Alopecia areata An appraisal of new treatment approaches and overview of current therapies Lauren C. Strazzulla, BA,a Eddy Hsi Chun Wang, PhD,b Lorena Avila, MD,a Kristen Lo Sicco, MD,a Nooshin Brinster, MD,a Angela M. Christiano, PhD,b and Jerry Shapiro, MDa New York, New York
Learning Objectives After completing this learning activity, participants should be able to identify different classes of treatment options including injections, topical therapy, systemic medications, and phototherapy; explain the evidence supporting the use of each treatment, and list potential adverse effects; categorize the expected treatment outcomes for each therapy; and describe how new basic science research and insights into immune mechanisms of alopecia areata contribute to the development of new therapies. JAK inhibitors and phosphodiesterase 4 inhibitors represent important new options for severe alopecia areata. A new algorithmic approach will be presented integrating these new treatment modalities. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Authors The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Planners The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).
Many therapies are available for the treatment of alopecia areata, including topical, systemic, and injectable modalities. However, these treatment methods produce variable clinical outcomes and there are no currently available treatments that induce and sustain remission. When making management decisions, clinicians must first stratify patients into pediatric versus adult populations. Disease severity should then be determined (limited vs extensive) before deciding the final course of therapy. The second article in this continuing medical education series describes the evidence supporting new treatment methods, among them Janus kinase inhibitors. We evaluate the evidence concerning the efficacy, side effects, and durability of these medications. An overview of conventional therapy is also provided with new insights gleaned from recent studies. Finally, future promising therapeutic options that have not yet been fully evaluated will also be presented. ( J Am Acad Dermatol 2018;78:15-24.) Key words: alopecia areata; alopecia totalis; alopecia universalis; corticosteroids; JAK inhibitors; minoxidil; topical immunotherapy.
APPROACH TO TREATMENT Key points d
Alopecia areata is unpredictable, and therefore no treatment may be appropriate for a subgroup of patients as spontaneous
From The Ronald O. Perelman Department of Dermatology,a New York University School of Medicine, and the Department of Dermatology,b College of Physicians and Surgeons, Columbia University, New York. Funding sources: None. Dr Shapiro is a consultant for Aclaris Therapeutics, Applied Biology, Incyte, Replicel Life Sciences, and Samumed. Dr Christiano is a consultant for Aclaris Therapeutics and a principal investigator for Pfizer. The other authors have no conflicts of interest to declare. Ms Strazzulla and Dr Wang contributed equally to this article.
remission rates range from 8% to 68%, depending on disease severity Extent of hair loss and age of the patient are the most important factors to consider when determining management approaches
Accepted for publication April 10, 2017. Correspondence to: Jerry Shapiro, MD, Department of Dermatology, New York University School of Medicine, 530 First Ave, Unit 7R, New York, NY 10016. E-mail: [email protected]
nyumc.org. 0190-9622/$36.00 Ó 2017 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2017.04.1142 Date of release: January 2018 Expiration date: January 2021
J AM ACAD DERMATOL
16 Strazzulla et al
Abbreviations used: AA: AT: AU: DPCP: JAK: SADBE: SALT: TAC:
alopecia areata alopecia totalis alopecia universalis diphenylcyclopropenone Janus kinase squaric acid dibutylester Severity of Alopecia Tool triamcinolone acetonide
Patients should be educated about hairpieces and camouflage techniques
Few treatment methods have been evaluated by randomized control trials to determine the most efficacious modalities to treat alopecia areata (AA), and therefore it is challenging for clinicians to guide patients regarding the best therapeutic options. However, extent of hair loss and patient age are the most important factors influencing the approach to treatment (Fig 1). Other factors to consider include cost, patient compliance, and the degree of psychosocial impact of hair loss on the patient.1 Patients should be referred to the National Alopecia Areata Foundation (www.naaf.org), which provides advice, support, opportunities to participate in research including clinical trials, and options to purchase products, such as hairpieces, scarves, and hats. It is important to note that in some instances it may be appropriate not to medically treat AA, if this is consistent with the patient’s wishes; however, most that seek dermatologic care desire therapeutic intervention. Counseling patients regarding the likelihood of spontaneous remission can help them make an informed decision on treatment. Rates of spontaneous remission range from approximately 8% for extensive disease ([50% scalp involvement) to as high as 68% for limited alopecia (\25% scalp involvement).2 Patients should also be advised on the products available to conceal hair loss. Individuals with [50% hair loss may wish to have a scalp prosthesis made. These can be bought readymade or can be customized for an individual, which can take several weeks. Hairpieces range from offering partial to full scalp coverage and can be made from human or synthetic fibers. In general, wigs made from human hair are more expensive and less durable. Another approach to minimizing the appearance of hair loss involves semipermanent hair additions that may be bonded, glued, or sewed to existing hairs and are worn for up to 8 weeks at a time (Fig 2). Those with eyebrow loss may consider artificial eyebrows that are glued to the superior orbital ridge.3 Alternatively,
patients may elect to undergo manual microblading, a semipermanent tattoo used to create the appearance of eyebrow hairs.
