|Year : 2017 | Volume
| Issue : 4 | Page : 261-266
Alopecia areata: Update on management
Julie S Kranseler, Robert Sidbury
Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, USA
|Date of Web Publication||29-Sep-2017|
OC.9.835, Seattle Children's Hospital, 4800 Sand Point Way NE Seattle, WA 98105
Source of Support: None, Conflict of Interest: None
Alopecia areata (AA) is a common autoimmune nonscarring alopecia. AA presents heterogeneously and is influenced by both environmental and genetic factors. Diagnosis is clinical after ruling out other local or systemic causes of alopecia. Standard first-line therapy is typically topical steroids, but the response can be frustrating. Novel treatment options have shown great promise in the management of the refractory disease. We review initial data on topical and systemic Janus kinase inhibitors (tofacitinib, ruxolitinib, and baricitinib), topical bimatoprost, simvastatin/ezetimibe, and excimer laser therapy among others within the context of a general approach to AA management.
Keywords: Alopecia areata, autoimmune, bimatoprost, corticosteroids, Janus kinase inhibitors
|How to cite this article:|
Kranseler JS, Sidbury R. Alopecia areata: Update on management. Indian J Paediatr Dermatol 2017;18:261-6
| Introduction|| |
Alopecia areata (AA) is a chronic, immune-mediated inflammatory disorder of anagen hair follicles leading to relapsing, nonscarring hair loss. The most common presentation is localized patches of hair loss on the scalp (alopecia focalis), however, more extensive forms can lead to diffuse hair loss throughout the entire body, including the eyelashes and eyebrows (alopecia universalis [AU]). AA can have tremendous psychosocial impact on patients and families. AA is associated with a significant prevalence of psychiatric disorders including major depressive disorder, generalized anxiety disorder and social phobia. Poor health-related quality of life (HRQoL) has been found in patients with AA, and greater severity correlates with lower HRQoL, particularly in pediatric populations. It is, therefore, crucial to address both the psychological and medical/clinical aspects of the disease in every patient.
Treatment can be challenging. While many improve spontaneously or respond to standard therapy, patients with more severe disease can be quite refractory. Up to 50% of patients experience spontaneous hair regrowth within 1 year but can relapse. Recent advances in the understanding of AA pathophysiology hold promise for better treatments in the future.
| Epidemiology|| |
AA is one of the most common autoimmune conditions with the prevalence of 1.5%–2% in the general population, without gender or racial proclivity. The onset of AA can occur at any age, but the peak incidence is in the second and third decades of life. Within the pediatric population specifically, incidence is highest between 1 and 5 years old. Patients who have an earlier onset of disease may develop more severe phenotypes. There is a significant genetic component with children having at least one affected parent courting increased risk closer to 6%. One in five affected individuals also have an affected first-degree relative. There is growing evidence of associations with a variety of human leukocyte antigen types, particularly DQ3, DQ7, DR4, DR5, and DPW4 alleles.
The prevalence of other autoimmune conditions in patients with AA is 16%, including thyroid disease, systemic lupus erythematosus (SLE), vitiligo, psoriasis, rheumatoid arthritis (RA), celiac, and inflammatory bowel disease. There is also an increased risk for atopic dermatitis in patients with alopecia, especially alopecia totalis (AT) and AU. As in psoriasis, AA can occur as a side effect of biological therapy with tumor necrosis factor (TNF)-alpha inhibitors used to treat other autoimmune conditions.
| Pathogenesis|| |
The pathogenesis of AA involves a complex interaction between genetic, environmental, and immune factors. Normal hair growth occurs in distinct cycles: active hair growth (anagen), follicular involution (catagen), and follicular rest and shedding of hairs (telogen). In AA, auto-reactive CD8+ lymphocytes attack anagen hair causing premature transition to catagen and telogen, resulting in hair loss. This process is driven by many immunologic factors including interferon (IFN)-gamma and IL-15, which are Janus kinase-Signal Transducer and Activator of Transcription (JAK/STAT)-dependent cytokines. Recent evidence suggests that programmed cell death protein 1 ligand (PD-L1) dysfunction may contribute to AA pathology. PD-L1 helps create follicular immune privilege that protects anagen hair follicles from autoimmune destruction. Triggers for AA can include emotional or physical stress, pregnancy, infections, and hormones.
