Randomized comparison of topical betamethasone valerate foam, intralesional triamcinolone acetonide and tacrolimus ointment in management of localized alopecia areata.

BACKGROUND: Alopecia areata (AA) is a common, non-scarring, patchy loss of hair at scalp and elsewhere. Its pathogenesis is uncertain; however, auto-immunity has been exemplified in various studies. Familial incidence of AA is 10-42%, but in monozygotic twins is 50%. Local steroids (topical / intra-lesional) are very effective in treatment of localized AA. AIM: To compare hair regrowth and side effects of topical betamethasone valerate foam, intralesional triamcinolone acetonide and tacrolimus ointment in management of localized AA.
MATERIALS AND METHODS: 105 patients of localized AA were initially registered but 27 were drop out. So, 78 patients allocated at random in group A (28), B (25) and C (25) were prescribed topical betamethasone valerate foam (0.1%) twice daily, intralesional triamcinolone acetonide (10mg/ml) every 3 weeks and tacrolimus ointment (0.1%) twice daily, respectively, for 12 weeks. They were followed for next12 weeks. Hair re-growth was calculated using "HRG Scale"; scale I- (0-25%), S II-(26-50%), S III - (51-75%) and S IV- (75-100%).
RESULTS: Hair re-growth started by 3 weeks in group B (Scale I: P<0.03), turned satisfactory at 6 weeks in group A and B (Scale I: P<0.005, Scale IV: P<0.001)), good at 9 weeks (Scale I: P<0.0005, Scale IV: P<0.00015), and better by 12 weeks of treatment (Scale I: P<0.000021, Scale IV: P<0.000009) in both A and B groups. At the end of 12 weeks follow-up hair re-growth (>75%, HRG IV) was the best in group B (15 of 25, 60%), followed by A (15 of 28, 53.6%) and lastly group-C (Nil of 25, 0%) patients. Few patients reported mild pain and atrophy at injection sites, pruritus and burning with betamethasone valerate foam and tacrolimus.
CONCLUSION: Intralesional triamcinolone acetonide is the best, betamethasone valerate foam is better than tacrolimus in management of localized AA.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Alopecia areata (AA) is a common, non-scarring, patchy loss of hair at scalp and elsewhere.[1] It accounts for 2% of new dermatological referrals in UK,[2] 1.7% in India[3] and life time risk is 1.7% in USA.[4] The familial incidence is 10-42%[5] and in monozygotic twins is 50%.[7] Alopecia areata is an autoimmune disorder.[89] The disease appears as a coin shaped patch anywhere or band-like lesion over occipital (ophiasis) or fore head (reverse ophiasis), which may progress into alopecia totalis or universalis.[1011] It may involve nails; as pitting, longitudinal or transverse striations, onychomedesis, onychogryphosis, and onychody-strophy.[3] Sometimes, concurrent atopic disorders,[10] diabetes mellitus,[12] and other autoimmune disorders may alter the course and prognosis.

Topical steroids are quite effective and frequently used for treatment of AA[13-16] but intralesional steroids are recommended as first line of therapy in UK,[17] USA[18] and KSA.[19] Other topical agents, like tretinoin,[20] minoxidil[21] and tacrolimus,[2223] have also shown promise. Nevertheless, systemic glucocorticoids, PUVA, thymopentin, cyclosporine-A, inosiplex, dapsone, Zink, methotrexate, interferon -1 alfa and biologicals are indicated for extensive disease.[2021] Cochrane review mentioned, “There is no good trial evidence of any treatment which provides long term benefit to patients with alopecia areata”.[24]

Hence, we aimed at randomized comparative trial of betamethasone valerate foam, intralesional triamcinolone acetonide and tacrolimus ointment for management of localized AA.

MATERIALS AND METHODS

The patients with localized alopecia areata attending dermatologic clinic of a tertiary care Hospital; in Southern Rajasthan, were screened for the study. The inclusion criteria were asymptomatic, non-scarring, patchy hair loss over scalp and elsewhere, patients age range 11 to 50 years in both genders who never received treatment for hair loss. The exclusion criteria were extreme ages (<10 or >50 years), pregnancy or lactation, extensive (more than 3 patches) or atypical alopecia areata (alopecia totalis, alopecia universalis, ophiasis, diffuse) and history of allergy to glucocorticoids or tacrolimus.