INTRALESIONAL CORTICOSTEROIDS Key points d
Intralesional corticosteroids are considered a first-line treatment method for limited disease, and can be used as adjunctive therapy in extensive disease Patients should be monitored for side effects, including skin atrophy, which may warrant dose modification or treatment discontinuation
Intralesional corticosteroids, most commonly triamcinolone acetonide (TAC), are the criterion standard for treating patchy AA of limited extent and for cosmetically sensitive areas, such as the eyebrows. Tan et al4 reported that 82.1% of 127 patients with limited AA showed [50% improvement with intralesional TAC injections for 12 weeks. Those with moderate to severe AA had poorer results, with 25% to 50% regrowth after 6 months.4 Another retrospective review of 10 patients with [50% scalp involvement who were treated with TAC injections showed those with a better response tended to be younger (33 vs 53 years of age) and had AA for a shorter duration of time (2.5 vs 16.7 years). One interesting observation was that in the responder group 5 of 6 patients had a positive pull test, while 4 of 6 had exclamation point hairs on examination. In the nonresponder group, all had a negative pull test and only 1 had evidence of exclamation hairs. Because the pull test and exclamation point hairs may be regarded as indicators of inflammation, this suggests that patients with clinical evidence of active inflammation are better candidates for intralesional TAC.5 It has been recently reported that 2.5 mg/mL TAC confers the same benefit as either 5 or 10 mg/mL in patients with patchy AA.6 Therefore, the authors recommend using low-dose TAC at a higher volume for the scalp (2.5 mg/mL, total volume 8 mL) and the same dose for the eyebrows with #0.5 mL volume into each eyebrow.6 Discontinuation of therapy may be considered if the patient fails to respond within 3 to 6 months. Though intralesional steroids as monotherapy may be inadequate for extensive AA, in the experience of the authors, this treatment can be used as an adjunctive therapy to systemic treatment and may accelerate the effects of oral corticosteroids and response to Janus kinase (JAK) inhibitors.7 Side effects include skin atrophy at the site of injection, which typically resolves after a few
J AM ACAD DERMATOL VOLUME 78, NUMBER 1
Strazzulla et al 17
Fig 1. Treatment algorithm for the management of alopecia areata. DPCP, Diphenylcyclopropenone; JAK, Janus kinase; SADBE, squaric acid dibutylester.
Fig 2. A and B, This alopecia areata patient has hair extensions braided onto existing hairs.
months. This may be avoided if lower volumes of corticosteroids are injected at or below the dermoepidermal junction.8 Caution should be exercised with injections near the eyes, such as into the eyebrows, because there is a small risk for increased intraocular pressure, glaucoma, and cataracts.9
TOPICAL CORTICOSTEROIDS Key points d
Topical corticosteroids may be used alone or in conjunction with other treatments, including intralesional corticosteroids Pediatric patients may prefer treatment with topical corticosteroids compared to injections
Topically applied corticosteroids likely provide some benefit in AA, especially in patients with
limited disease, although the results may be inferior to intralesional therapy. Evidence from split scalp studies has confirmed that regrowth results from local and not systemic effects of the medication.10 In 54 patients with patchy AA who applied either 0.25% desoximetasone or placebo twice daily for 12 weeks, complete regrowth was higher among the corticosteroid-treated group (57.7% vs 39.3%); however, the difference between the groups was not statistically significant. Of the patients who did not achieve complete regrowth, 19 opted for treatment with intralesional TAC, and while only 14 were available for follow-up, 13 of these patients achieved complete regrowth within 1 to 3 months. In fact, the response rate to intralesional TAC in this study was significantly better than to desoximetasone cream (P 5 .03).11 Others have also shown approximately a 60%
J AM ACAD DERMATOL
18 Strazzulla et al
Fig 3. A and B, This pediatric patient with alopecia areata was treated with 0.1% mometasone cream and 5% minoxidil solution twice daily, with (C and D) significant evidence of regrowth 2 months later. When the patient attempted to taper treatment, the alopecia returned.