| Diagnosis|| |
The diagnosis of AA is usually clinical. Patients typically present with oval to oblong patches of smooth bald scalp that appear abruptly and expand centrifugally. Occasionally, the patches have mild pruritus or burning, but most commonly are asymptomatic. The classic finding is the presence of exclamation point hairs, often predominately at the border of the lesion in the areas of active hair loss. These are short hairs that have broken off due to injury to precortical keratinocytes, with the proximal end of the hair narrower and lighter in color than the distal end  [Figure 1]. These hairs can be extracted with minimal traction, and occasionally, there are white hairs within these patches. Nail involvement is relatively common and includes pitting [Figure 2], trachyonychia, onychorrhexis, and onycholysis. Nails can be affected at any point during disease progression.
AA has several phenotypic expressions most commonly presenting with focal patchy involvement of the scalp. Alopecia ophiasis describes hair loss along the parietal and occipital scalp and can portend a more guarded prognosis. Alopecia sisaipho indicates frontal, temporal, and parietal scalp hair loss that can mimic androgenic alopecia. AT presents with complete scalp hair loss. Finally, AU is a term indicating complete body hair loss.
The differential diagnosis of AA can include tinea capitis (particularly in pediatric patients), trichotillomania, cicatricial alopecia, androgenetic alopecia, secondary syphilis, telogen effluvium, congenital triangular alopecia, and congenital ectodermal dysplasia. The systemic disease should be considered particularly with more diffuse loss including hypothyroidism, anemia, diabetes, severe illness, malnutrition, or malabsorption. Dermoscopy may be helpful and typically shows yellow [Figure 1] and black dots, broken hairs, and short vellus or tapered hairs. Scalp biopsy is rarely needed but shows inflammatory lymphocytic infiltrate around the lower hair follicles.
| Standard Treatment Paradigms|| |
Few randomized controlled AA trials exist for the treatment of AA particularly in pediatric populations. Determining the efficacy of different treatment modalities is further complicated by the fact that many patients recover spontaneously. There are currently no United States Food and Drug Administration (US FDA)-approved systemic treatments for AA. Localized AA can be treated with topical agents or reassurance as many patients resolve without treatment. More extensive AA including AT or AU can be quite challenging as spontaneous regrowth is rare and no proven therapies exist. Several systemic options can be considered including steroids, methotrexate, and cyclosporine among others [Table 1]. Cosmetic approaches to minimize appearance and psychological distress such as wigs are important considerations in some patients. Advocacy groups such as the National AA Foundation (naaf.org), with support groups for patients worldwide, can be important resources. Poor prognostic factors include extensive hair loss, history of atopy, concomitant autoimmune disease, childhood onset, family history of AA, duration of >1 year, and nail disease.
Treatment for pediatric patients is influenced by age. Children <10 years of age are generally treated with topical steroids, with second line options including topical anthralin, topical minoxidil, topical retinoids, and in select cases systemic therapy is considered. Children older than 10 years may use the same therapies, but providers will expand options to also consider intralesional steroids, contact immunotherapy (e.g., squaric acid dibutyl ester) or excimer laser therapies. Intralesional steroids are not contraindicated in younger children, but needle phobia and compliance with multiple injections are common barriers. Unproven treatments include topical and systemic tacrolimus, TNF-alpha inhibitors, topical latanoprost, and topical 5-fluorouracil. Topical minoxidil is sometimes used, but there are some concerns about hypotension or cardiovascular side effects when used over large surface areas. Phototherapy has a modest evidence base including ultraviolet B (UVB) and psoralen ultraviolet A though the latter is rarely used due to concern for carcinogenesis.
