Alopecia areata management

Watch Lynn Wilks describe the emotional impact on her of receiving a diagnosis of alopecia areata.

Dr Brett King, MD, PhD, of Yale School of Medicine provides an informative overview of alopecia areata diagnostics, highlighting important differential diagnoses that should be considered, as well as some of the challenges unique to the diagnosis of alopecia areata.

Clinical features of alopecia areata

Scalp hair loss in alopecia areata (AA) is most commonly patchy and well-demarcated, with complete loss of all terminal hairs in at least one area. The disorder is clinically classified according to the skin areas involved, the pattern, and the extent of hair loss (Table 1)¹.

Table 1. Clinical variants of alopecia areata with their characteristic manifestations (Adapted¹).

A gentle hair pull test at the periphery of the patch demonstrates easily pluckable hairs. Finding multiple hairs on at least five pulls suggests active progressive hair loss.

Microscopy in the acute phase may show dystrophic anagen hair roots pulled off easily with damaged proximal ends. Supportive clinical features include patchy body hair loss, eyebrow and eyelash hair loss, and fine pitting of nails ("sandpaper nails")¹.

Alopecia areata is commonly a clinical diagnosis, but trichoscopy and histopathology are valuable clinical tools to improve diagnostic accuracy

Differential diagnosis of alopecia areata

To make an effective management plan for AA, other hair loss disorders such as tinea capitis, trichotillomania, aplasia cutis, triangular alopecia, telogen effluvium and primary scarring alopecia need to be differentiated from AA (Table 2)¹.

Table 2. Differential diagnoses of patchy and diffuse alopecia areata (Adapted1).

DD, differential diagnosis; CDLE, chronic discoid lupus erythematosus.

Trichoscopy of alopecia areata

Dermoscopy is a simple and safe procedure that may contribute to diagnosing AA².

Trichoscopic features of AA are yellow dots and black dots (Figure 1A), broken hairs, "exclamation mark" hairs (tapered hairs) (Figure 1B), colour transition sign (black distal end advancing to white proximal end), and short vellus hairs (Figure 1C)^2,3.

Figure 1. Trichoscopic findings in alopecia areata. All photos used with permission by DermNet (https://dermnetnz.org/image-library). Attribution-non-commercial-noderivs 3.0 New Zealand (CC BY-NC-ND 3.0 NZ). (A) Yellow dots (yellow circles) are highly sensitive, but not a specific marker for alopecia areata, as they are associated with other hair loss conditions, such as androgenetic alopecia. Black dots, also shown, observable during alopecia areata, are pigmented hairs broken, or destroyed at scalp level. (B) Exclamation mark hairs have a thin, hypopigmented proximal end, and a thicker distal end, observable during the acute progressive phase of alopecia areata. (C) Short vellus hairs are thin hairs that mark active disease, or initial response to therapy for alopecia areata.

Detecting a combination of yellow dots and short vellus hairs enhances the sensitivity of an alopecia areata diagnosis. Black dots, exclamation mark hairs and broken hairs are other common findings associated with disease activity. Rarely reported features include upright regrowing hairs and pigtail (circle) hairs^2,3.

Several trichoscopy findings, rather than a single feature, are used to establish the diagnosis of alopecia areata. Short vellus hairs are observable in the initial stages of hair regrowth after treatment. AA subtypes are not associated with any specific trichoscopy findings^1,3.

Histopathology of alopecia areata

Histopathological examination can support a diagnosis of alopecia areata and help stage disease severity (Figure 2).

Figure 2. Histopathologic features of intense perifollicular fibrosis in a female who had circumscribed patches of alopecia areata for two months (Adapted⁴). Figure reused under Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0).

Non-sclerosing fibrous tracts in alopecia areata

Non-sclerosing fibrous tracts (residues of collapsed fibrous hair root sheaths) are observable during all stages of alopecia areata.

Peribulbar lymphocytic infiltrate

Another distinguishing feature of AA is a peribulbar lymphocytic infiltrate, called a “swarm of bees”. Staging features are telogen hairs alone, a combination of telogen and dystrophic anagen hairs and the extent of perifollicular cell infiltration and catagen conversion.

Trichotillomania

Trichotillomania is a condition with forced hair plucking that may show as follicular micro-haemorrhages. Telogen effluvium is a condition of diffuse hair loss that presents similarly to alopecia areata incognita (AAI); colour transition with proximal whitening observed in AAI helps differentiate them^1,5.

