile, better compliance, and reduced cost of treatment.[345678] Oral and intravenous corticosteroid pulse therapy has been used in the treatment of AA.[91011121314151617181920212223] Weekly azathioprine pulse (WAP) therapy has been shown to have better compliance and reduced cost of treatment, yet comparable efficacy, when compared to daily azathioprine in parthenium dermatitis.[78] In this open-label, randomized controlled, blinded, comparative and prospective study, we evaluated the effectiveness and side effect profile of WAP and betamethasone 5 mg on 2 days every week in the treatment of moderate-to-severe AA.

Materials and Methods

The study was approved by the Institutional Ethics Committee and written informed consent was obtained from each patient before enrollment.

Fifty consecutive patients of AA attending the outpatient department of our center were recruited. Patients of ≥18 years of age, with AA affecting ≥10% scalp area for at least 3 months, were included in the study [Table 1]. Patients having significant spontaneous regrowth of terminal hair, history of use of topical or intralesional therapy in the past 1 month and/or phototherapy and/or systemic therapy in the last 2 months, uncontrolled renal, hepatic, hematological or heart disease, or absolute contraindication to corticosteroids or azathioprine were excluded. Patients with alopecia universalis and pregnant or lactating women were also excluded. The diagnosis of AA in each patient was confirmed clinically by two dermatologists.

Table 1

Demographic data and disease profile of the two groups

Patient profile	Median (IQR)		P
	WAP (n=20)	Betamethasone (n=21)
Age* (years), mean±SD	25.85±1.84	25.90±1.17	0.98
Gender
Male**	16 (80)	13 (61.9)	0.31
Female**	4 (20)	8 (38.1)
Total duration of illness (years)	3.5 (1.58-8)	5 (1-7)	0.69
Duration of current episode (years)	1.58 (0.63-3)	1 (0.4-2)	0.39
Average SALT score at baseline	24 (14-58)	19 (14-55)	0.94
Involvement of body sites other than scalp	6 (30)	7 (33.33)	0.82
Number of patients with first episode of AA	13 (65)	11 (52.4)	0.41
Number of patients with recurrent AA	7 (35)	10 (47.6)

*Data expressed in mean±SD, **Data expressed as frequency (%). IQR: Interquartile range, SD: Standard deviation, SALT: Severity of Alopecia Tool, AA: Alopecia areata, WAP: Weekly azathioprine pulse

Recruited patients were randomized into two groups using random number table generated online, to receive either 300 mg azathioprine once weekly (WAP) or 5 mg betamethasone on 2 consecutive days every week for at least 4 months or till complete regrowth, whichever was earlier. Patients showing no regrowth or further decline at 4 months were shifted to a combination therapy consisting azathioprine 100 mg daily and betamethasone 5 mg on 2 consecutive days in a week. The treatment was withdrawn in patients who achieved complete scalp hair regrowth and they were further followed up for 5 months.

Clinical details of each patient were recorded and severity of the disease was determined using severity of alopecia tool (SALT) score.[11] Baseline photographs of the standard 4 views of scalp under standard lighting conditions with a standard camera and camera settings were taken at first and subsequent visits. Baseline routine laboratory investigations such as complete blood counts, liver and renal function tests, routine and microscopic urine and stool examination, chest X-ray, and electrocardiogram were performed. Female patients were counseled about the need for contraception during the treatment period and 3 months following treatment. Complete blood count and liver and renal function tests were repeated on follow-up at every 4 weeks for initial 3 months and then every 8 weeks.

Primary efficacy parameters were comparison of average percentage scalp hair regrowth, average change in SALT score from baseline and side effects in two groups at the end of 4 months of treatment. Secondary efficacy parameters included comparison of percentage of patients who achieved SALT-50, median global assessment score, patient global assessment based on visual analog scoring from 0 to 100 after 4 months of treatment, percentage of patients showing cosmetically acceptable hair regrowth, Investigator Global Assessment by evaluation of photographs on a VAS of 0–100, proportion of patients not responding or worsening, and percentage of patients showing relapse. Relapse was defined as any loss of regrown hair or new AA patches, during the follow-up period.

