Dermatology

Alopecia areata

Alopecia Areata (AA) 704.01

Are You Confident of the Diagnosis?

  • What you should be alert for in the history

The history is notable for a sudden onset of asymptomatic patchy, nonscarring hair loss that is often associated with spontaneous regrowth within 1 to 3 months. Recurrence is common and cannot be predicted. A prodrome of mild paresthesias, pruritus, tenderness or a burning sensation may precede hair loss but often times the hair loss is asymptomatic. Ninety-five percent of cases involve the scalp, but any hair-bearing area can be affected. Alopecia totalis is defined as a loss of 100% of scalp hair; Alopecia Universalis is loss of 100% of body hair.

  • Characteristic findings on physical examination

Characteristic findings include 1-4 cm well-demarcated round to oval patches of hair loss with exclamation point hairs at the periphery (Figure 1, Figure 2). Less commonly, patients may present with sudden onset whitening of the hair ("going white overnight"). AA may target pigmented follicles while sparing white/gray hairs, giving the illusion that the hair suddenly turned white. A positive hair pull test is present (with greater than five hairs shed with pulling small tufts of hair near the area of alopecia). Associated nail dystrophies are found in 10-66% of cases, including linear pitting and longitudinal striations.

Figure 1.

Alopecia areata. Typical patch of nonscarring alopecia.

Figure 2.

Note exclamation point hairs.

  • Expected results of diagnostic studies

AA is a clinical diagnosis. In clinically equivocal cases, when a biopsy may be obtained, the histopathology shows an early anagen bulb surrounded by lymphocytic infiltrate resembling a "swarm of bees."

  • Diagnosis confirmation

AA must be differentiated from trichotillomania, tinea capitis and secondary syphilis. Trichotillomania presents with irregularly-shaped, poorly circumscribed areas of alopecia, with broken hairs present throughout the lesion and a negative hair pull test. Tinea capitis presents as inflamed, scaling patches of alopecia with characteristic black dot hairs (if caused by Trichophyton tonsurans) throughout the patch; it is differentiated from AA by KOH microscopic examination and/or fungal cultures. Secondary syphilis presents with a moth-eaten pattern of irregular, diffuse patches of alopecia.

Who is at Risk for Developing Alopecia areata?

The lifetime risk is 1.7%. All races and males and females are affected equally. Sixty percent of cases present before 20 years of age; 7-37% have familial associations.

What is the Cause of Alopecia areata?

  • Etiology

AA is thought to be caused by an autoimmune attack of the base of the hair follicle that spares the stem cell compartment of the follicle, so regrowth of hair remains possible.

  • Pathophysiology

While AA is believed to be a TH1 lymphocyte–mediated autoimmune attack of the hair follicle, its pathophysiology is largely unknown. AA is thought to occur after the collapse of the hair follicles' immune privileged state following an unknown insult, leading to upregulation of MHC I complexes and follicular antigen presentation, which incites a T lymphocyte-mediated immune response to immunologically unfamiliar follicular antigens.

It was recently discovered to share common antigen encoded by gene ULBP3. ULBP3 gene proteins are not normally present on hair follicles but are abundant in hair follicles affected by AA. The same ULBP3 gene also plays an active role in rheumatoid arthritis, celiac disease, and insulin-dependent diabetes mellitus, further confirming the autoimmune nature of AA.

Systemic Implications and Complications

Twenty-five percent of cases are associated with a concomitant autoimmune disorder; reports include Addison's disease, diabetes mellitus, pernicious anemia, autoimmune thyroid disorders (Grave's disease and Hashimoto's thyroiditis) and vitiligo. Thyroid disorders are the most common conditions associated with AA, present in 8-12% of cases, along with a personal or family history of atopic dermatitis.

Vitiligo is the second most common associated autoimmune disorder, with a fourfold increased rate in patients with AA. AA is seen in patients with Trisomy 21 (Down's syndrome).

Treatment Options

Treatment options are summarized in Table I.

Table I.

