**9. Differential diagnosis**

Many other diseases may cause hair loss in a patchy or diffuse pattern [33, 34] (**Table 2**).

In children, tinea capitis, which is the most common dermatophyte infection seen in childhood and trichotillomania should be considered in differential diagnosis of alopecia areata. Clinically, patches of tinea capitis show scaling and signs of inflammation sometimes accompanied by cervical lymphadenopathy. Direct microscopic examination with potassium hydroxide, fungal culture, and trichoscopy can also help in the diagnosis [35]. In trichotillomania, diagnosis is straightforward when the patient or relatives accept the compulsive act of pulling. In dermatological examination, there are irregularly shaped patches and broken hairs of variable lengths. Residual hairs in patches of trichotillomania are anagen hairs firmly attached to the scalp; they are of normal texture and color, whereas residual hairs in alopecia areata are usually the exclamation mark hairs with their specific morphology, which are easily detached from the scalp. [33, 36] Rarely, alopecia areata and trichotillomania can coexist [37]. Histopathologically, there is an increase in catagen hairs, follicular hemorrhage, pigment casts, and trichomalacia, without the typical inflammatory infiltrate and miniaturization of hair follicles observed in alopecia areata [31, 36].

In adults, the differential diagnosis is usually between androgenetic alopecia and telogen effluvium. Patients with androgenetic alopecia usually demonstrate gradual loss of hair with


**Table 2.** Differential diagnosis of alopecia areata.

taneous tissue. Inflammatory infiltrate consists primarily of T lymphocytes and Langerhans cells, with occasional eosinophils, mast cells, and plasma cells [31, 32]. An early and typical feature is the presence of eosinophils in stellae and within hair bulbs [29]. Anagen hairs cycle through catagen then into telogen. A dense lymphocytic inflammation can cause breaking of the hair shaft with a trichorrhexis nodosa-like fracture. This is the exclamation point hair, which is in telogen phase and therefore shed [31, 32]. The horizontal section demonstrates a significant decrease in the anagen:telogen ratio. There is also a decrease in the number of

In the subacute stage, the number of catagen hairs is markedly increased [30]. The number of telogen hairs also increases after a few weeks. The amount of terminal hairs decreases and the

In the chronic stage, either no or a mild chronic peribulbar lymphocytic inflammation around the miniaturized hairs situated in the papillary dermis is observed [30, 31]. The terminal:vellus hair ratio decreases to 1.3:1 rather than 7:1, which is found in the normal population. Fibrosis is an uncommon finding. However, in approximately 10% of the patients with a long history

Of note, diagnosis of alopecia areata does not depend on the presence of an inflammatory infiltrate. Histopathological examination reveals increased numbers of telogen hairs in the acute and chronic stages, increased miniaturized hairs in chronic stage, and markedly increased

catagen hairs in the subacute stage, helping in the diagnosis of alopecia areata [30].

Many other diseases may cause hair loss in a patchy or diffuse pattern [33, 34] (**Table 2**).

In children, tinea capitis, which is the most common dermatophyte infection seen in childhood and trichotillomania should be considered in differential diagnosis of alopecia areata. Clinically, patches of tinea capitis show scaling and signs of inflammation sometimes accompanied by cervical lymphadenopathy. Direct microscopic examination with potassium hydroxide, fungal culture, and trichoscopy can also help in the diagnosis [35]. In trichotillomania, diagnosis is straightforward when the patient or relatives accept the compulsive act of pulling. In dermatological examination, there are irregularly shaped patches and broken hairs of variable lengths. Residual hairs in patches of trichotillomania are anagen hairs firmly attached to the scalp; they are of normal texture and color, whereas residual hairs in alopecia areata are usually the exclamation mark hairs with their specific morphology, which are easily detached from the scalp. [33, 36] Rarely, alopecia areata and trichotillomania can coexist [37]. Histopathologically, there is an increase in catagen hairs, follicular hemorrhage, pigment casts, and trichomalacia, without the typical inflammatory infiltrate and miniaturization of

In adults, the differential diagnosis is usually between androgenetic alopecia and telogen effluvium. Patients with androgenetic alopecia usually demonstrate gradual loss of hair with

terminal hairs with a slight increase in the number of vellus hairs [31].

of alopecia areata, fibrosis of the upper follicle can be detected [31].

vellus hair increases [31, 32].