Statistical analysis was done using STATA v11.2. (StataCorp, Texas, USA). Wilcoxon rank-sum test/t-test were applied for analyzing continuous variables. Chi-square test/Fisher exact test were used for analyzing categorical variables and a P<0.05 was considered statistically significant.

Results

A total of 50 patients, 36 males and 14 females, between 18 and 46 years of age (mean age 26.6 ± 7.38 years) were included in the study. There were 25 patients in each group of which 20 patients in azathioprine pulse and 21 patients in betamethasone group completed the study [Figure 1]. Five patients in azathioprine group and 4 in betamethasone group were lost to follow-up. Three patients were lost to follow-up due to change in residence and inability to follow-up. One patient shifted to alternative form of therapy after taking 2 weeks of treatment and five patients could not be contacted despite repeated attempts. The demographic data of the two groups were comparable [Table 1]. The per-protocol analysis of the outcome was done.

Figure 1

Flowchart showing the progression of the study

Primary efficacy parameter

The median SALT score at baseline (WAP=24 [14-58]; betamethasone group=19 [14-55]) and at 4 months (WAP=13.5 [5.5–26]; betamethasone group=8 [0-20]) as well as the percentage regrowth (WAP=44.52 [0-75.43]; betamethasone group=71.43 [11.11-100]) and change in SALT score from baseline to 4 month (WAP=9.5 [0-13.5]; betamethasone group=14 [4-19]) were comparable between the two groups [Table 2]. Sixteen (76.2%) patients in betamethasone group (n=21) developed facial puffiness/moon facies, 7 had weight gain, 5 each had reflux gastritis and steroid acne, 2 had striae distensae, and 1 patient had dermatophytic infection, whereas transient nausea lasting for a day with initial 1–2 doses was observed in 7 (35%) patients in WAP group (n=20). The side effects did not necessitate discontinuation of treatment in any patient. No significant changes in biochemical parameters were noted in either group.

Table 2

Comparison of median percent scalp hair regrowth based on Severity of Alopecia Tool score and change in average Severity of Alopecia Tool score from baseline to 4 month of treatment

Efficacy parameters	Median (IQR)
	WAP (n=20)	Betamethasone (n=21)
SALT score at baseline	24 (14-58)	19 (14-55)
SALT score at 4 month	13.5 (5.5-26)	8 (0-20)
Change in SALT score	9.5 (0-13.5) (P=0.009)	14 (4-19) (P=0.001)
Percentage regrowth at 4 month	44.52 (0-75.43)	71.43 (11.11-100)

IQR: Interquartile range, WAP: Weekly azathioprine pulse, SALT: Severity of Alopecia Tool

Secondary efficacy parameter

Eight (40%) patients in WAP group and 13 (61.9%) in betamethasone group achieved SALT-50 which was comparable in two groups (P=0.16). The median global assessment score at 4 months of treatment was 2 (The interquartile range [IQR]: 0–4) in WAP and 3 (IQR: 1–5) in betamethasone group which was also comparable (P=0.15) [Figures 2, 3 and Table 2].

Figure 2

Hair regrowth seen with weekly azathioprine therapy, at 0 week (a, d, g, and j), 16 weeks (b, e, h, and k), and 36 weeks (c, f, i and l)

Figure 3

Hair regrowth seen with twice weekly betamethasone therapy, at 0 week (a, d, g, and j), 16 weeks (b, e, h, and k), and 36 weeks (c, f, i and l)

The median patient global assessment score at the end of 4 months of treatment was 45 (IQR: 0–82.5) in WAP group and 90 (IQR: 10–100) in betamethasone group which was statistically significant (P=0.03). The median investigator global assessment score at the end of 4 months of treatment was 32.5 (IQR: 0–72.5) in WAP group and 95 (IQR: 15–100) in betamethasone group (P=0.02). Seven (33.33%) patients in betamethasone group and none in WAP group achieved complete hair regrowth by 4 months of treatment. Cosmetically acceptable regrowth was seen in 8 (40%) patients in WAP group and 13 (61.9%) in betamethasone group (P=0.16). On further follow-up at 9 months, 10 (50%) patients in WAP group and 13 (62%) patients in betamethasone group achieved complete hair regrowth. One patient in each group relapsed at 2 month after complete regrowth of hair during follow-up period.