response rate to topical corticosteroids.12 Results from a study with a predominantly pediatric population (19/28) revealed that those \10 years of age and those with an AA duration of \1 year tended to respond more frequently to treatment with topical corticosteroids (0.2% fluocinolone acetonide cream).12 We typically recommend 0.05% clobetasol propionate foam, a superpotent steroid. However, in children \10 years of age, the less potent mometasone is more commonly used (Fig 3). In our clinic, we have noted that this treatment can be an effective monotherapy for patchy alopecia, especially among pediatric patients who are unable to tolerate injections. Clobetasol propionate foam without occlusion is considered more cosmetically acceptable and convenient for the patient compared to other formulations. This treatment method was evaluated in 34 patients with moderate to severe AA enrolled in a randomized, double-blind placebo controlled trial spanning 24 weeks. After 12 weeks, greater hair regrowth was noted on 89% of scalp sites treated with clobetasol foam versus 11% of sites treated with placebo.13 Adverse effects of topical corticosteroids include mild itching, burning, acneiform eruption of the face (more common with ointment preparations than foam), striae, telangiectasia, and skin atrophy.14
MINOXIDIL Key point d
5% minoxidil foam or solution may be used as adjuvant therapy in alopecia areata
As a monotherapy for AA, minoxidil may be insufficient to promote complete hair regrowth. Nonetheless, many studies have suggested that it does stimulate hair growth in patients with AA, though less commonly in severe forms of the disease. For example, a long-term study of 30 patients evaluated the efficacy of 3% minoxidil twice daily compared to placebo for 12 weeks followed by 52 weeks of minoxidil treatment. At 12 weeks, the treated group had slightly more growth compared to the placebo group, but these results failed to reach statistical significance. At 64 weeks, the results seemed to correlate with the degree of initial hair loss. Of the patients with complete scalp hair loss at baseline, all demonstrated no or slight hair growth, while of the 20 patients with less than full scalp involvement, 45% had cosmetically acceptable hair growth.15 Another study evaluated 3% minoxidil solution in a double-blind placebo controlled protocol for 1 year that included 19 subjects with extensive AA ([50% scalp involvement). In the minoxidil group, 63.6% of patients had increased hair growth compared with 35.7% of those treated
J AM ACAD DERMATOL
Strazzulla et al 19
VOLUME 78, NUMBER 1
Fig 4. A and B, This female patient with alopecia areata developed hypertrichosis on her hands and face after 8 weeks of twice daily 5% minoxidil foam application.
with placebo. This study found that in patients treated with minoxidil on one side of the scalp, hair increased on both sides but grew earlier and denser on the treated side.16 Finally, minoxidil may help maintain hair growth stimulated by other treatments. Olsen et al17 found that in patients treated with a prednisone taper, those who also used 2% topical minoxidil (3 times daily) for $6 weeks after maintained hair growth more frequently than those treated with placebo. The authors recommend 5% minodixil as opposed to lower strengths because higher concentrations have been reported to be more effective, though there may be an increased likelihood of unwanted hair growth on other parts of the body compared to lower concentrations.18,19 Collectively, these results suggest that topical minoxidil may provide some benefit in patients with AA, though likely cannot alter the disease course or induce remission.15 This medication is easy to use, and side effects are usually mild, including scalp itching and dermatitis.16 Rarely, around 2% to 5% of patients may develop sparse vellus hairs on other parts of the body (Fig 4), and very infrequently some may experience tachycardia.20
ORAL CORTICOSTEROIDS Key point d
Short courses (6 weeks) of oral corticosteroids are often sufficient to stimulate hair regrowth; however, the side effect profile precludes long-term use and the likelihood of relapse is significant
Systemic corticosteroids are widely used in autoimmune diseases and have demonstrated a significant benefit in most clinical variants of AA, with reduced efficacy in ophiasis and alopecia universalis (AU) types.21 In a study of 32 patients who completed at least a 6-week course of