Out of 105 selected cases, 78 completed the study and only they were analyzed for therapeutic response. They were randomly allocated to group-A (28), B (25) and C (25), which were prescribed topical betamethasone valerate foam (0.1%) twice daily, intra-lesional triamcinolone acetonide (10 mg/ml) every 3 weeks, and tacrolimus ointment (0.1%) twice daily, for 12 weeks. They were followed for next 12 weeks. The baseline picture and hair re-growth patterns during treatment and after 12 weeks were recorded on transparent sheets with the help of marker and were compared. This helps in assessing the hair growth pattern. Also clinical photographs were taken at every visit. The responses were analyzed by “Hair Re-growth Grade” (HRG) scale as: Scale-I (0-25%), S-II (26-50%), S-III (51-75%) and S- IV (76-100%). Important laboratory tests like, CBC, TEC/VEC, fasting blood sugar, thyroid function tests, skin scraping/hair clipping for KOH mount and urine examination were done in all cases, but other relevant tests were done in special cases.

RESULTS

There was preponderance of age group 21-30 years (32, 41% cases), followed by 11-20 years (23, 29.5% cases), 31-40years (18, 23%) and 41-50 years (5, 6.4% cases) [Table 1]. The majority of patients were males (Male/Female ratio = 2.3 [Table 1]. The duration of illness before reporting was less than 6 months in 97cases (92.4%) but in 8 cases (7.6%) duration was >6 months. Family history were evident for hypertension, atopic disorders, AA, diabetes mellitus, vitiligo and thyroid disorder in 18 (17.1%), 10 (9.5%), 8 (7.6%), 6 (5.7%), 3 (2.9%) and one (0.9) of 105 cases, respectively [Table 2].

Table 1

Age and sex distribution of AA patients (in regular and defaulters)

Table 2

Localization of alopecic patches on scalp and face (n=105)

Scalp alone was affected in majority of cases but few cases showed simultaneous scalp and face involvement. Parietal area was predominantly involved (47, 44.8% cases) as compared to other sites. Beard, moustache and eye brows were affected in 16 (15.2%), 5 (4.8%) and 2 (1.9%) cases, respectively [Figures 1 and 2]. [Table 3] nail changes, like pitting, transverse/ longitudinal striations, Beau's lines and leuconychia were noticed in 14 cases (13.3%), 12 (11.4%), 2 (1.9%), and one (0.9%) case(s), respectively.

Figure 1

Treatment response with intra-dermal triamcinolone acetonide (a) Pre-treatment (b) Post-treatment

Figure 2

Treatment response with betamethasone valerate foam (a) Pre-treatment (b) Post-treatment

Table 3

Concurrent dermatological or systemic disorders in AA patients (n=105)

The therapeutic response started earliest in group B by 3 weeks (Scale I: P<0.03), progressed satisfactorily at 6 weeks in A and B (Scale I: P<0.005, Scale IV: P<0.001), good at 9 weeks (Scale I: P<0.0005 and Scale IV: P<0.00015), and better at 12 weeks of treatment in group A and B cases, respectively.(Scale IV: P<0.000009) [Table 4]. The highest recovery (HRG>75 %) in group A and B at 12 weeks of follow-up was seen in 12 (42.9%) and 16 (60%) cases, respectively, but tacrolimus showed such response in no patient (P<0.0000079) [Table 4]. The comparison of proportions was done by “Chi Square Test” using EPI-6 table. The adverse effects of triamcinolone acetonide injections were local pain and atrophy in 6 cases, itching and burning in 3 and 2 cases, respectively. Betamethasone valerate foam and tacrolimus induced localized itching in 3 cases each. Nobody reported serious systemic side effects.

