|Year : 2023 | Volume
| Issue : 1 | Page : 3-12
An updated review on current treatment of alopecia areata and newer therapeutic options
Karan Malhotra1, Bhushan Madke2
1 Department of Dermatology, Venereology and Leprosy, Desun Hospital, Kolkata, West Bengal, India
2 Department of Dermatology, Venereology and Leprosy, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research (DMIHER) (Deemed to be University), Wardha, Maharashtra, India
|Date of Submission||09-Mar-2021|
|Date of Decision||14-Mar-2022|
|Date of Acceptance||14-Jun-2022|
|Date of Web Publication||19-Apr-2023|
480 Parnasree, Kolkata 700 060, West Bengal
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Alopecia areata (AA) is a dermatological disease that causes nonscarring hair loss. It can occur at any age and has an unpredictable and variable evolution in individuals. The aim of this review is to provide an update on the novel therapies currently being used, as well as upcoming therapeutic options in the treatment of AA.
Keywords: Alopecia areata, immunosuppressant, management, new drugs, therapy
|How to cite this article:|
Malhotra K, Madke B. An updated review on current treatment of alopecia areata and newer therapeutic options. Int J Trichol 2023;15:3-12
| Introduction|| |
Alopecia areata (AA) is an immune-mediated disease that produces nonscarring hair loss. AA may occur as an acute self-limiting disorder with one to five patches that resolve within 6–12 months, as a chronic disorder with multiple patches relapsing and remitting over many years, or as total hair loss of the scalp or universal loss of every terminal hair on the body. AA has a reported incidence of 0.1%–0.2%, with a lifetime risk of 1.7%.
The onset of AA typically occurs before 40 years of age; however, late onset is also well described. Men and women appear to be equally affected, and there is no known racial predisposition.
The response of AA to treatment is unpredictable. Some patients regrow spontaneously without medical intervention within 12 months. Even during a course of successful treatment, minor relapses can occur. It is not uncommon for a patient to develop a new lesion of AA on one part of the scalp while simultaneously experiencing regrowth in a recently treated patch of AA on another part of the scalp.
| Treatment of Alopecia Areata|| |
AA is a benign condition in majority of the affected individuals, and spontaneous remission is common. Treatment is mainly directed toward halting the disease activity as there is no evidence that the treatment modalities influence the ultimate natural course of the disease. Treatment modalities depend upon the extent of hair loss and the patient's age. The management of AA should focus on both regrowth and maintenance of hair growth. The outcome is unpredictable because of frequent relapses. Given the chronic nature of AA, most therapies lose efficacy after being discontinued.
| Current Treatments|| |
The need for new therapies for AA exists due to the limited efficacy provided by most currently available treatments, especially in cases of extensive hair loss.
| Topical Therapy|| |
The first-line treatment for most patients with patchy AA is a topical corticosteroid. Addressing the impressive inflammatory process occurring in AA, corticosteroids have by far been the most commonly used treatment modality. They are a good option in children because of their painless application and wide safety margin. Treatment must be continued for a minimum of 3 months before regrowth can be expected, and maintenance therapy often is sometimes necessary. Topical corticosteroids have limited benefits in patchy AA and can be associated with folliculitis. A study conducted by Das et al. revealed 70% hair regrowth at the end of 3 months with the use of topical steroids.
Intralesional corticosteroids are widely used in the treatment of AA. In fact, they are the first-line treatment in localized conditions involving <50% of the scalp. Hydrocortisone acetate (25 mg/ml) and triamcinolone acetonide (5–10 mg/ml) are commonly used. Intralesional triamcinolone acetonide 5–10 mg/ml is injected locally every 4–6 weeks in multiple 0.1 ml injections approximately 1 cm apart. The solution is injected in or just beneath the dermis, and a maximum of 3 ml on the scalp in one visit is recommended. It results in localized hair growth in about 60% of treated sites.