Tools for assessing alopecia areata

Clinicians use the Severity of Alopecia Areata Tool (SALT) score to assess the severity of hair loss in four quadrants (left, right, front, and back) and response to treatment (Figure 3A). A baseline SALT score of >25% is considered severe AA. After treatment, a 50–90% improvement in SALT score indicates success. Modified SALT-II is a refined score that divides the scalp into 1% areas (Figure 3B). SALT I and SALT II scores rely on visual assessment without documenting specific areas of hair loss⁵.

(A)

(B)

Figure 3. SALT I and SALT II assessment measures for alopecia areata (Adapted⁵). (A) The Severity of Alopecia Areata Tool (SALT) score is calculated in quadrants across four scalp areas, then summed to generate the SALT score. (B) Modified SALT II Visual Aid and computation of ALODEX score density for each 1% of scalp area. Density is scaled from 0–10 according to the percentage of terminal hair loss (100% hair loss = 10; 90% = 9; 80% = 8; and no hair loss = 0). The density assignments in each of the 1% scalp areas in a quadrant are added; the total is divided by the maximum grade of hair loss for the percent hair loss for that quadrant. The sum of each quadrant’s score is the ALODEX score.

Other than SALT scores, the following metrics can be used for assessing alopecia areata⁵:

• The Alopecia Areata Progression Index (AAPI) can be calculated with the hair pull test and trichoscopy
• Patient assessment of the extent of hair loss and quality of life assessments
• Photography can be used by patients with severe AA subtypes to self-assess treatments

Prognosis of alopecia areata

The following clinical features are predictors for AA progressing to alopecia totalis (AT) or alopecia universalis (AU)^5,6:

• Onset before puberty
• Chronic lesions lasting >1 year
• Family members with a diagnosis of AA
• Associated atopy (atopic dermatitis, asthma, hay fever/allergic rhinitis)
• Associated autoimmune diseases (thyroid disease, vitiligo, rheumatoid arthritis, type 1 diabetes)
• Associated depression or obesity

Although several treatments can be effective against alopecia areata, patient Lynn Wilks cautions that “As patients, we have to fight. We have to fight to try to persuade a dermatologist” to consider a specific treatment, that for various reasons, the clinician does not prescribe.  

Patients with alopecia areata (AA) benefit more if they are managed by a dermatologist who is interested in hair loss and is informed about treatment advances. If this level of care is not available, patients have the option of accessing informed care remotely through online tele-dermatology.

Several pharmaceutical and non-pharmaceutical treatments for alopecia areata are used in clinical practice, with varying effectiveness and tolerability

Treatment algorithm for alopecia areata

Figure 4 shows a pharmaceutical and non-pharmaceutical treatment algorithm for alopecia areata.

Figure 4. Treatment algorithms for AA (Adapted⁷). AA, alopecia areata; AT, alopecia totalis; AU, alopecia universalis; CS, corticosteroids; MTX, methotrexate; JAKis, Janus kinase inhibitors; SALT, Severity of Alopecia Areata Tool.

Individual treatment plans for alopecia areata depend on patient age, disease severity, duration, and comorbidities. None of the current therapeutic options, including topical therapy, intralesional treatment, phototherapy, non-prescription therapies, systemic therapy, for AA, is explicitly recommended in the AA consensus study, due to paucity of randomised clinical trials to aid in the selection of available therapies^7,8.

Pharmaceutical treatments for alopecia areata

Topical and intralesional corticosteroids

Topical steroid lotions, foams and shampoos are recommended for limited patchy AA to hasten hair regrowth. Topical agents that have been used include clobetasol propionate 0.05% foam twice daily on five consecutive days per week with or without occlusion and mometasone furoate 0.1% twice daily on five consecutive days per week for 6 months. Treatment should be continued for at least three months, but stopped after six months if there is no effective response. An occasional complication of topical clobetasol is folliculitis (hair follicle inflammation)^9,10.

Intralesional steroid (ILC) treatment involves subcutaneous injection of a slow-release steroid (hydrocortisone acetate or triamcinolone acetonide) by fine needle injection or micro-needling. Adults with less than 50% scalp involvement can be given triamcinolone acetonide 2.5–10 mg/mL (maximum volume 3 mL per session) as first-line therapy. For the eyebrows, 2.5 mg/mL can be used (0.5 mL for each eyebrow). Triamcinolone acetonide is injected intradermally with a 0.5-inch long, 30-gauge needle as multiple 0.1-mL injections at 1-cm distances with a BD insulin syringe. Injections are repeated every 4–6 weeks. Hair regrowth is observable in 4–8 weeks. If there is no improvement after six months of treatment, the ILC should be stopped.

A frequent, but transient adverse effect, is cutaneous atrophy at the site. ILCs are not suitable for rapidly progressive patchy AA, AT, or AU, as they cannot prevent disease development at sites that are not injected, or children <10 years of age with AA^11-13.

