Alopecia areata: Diagnosis, management, and emerging therapies

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Reference: May 2025 | Issue 5 | Vol 11 | Page 22

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Alopecia areata (AA) is a chronic, inflammatory, autoimmune disease characterised by partial to total non-scarring scalp or body hair loss, leading to a high psychological and economic, disease burden.¹ Nail involvement is commonly seen in up to two-thirds of cases.²

Incidence of AA ranges between 0.6-3.8 per cent in the general population,¹ and it affects individuals of any age, with approximately three-quarters presenting with symptoms before 40 years of age.³ There is a tendency for men to be diagnosed earlier than women.⁴

Although the exact cause of AA is unknown, genetic and immunological factors appear to play an integral role. Triggers for its development include hormonal change, traumatic events, emotional and/or physical stressors. 

Clinical presentation

The typical AA patient presents with a single or multiple focal patches of non-scarred hairless skin of either oval or round demarcated shape. The size and site of the patches is generally random. Occasionally, the patient is able to tell when their hair started to fall off, however, in most cases, the exact disease duration cannot be ascertained.

The skin constituting the affected patches is generally normal and smooth. A slightly pinkish colour of the area may be observed in some cases, and on rare occasions, a soft doughy infiltration may be felt. The patches are usually asymptomatic; however, some patients do describe a degree of paraesthesia, dysesthesia, or pruritus preceding the actual hair loss process.

Classification

AA can be classified according to pattern or extent. When it comes to classification by pattern, there are the patchy, reticular, ophiasis, sisaipho, diffuse, and perinivoid types. Patchy AA is the commonest form and occurs in two-thirds of patients. 

The reticular type, also known as alopecia reticularis, describes the picture of various active, stable, or regrowing patches which may fuse to form a mosaic pattern, while ophiasis is a band-like pattern of hair loss which follows along the occipital hairline and extends towards the temples. This type of AA is often more resistant to treatment and has a more complex prognosis. An ophiasis type that winds along the frontal hairline is more unusual, and should be distinguished from frontal fibrosing alopecia.

Sisaipho is the opposite of ophiasis, whereby hairs are lost centrally, but the margins of the scalp are spared. This type may mimic androgenetic alopecia.

Diffuse AA affects the whole scalp, but does not generally affect all of the hairs. This is usually diagnosed by a high positive pull test along with the presence of patches and dermoscopic signs of AA, however, a biopsy might be needed in unclear cases. Some patients may have AA affecting eyebrows or eyelashes, or patches on the body or beards, in the presence or absence of scalp alopecia.

Perinovoid AA is a rare and atypical form of the condition, characterised by patches surrounding a nevus. Finally, alopecia totalis is defined as complete alopecia of the scalp and occurs in approximately 10-20 per cent of patients. The loss of all scalp and body hairs are termed alopecia universalis.

Associated nail changes have also been described in alopecia. Typical changes include small shallow pits (in more than 30 per cent of cases) and trachyonychia (in more than 10 per cent of cases). Suggested signs of acute nail involvement include periungual erythema and a red-spotted lunula.²

Pathogenesis

A consistent histopathological feature of both acute and chronic AA is peribulbar infiltration, and a clinical improvement after administration of immunosuppressive therapies illustrates that inflammation plays an essential role in its aetiology. The primary effectors in immunopathogenesis of AA are interferon-gamma (IFN-γ), interleukin-15 (IL-15), pro-apoptotic molecule-secreting CD8+NKG2D+ T-cells, CD4+ T-cells, natural killer (NK) cells, and plasmacytoid dendritic cells (pDC) which collectively bring about the inflammatory response within the hair follicle, disrupting its growth cycle, including the Janus kinase/ signal transducers and activators of transcription (JAK /STAT) pathway, ultimately resulting in premature hair loss.³

Diagnosis

Diagnosis of AA can often be made solely by inspection, noting patches of hair loss or large areas of alopecia with preservation of follicular ostia. Sometimes, poliosis (preservation of long white hairs), or canieties subita (also called Marie Antoinette syndrome or Thomas More syndrome, which refers to hair suddenly turning white in response to stress) may be present. Nail assessment may also reveal diagnostic features.

It is important to take a detailed personal and family history of AA along with other health conditions such as atopy, thyroid disease, and other autoimmune diseases. Unless there is doubt regarding associated thyroid disease, no laboratory tests are required for AA patients.

A positive pull test or dystrophic anagen hairs at the margins of lesions suggest pathogenetic activity. Another finding indicating acute disease would be exclamation mark hairs, which are essentially short, fragile, broken hairs which taper proximally. There may also be comedo-like cadaver hairs.