Lower concentrations of 2.5 mg/ml are used for eyebrows and face. Regrowth usually is seen within 4–6 weeks in responsive patients. Skin atrophy at the sites of injection is a common side effect, particularly if triamcinolone is used, but this usually resolves after a few months. Relapses often occur.
Repeated injections at the same site or the use of higher concentrations of triamcinolone should be avoided as this may lead to prolonged skin atrophy. Pain limits the practicality of this treatment method in children who are <10 years of age. Severe cases of AA, alopecia totalis, alopecia universalis, as well as rapidly progressive AA, respond poorly to this form of treatment. A study by Ganjoo and Thappa revealed 47% regrowth at 12 weeks and 95% regrowth at 24 weeks with intralesional triamcinolone acetonide at intervals of 4 weeks.
Topical contact sensitizers [Table 1]
|Table 1. The expansions of DPCP, SADBE and DNCB are given at the end of the table as foot note|
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Contact immunotherapy was introduced in 1976 by Rosenberge and Drake. Later, potent contact allergens namely dinitrochlorobenzene (DNCB) and diphenylcyclopropenone (DPCP) replaced the allergens that were used earlier. DNCB is mutagenic against Salmonella More Details tymphimurium in the Ames test and is no longer used. Squaric acid dibutyl ester and DPCP are not mutagenic. DPCP is more stable in solution and is usually the agent of choice.
Contact immunotherapy can be effective in cases of patchy AA and alopecia totalis. These therapies induce a contact dermatitis in affected areas and are thought to modulate T cell activity, with variable treatment outcomes. Adverse effects include persistent dermatitis, painful cervical lymphadenopathy, generalized eczema, blistering, contact leukoderma, and urticarial reaction. Systemic manifestations such as fever, arthralgia, and yellowish discoloration of hair are noted more often with DNCB. A study by Ibrahim et al. revealed complete hair regrowth in 62.5% of patients with DPCP.
Anthralin (dithranol) is a topical immunotherapeutic agent found to adequately treat AA, especially in conjunction with concomitant DPCP. The exact mechanism of action is unknown but is believed to be through immunosuppressant and anti-inflammatory properties, with the generation of free radicals. Inhibition of the expression of tumor necrosis factor (TNF)-α and TNF-β was shown in mouse models with AA effectively treated with anthralin.
It is used at concentrations ranging from 0.5% to 1% for 20–30 min after which the scalp should be washed with shampoos to avoid excessive irritant effects. The applications are made initially every other day and later on daily. Adverse effects include pruritus, erythema, scaling, staining of treated skin and fabrics, folliculitis, and regional lymphadenopathy., A study by Wong et al. showed complete response (>90% regrowth) in 25% of patients and good response (50%–90% regrowth) in 39.5% of patients with the use of anthralin.
Topical minoxidil therapy is usually an adjunct therapy for AA and tends to work better in less extensive cases.
It is a direct-acting arteriolar vasodilator, which acts specifically to open the potassium channels. Minoxidil exerts its effect after transforming into its active metabolite, minoxidil sulfate. The enzyme called sulfotransferase, which is found in the scalp, causes this conversion. Minoxidil converts to its sulfate form most likely at the lower outer root sheath. The exact mechanism of minoxidil promoting hair growth is not fully known. Studies demonstrate that minoxidil increases the amount of intracellular Ca2+, which in turn upregulates the enzyme adenosine triphosphate (ATP) synthase. A recent study demonstrated that ATP synthase promotes stem cell differentiation. Thus, minoxidil-induced Ca2+ influx increases stem cell differentiation and therefore plays a key role in the facilitation of hair growth.
5% minoxidil solution is usually recommended as a treatment option in AA. No more than 25 drops is applied twice per day regardless of the extent of the affected area. Initial regrowth can be seen within 3 months, but continued application is needed to achieve cosmetically acceptable regrowth. Minoxidil has also been studied in combination with anthralin, topical betamethasone propionate, and prednisolone. Minoxidil is of little benefit to patients of severe AA, alopecia totalis, or alopecia universalis. The possible side effects from minoxidil are headache, allergic and irritant contact dermatitis, and hypertrichosis, which is usually reversible with the interruption of the treatment. A study by El Taieb et al. found minoxidil to be effective in 81% of cases with patchy AA.