prednisone at a dose of \0.8 mg/kg, 47% showed [25% regrowth, while 25% of the patients had [75% regrowth. Notably, 50% of these patients had alopecia totalis (AT) or AU.17 This study shows that a short course of steroids is often sufficient to treat AA (Fig 5), though others have described patients treated with 3 to 5 months of therapy, and at a dose of 20 to 30 mg/day with similar results.4 However, the response to pulse steroids may not be durable, and many patients will relapse within 4 to 9 weeks after discontinuing steroids.22 The side effects of steroids generally preclude their long-term use. These include suppression of the pituitaryeadrenal axis, effects on bone growth or integrity, ocular changes, and worsening of hypertension or diabetes.23
METHOTREXATE Key point d
Methotrexate may be effective for patients who fail standard therapy
Successful treatment of AA with methotrexate has been reported in both adult and pediatric populations. Chartaux and Joly24 described 33 patients with either AT or AU (mean disease duration, 7.7 years) who failed standard therapy and found that methotrexate (15-25 mg) alone or in combination with oral corticosteroids (prednisone 10-20 mg/day) resulted in complete hair regrowth in 63% of those on combined treatment and 57% of those treated with methotrexate alone. Another study by Royer et al25 examined 14 children with severe AA who had failed to respond to conventional treatment. These patients were treated with a mean dose of 18.9 mg methotrexate (range, 15-25 mg), and 8 of 14 also received oral corticosteroids. Of the 13 children available for assessment, 5 had a successful response with [50% regrowth (4 of these were also treated with short-term corticosteroids) and started responding after approximately 4.4 months.25 These
20 Strazzulla et al
J AM ACAD DERMATOL
Fig 5. A 28-year-old Asian female with acute diffuse and total alopecia areata at the initial visit (A-C) underwent treatment with 40 mg prednisone taper over 8 weeks combined with monthly intralesional corticosteroids, 5% minoxidil foam, and clobetasol solution twice daily. D-F, Significant regrowth was observed 8 weeks later.
results suggest that methotrexate may be a viable treatment option for refractory and severe AA.
TOPICAL IMMUNOTHERAPY Key points d
Diphenylcyclopropenone has a success rate of approximately 60% to 70%, and is an option for the treatment of patients with extensive disease ([50% scalp involvement) Patients who do not respond to diphenylcyclopropenone may be treated with squaric acid dibutylester
Topical immunotherapy, including squaric acid dibutylester (SADBE) and diphenylcyclopropenone (DPCP), causes an allergic contact dermatitis and through an incompletely understood mechanism may cause antigenic competition, changing the milieu of immune cells surrounding hair follicles.26 There is evidence to support its use in extensive AA, even for pediatric patients [10 years of age (Fig 6).1,27-30 Patients who will undergo treatment with DPCP should first be sensitized using 2% DPCP to a circular area 4 cm in diameter. DPCP should be obtained from a pharmacy familiar with compounding it in acetone. Next, 0.001% DPCP is applied unilaterally beginning 1 week later with an increase in the concentration during each subsequent week until the patient develops a desired
mild tolerable dermatitis (with pruritus and erythema) that lasts 36 hours. Once the concentration that is effective for the patient is determined, this should be applied by the physician or nurse on a weekly basis. During the 48 hours after treatment, DPCP should remain on the scalp and should be covered to prevent exposure to light, which degrades the molecule. Once there is a trichogenic response on one side, then both sides are treated.31,32 A greater risk for relapse after discontinuation of DPCP may be observed if the dose is not tapered, and therefore patients should be advised that treatment should not be interrupted suddenly.33 A recent study reviewed 20 years of experience using DPCP for AA and found an overall response rate of 72.2%.34 Durdu et al35 reported that the efficacy of DPCP may be enhanced by combination therapy with anthralin (0.5-1.0%), which causes an irritant dermatitis. This study included 74 treatment-resistant patients, 47 of whom were treated with combination DPCP and anthralin. Combination therapy was shown to be more effective (88% of patients had [50% regrowth vs 54.5% for DPCP alone), elicited faster hair growth (regrowth duration was 4 weeks shorter), and importantly regrowth of eyelashes, eyebrows, and beard was also significantly better among the combination group. No significant differences in relapse rates between the 2 groups were identified.35
J AM ACAD DERMATOL
Strazzulla et al 21
VOLUME 78, NUMBER 1
Fig 6. A-D, A 12-year-old female with alopecia areata who was noted on the initial examination to have sparse hairs only on the top of her scalp and who was treated with 1.5% diphenylcyclopropenone.