Dermoscopy may be helpful, most commonly revealing yellow dots which are keratotic plugs in hair follicular ostia; however, this finding is not specific for AA. Should history and examination be inconclusive, then a biopsy would confirm the diagnosis. Histology typically shows lymphocytic infiltration in the peribulbar area.²

There are various conditions which may mimic AA. In the paediatric population, tinea capitis should be considered, usually presenting with an inflammatory picture. Of note, it is sometimes difficult to distinguish diffuse AA from telogen effluvium; however, the presence of dystrophic hairs and dermoscopic signs are useful in the differentiation between the two.  Other differential diagnoses of AA include congenital hypotrichosis, loose anagen hair, ectodermal dysplasia, and trichotillomania, among others.²

Outcomes and associations

The disease course in AA is unpredictable. Progression or recurrences may occur at any stage. However, the overall prognosis is reassuring, as 80 per cent of patients have spontaneous hair regrowth within 12 months of the first AA presentation.⁵ Poorer outcomes are linked to a positive familial history of AA, childhood onset of disease, atopic dermatitis, nail involvement, and the presence of chronic lesions for more than one year.²

Apart from alopecia and nail involvement, AA is associated with a number of simultaneous, and possibly disease-modifying, conditions, including atopic diseases (eg, allergic rhinitis), hidradenitis suppurativa, autoimmune diseases (eg, psoriasis), coeliac disease, irritable bowel syndrome, migraine, thyroid disorders, insulin resistance, and ophthalmic abnormalities, amongst others.³

Individuals with AA may also develop psychiatric comorbidities such as anxiety, social phobia, sleep disturbances, depression, and paranoia due to the change in physical appearance, which significantly impacts self-esteem and quality of life.¹

Current treatment options

Several treatments are currently available for AA, depending on the severity of hair loss. The preferred initial treatment of patients with mild AA, that is, those with less than 50 per cent of their scalp hair and with patchy or limited loss of hair, are intralesional corticosteroid injections (CSIs).

The main mechanism of action of corticosteroids for AA is immunosuppression achieved through suppression of the T-cell-mediated immune attack on hair follicles. Triamcinolone acetonide at a dose of 2.5 to 10mg/mL is a commonly used intralesional CSI.⁶  

Although considered less effective than intralesional injections, the use of topical corticosteroids in the form of foam, cream, lotion, or ointment can be used for the treatment of AA as well.⁷ Topical corticosteroids are presently also the preferred initial treatment option for paediatric patients and for adult patients who are unable to tolerate CSIs.⁶

Another pharmacological option for mild AA is minoxidil. This drug works by opening potassium channels, hence inducing vasodilation which in turn, improves blood flow to the hair follicles. It also works by promoting vascular endothelial growth factor (VEGF) expression, stimulating proliferation of dermal papilla cells, and inhibiting collagen synthesis.

Hair regrowth with minoxidil is usually visible after three to six months of regular use, with peak efficacy achieved at around one year. Minoxidil is available as a foam or topical solution (2% or 5%). Although the 5 per cent solution is more effective than the 2 per cent, women are usually advised to use the 2 per cent minoxidil solution in view of possible side-effects.⁸ It can be used as an adjunct to corticosteroids and other AA treatments.⁶ The commonest adverse effects related to this drug include itching, scalp irritation, and hypertrichosis.⁸

It is important to note that hair loss resumes on cessation of minoxidil. An emerging alternative to topical application is low-dose minoxidil at 0.25 to 5mg per day, and studies have suggested that this offers patient adherence when compared to topical use of the drug.9 However, side effects such as hypotension, oedema, and hypertrichosis have also been reported.⁸

Other therapeutic modalities used in limited hair loss include pulse corticosteroids, topical immunotherapy (also known as contact immunotherapy), short-contact topical anthralin cream, and dupilumab. Pulse corticosteroids are considered effective in both mild and severe cases of AA.

Topical immunotherapy includes the process of application of an allergen to the scalp which leads to stimulation of hair regrowth by inducing an inflammatory reaction – with the two most commonly used allergens being diphenylcyclopropenone and squaric acid dibutylester. This therapeutic method, similar to pulsed corticosteroids, can be also used for both mild and severe cases of AA.⁶

Moderate to severe AA, characterised by more than 50 per cent hair-loss of the scalp, is an indication for systemic treatment. Oral JAK inhibitors and topical immunotherapy are the preferred initial treatment options for this cohort of patients.⁶ JAK inhibitors block the activity of JAK enzymes, thereby interfering with the inflammatory IFN-γ and IL-15 signaling pathways which play a role in hair follicle miniaturisation and hair loss in the immunopathogenesis of AA. Through modulation of these mentioned pathways, these drugs are able to promote hair regrowth and lengthen the anagen phase of the hair cycle.⁸

Currently, there are only two JAK inhibitors approved by the European Medicines Agency (EMA) for the use in severe AA – baricitinib, for use in adults, and ritlecitinib, for patients aged 12 and over.¹⁰ Baricitinib is an oral selective JAK1 and JAK2 inhibitor and the current recommended dose for patients with severe AA is 2mg once daily, with the possibility to up-titrate the dose to 4mg if needed.¹¹ If the patient has complete or near-complete hair loss, then starting with a 4mg once-daily dose should be considered, and could be decreased to 2mg once-daily when adequate hair growth is noted.

