Role of vitamin D in the pathogenesis of various autoimmune disorders has attracted the curiosity of many investigators recently. Alopecia areata (AA) is a noncicatricial hair loss that can involve any hairy body part but is noticed most in scalp and face. Incidence of AA is estimated at ∼1% in dermatology clinics, and the lifetime risk of developing AA is ∼1.7% 1. It is usually a self-limiting condition in which spontaneous regrowth of hair may occur within 1 year of developing of the disease. Intralesional or topical corticosteroids and minoxidil are used as the common treatment modalities 2. Systemic steroids, topical sensitizers, platelet-rich plasma, and immunosuppressive drugs have been investigated to discover promising alternative treatments 2. Although the exact pathophysiology of AA is not completely known, an autoimmune etiology is widely accepted for its pathogenesis. Some studies have reported that low serum vitamin D3 and decreased expression of vitamin D receptor in hair follicular metrical cells are associated with AA 3–7. In one published case report, a 7-year-old boy with reduced vitamin D receptor expression in AA was treated successfully using topical calcipotriol 8. Another retrospective study showed improvement in AA with topical calcipotriol 9. We did not find any randomized clinical trial evaluating calcipotriol for AA. In psoriasis, studies have shown synergistic effects of calcipotriol with narrowband ultraviolet B (NBUVB) phototherapy 10,11. Moreover, NBUVB helps in reducing local irritation caused by calcipotriol 10,11. We could not find documentation of such a synergism in AA. These concepts laid the foundation of the present study, which compared the efficacy and safety of these two treatment modalities with each other and with the placebo.
Patients and methods
This is a prospective, randomized evaluator-blinded open-labeled parallel arm comparative single-center study that has been conducted in patients with AA after approval from the Institution Review Board, Government Medical College, Bhavnagar, Gujarat, India (IRB No. 431/2014). This trial was registered in Clinical Trial Registry of India (Registration No. CTRI/2015/11/006363). The study has been conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use–Good Clinical Practice guidelines and Declaration of Helsinki between May 2014 and June 2015 at the Department of Dermatology, Venereology and Leprosy, Sir Takhtasinhji General Hospital, Bhavnagar, Gujarat, India. Simple randomization was used to allocate the patients into three treatment arms. We were unable to find any randomized controlled trail during literature search that could give an idea about the expected effect size. Based on experience of senior faculties and prevalence of the disease, we were expecting at least 50% of patients with clinical improvement in calcipotriol group, so we decided to have a sample of 60 patients randomized in three groups in a ratio of 2 : 2 : 1. Allocation concealment was performed using sequentially numbered, opaque, sealed envelope method. Group A patients received topical calcipotriol (0.005%) ointment once a day for 12 weeks, group B patients received topical calcipotriol (0.005%) ointment once a day along with NBUVB (311 nm) phototherapy twice a week, and group C patients received placebo (topical white soft petroleum jelly daily) for 12 weeks. Phototherapy was given with a local phototherapy machine comb model (Dermaindia, Chennai, India). Phototherapy dose began with 200 mJ/cm2 exposure, and increased by 40 mJ/cm2 on successive visits up to 12 weeks, limiting to maximum exposure of 680 mJ/cm2 or complete remission. Blinding of the patients was not possible as exposure to phototherapy machine was required in group B patients, but all patients were evaluated by the single evaluator who was blinded to treatment allocation.
Patients older than 5 years and younger than 65 years with clinical lesions of AA on face and scalp who were also confirmed with trichoscopy, patients having lesions with any Severity of Alopecia Tool (SALT) score except for alopecia totalis or universalis, and patients having lesions with no evidence of regrowth present at baseline and had not been treated for at least 6 weeks were considered for the study. Pregnant female, nursing mother, patient with known photosensitivity, patient with sensitivity to any component of topical calcipotriol preparation, patient with other autoimmune disorders requiring immunosuppressive treatment or patient with infection/eczematization on a local part that would alter the study outcome were excluded from the study. Baseline characteristics are shown in Table 1. Written informed consent was obtained from the patients aged more than 18 years, whereas for the patients younger than 18 years, consent was obtained from the parents with a pediatric assent.