For patients who fail to respond successfully to DPCP, therapy with SADBE may be tried, with a similar efficacy as DPCP.28,33,36 Of note, a recent study on SADBE reported that, unlike DPCP, an initial eczematous reaction to sensitization is not required for successful treatment. These investigators reported that of the 4 patients who chose not to undergo sensitization or who did not exhibit a response, all had regrowth.37 Regarding efficacy, in a study of 54 patients with different clinical subtypes of AA treated with SADBE (3%) therapy, 79.6% of patients experienced complete regrowth compared to 50% regrowth in controls. Patients with more severe disease required significantly greater treatment times on average (AU, 45 weeks; AT, 32 weeks; patchy AA, 29 weeks). Over a follow-up period of 2 to 8 years, those treated with SADBE had reduced severity of relapse compared to the control group.38 Topical sensitizers should not be used in pregnant women because the teratogenic effects and degree of systemic absorption of these compounds are unknown. Side effects from topical sensitizers include severe eczema and cervical and occipital lymphadenopathy, among others.34
NOVEL THERAPEUTIC METHOD USING JANUS KINASE INHIBITORS Key points d
Oral Janus kinase inhibitors, including tofacitinib, ruxolitinib, and baricitinib, have
been shown to be efficacious in alopecia areata The durability of response to these medications is variable, and most patients experience recurrence of hair loss after discontinuation Topical Janus kinase inhibitors may also be effective but have not been fully evaluated
JAK inhibitors have already demonstrated efficacy in multiple inflammatory diseases, such as psoriasis, rheumatoid arthritis, and vitiligo, with further new successful reports in treating TH2-driven diseases, such as atopic dermatitis.39-43 Dramatic hair regrowth was observed in preclinical studies using JAK inhibitors in C3H/HeJ mice, and this provided a strong rationale to test these medications in humans.44 The first reports demonstrating efficacy of a JAK inhibitor in AA were a patient with AU treated with tofacitinib who experienced extensive hair regrowth, and 3 patients treated with ruxolitinib who had changes in biomarkers to resemble healthy controls.44,45 These early case reports were then corroborated by 2 open-label studies. One study was an open-label trial of ruxolitinib in patients with moderate to severe AA. Of the 12 patients in this study (treated with 20 mg twice daily for 3-6 months), the results were impressive, with 75% of patients responding successfully and an average regrowth of 92% at the end of treatment
J AM ACAD DERMATOL
22 Strazzulla et al
among responders. However, during a 3-month, treatment-free follow-up period, 3 of 9 responders had marked shedding, while 6 had some shedding. Baseline scalp biopsies from these AA patients revealed gene expression profiles with elevated immune pathways that normalized after ruxolitinib treatment. In addition, responders appeared to demonstrate high interferon and cytotoxic T lymphocyte scores at baseline, while those who were nonresponders were noted to have lower interferon and cytotoxic T lymphocyte scores at baseline. The investigators speculated that nonresponder patients may therefore have an alternative etiology for their hair loss separate from the interferon-driven mechanism targeted by JAK inhibitors.46 The second open-label study evaluated oral tofacitinib (5 mg twice daily) in 66 patients with various forms of AA. This study found that overall 64% of patients responded to treatment and 32% achieved an improvement in the Severity of Alopecia Tool (SALT) score of [50% after 3 months of therapy. These findings were also corroborated by normalization of gene expression biomarkers in scalp biopsy specimens after treatment. To assess durability of response, patients were reevaluated during a 3-month treatment-free follow-up period. However, only 20 patients were available for follow-up, and all experienced hair loss (median 8.5 weeks after stopping treatment). Neither age nor sex appeared to correlate with change in SALT score, though subtype did affect mean percentage change in SALT; those with patchy AA showed a 34% greater change compared to AU (P 5 .0005), while ophiasis had a 48% greater change compared to AU (P 5 .006). Each additional year of disease resulted in a decrease in percentage change of SALT score by 0.78 (P 5 .0247).47 A third larger retrospective analysis of 90 patients with AA (the majority with AU or AT) treated with tofacitinib revealed an overall response rate of 77% (moderate, intermediate, or complete response). While this study failed to find a significant correlation between patient age and change in SALT score, a reduced likelihood of response to treatment in those with a [10-year duration of AA was identified.48 Finally, the use of tofacitinib among adolescents was recently reported in a retrospective study that demonstrated regrowth in 9 of 13 patients with AA between 12 and 17 years of age. Tofacitinib given at 10 to 15 mg daily was well tolerated among these patients and no serious adverse events reported; however, the potential side effects should be carefully weighed in pediatric patients.49