112 Hair and Scalp Disorders

**9. Differential diagnosis**

hair follicles observed in alopecia areata [31, 36].

the typical distribution pattern. The pull test is usually negative in androgenetic alopecia [8]. In some cases, a scalp biopsy may be required to establish correct diagnosis. Many miniaturized hairs are found in both androgenetic alopecia and alopecia areata, but higher telogen hair counts and a decreased anagen to telogen ratio favors diagnosis of alopecia areata. Although a perifollicular lymphohistiocytic infiltrate may be observed in androgenetic alopecia, it is usually confined to the upper follicle [31]. Telogen effluvium may be difficult to differentiate from diffuse alopecia areata. In alopecia areata, hair pull test show either telogen or dystrophic anagen hairs, while they are purely telogen in telogen effluvium [2]. Upon histopathologic examination of horizontal sections of scalp biopsies, chronic telogen effluvium shows follicular counts that are similar to that of normal controls [31].

Cicatricial alopecia is characterized by patchy hair loss with loss of follicular orifices. Erythema, scaling, and pustulation may be observed in contrast to smooth, normal skin of alopecia areata patches [15]. Other forms of alopecia, such as syphilis, loose anagen syndrome, congenital triangular alopecia, and early lupus erythematosus, should also be considered [31]. Congenital triangular alopecia is a developmental abnormality of hair follicles that usually presents after 2 years of age as a triangular or round patch of hair loss near the frontotemporal hair line. Histopathological examination reveals vellus hairs [34]. Side pins used to keep the hair in place, may cause pressure alopecia, which presents with a patch of hair loss mimicking patches of alopecia areata [38]. Traction alopecia must be differentiated from alopecia areata, especially of ophiasis pattern [39].

#### **10. Management**

Currently, there is no curative or preventive treatment for alopecia areata. The main goal of therapy is to suppress the disease activity [16].

#### **10.1. Intralesional corticosteroids**

Intralesional corticosteroids have been used in treatment of alopecia areata, since 1958 [38]. Intralesional corticosteroids are considered as the first-line agents in limited alopecia areata. Injections are made every 4–6 weeks into the deep dermis using a 0.5-inch long 30-gauge needle. For lesions of the scalp, 0.1 mL of triamcinolone acetonide at concentration of 5 mg/mL is injected at 1-cm intervals. Intralesional corticosteroid application is also effective for beard and eyebrow alopecia areata at a concentration of 2.5 mg/mL. Maximum dose of triamcinolone acetonide should be limited to 3 mL for scalp, 0.5 mL for each eyebrow and 1 mL for beard [40]. Hair regrowth is usually observed within 4 weeks and intralesional corticosteroids should be discontinued, if there is no improvement in 6 months [28]. In some patients, resistance to steroid therapy can be explained by a decreased expression of thioredoxin reductase 1, an enzyme that activates the glucocorticoid receptor in the outer root sheath [41]. The most common side effect observed is atrophy, which may be prevented by avoiding superficial injections, and reducing the concentration and volume of injections [42]. Other side effects include hypopigmentation, depigmentation, and telangiectasias [40].

#### **10.2. Topical corticosteroids**

Midpotent and potent topical corticosteroids in forms of lotions, creams, and ointments are widely used in spite of the fact that evidence of their effectiveness is limited [42, 43]. In a double-blind placebo-controlled study, rate of complete hair growth was not statistically significant with 12 weeks use of 0.25% desoximetasone cream, twice daily, when compared with placebo [44]. A half-head comparison trial performed with 0.05% clobetasol propionate foam and vehicle found at least 50% regrowth of hair after 12 weeks of clobetasol treatment. Blood levels of cortisol and ACTH were not affected during the trial [45]. A recent study showed that twice daily treatment with clobetasol propionate 0.05% cream used in 2 cycles of 6 weeks on, 6 weeks off regimen for a total of 24 weeks was more effective than hydrocortisone 1% cream used in the same regime. Compared with only 33.3% of the children in the hydrocortisone group, 85% of the children in the clobetasol group had at least 50% reduction in the surface area with hair loss at 24 weeks [46]. Folliculitis is a common side effect; skin atrophy and telangiectasia can rarely be observed [47].