Tacrolimus is a topical calcineurin inhibitor that inhibits transcription following T cell activation of several cytokines, including interleukin (IL)-2, interferon (IFN)-gamma (IFNG), and TNF-α. The results of topical tacrolimus in the treatment of AA have not been encouraging. Jiang et al. reported that tacrolimus stimulated hair growth in mice, although subsequent studies have shown conflicting results. Price et al. reported a study in which none of the patients had terminal hair growth in response to tacrolimus ointment 0.1% applied twice daily for 24 weeks.
Tretinoin and bexarotene have been tried in AA with mixed results. Irritation of the skin is a very common side effect. Talpur et al. conducted a prospective “half-head” trial of 1% bexarotene gel, applied twice daily to areas of AA for up to 6 months. During the 6-month half-head treatment phase, the investigators noted that five patients (12%) showed at least 50% hair regrowth on the treated side; six patients (14%) showed at least 50% regrowth on both treated and nontreated sides (postulated due to diffusion of gel or due to noncompliance to protocol), and the treatment was well tolerated.
Latanoprost and bimatoprost have been used in the treatment of AA involving the eyelashes. However, the results obtained are not satisfactory.,
| Systemic Therapy|| |
The progress of AA is halted by systemic steroids, but many authors have reported poor results with this form of therapy. The suggested dosages are 0.5–1 mg/kg/day for adults and 0.1–1 mg/kg/day for children. Treatment duration ranges from 1 to 6 months, but prolonged duration should be avoided to prevent the side effects of corticosteroids. Side effects profile of corticosteroids in conjunction with long-term treatment requirements and high relapse rates makes systemic corticosteroids a more limited option. In addition to the daily oral administration of corticosteroids, there are several reports of high-dose pulsed corticosteroid treatments employing different oral and intravenous regimens.,, Pulsed administration employs a high-dose oral corticosteroid on 2 consecutive days every week with a gap of 5 days between the two pulses. This modality of treatment is known as oral minipulse therapy (OMP), and it has been tried in many skin diseases in addition to AA., In a study, OMP showed 71.43% regrowth of hair at a dose of 5 mg/day for 2 consecutive days after a mean duration of 4 months.
Azathioprine is an immunosuppressive agent. It has demonstrated hair regrowth in about half of the patients with a dosage regimen of 2.5 mg/kg body weight/day in a study. Saoji et al. showed good response to azathioprine at a dose of 1 mg/kg body weight/day in pediatric patients.
This drug has proven effective in the treatment of AA because of its immunosuppressive and hypertrichotic properties. It is used in severe forms of AA not responding to treatment. A systematic review showed 66% response to cyclosporine at a dose of 4–6 mg/kg body weight/day for a mean duration of 5.77 months.
Methotrexate either alone or in combination with prednisolone has been used in the treatment of AA in various studies with variable success rates.
A study showed regrowth of hair in 63.2% of patients who received methotrexate at a dose of 0.2–0.4 mg/kg body weight/week.[Table 2]
|Table 2: Summary of evidence of response to various immunosuppressants in alopecia areata|
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Sulfasalazine has shown good hair regrowth in the treatment of AA because of its immunomodulatory and immunosuppressive actions. The treatment is started at a lower dose, usually in the range of 500 mg twice daily, and then, the dose is gradually increased to 1 g three times a day. Sulfasalazine helps in AA because it causes inhibition of T cell proliferation and natural killer (NK) cell activity and also inhibits antibody production. It also inhibits the secretion of IL-2, IL-1, TNF-gamma, IFNG, and even IL-6.
TNF inhibitors such as adalimumab, infliximab, and etanercept have been tried in AA, but the results have not been encouraging.