Treatment options for alopecia areata
MEDICAL TREATMENTS SURGICAL TREATMENTS PHYSICAL TREATMENTS
TOPICAL/INTRALESIONAL SYSTEMIC
Intralesional corticosteroids Systemic corticosteroids Pulsed infrared diode laser Phototherapy
Topical mid potent corticosteroid Sulfasalazine Excimer laser
Retinoid + topical mid potent corticosteroid Cyclosporine
Minoxidil Methotrexate
Contact sensitizer: Diphenylcyclopropenone (DPCP), Squaric acid & Dinitrochlorobenzene (DNCB) PUVA
Anthralin

Optimal Therapeutic Approach for Alopecia areata

There are currently no randomized, double-blind, placebo-controlled studies on a large scale that investigate treatment of alopecia areata. The treatments discussed below are not FDA-approved.

For patients with alopecia totalis/universalis (AT/AU), treatment results are in general unsatisfactory.

First-line Therapies

Adults and children with localized disease

Observation alone may be all that is needed, as regrowth typically occurs in 1-3 months.

Intralesional triamcinolone acetonide 5.0-10 mg/mL injections are the therapy of choice. Injections are repeated every 4-6 weeks. It is important to perform dermal injections. In one study, 86% of cases showed regrowth of hair, typically starting in 4-8 weeks. If no response is seen within 6 months, injections should be stopped.

Topical mid-potent corticosteroid. Apply nightly to affected area. The author a prefers fluocinonide solution. If no response is seen within 6 months, consider alternative treatment.

Tretinoin 0.025% gel applied every night followed by a mid-potency topical corticosteroid solution applied every morning. In theory, the tretinoin causes irritation (if too irritating, apply every other night) and enhances local topical steroid penetration. A trial of 6 months is performed before deeming treatment a failure.

Topical minoxidil solution. Nightly application of topical 2% or 5% minoxidil solution or foam can also be added to any of the above regimens. The minoxidil acts as a hair growth promoter.

Adults and children with diffuse scalp disease that is cosmetically unacceptable and AT/AU

Topical immunotherapy using squaric acid dibutyl ester (SADBE), diphenylcyclopropenone (DPCP) or dinitrochlorobenzene (DNCB). Up to 60% of patients, by report, show some regrowth of hair within 6 months.

The author uses squaric acid and will briefly discuss the treatment protocol. These treatments require a sensitization treatment (e.g., 2% squaric acid). Once sensitized, a series of gradually increasing concentrations are applied to the upper, inner arms or upper buttocks (e.g., squaric acid 0.001%, 0.01%, 0.1%, and 1.0%). Most patients react to squaric acid 0.1% or 1.0%.

The author provides the patient with a prescription for at home, weekly application after careful instruction. Contact sensitizers can have serious complications, including severe allergic contact dermatitis, generalized hypersensitivity reaction (<3%), hypo- or hyperpigmentation at application sites, and lymphadenopathy. Referral to a specialist with experience with this treatment is recommended.

Systemic steroids for the patient who presents with active, diffuse shedding. The author prescribes prednisone 40 mg for 7 days, then 30 mg for 7 days, 20 mg for 7 days, and 10 mg for 7 days. The side effects of steroids must be discussed in detail. This is a onetime treatment due to long-term, systemic side effects. Warn the patient that regrowth from systemic steroids is often short-lived. Steroids may work initially, but they have numerous side effects and a high relapse rate, and thus are seldom used for the treatment of AA.

Second-Line Therapies

Anthralin. For treatment resistant, localized and diffuse disease, short contact with anthralin 1.0% cream for 20 minutes each night is another treatment option. The major side effects include skin irritation and staining. A 6-month trial is warranted before declaring treatment failure.

Phototherapy. The author does not use topical or systemic phototherapy for patients with AA because of the lack of a treatment endpoint and of ultraviolet (UV) light-induced damage to the skin.

Third-Line Therapies

Systemic and laser therapies (including methotrexate, cyclosporine, sulfasalazine, excimer laser, and infrared diode laser) are third line treatments for treatment-resistant AA. Data is lacking for most of these therapies, requiring the clinician to proceed with caution when considering these options.