#### **10.3. Topical immunotherapy**

Topical immunotherapy is the most effective treatment option for patients with chronic severe alopecia areata, with greater than 50% scalp involvement [48].

Topical immunotherapy consists of applying a contact allergen to induce a low-grade chronic dermatitis. The mechanism of action is still unclear. Antigenic competition, induction of lymphocyte apoptosis, and diversion of the T cell response from the hair follicle to the epidermis are among the various suggested theories [49–60].

Dinitrochlorobenzene was the first topical sensitizer to be used in the treatment of extensive alopecia areata; however, it was abandoned because of its mutagenic effects [42, 51]. Squaric acid dibutylester (SADBE) and diphenylcyclopropenone (DPCP) are the two compounds still in use today. Although SADBE is an ideal immunogen that is not found in the natural environment and is not known to cross-react with other chemicals, DPCP is preferred because it is cheaper and is more stable in acetone for storage [42, 51]. DPCP is a very light sensitive compound and should be stored in amber bottles to protect it from exposure to ultraviolet and fluorescent lights [51].

Topical immunotherapy begins at first visit by the sensitization of the patient with 2% DPCP applied to a 5-cm circular area on the scalp. Two weeks later, a 0.001% DPCP solution is applied to the same half of the scalp. The concentration of DPCP is increased gradually each week to produce mild inflammation that manifests as pruritus and erythema lasting for 36–48 h. After establishing the appropriate concentration for the patient, subsequent therapy is continued once weekly with the same concentration [52]. DPCP should be left on the scalp for 48 h and the treated area must be protected from the sun during this time. Treatment of both sides is recommended only after achieving hair regrowth on the treated side. If there is no improvement in 6 months, DPCP is less likely to be successful; however, improvement in these "non-responder" patients with longer courses of DPCP therapy has been reported [42, 53]. If the patient does not develop an allergic reaction to 2% DPCP, SADBE can be tried [42]. The procedure with SADBE treatment is similar to DPCP.

The response rates of DPCP treatment in alopecia areata ranges from 5% to 85%. Patients with earlier onset of the disease or more extensive involvement were shown to be less likely to respond to diphenylcyclopropenone therapy [53].

Topical immunotherapy is generally well tolerated by most of the patients. The most commonly seen side effects are eczema, autoeczematization, blistering, and swelling of regional lymph nodes [54]. When a vesicular or bullous reaction develops, the patient should wash off the contact sensitizer and a topical corticosteroid should be applied to the affected area. Facial and scalp edema, contact urticaria, flu-like symptoms, erythema multiforme-like reactions, and pigmentary disturbances manifesting as hyperpigmentation, hypopigmentation, dyschromia in confetti, and vitiligo can also occur [42, 55, 56]. Patients may complain of burning sensation, after application of SADBE. Persistent allergic contact dermatitis of the primary site of sensitization, severe generalized dermatitis and systemic reactions characterized by fever, and arthalgias are among the rarely observed side effects [54].

#### **10.4. Minoxidil**

**10.1. Intralesional corticosteroids**

114 Hair and Scalp Disorders

**10.2. Topical corticosteroids**

angiectasia can rarely be observed [47].

**10.3. Topical immunotherapy**

hypopigmentation, depigmentation, and telangiectasias [40].

alopecia areata, with greater than 50% scalp involvement [48].

are among the various suggested theories [49–60].

