How effective is intralesional injection of triamcinolone acetonide compared with topical treatments in inducing and maintaining hair growth in patients with alopecia areata? A Critically Appraised Topic
Authors: J.M. Kassim, A.R. Shipman, W. Szczecinska, T.W. Siah, M. Lam, J. Chalmers, A.E. Macbeth
Journal: British Journal of Dermatology (2014)

How effective is intralesional injection of triamcinolone acetonide compared with topical treatments in inducing and maintaining hair growth in patients with alopecia areata? A 23-year-old man with an 18-month history of patch-type alopecia areata (AA) of his scalp has failed to respond to topical clobetasol propionate and tacrolimus ointments. He enquired about intralesional steroid injections and wondered if this would be helpful in the treatment of his condition, which is causing a lot of concern and having a considerable psychological impact to the extent of preventing an active social life owing to embarrassment and low self-esteem. AA is a presumed autoimmune disease of the hair follicles leading to hair loss, and has a lifetime prevalence of 1·7%.1 AA affects all age groups with no preponderance for a specific sex or ethnicity. Overall, 20% of affected individuals have an associated family history of AA with a possible genetic predisposition.2 Spontaneous remission may occur in up to 80% of patients, with limited patchy hair loss of < 1 years' duration.3 Despite this possibility of spontaneous regrowth, data from secondary and tertiary centres show that 14–25% of patients with AA progress to total loss of scalp hair, from which a full recovery is rare.4, 5 The use of intralesional corticosteroids for the treatment of AA varies between centres, and the aim of this critically appraised topic is to examine current evidence to guide clinical decision making. In particular, we were interested in identifying the best evidence with regard to the method of injection, frequency and dosage, and whether short-term hair regrowth was sustained. The frequency and reversibility of adverse events, such as steroid atrophy, or hypopigmentation in those with darker skin types, was also of interest. A search was performed of PubMed, Medline, Embase, the Allied and Complimentary Medicine Database (AMED), and the Cochrane Controlled Trials Registry, using the combined search terms 'alopecia areata' AND 'triamcinolone' OR 'intralesional corticosteroid' from inception until May 2013. AMED is a bibliographical database produced by the Healthcare Information Service of the British Library, which covers a selection of journals in three separate subject areas: (i) professions allied to medicine, including physiotherapy, occupational therapy, rehabilitation, speech and language therapy, and podiatry; (ii) complementary medicine (iii) and palliative care. Guidelines, systematic reviews with meta-analyses, randomized controlled trials (RCTs), cohort studies and case series with more than five participants were sought in which intralesional triamcinolone acetonide (ITA) was used to treat AA. Triamcinolone acetonide has low solubility, so it is slowly absorbed from the injection site, ensuring maximum action and minimal systemic effects. It is preferred to other intralesional steroids because it is less atrophogenic.6 For these reasons, we decided to focus only on papers assessing ITA and not other corticosteroids. In total, 76 papers were identified of which 64 were excluded (42 duplicates, nine literature reviews, five case reports, eight unobtainable/translation unavailable; Fig. 1). The remaining 12 included studies are a Cochrane systematic review, a national guideline, four controlled, nonrandomized clinical trials, five prospective cohort studies and one retrospective case series that examined the efficacy of ITA as the primary outcome. No placebo-controlled RCTs were found. A summary of the included studies is shown in Table 1. The 2006 Cochrane systematic review of interventions for AA7 evaluated the effectiveness of all topical and systemic interventions for AA and included 17 RCTs of therapies. No RCTs of ITA were found, despite common use of this agent. By the nature of this high-quality systematic review, only RCTs were included, with no evaluation of case series or case–control or cohort studies. A conclusion of the Cochrane review was that more RCTs are needed in the field of AA.7 The British Association of Dermatologists' 2012 guidelines for the management of AA8 suggest 'no treatment' as the best option in many cases of AA owing to high rates of spontaneous remission. The guideline recommends ITA only for patchy hair loss of limited extent and for cosmetically sensitive areas such as the eyebrow, and was based on three case series,9-11 which are included later in this review. However, a critical appraisal of these studies was not included in the guideline. ITA was not recommended for rapidly progressive or extensive alopecia. The first controlled clinical trial (CCT), by Frentz in 1977,12 used a split-body design to examine 12 patients with