Seven (35%) patients in WAP group and 5 (23.8%) in betamethasone group did not experience any regrowth or had further decline in scalp hair coverage at the end of 4 months of treatment.

Discussion

Corticosteroids have been the most commonly used agent in the treatment of AA. These have been used in various doses and regimens with a success rate varying from 47% to 81.3%.[91011121314222324252627] Pulse regimens of corticosteroids with methylprednisolone and dexamethasone used as monthly as well as weekly doses have resulted in improvements ranging from 37.8% to 81.3%.[12131415161718192021222327] Side effects are considered to be fewer with pulse regimens than daily corticosteroid doses [Table 3].[1112131415161718192021]

Table 3

Summary of studies using pulsed corticosteroid in alopecia areata

Authors	Number of patients	Dose	Response	Side effects
Senila et al.[12]	32	500 mg infusion of methylprednisolone on 3 days every month for 3 months	26 (81.3%)	Facial flushing (17), headache and dizziness (9), asthenia (5), and palpitations (6)
Nakajima et al.[13]	139	Single cycle of 3 days methylprednisolone 500 mg infusion	59.4% in disease duration <6 months, 15.8% in disease duration >6 months	No serious side effects
Friedli et al.[14]	45	Single cycle of 3 days methylprednisolone 500 mg infusion	13 (65%)	No serious side effects
Seiter et al.[15]	30	500 mg infusion of methylprednisolone on 3 days every month for 3 months	12 (40%)	No serious side effects
Staumont-Sallé et al.[16]	30	500 mg infusion of methylprednisolone on 3 days every month for 3 months	10 (33.3%)	Tiredness (11), headache and flush (9), nausea and vomiting (7), and transient hyperglycemia (6)
Sharma and Gupta[17]	30	5 mg dexamethasone two consecutive days every week	16 (63.3%)	Minor side effects (8)
Lalosevic et al.[18]	65	Oral dexamethasone solution (equivalent to 5 mg/kg of prednisolone), in a single dose every 4 weeks for 6, 9, or 12 months with topical clobetasol propionate 0.05% ointment under occlusion	37 (56.9%)	No serious side effects
Yeo et al.[19]	82	Methylprednisolone, 1 g/day, twice a day for 3 consecutive days for adults and 10 mg/kg/day weekly for 3 weeks for children for 6 months	53 (64.6%)	GI discomfort, headache, dizziness, facial flushing, and palpitation in 16 (19.5%) patients
Yoshimasu et al.[20]	55	500 mg/day of methylprednisolone infusion for 3 days for 6 months	Group 1 (<25%, 25%-49% hair loss): 100% growthGroup 2 (50%-74%, 75%-99% hair loss):83% and 82% growth	Myalgia and numbness (10), limbs edema (4), stomach discomfort (2), infection (2), arthralgia (1), burning sensation (1)
Khaitan et al.[11]	16	Betamethasone mini-pulse therapy for 6 months	12 (75%)	Cushingoid facies and weight gain (2), acneiform eruption (2), mild gastric discomfort (3)
Jang et al.[21]	37	Betamethasone mini-pulse therapy for 3 months	14 (37.8%)	Weight gain (11), facial edema (9), acneiform eruption (6), GI symptoms (4), headache/dizziness (4), skin atrophy (2)