Sulfasalazine, started at 0.5 g twice daily for 1 month, then 1 g twice daily for 1 month, followed by 1.5 g twice daily for 4 months was found to be effective in 23% of patients in a study by Ellis et al. However, the relapse rate was 45.5%. Adverse effects included gastrointestinal upset, rash, and headache. If results are not seen within 4-6 months, therapy should be discontinued. Sulfasalazine and other Immunomodulators may work initially, but they have numerous side effects and a high relapse rate, and thus are seldom used for the treatment of AA.

Cyclosporine. Studies on cyclosporine therapy, both alone and in combination with methylprednisolone, have had success rates ranging from 25-76.6%. One study treated 6 patients with 6 mg/kg per day of cyclosporine for 12 weeks. Response to treatment occurred in all patients; however, within 3 months of discontinuation of cyclosporine therapy, all patients relapsed. It is important to note that AA has also been observed in transplant patients on cyclosporine. Due to conflicting evidence, lack of large randomized placebo-controlled studies, and the harsh side effect profile, cyclosporine is rarely used for the treatment of AA.

Methotrexate. One study using 20-25 mg per week methotrexate combined with 20 mg per day prednisone found a total recovery of 64% of AA patients in the study. This data needs to be confirmed with large randomized placebo-controlled studies before efficacy can be commented upon.

Psoralen plus UVA (PUVA) was found to be an ineffective and nondesirable treatment for AA by Alkhalifah et al., due to its high relapse rates, lack of randomized controlled trials, and the increased risk of skin malignancies. Consequently, PUVA is rarely used for the treatment of AA.

Excimer Laser and pulsed infrared diode laser were found in two trials to be 76-94% effective in causing regrowth in patients with AA after 2 months; long-term efficacy is still in question. The initial fluences of the 308nm excimer laser are started 50 mJ/cm2 less than the minimal erythema dose and increased by 50 mJ/cm2 every two sessions. Treatment is twice weekly for up to 24 sessions. Regrowth was seen in 41.5% of patches. Infrared irradiation using several different protocols has been shown to be somewhat effective. However, larger randomized control trials are still needed to validate these findings.

Treatment of AA involving the eyebrow

Intralesional triamcinolone acetonide (5 mg/cc) every 4-6 weeks and topical minoxidil applied twice daily. Inject dermally in order to avoid atrophy. Trophy reverses to normal after 3-6 month period. The author generally injects 0.3-0.4 cc to each eyebrow per session. Regrowth is typically seen after 4-8 weeks. Remember that corticosteroid injection for eyebrows can be very effective, as discussed above, and patients appreciate the positive impact that eyebrows have on appearance.

Treatment of AT/AU

AT and AU have poor prognoses, with disappointing results. Topical immunotherapy as discussed above is the treatment of choice for widespread disease. The author focuses on impact of quality of life. If impacted negatively, a 6-month trial of immunotherapy is warranted. Unfortunately, long-term data is not available and in the author's experience, relapse is common. The most important aspect of treatment is psychological support for both the patient and the family.

Education is critical for AA, especially for AT/AU. Refer to the National Alopecia Areata Association for both adults and children and/or to the Children's Alopecia Project.

A hair piece is recommended in the setting of extensive hair loss.

The most important aspect of treatment is psychological support for both the patient and the family.

Patient Management

The course of AA is unpredictable. Most patients will experience regrowth of hair in 1-3 months with or without therapy. Relapse is common. Poor prognostic factors include long duration of disease, diffuse disease, ophiasis pattern (hair loss limited to periphery of scalp), family history of AA, disease at a location other than the scalp, onset in childhood, associated autoimmune disorders, associated atopic dermatitis. and associated nail dystrophy.

Patient education is necessary to alleviate anxiety and false hopes. AA can lead to psychologic distress; counseling and support services should be offered. All patients should be given contact information for the National Alopecia Areata Foundation and for children, the Children's Alopecia Project.

Unusual Clinical Scenarios to Consider in Patient Management

The psychological stress of losing one's hair can be overwhelming for patients. Referring for counseling services may be necessary.

What is the Evidence?

Alkhalifah, A, Alsantali, A, Wang, E, McElwee, KJ, Shapiro, J. "Alopecia areata update: part I. Clinical picture, histopathology, and pathogenesis". J Am Acad Dermatol. vol. 62. 2010. pp. 177-88.