subtotal or universal AA at a tertiary centre in Denmark, treating a half head of six patients with ITA [5 mg mL−1, 2–4 treatments every 4 weeks, up to 17 mg in each treatment, from a needleless system (a jet injector)] and a half head of a further six patients with contact ultraviolet radiation from a mercury arc source, without randomization. The untreated half head acted as a control. The primary outcome measure of 'regrowth' was assessed by both investigator and patient. Half of those (three of six) receiving ITA had some regrowth compared with baseline, but growth diminished over time. The results of the other half head acting as the control were not discussed. Half (three of six) had no noticeable hair regrowth after injections. The study concluded that ITA inhibited spontaneous regrowth, but it lacked blinding or randomization and was based on a subjective and poorly defined outcome measure in a small sample of patients with extensive AA. In another CCT in 1996, Narahari13 compared the efficacy of ITA (10 mg mL−1) with topical dithranol 1·15% cream in 100 patients with AA. Exclusions before analysis included 12 patients lost to follow-up and 19 patients with spontaneous hair growth, implying attrition bias. Complete regrowth of hair was seen in 49% (18/37) of patients with ITA and 62% (20/32) of patients on topical dithranol (P = 0·25). Adequate response was classified as 'uniform eruption of hair from hair follicles in the lesional skin' and was seen in 84% (31/37) of patients receiving ITA and 59% (19/32) of patients using topical dithranol (P = 0·02). Adverse events were skin atrophy (10%, four of 37) in the ITA group and irritant contact dermatitis (6%, two of 32) with topical dithranol. At 12 months, patients who received injection had a statistically significant increase in relapse rates: 57% (21/37) compared with 12% (four of 32) in patients using dithranol. The author concluded that ITA induced a better but more temporary response rate compared with dithranol. We noticed a selection bias (single lesion on scalp and disease duration < 6 months) and inadequate randomization. Kubeyinje and C'Mathur14 performed an open-label CCT in 1997 comparing the efficacy and safety of combined daily tretinoin 0·05% cream and monthly ITA (40 mg, n = 28) with monthly ITA alone (40 mg, n = 30). At 16 weeks, > 90% regrowth was seen in 86% (24/28) of patients with combination therapy compared with 67% of patients on single therapy (P < 0·01). The tools used to assess hair regrowth were not explained. Despite the aims of the study, the safety of the therapy and occurrence of adverse events were not mentioned. The patient selection criteria were not clear, including duration of disease, and the number of patients with extensive alopecia included in the study (one in each arm) was too low. There was no randomization or blinding of participants or clinicians. The most recent CCT is a prospective study by Kuldeep et al. in 2011.15 They recruited 108 patients, but analysed 78 with three or fewer patches of AA, comparing hair regrowth and adverse effects in a three-arm study of topical betamethasone valerate foam 0·1% (n = 28), ITA 10 mg mL−1 (n = 25) and tacrolimus ointment 0·1% (n = 25). Overall, 60% (15/25) of those treated with ITA reached the presumed end point of > 75% hair regrowth at 12 weeks compared with 54% (15/28) with topical betamethasone valerate foam and no response (0/25) in the tacrolimus group. However, there was no prespecified primary outcome measure, and the data analysis included many subgroup analyses. The adverse effects were more numerous in the ITA group, including local pain and atrophy (six of 25, 24%), compared with three patients in each of the other two treatment groups with itching alone. Due to the methodological flaws, such as lack of randomization and allocation concealment methods, lack of patient or assessor blinding, failure to include all assigned participants in the analysis, and lack of sample size or power calculations, there is a high risk of bias in this study. Conclusions cannot be drawn regarding the superiority of one treatment over another based on these findings. In 1971, Porter and Burton9 compared the effects of ITA and its less soluble derivative triamcinolone hexacetonide (THC) in a controlled cohort of patients with AA aged 11–58 years, at a U.K. secondary care centre. ITA, 1 mg in 0·1 mL, was injected into 25 sites in 17 patients, and intralesional THC, 1 mg in 0·2 mL, was injected into 34 sites in 11 patients. Each site was injected only once. Hair regrowth was measured by taking the mean length of several terminal hairs that had grown at the injected sites. Regrowth was seen in 97% (33/34) of sites injected with THC, and in 64% (16/25) of sites injected with ITA. The study demonstrated continued hair growth for at least 9 months after a single injection in both groups. The hair regrowth assessment was not a validated tool, although this study pre-dates currently recognized validation methods for clinical end points, and there was no