Assessment of the patients
The patients were examined at 6- and 12-week follow-up visits. Clinical photographs were taken on each visit and were evaluated for size of the lesion, and SALT score was calculated 12,13. For lesions involving nonscalp area, percentage of area involvement was evaluated at every visit. Percentage of improvement was calculated at each visit using following formula 12:
Based on the percentage of improvement, patients who showed more than or equal to 50% improvement were considered as clinically improved and less than 50% were considered as no clinical improvement. Patients who showed worsening of lesion were considered into no clinical improvement. Trichoscopy and TrichoScan of a lesion were undertaken with contact mode polarized dermoscope and computer-assisted TrichoScan software (TrichoScan Professional 188.8.131.52; Freiburg, Germany) using a high-resolution digital camera. Values of total hair count at each visit were recorded as a secondary outcome measure. Patient satisfaction grading with five grades standard ordinal scale feedback for the response was taken from each patient, and they were graded as ‘very good,’ ‘good,’ neutral, ‘poor,’ and ‘very poor.’ Detailed history and examination was carried out for evaluating adverse reactions if present, in all patients.
Data were expressed in mean±SEM or percentage. Mean percentage of improvement and total hair count were compared between the groups using one-way analysis of variance test followed by Tukey–Kramer multiple comparison test. Categorical data like proportions of clinically improved patients, patient satisfaction grades, and adverse drug reactions were compared using χ2 test. GraphPad InStat software (version 3.06, GraphPad Software Inc., La Jolla, California, USA) was used for all statistical calculations.
A total of 60 patients with AA were included in the present study. One patient in group B and two patients in group C did not come for follow-up visits as they were not satisfied with treatment. We evaluated 57 patients who completed this study. In group A, 17 patients were male and seven were female, with an average age of 21.8 years; in group B, 19 patients were male and four were females, with an average age of 23.3 years; and in group C, nine patients were male and one was female, with an average age of 24.7 years. Flow of study participants is shown in the consort diagram.
Severity of Alopecia Tool scoring
Average 20.8 and 21.3% improvements were found in SALT scores in groups A and B patients, respectively, as compared with 0.0% in placebo group at first follow-up visit. This improvement was statistically significant (P<0.05). At the end of the study period, average 52.8, 69.6, and 3.9% improvements were noted in SALT scores in groups A, B, and C patients, respectively. Percentage of improvement was significantly higher in groups A and B patients as compared with group C patients (P<0.05) (Fig. 1). However, there was no statistical difference between groups A and B patients at the end of study period. Overall, 62.5 and 73.9% of the patients from groups A and B clinically improved, respectively (Table 2). During the first 6-week duration, none of the patients from any study group showed a complete improvement. Moreover, 33.3 and 52.2% of the patients from groups A and B showed complete improvement, respectively, as compared to 0% in placebo group (Table 2; P=0.003).
Trichoscopy and hair count (TrichoScan)
Improvement in the secondary outcome measure (total hair count by TrichoScan) was found to be in line with the primary outcome measure. Total hair count was increased significantly in groups A and B patients as compared with placebo group at the end of study period (P<0.05) (Fig. 2). However, this difference was not found statistically significant between patients of groups A and B. In trichoscopy, polycyclic yellow dots seemed to be the most consistent finding in patients of AA, which was present in all 57 patients (Fig. 3). We observed reduction in yellow dots, black dots, white dots, and exclamation mark hair in both active treatment groups but not with the placebo group (Fig. 3).
Participants of treatment group B were more satisfied with treatment than treatment group A, but the difference was not significant statistically (Table 3). Patients of both the treatment groups showed statistically more significant satisfaction with the treatment as compared with the placebo (P=0.009).
Adverse drug reactions
Adverse drug reactions like erythema, burning irritation, and exfoliation were noted in study treatment groups (Table 4). No major or serious adverse reactions were reported during the course of this study, and none of the patient had to be dropped out from the study owing to adverse effects of treatments. We observed fewer incidences of adverse drug reaction to combination treatment as compared with topical calcipotriol monotherapy, although the difference was not significant statistically.