Baricitinib has been reported in a patient with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome with concomitant ophiasis type AA. Though the ophiasis pattern of AA tends to be recalcitrant to treatment, improvement was noted shortly after initiating baricitinib, with complete regrowth after 9 months of treatment.50 The use of ruxolitinib is also supported by a case report of a patient with AU being treated for essential thromobocytopenia (15 mg twice daily) who showed near complete regrowth after 10 months of treatment, and in a patient treated for AA along with chronic mucocutaneous candidiasis.51,52 Finally, 2 cases of successful treatment of AU with tofacitinib have been reported.53 In general, side effects of JAK inhibitors include (potentially serious) infections, viral reactivation, bone marrow disruption, transaminase changes, and a theoreticaldthough unprovendrisk for malignancy.46,54,55 Given the serious adverse effects that could potentially result from long-term systemic JAK inhibitor therapy, some have considered the use of topical JAK inhibitors in place of systemic agents. However, this treatment modality has not yet been evaluated in large studies. One case reported a patient with AU who had previously failed most available treatment methods (including oral prednisone, intralesional corticosteroids, sulfasalazine, and topical immunotherapy) and was then treated with topical ruxolitinib 0.6% cream twice daily to the scalp and eyebrows. After 12 weeks, the eyebrows were improved and there was regrowth of 10% of the scalp hairs.56 These encouraging results suggest that topical JAK inhibitors warrant additional study and could be improved by more sophisticated formulations targeting the hair follicle and reticular dermis.
FUTURE DIRECTIONS Key point d
Existing medications are being evaluated for their utility in AA
Statins may have antiinflammatory properties,57 and recently 40 mg/10 mg daily simvastatin/ ezetimibe for 24 weeks was investigated in patients with AA (40-70% scalp involvement). Of the 19 patients who completed the study, 14 were considered responders, suggesting that this treatment method should be explored in future studies.58 Apremilast, an oral phosphodiesterase-4 inhibitor, has been shown to prevent AA development in human scalp skin grafts in mice and is currently under investigation in a clinical
J AM ACAD DERMATOL VOLUME 78, NUMBER 1
trial.59 A topical phosphodiesterase-4 inhibitor, crisaborole, is now commercially available for the treatment of mild to moderate atopic dermatitis and could also be useful in AA.60 Overall, there may be new treatment options on the horizon for patients with AA. REFERENCES 1. van der Steen PHM, van Baar HMJ, Happle R, Boezeman JBM, Perret CM. Prognostic factors in the treatment of alopecia areata with diphenylcyclopropenone. J Am Acad Dermatol. 1991;24:227-230. 2. Tosti A, Bellavista S, Iorizzo M. Alopecia areata: a long term follow-up study of 191 patients. J Am Acad Dermatol. 2006; 55:438-441. 3. Draelos ZD. Camouflage technique for alopecia areata: what is a patient to do? Dermatol Ther. 2011;24:305-310. 4. Tan E, Tay YK, Goh CL, Chin Giam Y. The pattern and profile of alopecia areata in Singaporeea study of 219 Asians. Int J Dermatol. 2002;41:748-753. 5. Chang KH, Rojhirunsakool S, Goldberg LJ. Treatment of severe alopecia areata with intralesional steroid injections. J Drugs Dermatol. 2009;8:909-912. 6. Chu TW, AlJasser M, Alharbi A, Abahussein O, McElwee K, Shapiro J. Benefit of different concentrations of intralesional triamcinolone acetonide in alopecia areata: an intrasubject pilot study. J Am Acad Dermatol. 2015;73:338-340. 7. Strazzulla L, Avila L, Lo Sicco K, Shapiro J. Image gallery: treatment of refractory alopecia universalis with oral tofacitinib citrate and adjunct intralesional triamcinolone injections. Br J Dermatol. 2017;176:e125. 8. Madani S, Shapiro J. Alopecia areata update. J Am Acad Dermatol. 2000;42:549-566. 9. Carnahan MC, Goldstein DA. Ocular complications of topical, peri-ocular, and systemic corticosteroids. Curr Opin Ophthalmol. 2000;11:478-483. 