Systemic corticosteroids

High doses of daily and weekly oral or intravenous prednisolone pulse therapy have shown effective hair regrowth. However, the response may be insufficient for some patients to balance the adverse effects of systemic corticosteroids, and hair growth can be sustained only during treatment^14,15.

Severe AA with >30% scalp involvement is often treated with oral or intravenous prednisolone. Four pulses of 300 mg oral prednisolone at 4-week intervals show cosmetically acceptable hair growth in more than half the treated patients after 2–3 months of therapy. High remission rates have been reported with three pulses of 500 mg of intravenous methylprednisolone on 3 consecutive days at 4-week intervals. The best results are obtained by starting intravenous therapy within 6 months of disease onset, and response rates for AT and AU are unsatisfactory¹⁰.

Some patients (17–20%) with patchy AA respond to a potent topical allergen on a small scalp area. Initial application of these allergens causes sensitisation, and subsequent weekly application induces contact dermatitis.

Immunotherapy has some transient side effects, such as severe dermatitis and occipital/cervical lymphadenopathy. It is a long-term treatment of more than six months, and relapses are common.

Response to pharmaceutical treatments in severe alopecia areata

Pharmaceutical treatments can induce hair growth in AA, but the response remains poor for severe AA subtypes (AT, AU, or a combination) due to a high level of immune reactivity. Typically, treatments are given for the severe subtypes if remission rates are better than the spontaneous remission rates of AA, half-side treatment of AT/AU is effective, and toxicity is minimal^2,10.

Investigational treatments for alopecia areata

There is a need for new treatments to better target the complex pathogenesis of AA. Genome-wide association studies and functional immunological studies have identified the CD8+NKG2D+ T cells as major effectors of AA pathogenesis, promoting hair follicle inflammation through interferon-γ (IFNγ) and interleukin-15 (IL-15) signaling pathways. Janus kinase signal transducer and activator of transcription proteins (JAK/STAT) pathways are the new targets of promising treatments for alopecia areata^1,7,10.

As IFNγ and other cytokines signal through pathways involving JAK/STATs, these pathways are targeted for therapeutic intervention with JAK inhibitors⁷

Non-pharmaceutical treatments for alopecia areata

Excimer laser and light treatment

Excimer laser, an ultraviolet laser, can achieve cosmetically acceptable results in many patients with AA. However, closer examination has shown that the apparent hair regrowth can be just a thickening of the hair shaft without any increase in the hair count.

Successful hair regrowth (65% of patients) has been observed with photochemotherapy in all subtypes of alopecia areata. Psoralen and ultraviolet A (PUVA; oral or topical psoralen, local or whole-body ultraviolet light therapy) has been used successfully¹⁶.

Cosmetic strategies

Women with extensive alopecia use concealments such as wigs, hairpieces, or bandanas. Men tend to shave their heads or conceal them with a wig. Semi-permanent tattooing of the eyebrows is often used as a disguise¹⁷.

Emotional wellness

To help patients adjust to AA, and to set achievable and meaningful long-term goals, the physician should be sensitive to the psychological effects of AA^18-20.

In all subtypes of AA, mindfulness-based cognitive therapy, hypnotherapy, psychotherapy and coping strategies can improve patient quality of life and mental health. Patients with high emotional distress should be referred to specialists in the psychosocial field and encouraged for active coping strategies^21,22.

For severe AA, and for children and their parents, comprehensive psychiatric assessments and expert assistance from a clinical psychologist or patient support groups may be necessary

In the video below, Professor Rodney Sinclair (University of Melbourne) notes that “…in alopecia areata, we would love to able to start the patient on a treatment, fix their disease, put them into remission, and then stop the treatment. That’s the holy grail for dermatologists. We’re starting to see this emerge with alopecia areata.”

The JAK/STAT signalling pathways as a target for alopecia areata

Cytokines involved in the pathogenesis of AA operate through the Janus kinase signal transducer and activator of transcription proteins (JAK/STAT) signalling pathways (Figure 5)²³.

Figure 5. Cytokine signalling through the JAK/STAT pathway (Adapted²³). DNA, deoxyribonucleic acid; STAT, signal transducer and activator of transcription; JAK, janus kinase inhibitors.

Up to 50% of AA patients can show more than 50% regrowth^24,25. Treatment should persist to protect efficacy^24,25.