Various treatment modalities (including allopathic and nonallopathic) for AA have been described in literature, with a variable clinical outcome. Contact immunotherapy and corticosteroids are documented as the most effective treatment for AA, but sometimes these treatments also fail 8. Resistant AA is a growing challenge, and need for more treatment options still exists. We treated two cases of AA that were resistant to multiple conventional treatments but showed improvement with topical calcipotriol therapy. At first, it was presumed that potent growth inhibiting potential of calcipotriol might theoretically induce hair loss, but Kuijpers et al. 14 reported no effect of calcipotriol in hair growth in cases of scalp psoriasis. Moreover, literature also correlates association between a reduced level of 25-hydroxyvitamin D and AA 5,7. In the present randomized controlled trial, efficacy and safety of calcipotriol was evaluated against placebo for treatment of AA. In the present study, calcipotriol alone and with NBUVB phototherapy showed a significant effect in percentage improvement of SALT score and total hair count as compared with placebo (Figs 1 and 2). We did not find complete clinical improvement in any patient at 6-week follow-up visit, whereas 33.3 and 52.2% of the patients showed complete improvement from calcipotriol and calcipotriol+NBUVB phototherapy groups, respectively, at 12-week follow-up visit. It suggests that calcipotriol (0.005%) topical application requires 12 weeks or more duration for its complete effect. Complete improvement was noted in the present study, which was higher than a retrospective study conducted by Çerman et al. 9 (33.3 and 52.2% vs. 27.1%). However, the proportion of clinically improved patients was little lower (62.5 and 73.9% vs. 75%) 9. Differences in the study design must be the possible reason for differences in clinical outcome of these two studies. In a study with 22 patients, Narang et al. 7 also used calcipotriol as a treatment agent for AA where they found 50% improvement (SALT50) in six (27.3%) patients and 100% improvement (SALT100) in two (9.1%) patients. It is interesting that patients with low baseline serum vitamin D3 levels responded better to treatment as reported by Narang et al. 7. Calcipotriol may have a complex mechanism that involves B cells, T cells, dendritic cells and toll-like receptors. Inhibition of conversion of monocytes into dendritic cells, shifting of T cell response towards Th2 dominance and inhibition of autoantibody production from B cells are possible immune-mediated mechanisms by calcipotriol in AA 8. Moreover; vitamin D has an important role in regulation of the hair cycle, which is impaired in AA 15. Higher values for the percentage improvement in SALT score, total hair count, clinically improved and for complete remission were noted with calcipotriol+NBUVB phototherapy group than calcipotriol alone but could not achieve statistical significance. It may be owing to low sample size in this study. It is noteworthy that one patient with alopecia subtotalis who suffered for 18 months showed 53.3% improvement in SALT score at the end of study. In one study, NBUVB phototherapy did not show its effectiveness in patients of AA as a monotherapy 16. Role of NBUVB in AA is not much evident, but it is suggested that a small fraction of NBUVB can penetrate up to the deeper dermis and subcuticular adipose tissue where actual pathology of AA takes place. NBUVB alone and in combination with calcipotriol was reported to be effective in cases of psoriasis in some studies 10,11. NBUVB can alter the pathogenesis in epidermis and papillary dermis for psoriatic lesions 10,11. Higher efficacy with calcipotriol+NBUVB phototherapy as compared with calcipotriol alone may be established in trial with a large sample size.
In the present study, TrichoScan was found as useful tool as SALT score to evaluate the treatment response, because SALT score was in accordance with the total hair count determined by TrichoScan. TrichoScan can be used to monitor the hair growth in cases of AA 17. We observed some hair growth in two participants who received placebo, but none of them improved clinically. Various studies that included placebo as a treatment arm reported variable clinical response but none of those observed complete remission 18–21. Although AA is a self-limiting condition, a longer duration is required for spontaneous hair regrowth. Patient satisfaction was significantly more in groups A and B study participants, which can be correlated with a better clinical outcome in these groups. A psychological effect owing to the presence of phototherapy machine as a part of combination treatment may be the cause of higher satisfaction in group B participants. Incidences of cutaneous adverse effects like burning and irritation were reported nonsignificantly less in combination treatment. NBUVB phototherapy has a property to reduce irritation caused by calcipotriol 22. This study had several limitations. Owing to the smaller sample size, we could not perform subgroup analysis for age groups, sex and different SALT score categories. Moreover, we could not measure serum vitamin D3 level and correlate it with treatment outcome owing to lack of facility. We could not calculate the exact sample size too, which was required for this study. However, post-hoc study power was calculated using clinical improvement of 62.5% in calcipotriol group (n=24) and 0% in placebo group (n=10) with alpha error 5%. Power of the study was 99.6%.
In conclusion, patients of AA showed better improvement with calcipotriol (0.005%) ointment with or without NBUVB phototherapy as compared with placebo. Patients who were treated with calcipotriol (0.005%) ointment and NBUVB phototherapy showed nonsignificant higher proportion of complete improvement with fewer adverse effects as compared with treatment with calcipotriol alone. However, it should be confirmed in a study with a larger sample size correlating treatment response with the serum vitamin D level.
The authors acknowledge Ms. Adity Patil for helping us in correcting language errors in manuscript.
Present study was accomplished with the regular supplies provided by government to the hospital and department where study was conducted.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2018 Egyptian Women's Dermatologic Society
alopecia areata; narrowband ultraviolet B phototherapy; placebo; topical calcipotriol; vitamin D deficiency