10. Tosti A, Piraccini BM, Pazzaglia M, Vincenzi C. Clobetasol propionate 0.05% under occlusion in the treatment of alopecia totalis/universalis. J Am Acad Dermatol. 2003;49:96-98. 11. Charuwichitratana S, Wattanakrai P, Tanrattanakorn S. Randomized double-blind placebo-controlled trial in the treatment of alopecia areata with 0.25% desoximetasone cream. Arch Dermatol. 2000;136:1276-1277. 12. Pascher F, Kurtin S, Andrade R. Assay of 0.2% fluocinolone acetonide cream for alopecia areata and totalis. Dermatology. 1970;141:193-202. 13. Tosti A, Iorizzo M, Botta GL, Milani M. Efficacy and safety of a new clobetasol propionate 0.05% foam in alopecia areata: a randomized, double-blind placebo-controlled trial. J Eur Acad Dermatol Venereol. 2006;20:1243-1247. 14. Takeda K, Arase S, Takahashi S. Side effects of topical corticosteroids and their prevention. Drugs. 1988;36:15-23. 15. Price VH. Topical minoxidil (3%) in extensive alopecia areata, including long-term efficacy. J Am Acad Dermatol. 1987;16: 737-744. 16. Price VH. Double-blind, placebo-controlled evaluation of topical minoxidil in extensive alopecia areata. J Am Acad Dermatol. 1987;16:730-736. 17. Olsen EA, Carson SC, Turney EA. Systemic steroids with or without 2% topical minoxidil in the treatment of alopecia areata. Arch Dermatol. 1992;128:1467-1473. 18. Fiedler-Weiss VC. Topical minoxidil solution (1% and 5%) in the treatment of alopecia areata. J Am Acad Dermatol. 1987; 16:745-748.
Strazzulla et al 23
19. Dawber RPR, Rundegren J. Hypertrichosis in females applying minoxidil topical solution and in normal controls. J Eur Acad Dermatol Venereol. 2003;17:271-275. 20. Blume-Peytavi U, Hillmann K, Dietz E, Canfield D, Bartels NG. A randomized, single-blind trial of 5% minoxidil foam once daily versus 2% minoxidil solution twice daily in the treatment of androgenetic alopecia in women. J Am Acad Dermatol. 2011;65:1126-1134. 21. Friedli A, Labarthe MP, Engelhardt E, Feldmann R, Salomon D, Saurat JH. Pulse methylprednisolone therapy for severe alopecia areata: an open prospective study of 45 patients. J Am Acad Dermatol. 1998;39:597-602. 22. Michalowski R, Kuczy nska L. Long-term intramuscular triamcinolon-acetonide therapy in alopecia areata totalis and universalis. Arch Dermatol Res. 1978;261:73-76. 23. Kern F, Hoffman WH, Hambrick GW, Blizzard RM. Alopecia areata: immunologic studies and treatment with prednisone. Arch Dermatol. 1973;107:407-412. 24. Chartaux E, Joly P. Long-term follow-up of the efficacy of methotrexate alone or in combination with low doses of oral corticosteroids in the treatment of alopecia areata totalis or universalis [in French]. Ann Dermatol Venereol. 2009;137: 507-513. 25. Royer M, Bodemer C, Vabres P, et al. Efficacy and tolerability of methotrexate in severe childhood alopecia areata. Br J Dermatol. 2011;165:407-410. 26. Happle R. Topical immunotherapy in alopecia areata. J Invest Dermatol. 1991;96:71S-72S. 27. Iorizzo M, Tosti A. Treatments options for alopecia. Exp Opin Pharmacother. 2015;16:2343-2354. 28. Rokhsar CK, Shupack JL, Vafai JJ, Washenik K. Efficacy of topical sensitizers in the treatment of alopecia areata. J Am Acad Dermatol. 1998;39:751-761. 29. Hull S, Pepall L, Cunliffe WJ. Alopecia areata in children: response to treatment with diphencyprone. Br J Dermatol. 1991;125:164-168. 30. Tosti A, Guidetti MS, Bardazzi F, Misciali C. Long-term results of topical immunotherapy in children with alopecia totalis or alopecia universalis. J Am Acad Dermatol. 1996;35:199-201. 31. Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J. Alopecia areata update: part II. Treatment. J Am Acad Dermatol. 2010;62:191-202. 32. Shapiro J, Tan J, Ho V, Abbott F, Tron V. Treatment of chronic severe alopecia areata with topical diphenylcyclopropenone and 5% minoxidil: a clinical and immunopathologic evaluation. J Am Acad Dermatol. 1993;29:729-735. 33. Ohlmeier MC, Traupe H, Luger TA, B€ ohm M. Topical immunotherapy with diphenylcyclopropenone of patients with alopecia areataea large retrospective study on 142 patients with a self-controlled design. J Eur Acad Dermatol Venereol. 2012;26:503-507. 34. Lamb RC, Young D, Holmes S. Retrospective review of diphencyprone in the treatment of alopecia areata. Clin Exp Dermatol. 2016;41:352-358. € 35. Durdu M, Ozcan D, Baba M, Sec¸kin D. Efficacy and safety of diphenylcyclopropenone alone or in combination with anthralin in the treatment of chronic extensive alopecia areata: a retrospective case series. J Am Acad Dermatol. 2015; 72:640-650. 36. Hill ND, Bunata K, Hebert AA. Treatment of alopecia areata with squaric acid dibutylester. Clin Dermatol. 2015;33: 300-304. 37. Vedak P, Kroshinsky D. Squaric acid sensitization is not required for response in the treatment of alopecia areata. J Am Acad Dermatol. 2015;73:471-476.