Ritlecitinib is an oral selective JAK3/TEC kinase inhibitor which, unlike baricitinib, has been approved for patients as young as 12 years old suffering from severe AA. The recommended dose of this drug for adults and patients aged 12 and over is a once-daily dose of 50mg.

Deuruxolitinib is a an oral selective JAK1 and JAK2 inhibitor which has been approved by the United States Food and Drug Administration (US FDA) for the treatment of AA for patients aged 18 and over,⁶ however, this drug has not been approved by the EMA for use in Europe yet. In spite of the fact that JAK inhibitors have been proven useful in AA, they are considered expensive and have associated risks including thrombosis, increased susceptibility to infections, acne, headache, and cardiovascular events, especially with lengthened use. Additionally, once treatment is discontinued, the patients may lose their regrown hair once again.⁸

Other alternative systemic treatment options for AA are glucocorticosteroids and steroid-sparing agents, which are used off-label in such patients.¹⁰ Whilst glucocorticosteroids such as prednisolone, dexamethasone, and betamethasone may be used, there is no current consensus on which option and dose is preferred.

Steroid-sparing agents, particularly methotrexate, cyclosporine, and azathioprine, can be used either as monotherapy or in combination with steroids; however, again there is no current census regarding which of these agents is superior for the treatment of AA. Most of the patients on these treatments also receive serial CSI with triamcinolone.⁶

Non-systemic treatment options

For patients who are either refractory to, or unsuitable for, systemic treatment for AA, non-systemic treatment options such as light therapy and platelet-rich plasma (PRP), may be used.⁶ Light therapy, also known as phototherapy, whereby the skin is exposed to ultraviolet (UV) light for a specific amount of time, is based on the fact that AA patients are typically low in vitamin D3 and vitamin D receptors,¹² and narrow-band UV B is able to augment vitamin D3 levels. Other types of light therapy which may be used for AA include broadband UV B, psoralen UV A, UV A-1, excimer laser or excimer lamp.

PRP makes use of the patient’s own blood cells and platelets together with blood plasma in order to help with tissue regeneration and wound healing. Platelets are responsible for the release of growth factors and cytokines such as VEGF, ECF, TGF, IGF, and IL-1, all of which play an essential role in the rejuvenation of the skin and hair follicles.⁶

Gas therapy (with hydrogen, hyperbaric oxygen, or nitric oxide) and microneedling have also been mentioned in the literature as alternative non-systemic therapies.¹³ Cosmetic treatments including dermatography (micropigmentation/ paramedical tattooing) and the use of wigs also play a role in the management of this condition.¹⁴

Advancements and developments

Apart from drugs targeting the JAK enzyme (Table 1), there is also research investigating the efficacy of molecules acting on other parts of the pathogenetic processes taking place in AA. These drugs include monoclonal antibodies, T-helper-2 (TH2) pathway inhibitors, dihydroorotate dehydrogenase (DHODH) inhibitors, tyrosine kinase 2 (TYK2) inhibitors, and antibodies targeting some of the specific interleukins.⁶

Bempikibart, an anti-IL-2 monoclonal antibody, and rezpegaldesleukin, an IL-2 modulator, are currently being investigated in Phase 2A (started in September 2023)²² and Phase 2B (started in May 2024)²³ trials, respectively.

An anti-OX40 monoclonal antibody by the name of IMG-007 is also being investigated for use in AA treatment in
a phase 2A trial which started in October 2023.²⁴ Further research into the use of TH2 inhibitors such as tralokinumab and dupilumab in the treatment of AA is needed.^25,26

Ongoing studies are also being carried out for TYK2 inhibitors and DHODH. A case report in 2023 showed the first case of successful rapid hair growth with the TYK2 inhibitor deucravacitinib,²⁷ while a Phase 2A study is currently being carried out to evaluate the use of farudodstat, a potent DHODH inhibitor, for treatment for AA patients.²⁸

Apart from drug targets, the future of AA management may involve emerging strategies such as gene therapy, stem cell therapy, and laser- and energy-assisted drug delivery (LEADD).⁶ Research into the genetics of AA is also ongoing, with a particular focus on gene silencing, insertion, and editing with the aim to modulate hair growth.²⁹ Stem cell therapy is also being investigated for therapeutic potential,³⁰ as are combination therapies and laser- and energy-assisted delivery of drugs.^31,32

Conclusion

AA is a disease which poses a burden on both the affected individuals and the healthcare system, hence the need for appropriate and effective treatment options. Significant progress has been made in understanding the pathogenesis of AA, which has led to advancements in treatment options for this disease. While ongoing research is promising, further studies are required to ensure that AA patients are getting the best treatment options with the least adverse effects possible.