| New Directions in Treatment|| |
Janus kinase inhibitors
The most exciting class is the JAK inhibitors. The JAK-STAT signaling pathway represents a convergence of many different pro-inflammatory processes within the body. JAK is a cytoplasmic tyrosine kinase. The JAK-STAT pathway has direct effects on FN-α/β, IFN-γ, IL-2 receptor common γ-chain interleukins (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), IL-5, IL-6, IL-12, IL-13, and IL-23 in addition to indirect effects on TNF–alpha, IL-1, IL-17 and IL-23. JAK inhibitors have been extensively studied for the treatment of psoriasis and have results comparable to TNF-alpha inhibitors such as Etanercept. They are also being studied for the treatment of vitiligo, atopic dermatitis, graft versus host disease, cutaneous T cell lymphoma, and SLE.
JAK inhibitors are targeted anti-inflammatory drugs that promote activation of hair follicle stem cells. Mouse models have shown significant hair regrowth. Ruxolitinib is a JAK 1 and 2 inhibitor. It is currently US FDA approved for myelofibrosis but is being tested for many dermatologic conditions. There have been multiple case reports looking topical and systemic use in AA. In addition, there has been one open-label clinical trial by Mackay-Wiggan et al. that at a dose of 20 mg BID, found that 75% of patients had hair regrowth of up to 92% after 3–6 months. The most common adverse effect noted in the trial was a modest increase in particularly urinary tract infections. Baricitinib is another JAK 1 and 2 inhibitor. It is currently being tested in Phase 2 and Phase 3 trials for RA, psoriasis and atopic dermatitis. A single case report described full scalp hair regrowth after 9 months in a patient with CANDLE syndrome (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature) and AA.
Tofacitinib is a JAK 1 and 3 inhibitor currently US FDA approved for RA. It has been used off-label for many dermatologic conditions including psoriasis, dermatomyositis, and vitiligo. There have been many case reports showing efficacy in both AA and AU with 5 mg BID dosing. In one of the largest trials Liu et al. showed >50% improvement in Severity of Alopecia Tool (SALT score) in 42% of the ninety enrolled patients, though there were better results in localized disease. Most patients had relapses within 2-3 months of drug cessation, indicating the probable need for long-term therapy to maintain disease quiescence. Associated nail dystrophy has also shown clinical improvement in patients with AU. Infection risks are comparable to other systemic immunomodulatory medications used for AA. Decreased vaccination response is also a concern. Recently, the US FDA rejected a supplemental new drug application for the use of tofacitinib in psoriasis though additional studies are ongoing. This failure likely had much to do with the availability of other relatively safe, effective systemic options for psoriasis making the “safety bar” higher to clear. This is not the case with AA.
Given concerns for potential side effects and cost associated with systemic JAK inhibitors, recent studies have also begun to look at using topical JAK inhibitors in pediatric patients. In series of 6 patients treated with topical JAK inhibitors (both tofacitinib and ruxolitinib in liposomal bases), 4 patients had some hair regrowth without any serious adverse effects. Craiglow et al. showed that 69% of adolescents had hair regrowth with a mean of 93% improvement in SALT score in a different cohort. The lack of a control group complicates interpretation of these studies. Other studies have shown success in focal eyebrow disease.
JAK inhibitors are especially promising for those with AT or AU though high relapse rates suggest the need for long-term maintenance therapy. Larger long-term safety studies addressing are needed before JAK inhibitors can be routinely recommended as part of the regular arsenal for this otherwise medically benign disease. Current monitoring recommendations include a complete blood count, comprehensive metabolic panel, fasting lipid panel, HBV, HCV, HIV, and tuberculosis screens and then follow-up 1 month after treatment and then every 3 months. The most common adverse events are nasopharyngitis and upper respiratory infections though cutaneous infections, gastrointestinal complaints, herpes zoster, and laboratory abnormalities such as anemia, neutropenia (cytopenias more common with ruxolitinib due to JAK2 inhibition) and mild hyperlipidemia have been seen. Finally, the cost is a barrier as JAK inhibitors are extremely expensive. Further characterization of AA inflammation will help to better target treatment with JAK inhibitors.