24 Strazzulla et al
38. Dall’Oglio F, Nasca MR, Musumeci ML, et al. Topical immunomodulator therapy with squaric acid dibutylester (SADBE) is effective treatment for severe alopecia areata (AA): results of an open-label, paired-comparison, clinical trial. J Dermatolog Treat. 2005;16:10-14. 39. Levy LL, Urban J, King BA. Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate. J Am Acad Dermatol. 2015;73:395-399. 40. Ports WC, Khan S, Lan S, et al. A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis. Br J Dermatol. 2013;169:137-145. 41. Strober B, Buonanno M, Clark JD, et al. Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment. Br J Dermatol. 2013;169: 992-999. 42. Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009;60:1895-1905. 43. Craiglow BG, King BA. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed therapy. JAMA Dermatol. 2015;151:1110-1112. 44. Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20:1043-1049. 45. Craiglow BG, King BA. Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis. J Invest Dermatol. 2014;134:2988. 46. Mackay-Wiggan J, Jabbari A, Nguyen N, et al. Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata. JCI Insight. 2016;1:e89790. 47. Crispin MK, Ko JM, Craiglow BG, et al. Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata. JCI Insight. 2016;1:e89776. 48. Liu LY, Craiglow BG, Dai F, King BA. Tofacitinib for the treatment of severe alopecia areata and variants: a study of 90 patients. J Am Acad Dermatol. 2017;76:22-28.
J AM ACAD DERMATOL
49. Craiglow BG, Liu LY, King BA. Tofacitinib for the treatment of alopecia areata and variants in adolescents. J Am Acad Dermatol. 2017;76:29-32. 50. Jabbari A, Dai Z, Xing L, et al. Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib. EBioMedicine. 2015;2:351-355. 51. Pieri L, Guglielmelli P, Vannucchi AM. Ruxolitinib-induced reversal of alopecia universalis in a patient with essential thrombocythemia. Am J Hematol. 2015;90:82-83. 52. Higgins E, Al Shehri T, McAleer MA, et al. Use of ruxolitinib to successfully treat chronic mucocutaneous candidiasis caused by gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation. J Allergy Clin Immunol. 2015;135:551. 53. Gupta AK, Carviel JL, Abramovits W. Efficacy of tofacitinib in treatment of alopecia universalis in two patients. J Eur Acad Dermatol Venereol. 2016;30:1373-1378. 54. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807. 55. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367:495-507. 56. Craiglow BG, Tavares D, King BA. Topical ruxolitinib for the treatment of alopecia universalis. JAMA Dermatol. 2016;152: 490-491. 57. Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov. 2005;4:977-987. 58. Lattouf C, Jimenez JJ, Tosti A, et al. Treatment of alopecia areata with simvastatin/ezetimibe. J Am Acad Dermatol. 2015; 72:359-361. 59. Keren A, Shemer A, Ullmann Y, Paus R, Gilhar A. The PDE4 inhibitor, apremilast, suppresses experimentally induced alopecia areata in human skin in vivo. J Dermatol Sci. 2015;77:74-76. 60. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75:494-503.e4.