All types of psoralen and ultraviolet-A (UVA) (PUVA) (oral PUVA, topical PUVA, and local or whole-body UVA irradiation) have been used with success rates of up to 60%–65%.,,
Narrowband ultraviolet-B is among the most effective treatment options in a number of immune-mediated skin diseases, but the same efficacy has not been found in AA.,
Excimer laser and excimer light
Excimer laser and excimer light are two more recent additions to the phototherapeutic armamentarium for many skin and hair disorders. Some clinical studies have documented the efficacy of excimer laser and excimer light in AA. The treatment is well tolerated with erythema of the skin as the only adverse effect reported.,
Various nonconventional therapeutic agents have been used in AA. These include topical azelaic acid, onion juice, and topical 5-fluorouracil. The efficacy and safety of these therapeutic agents are variable.
Cosmetic treatments for patients with AA include the following.
- Dermatography has been used to camouflage eyebrows of patients with AA
- Wigs or hair pieces are useful for patients with extensive disease.
| Novel Therapies|| |
Oral Janus kinase inhibitors
There are currently six Janus kinase (JAK) inhibitors which have been reported to be successful in treating AA. These are tofacitinib, ruxolitinib, baricitinib, CTP-543, PF-06651600, and PF-06700841. These are oral medications.
JAK inhibitors work on the JAK signal transducer and activator of transcription (STAT) pathway. There are four JAKs, JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2), which are expressed in hematopoietic cells. There are seven STATs that bind the phosphorylated cytokine–receptor complex and subsequently undergo phosphorylation by a JAK. The STATs are then translocated to the nucleus where they bind DNA and activate target gene transcription. The JAK-STAT pathway plays a significant role in the maintenance of innate and adaptive immunity, and the defects can lead to immune-related and hematologic disorders as seen with atopy (STAT6), Behcet's disease (JAK2, STAT3), and systemic lupus erythematosus (TYK2, STAT4).
Involvement of the JAK-STAT pathway in AA as well as the reversal of AA with JAK inhibitors was first demonstrated in mice in 2014.
JAK inhibitors are oral drugs, with convenient dosing regimens that have been demonstrated to be effective and safe in large-scale studies for the treatment of diseases such as rheumatoid arthritis and psoriatic arthritis. JAK inhibitors are selective but not specific for a single JAK and thus can affect various immunologic pathways.
The basis for JAK inhibitor use in AA stems from the understanding of JAK protein kinase pathways implicated in AA, which work as downstream effectors of the IFNG and γc cytokine receptors. In AA, JAK-STAT inhibition interferes with the positive feedback loop between the follicular cell and the cytotoxic CD8 + NKG2D + T cells in AA. Key genes in the JAK-STAT pathway related to hair growth include STAT5A/B, STAT3, JAK1, JAK3, and Socs2/3, highly expressed in catagen and telogen phases but suppressed in the early anagen phase.
The recommended dose of tofacitinib in AA is 5 mg BID and that of ruxolitinib is 15–20 mg BID.
The recommended dose of baricitinib in AA based on several studies is 4 mg daily.
A study by Khan et al. showed 72.4% of responders (good responders 45.7% and partial responders 21.4%) with oral JAK inhibitors. The mean time to initial hair growth was 2.2 ± 6.7 months, and the time to complete hair regrowth was 6.7 ± 2.2 months.
More importantly, the understandable euphoria surrounding JAK inhibitors in the AA field must not blind one to potential risks. Side effects that have been noted already include nausea, headaches, increase risk of infection (including herpes [cold sore] virus reactivation), anemia, high cholesterol, and potentially increased risk of blood clots. There are reports of relapse following discontinuation of this treatment. Reactivation of tuberculosis has been reported with baricitinib and tofacitinib use in patients with RA., Gastrointestinal perforations have also been reported in patients taking JAK inhibitors.