Table 4

Comparison of proportions (Hair re-growth at 3, 6, 9 and 12 weeks)

DISCUSSION

Alopecia areata usually develops before the age of 30 years; probably due to preferential involvement of dark hairs by the disease.[2] Sharma et al,[3] have also reported 80% of their cases below 30 years of age. This study also showed high incidence in those below 30 years [Table 1]. The incidence of AA has been equal in both genders;[34] in contrast to male predominance (M: F=2.3) in this study [Table 2]. It may be because of genetic predisposition,[56] better health awareness and access to health facilities and prevalence of stressful events in males. The onset of AA is insidious; especially over parietal/temporal area of scalp,[3] which was substantiated by similar picture (in 76% cases) of this study. Nail changes, like pitting, striations, Beau's lines and dystrophy have been reported in 7-66% of AA patients[34] while index study showed nail changes in 29 of 105 (27.6%) patients. About 10-42% of AA patients have family history of alopecia areata,[3-6] especially with atopic diatheses,[10] and similar picture was depicted in this study also. The concurrence of autoimmune diseases, like vitiligo,[11] diabetes mellitus[12] and thyroid disorder,[11] have been reported previously and in this study too, which make us vigilant about injudicious/prolonged use of steroids.

The hair cycle in AA is halted at anagen III rather than anagen IV and hair roots are not at all destroyed by chronic inflammatory process.[11] So, there are always chances of hair re-growth in AA, with immuno-reactants. The main stay of its therapy is local steroids, because of their potent anti-inflammatory action,[13-20] however, some reports showed promise with SADBE,[20] DPCP,[20] minoxidil[21] and tacrolimus.[2223]

Madani et al,[20] in University of Columbia and British Columbia conducted a comparative trial of different regimens in AA patients and reported very good hair re-growth with local steroids in majority of cases. The potent topical corticosteroids, as a foam or non-foam preparations (under occlusion) seem to be effective in treating AA over scalp.[1516] These regimens were painless and effective but needed longer treatment. Mancuso et al,[24] found better hair re-growth with betamethasone valerate foam as compared to betamethasone dipropionate lotion in patchy AA. Tosti et al,[25] studied 28 patients of alopecia totalis /universalis treated with clobetasol propionate ointment under polythene occlusion, daily for 6 months and reported significant hair re-growth. Although, systemic absorption of the drug was not reported, but folliculitis, telangiectasia, striae, pigmentary alteration and atrophy were common side effects. The index study also showed similar response to topical betamethasone valerate foam. The Centre for Adverse Drug Reaction Monitoring,[26] has reported facial skin damage with potent topical corticosteroids. So, it is safer to use potent corticosteroids over face, for less than 2 weeks.

National Guidelines from British Association of Dermatologists,[18] recommend intralesional corticosteroid therapy as the first line treatment for localized patchy AA, with approximate success rates of 60-75%.The prospective study using triamcinolone acetonide (5-10 mg/ml), intradermal, at 2-6 weeks interval reported localized hair re-growth at 60-70% of injection sites.[17] The index study also substantiated significant re-growth (>75%, P<0.000009) with intralesional triamcinolone acetonide and betamethasone valerate foam. The minor side effects (pain, burning and atrophy at injection sites) were reported by some cases, which might be minimized by using 5mg/ml strength of the drug and increased duration between successive injections.

Oral tacrolimus is a potent immuno-suppressant, often used in patients of organ transplantation where cyclosporine-A is contraindicated.[22] The experimental study on bald rats and C3H/HEJ mouse suggested possible role of tacrolimus in treatment of AA.[23] However, it's use in human AA are limited,[2227] especially in those who are sensitive to topical steroids. Some trials showed failure of tacrolimus in AA patients.[2829]

About 30% of untreated patchy AA patients will eventually have complete hair loss. Hence, we also support prompt treatment of AA with local steroids, in a systematic control way.[30] The poor prognostic factors are early onset, atypical AA, concurrence of atopy, auto immune disorders, nail dystrophy and prolonged illness We agree the number of patients were few, follow-up was short and there was no control, however, it reflects the view of triamcinolone acetonide (intralesional) as the treatment of choice for scalp AA.