Another new agent in the treatment of AA is the prostaglandin analog bimatoprost. Borchert et al. showed a marked response versus vehicle in the treatment of eyelash hypotrichosis due to both AA and chemotherapy. The results were sustained at 5-month follow-up in contrast to the high rate of relapse seen after discontinuation of JAK inhibitors. Adverse events were mild and included conjunctival hyperemia, conjunctivitis, and eczema. Other smaller studies, including pediatric case reports, showed the efficacy of bimatoprost drops in the treatment of scalp AA. Several other older adults RCT's showed efficacy for eyebrow and eyelash hair loss. Other adult studies have demonstrated significantly better results with topical bimatoprost compared with topical steroids. This suggests a possible treatment for scalp AA.
Methotrexate is a commonly used treatment for psoriasis and other inflammatory skin disorders. Anecdotal support coupled with several recent studies suggests a possible role in AA treatment. In a cohort study of children aged 8–18 years with treatment-resistant AA, nearly four in ten patients had >50% hair regrowth without relapse. The majority of responders also received corticosteroids during the treatment course. A recent pediatric case series demonstrated similar efficacy without any limiting side effects that limited. Cyclosporine and azathioprine have good efficacy in smaller studies but are not indicated for due to the potential for serious side effects and high relapse. In addition, there is a concern that some patients have developed AA while taking cyclosporine for other indications.
Cryotherapy is appealing due to modest and well-characterized serious side effects, but efficacy has been inconsistently demonstrated. In a retrospective study by Jun et al. 61% of patients responded after 3 months of therapy, with better response rates in patients with shorter intervals between therapy and first occurrence of disease. Loi et al. showed some good preliminary data in a small case control study that simvastatin/ezetimibe may have immunomodulatory benefits, including in the treatment of AT and AU.,
Laser therapy remains unproven though there are a growing number of devices that have been trialed. Excimer laser, using high dose long-wave monochromatic UVB radiation, triggers apoptosis of T cells and induces immunological action through mediators such as IL-4, IL-10, prostaglandin E2, platelet-activating factor, histamine, and cis-urocanic acid. Hair growth only occurs on treated patches and benefit has only been seen with localized AA, and atopy may be a poor prognostic indicator. Adverse effects included erythema, crusting, vesicle formation, and hyperpigmentation. Other trials have shown some benefit with monochromatic excimer light; one report even showed improvement with AU. Modalities that have shown a mixed response in the literature include Diode lasers and UVA. Less encouraging are studies that have looked at neodymium: yttrium-aluminum-garnet, Fractional CO2 laser, narrowband UVB phototherapy, and light emitting diode.
Micronutrient deficiencies have an important role in normal hair growth, and small studies have examined the role of supplementation as a primary or adjunct therapy for AA. Preliminary studies suggest that serum Vitamin D, Vitamin A, zinc, and folate levels tend to be lower in patients with AA as compared to controls, but there remains no evidence that supplementation benefits AA.
Myriad other systemic treatments have been tried including Sulfasalazine and TNF-alpha inhibitors. The latter has shown no efficacy, and there are some reports they may even precipitate AA. Finally, platelet rich plasma has proven ineffective for the treatment of noncicatricial alopecias.
| Conclusion|| |
AA is a common autoimmune disorder with inadequate treatment options particularly for pediatric patients. A growing body of research suggests that certain systemic therapies may provide benefit for patients with refractory disease. The most promising newer treatments include topical and systemic JAK inhibitors (tofacitinib, ruxolitinib, and baricitinib), topical bimatoprost, simvastatin/ezetimibe and excimer laser therapy however there remains a dearth of randomized controlled trials. Safety data are critical particularly for a disease that is medically benign. Conversely, efficacy data are essential for a disease that can be psychosocially devastating. Recent progress offers hope for more effective treatment on the horizon.
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Conflicts of interest
There are no conflicts of interest.
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