GI: Gastrointestinal

Betamethasone pulse has been used in a dose of 5 mg twice in a week in 16 patients of extensive AA, of which 12 (75%) patients experienced good to complete regrowth after 6 months of treatment, while the hair growth was unsatisfactory in 2 (12.5%) patients and 2 patients did not show any regrowth.[11] Jang et al. performed a comparative study of oral cyclosporine (n=51) and betamethasone mini-pulse therapy (n=37) and reported ≥50% of terminal hair regrowth in 54.9% and 34.8% patients, respectively.[21]

Although the corticosteroids used in various regimens have shown good response but have caused side effects even when used in pulsed regimens, and in some patients, the therapy had to be discontinued due to these side effects.[121314151617181920212223] Azathioprine has been shown to be efficacious in the treatment of AA with lesser side effects.[2]

In our study, we used betamethasone 5 mg twice in a week and compared it with weekly 300 mg doses of azathioprine. Betamethasone is a long-acting corticosteroid (plasma half-life=300 min) and a dose of 0.75 mg is considered as an equivalent dose to 5 mg of prednisolone. Weekly 300 mg of azathioprine was used to improve the compliance and to reduce the cost of treatment.

On comparison with previous studies, our betamethasone group patients had >75% hair regrowth in 62% patients, which was comparable to Senila et al., Nakajima et al., Friedli et al., Sharma and Gupta, Khaitan et al., Lalosevic et al., and Yeo et al.,[101213171819] but our results were better than the results reported by Seiter et al., Jang et al., and Staumont-Salle et al., which can be explained by a shorter duration of therapy in these studies.[141521] Although corticosteroid-induced side effects were more frequently observed in our study than studies by Nakajima et al., Friedli et al., Seiter et al., Lalosevic et al., and Staumont-Salle et al., probably because of use of high dose shorter courses of corticosteroids in these studies, which also resulted in higher frequency of palpitations, headache, nausea, and dizziness in their studies.[121314152127] Weight gain, Cushingoid appearance, and transient gastrointestinal discomfort were the most common side effects noted in our series as also with Khaitan et al. and Jang et al.[1121] Relapse rate was much lower in our series (4.76%), compared to Nakajima et al. (16.7%), Friedli et al. (30.76%), Yeo et al. (20.0%), Lalosevic et al. (16.9%), and Seiter et al. (41.66%).[1213141819]

Azathioprine, a purine antagonist, has been used in the treatment of AA.[28] In a study by Farshi et al., on 20 patients with moderate-to-severe AA, azathioprine in the dose of 2 mg/kg/day was administered.[2] There was 52.3% mean regrowth with a significant reduction in mean hair loss (72.7% to 33.5%) after 6 months of treatment and treatment had to be discontinued in one patient due to deranged liver function test. In our study, the mean hair regrowth was 44.52% which was comparable to the study by Farshi et al., however, none of the patients in our study experienced serious side effects warranting discontinuation of therapy, which suggested safety of weekly azathioprine regimen. The relapse rate and long-term follow-up were not systematically documented in the study by Farshi et al. In our study, one patient had relapse of disease after 2 months of discontinuing treatment. The thiopurine methyltransferase (TPMT) estimation was not done due to lack of laboratory facilities. Moreover, it has been shown that prior estimation of TPMT does not predict azathioprine-induced side effect/toxicity and routine hematological and biochemical investigations are adequate for follow-up monitoring.[2930] In addition, a lower frequency of mutant TPMT alleles have been shown in Southwest Asian population (India, Pakistan), which further reduced the necessity of TPMT levels estimation.[31] Lack of a placebo group was a limitation of our study.

Conclusion

Both weekly betamethasone and WAP therapy appear to be effective in the treatment of AA. Although more patients in betamethasone group had regrowth after 4 months of treatment, which was associated with a higher global assessment score in this group, this difference was not statistically significant (P=0.15). However, several patients in betamethasone group had corticosteroids induced side effects; therefore, azathioprine can be used as a better tolerated and effective substitute for corticosteroids, particularly in patients who cannot be treated with corticosteroids due to any contraindication or to avoid corticosteroid-induced side effects. Further studies, however, are needed to confirm our findings.

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.