definition of successful hair regrowth. The method of randomization to treatment groups is not clear, and sample size and power calculations were omitted. In 1973 Abell and Munro10 treated a cohort of 84 patients with AA in a U.K. tertiary centre with ITA using a needleless injector (Porto Jet). As a within-patient control, 15 of the patients received needless injection of sterile normal saline on the other half of their scalp. Overall, 92% (61/66) of those with limited AA showed regrowth at 6 weeks, but only 71% (47/66) maintained regrowth at 12 weeks. In total, 61% (11/18) of patients with alopecia totalis (AT) showed initial regrowth at 6 weeks, and only 28% (five of 18) were able to maintain this at 12 weeks. Spontaneous regrowth occurred in 12% (eight of 66) of patients with limited AA and 22% (four of 18) with AT. In the control group, 7% (one of 15) showed regrowth at 6 weeks, which was maintained at 12 weeks. The study included a small number of patients who had localized beard alopecia and eyebrow alopecia. Adverse effects among the 84 patients included haemorrhage, atrophy (n = 2), pain (n = 2) and a depressed plasma cortisol level (n = 1). Despite this being a cohort study, there is no mention of patient selection, methods of randomization to the control group, and methods of blinding of participants and clinicians. Kubeyinje11 reported a further noncontrolled cohort of 62 patients with AA from Saudi Arabia studied between December 1990 and November 1993 and treated with ITA (40 mg), injected monthly for 12 months. Overall, 68% (42/62) of participants experienced complete regrowth at 16 weeks. In total, 78% (35/45) of patients with fewer than five patches showed complete hair regrowth at 16 weeks, compared with 41% (seven of 17) of patients with more than five patches. Patients with patches < 3 cm diameter showed more frequent complete regrowth at 16 weeks than patients with larger patches [81% (34/42) vs. 40% (eight of 20)]. There were no adverse reactions reported. More than half of the patients were followed up for 2 years and none relapsed on this time scale. There was no randomization, blinding or control, increasing the likelihood of selection and performance bias in this study. Only those who 'complied' with treatment were included, and so important information about adverse effects may be lacking. Also for this reason this report may over- or underestimate the success of treatment. In a prospective cohort study, Wahab16 treated 40 patients with AA aged 10–50 years with ITA in 2006. These patients had previously failed to respond to potent topical steroids. Disease was present for < 6 months in 62% (25/40) of participants. ITA (3–5 mg mL−1, 1 mL cm−2) was given monthly for 3–5 months, and participants were followed up monthly for a year. Hair regrowth was defined as complete (good), incomplete (fair) or no growth (poor), without an objective definition or validated assessment tool. Complete hair regrowth occurred in 65% (26/40) of all participants, with incomplete hair growth in a further 12% (five of 40). Relapse occurred in 12% of patients (five of 40) within 1 year. In patients with 'extensive alopecia', 25% (one of four) had complete hair regrowth. This small study did not include a control arm, was unblinded and had a subjective end point. The authors concluded that there was lack of efficacy in 'extensive' AA; however, this subgroup contained only four individuals. A prospective cohort study by Ganjoo and Thappa in 201317 included 65 patients aged 10 years and over with AA, treated with ITA in a tertiary dermatology unit in India. Alopecia was graded using the Alopecia Grading Score, the Regrowth Scale and dermoscopy. Patients were injected with ITA (5 mg mL−1, 0·1 mL per 1 cm2 site) every 4 weeks for a maximum of 24 weeks, but injections were stopped once response was achieved. Clinically significant hair regrowth (> 75%) was achieved in 47% (28/60) of patients at 12 weeks and 95% (57/60) at 24 weeks. Vellus hairs on dermoscopy may have been an early indicator of successful treatment. Atrophy occurred in 16% (11/70) of treated patches. Skin hypopigmentation or depigmentation was not seen. ITA was effective in treating AA at a relatively low dose in this study, and a greater response was observed when it was given for a longer duration; however, the patient group selected (disease duration < 1 year, one to three patches of AA and < 50% scalp area involved) is known to have a high spontaneous remission rate. Patients lost to follow-up (n = 5) were not included in the analysis, which may imply attrition bias, and the authors do not specify by what method participants were recruited. In this cohort study, there were no controls or randomization. In 2009, Chang et al.18 retrospectively reviewed the case notes of 14 adult patients with extensive AA (> 50% scalp involvement). Patients were treated with ITA (5–10 mg mL−1) between June 2003 and December 2006. ITA was repeated every 4–6 weeks, and response was assessed 4–8 weeks following treatment. Response was deemed