Topical Janus kinase inhibitors
Topical JAK inhibitors to treat AA are still being studied. Few studies have shown that topical JAK inhibitors do not show satisfactory results for scalp hair regrowth; however, they have shown some improvement with eyebrow and eyelash regrowth.
The two main topical JAK inhibitors that have been tested and have shown some success with eyelash and eyebrow regrowth are tofacitinib 2% ointment and ruxolitinib 0.6% cream. Craiglow reported a case of successful treatment of localized AA with topical tofacitinib 2% solution.
These have been fairly well tolerated with no complications. The application on the skin reduces the risk of side effects compared with the oral form.
Ustekinumab reduces inflammation by blocking the activity of chemical signaling molecules (called cytokines), specifically IL-12 and IL-23, that trigger inflammation. It is commonly used in psoriasis and Crohn's disease. It has been shown in a small case series that it can help hair regrowth in moderate-to-severe AA.
It is injected under the skin of the stomach, thighs, or upper outer arms. Initially, patients have an injection on week 4 of treatment and after that every 12 weeks.
It can increase the risk of serious infections. Patients can experience reactions at the injection site, fatigue, headaches, and sinusitis.
Dupilumab is a biologic medication given through a subcutaneous injection that works by blocking IL-4 and IL-13.
One study has shown a significant improvement in alopecia totalis following dupilumab treatment, whereas another paper reported cases of AA developing shortly after starting dupilumab for their eczema. Therefore, further clinical trials are needed to assess the role of dupilumab in the treatment of AA.
It is an injection every 2 weeks. It is shown to be very well tolerated with minimal side effects.
The side effects reported are conjunctivitis, injection-site reactions, headache, blepharitis, keratitis, eye pruritus, dry eyes, oral herpes, or other herpes simplex virus infections. Dupilumab is classed as a high-cost drug.
Apremilast is an inhibitor of the phosphodiesterase 4 (PDE4), which reduces inflammation. PDE4 has been found to be expressed in patients suffering with AA. There have been variable results reported in the literature up till now, including good hair regrowth and a study showing no treatment response. The main side effects are diarrhea, headache, nausea, fatigue, and weight loss.
Abatacept is a fusion protein of cytotoxic T lymphocyte associated antigen 4. It improves inflammation by reducing the activation signals to the white blood cells. It is given as an injection under the skin, consisting of weekly injections for 6 months, with an additional 6 months of follow-up. It is still being reviewed in a clinical trial for AA and the results are currently pending. The side effects that have been reported up till now are risk of serious infection, injection-site reaction, sinusitis, headaches, and high blood pressure.
The results are variable with injections of platelet-rich plasma (PRP) in the treatment of AA. The procedure involves an autologous blood product of centrifuged whole blood with subsequent extraction of various proportions of the plasma and platelets or buffy coat. PRP is rich in platelets and growth factors (GFs), such as platelet-derived GF, fibroblastic GF, epithelial GF, insulin-like GF, transforming GF, and vascular endothelial GF. When the alopecic areas are injected locally, PRP can affect hair growth via induction and maintenance of the anagen phase of the growth cycle. PRP injections may have limited benefit in patients with chronic and severe cases of AA, as global treatments are needed and injections can be painful. PRP treatments for AA are usually well tolerated.
It is a PDE4 antagonist. It is a potential target for treatment of AA as PDE4 is highly expressed in AA.
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It is a parathyroid hormone (PTH) receptor agonist. Activation of the PTH/PTH-related protein receptor stimulates β-catenin within the hair follicle, which promotes the transition of hair follicles into an anagen growth phase.
It is a histamine 1 receptor antagonist. Fexofenadine may cause an indirect effect through improvement of atopic dermatitis in atopic AA patients. IFNG production from T cells and intercellular adhesion molecule 1 expression on the epithelial cells involved in AA may be reduced by fexofenadine. Substance P, which may play a role in AA, is decreased by fexofenadine.