A recent meta-analysis concluded that JAK inhibitors are effective and generally well-tolerated in the treatment of AA when administered orally, whereas topical or sublingual administration is less effective. In randomised control trials (RCT), the JAK inhibitors baricitinib, ritlecitinib, and brepocitinib show approximately equivalent efficacy for AA; however, in single-arm trials, non-RCTs and extension periods of RCT, ruxolitinib (vs tofacitinib) and AA (vs alopecia totalis [AT] or alopecia universalis [AU]) are associated with better efficacy outcomes. Due to the high recurrence rate after JAK inhibitor cessation, continuous treatment is important²⁶.

First-generation JAK inhibitors for alopecia areata

The first generation of JAK inhibitors are non-selective. That is, they affect more than one JAK family member, and inhibit multiple cytokines. These non-selective JAK inhibitors—ruxolitinib, tofacitinib and baricitinib—show promise for the treatment of AA⁷.

Baricitinib for alopecia areata

Baricitinib (2 mg and 4mg) is an oral, selective, reversible JAK1/JAK2 inhibitor approved in the United States (US), European Union (EU), and Japan for adults with severe AA^7,27. Table 3 summarises outcomes with baricitinib from the BRAVE-AA1 and BRAVE-AA2 trials²⁷.

Table 3. Outcomes with baricitinib from the BRAVE-AA1 and BRAVE-AA2 trials (Adapted²⁷).

*P<0.001 compared with the placebo arm. †P=0.003 compared with the placebo arm. ‡P=0.001 compared with the placebo arm. §P=0.002 compared with the placebo arm. AA, alopecia areata; PRO, patient reported outcomes; SALT, Severity of Alopecia Tool; SD, standard deviation.

The most common adverse reactions of prolonged baricitinib treatment (~1.5 years) are upper respiratory tract infections, nasopharyngitis, headache, and mild facial acne^27,28.

Ruxolitinib for alopecia areata

Phase 2 clinical trials of oral ruxolitinib for 3–6 months show a 92% hair growth response in most (75%) patients with moderate to severe AA (Figure 6)²⁹

Figure 6. Response to treatment with oral ruxolitinib for alopecia areata²⁹. Figure reused under Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0). Participants 1, 2, 3, 4, 8, 9, 10, 11, and 12 are represented in paired photographs (“a” is baseline; “b” following ruxolitinib treatment).

No serious adverse effects have been reported, and there was no discontinuation of therapy^19,29. Ruxolitinib for alopecia areata is not approved for use in the US or the EU.

Tofacitinib for alopecia areata

Tofacitinib, used as a 2% topical application twice a day, is efficacious for children with AA, with 80–95% scalp hair regrowth (Figure 7)³⁰.

Figure 7. Tofacitinib local application in children with alopecia areata (Adapted³⁰). Figure reused under Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0). (A) 14-year-old female with multiple patches of non-cicatricial AA at baseline. (B) Near complete response to treatment in 14-year-old female with recalcitrant alopecia areata after 3 months of tofacitinib therapy.

In a systematic review and meta-analysis of the efficacy and safety of tofacitinib for treatment of alopecia areata in children, side effects such as diarrhoea and mild liver transaminases abnormalities were observed in several patients³¹.

Tofacitinib for alopecia areata is not approved for use in the US or the EU.

First-generation JAK inhibitors for children with alopecia areata

Topical applications are preferred for children and patients with limited hair disease. Daily oral tofacitinib shows more than 50% improvement in the Severity of Alopecia Areata Tool (SALT) scores with limited reported adverse effects^7,30.

JAK inhibitors used for severe AA in children have shown promising results, with either complete regrowth, or at least a 50% reduction in SALT. Even with long-term oral or intravenous therapy with JAK inhibitors for severe AA, adverse events tend to be minor and, in some patients, reversible. The most reported adverse events include liver transaminase elevation, upper respiratory tract infection, and eosinophilia³¹.

Second-generation JAK inhibitors for alopecia areata

Studies are emerging for second-generation JAK inhibitors, which can specifically inhibit a single JAK family isoform and selectively block the culprit cytokines (Figure 8)³².

Figure 8. Selective blockade (inhibition) of JAK molecules (Adapted³²). Note: Ritlecitinib is an inhibitor of JAK3, and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family. JAK, Janus kinase; EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor; GH, growth hormone; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; OSM, oncostatin M; TPO, thrombopoietin; TYK, tyrosine kinase.

The limited inhibitory effects of second-generation JAK inhibitors may reduce the risk of long-term or serious adverse events. Second-generation JAK inhibitors under investigation for AA include abrocitinib, upadacitinib, brepocitinib and ritlecitinib³³.

Second-generation JAK inhibitors brepocitinib and ritlecitinib for alopecia areata show improved SALT scores and positive biomarker profiles after 12 weeks of therapy³³