as 'complete' or 'near complete' cosmetically acceptable regrowth at 4–8 weeks. Four patients were lost to follow-up and 60% (six of 10) of the remaining patients were deemed responders. Four of these six participants had disease duration of < 1 year, suggesting a high chance of spontaneous regrowth. Three patients had mild local dermal atrophy. The assessment of hair regrowth was too subjective, without the use of a standardized or validated method. The study was limited in many ways by its retrospective nature, small numbers and selection of only patients with extensive alopecia, attrition bias, lack of control group and blinding. All of the studies included here except one12 suggest that intralesional steroids are effective in treating AA, with varying degrees of success. The studies suggest that ITA is most effective in patients with limited AA and a shorter duration of disease. Patients with extensive AA or AT and longer duration of the disease (> 1 year) showed poor response. The studies included here were limited in many ways. Firstly, four of these studies had no control group.11, 16-18 It is well known that spontaneous regrowth is higher in patients with alopecia that is limited and of short duration,4 and most studies recruit patients from this category. Similarly, if a study uses only those with extensive and persistent disease, the results are likely to be poor, although it is important to ascertain efficacy in this group to guide the clinician. Some studies did not mention the severity of alopecia or duration of the disease and therefore there may be unstated selection bias in those studies. One study16 included only patients who had failed to respond to potent topical steroids. Moreover, the patients were often not followed for a sufficient duration to ascertain maintenance of regrowth. The longest duration of follow-up was 18 months;9 where six of the 11 patients receiving ITA had continued hair growth at the sites of injection, progression of the rest of the scalp to AT occurred in two patients. One of the aims of treatment in AA is to achieve cosmetically acceptable hair regrowth to enable the patient to have a healthy social life. Most of the studies, with the exception of one,12 did not attempt to assess patient-rated outcome measures. Adverse events from intralesional steroid injections, such as pain and skin atrophy at sites of injection, were observed in up to 24% of cases.15 These studies suggest that intralesional corticosteroids may provide some benefit for the treatment of patch-type alopecia, but the quality of this evidence is poor. There was no adequate randomization or blinding, making the possibility of selection and performance bias likely. For this reason, conclusions are not possible regarding superiority, or inferiority, over other treatments.13-15 Primary outcome measures were not consistent or reported in a way that can be compared between papers. Standardized, validated assessment tools are required. Variation in method of administration, dosage and frequency also limits comparison of studies. Clinically, ITA is a well-recognized treatment among dermatologists, and has relatively low cost and primarily local and minor adverse effects. A large, multicentre RCT comparing intralesional steroid and continued topical steroid with placebo injection and standard topical steroid therapy in adults with AA of at least 6 months' duration is needed to assess superiority of ITA over continued topical therapy in terms of efficacy, sustained regrowth at follow-up and adverse effects. Further studies including dose variation and comparison of method of administration are also required. Use of validated hair regrowth tools, such as the Severity of Alopecia Tool score, defined by consensus by Olsen et al.,19 and the hair regrowth scale, longer follow-up of ≥ 1 year and patient-rated outcome measures, such as the Alopecia Areata Quality of Life Index,20 should all be included. Any conclusions are limited by the paucity of evidence, examined up to May 2013. The studies are small, prone to bias and a different regime is used for each, so the findings of this Critically Appraised Topic cannot be conclusive. There is a suggestion from the literature that intralesional steroids may be of some benefit for AA, but without RCTs the decision to use this treatment will depend on the individual and perceived benefits, risks, tolerability and costs of the procedure. We proceeded to treat our patient with ITA after discussing the potential risks and benefits. We used a 10 mg mL−1 solution, injecting boluses of 0·1 mL in an area of 1 cm,2 1 cm apart, repeated every 2 weeks on three occasions until regrowth was seen. Regrowth lasted for 6 months. We would like to thank Professor Hywel Williams for his guidance and comments on an earlier version of this manuscript. All authors are members of the U.K. Dermatology Clinical Trials Network (DCTN) Trainee Group and have received expertise from the U.K. DCTN team. A.E.M. is funded by Addenbrooke's Charitable Trust. None declared.