Statins are antihyperlipidemic agents that are immunomodulatory and work synergistically to decrease C-reactive protein. Studies show varying efficacy in the treatment of AA.,,
Oral zinc sulfate
Serum zinc levels have been found to be lower in patients with AA than in control population. A study has demonstrated hair regrowth in AA patients after oral zinc gluconate administration.
AA is associated with Vitamin D deficiency. A lack of expression of 1,25-dihydroxy vitamin D3 receptor (VDR) is associated with reduced growth of hair follicles. The decreased expression of VDR in AA is related to decreased expression of Wnt/β-catenin signals, which inhibits hair follicle proliferation and differentiation. Calcipotriol has been shown to promote hair regrowth in AA., Vitamin D contributes to the maintenance of immune privilege of the hair follicle by decreasing IFNG, downregulation of Natural Killer Group 2D receptor (NKG2D)- and C-X-C Chemokine Receptor 3 (CXCR3)-activating ligands, JAK/STAT inhibition, and attenuation of oxidative stress.
| Future Therapies|| |
Several other novel therapies are being tested in clinical trials.
- Recent advances in the understanding of the microbiome and its role in autoimmunity is a popular area of study. Microbiome dysbiosisis seen in patients with AA and two patients with AA experienced hair regrowth after receiving fecal transplant for the treatment of Clostridium difficile.,, Adverse effects associated with fecal transplants include transmission of multiresistant organisms, fever, vomiting, diarrhea, bacteremia, and peritonitis,
- Human bone marrow-mesenchymal stromal cells mediate inhibition of IFNG and CD3 and CD8+ NKG2D+ T cell infiltration which protects against the collapse of the hair follicle immune privilege
- Human umbilical cord blood-mesenchymal stromal cells can accelerate the initiation of the hair follicle telogen–anagen transition, increase the number of hairs in vivo, and enhance expression of proteins related to hair induction in vitro.
Human hematopoietic mesenchymal stem cells stimulate the Wnt/β-catenin pathway and phosphorylation of STAT1 and STAT3. Human autologous adipose-derived adult cells of stromal vascular fraction have reported to increase hair growth in AA. A phase II clinical trial assessing stem cell educator therapy combined with minoxidil for the treatment of AA is in underway (NCT04011748).
It binds the γc receptor of lymphocytes to selectively block IL-2, IL-15, and IL-9 signaling. A phase II placebo-controlled clinical trial (NCT03532958) is in preparation.
It is a laser technique that produces columns that extend into the reticular dermis stimulating a controlled wound-healing environment. A clinical trial evaluating the effect of trans-epidermal delivery of triamcinolone acetonide or PRP using fractional carbon dioxide laser or microneedling for the treatment of AA (NCT04147845) is currently ongoing.
It is an anti-IL-13 monoclonal antibody blocking the Th2 axis. A study testing the efficacy of tralokinumab in subjects with moderate-to-severe AA has been completed, with analysis pending (NCT02684097).
Gene therapy in alopecia
It is an intralesional injection of oligonucleotides and small-interfering RNAs (siRNAs). A study shows that controlled delivery of T-box 21 siRNA ameliorates AA.
New drug treatment opportunities based on the results of a genome-wide association study, which implicate T cell and NK-cell activation pathways, are leading to new approaches in future clinical trials of AA. Special attention is being given to the UL 16-binding protein (ULBP3) gene cluster on chromosome 6q25, as these genes make the NKG2D-activating ligand or signal that can trigger the NKG2D receptor, initiating an autoimmune response. A greater expression of ULBP3 has also been found in hair follicles in scalp biopsy specimens from patients with active disease. It is now postulated that the characteristic T cell “swarm of bees” infiltrate seen in AA is the result of T cells being attracted to the hair follicle by NKG2D-activating ligands.
Future treatment approaches for alopecia areata include use of drugs that
- Block the NKGD-activating ligand and NKG2D receptor interaction
- Halt activated T cells
- Modification of the inflammatory cytokine network.
Many drugs currently being used or being evaluated for other autoimmune diseases that work through these mechanisms might prove to be very effective in AA.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]