(Alkhalifah et al. present an in depth review of AA, including demographics, clinically relevant pearls, differential diagnoses, prognostication, associated abnormalities, work-up, pathology, pathogenesis, autoimmune theory, genetics of AA, and environmental risk factors associated with AA.)

Alkhalifah, A, Alsantali, A, Wang, E, McElwee, KJ, Shapiro, J. "Alopecia areata update: part II. Treatment". J Am Acad Dermatol. vol. 62. 2010. pp. 191-202.

(Alkhalifah et al. present an in-depth review of the literature regarding therapeutic approaches to AA. Intralesional, topical, systemic, physical and laser therapies are discussed. Future therapeutics currently under investigation are also mentioned.)

Alexis, AF, Dudda-Subramanya, R, Sinha, AA. "Alopecia areata: autoimmune basis of hair loss". Eur J Dermatol. vol. 14. 2004. pp. 364-70.

(Alexis et al. discuss the clinical features and pathophysiology of AA, and provide an in-depth discussion into the evidence for an autoimmune basis for AA.)

Lebwohl, MG, Heymann, WR, Berth-Jones, J, Coulson, I. "Treatment of skin disease: comprehensive therapeutic strategies". Elsevier Health. 2010.

(Lebwohl et al. review the numerous treatments of AA, breaking them down into first, second and third line treatments. All recommendations are supported by data from the literature.)

Kos, L, Conlon, J. "An update on alopecia areata". Curr Opin Pediatr. vol. 21. 2009. pp. 475-80.

(Kos and Conlon provide an in-depth review featuring the pathogenesis, associated diseases, prognosis, and treatment of AA.)

Marks, JG, Miller, JJ. Principles of dermatology. Elsevier health. 2006.

(Marks and Miller, from the Hershey Medical Center Department of Dermatology, provide an overview of AA, including demographics, presentation, examination findings, diseases with similar presentations and unique findings for each, biopsy findings, common therapies, course and complications of AA, and proposed pathogenesis.)

Mukherjee, N, Morrell, DS, Duvic, M, Stewart, PW, Glodsmith, LA. "Attitudes of dermatologists in the southeastern United States regarding treatment of alopecia areata: a cross-sectional survey study". BMC Dermatol. vol. 9. 2009. pp. 11.

(Mukherjee et al., from the University of North Carolina, sent out questionnaires to dermatologists in the southeastern United States in reference to their strategies regarding the treatment of AA in children vs. adults and in patchy versus total alopecia. They found the treatment of AA is inconsistent and called for a need for stronger evidence-based medicine regarding treatment options.)

Muller, SA, Winkelmann, RK. "Alopecia areata. An evaluation of 736 patients". Arch Dermatol. vol. 88. 1963. pp. 290-7.

(A total of 736 cases of AA seen over a 10-year period at the Mayo Clinic were analyzed. This reference provided an overview of demographics, course, characteristics, associated disorders and prognosis associated with AA.)

Petukhova, L, Duvic, M, Hordinsky, M, Norris, D, Price, V, Shimomura, Y. "Genome-wide association study of alopecia areata implicates both innate and adaptive immunity". vol. 466. 2010. pp. 113-7.

(Petukhova et al. compared 1054 patients with AA to 3278 controls in a genome-wide association study, which identified 139 single nucleotide polymorphisms significantly associated with AA. They break down genomic regions associated with AA and describe how the products of these regions propagate the disease process.)

Xing, L, Dai, Z, Jabbari, A, Cerise, JE, Higgins, CA, Gong, W, de Jong, A, Harel, S, DeStefano, GM, Rothman, L, Singh, P, Petukhova, L, Mackay-Wiggan, J, Christiano, AM, Clynes, R. "Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition". Nat Med.. vol. 20. 2014. pp. 1043-9.

Jabbari, A, Dai, Z, Xing, L, Cerise, JE, Ramot, Y, Berkun, Y, Sanchez, GA, Goldbach-Mansky, R, Christiano, AM, Clynes, R, Zlotogorski, A. "Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib". EBioMedicine. vol. 2. 2015 Feb 26. pp. 351-5.

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