Intralesional corticosteroids have been used in treatment of alopecia areata, since 1958 [38]. Intralesional corticosteroids are considered as the first-line agents in limited alopecia areata. Injections are made every 4–6 weeks into the deep dermis using a 0.5-inch long 30-gauge needle. For lesions of the scalp, 0.1 mL of triamcinolone acetonide at concentration of 5 mg/mL is injected at 1-cm intervals. Intralesional corticosteroid application is also effective for beard and eyebrow alopecia areata at a concentration of 2.5 mg/mL. Maximum dose of triamcinolone acetonide should be limited to 3 mL for scalp, 0.5 mL for each eyebrow and 1 mL for beard [40]. Hair regrowth is usually observed within 4 weeks and intralesional corticosteroids should be discontinued, if there is no improvement in 6 months [28]. In some patients, resistance to steroid therapy can be explained by a decreased expression of thioredoxin reductase 1, an enzyme that activates the glucocorticoid receptor in the outer root sheath [41]. The most common side effect observed is atrophy, which may be prevented by avoiding superficial injections, and reducing the concentration and volume of injections [42]. Other side effects include

Midpotent and potent topical corticosteroids in forms of lotions, creams, and ointments are widely used in spite of the fact that evidence of their effectiveness is limited [42, 43]. In a double-blind placebo-controlled study, rate of complete hair growth was not statistically significant with 12 weeks use of 0.25% desoximetasone cream, twice daily, when compared with placebo [44]. A half-head comparison trial performed with 0.05% clobetasol propionate foam and vehicle found at least 50% regrowth of hair after 12 weeks of clobetasol treatment. Blood levels of cortisol and ACTH were not affected during the trial [45]. A recent study showed that twice daily treatment with clobetasol propionate 0.05% cream used in 2 cycles of 6 weeks on, 6 weeks off regimen for a total of 24 weeks was more effective than hydrocortisone 1% cream used in the same regime. Compared with only 33.3% of the children in the hydrocortisone group, 85% of the children in the clobetasol group had at least 50% reduction in the surface area with hair loss at 24 weeks [46]. Folliculitis is a common side effect; skin atrophy and tel-

Topical immunotherapy is the most effective treatment option for patients with chronic severe

Topical immunotherapy consists of applying a contact allergen to induce a low-grade chronic dermatitis. The mechanism of action is still unclear. Antigenic competition, induction of lymphocyte apoptosis, and diversion of the T cell response from the hair follicle to the epidermis

Dinitrochlorobenzene was the first topical sensitizer to be used in the treatment of extensive alopecia areata; however, it was abandoned because of its mutagenic effects [42, 51]. Squaric acid dibutylester (SADBE) and diphenylcyclopropenone (DPCP) are the two compounds still in use today. Although SADBE is an ideal immunogen that is not found in the natural environment and Topical minoxidil solution, approved by Food and Drug Administration and Health Canada for the treatment of androgenetic alopecia, can be used in alopecia areata. Evidence for the effectiveness of using 3% minoxidil, twice daily, was shown in a double-blind placebo controlled study [57]. A dose response effect exists, with the 5% solution being more effective than the 2% solution. However, few patients achieve cosmetically significant regrowth [58]. Minoxidil 5% solution, twice daily, is used in combination with topical or intralesional corticosteroids. Contact dermatitis and hypertrichosis are the most common side effects. Minoxidil foam, which does not contain propylene glycol, has less irritating effects than the solution [59].

#### **10.5. Anthralin**

Anthralin, 0.5–1%, short contact therapy is used as alternative treatment although evidence for its efficacy depends on case series without controls [47].

Anthralin 1% cream is applied daily for 15 or 20 min initially and then washed. The contact time is increased by 5 min weekly up to 1 h or to the time required to cause a low-grade dermatitis. Once the contact time sufficient to produce the mild dermatitis is found, subsequent therapy is continued daily for the established period of time. Anthralin should be applied at least 3 months before evaluating the response to treatment. Side effects include severe irritation, folliculitis, regional lymphadenopathy, and staining of skin, clothes and fair hair. Patients should avoid eye contact with this chemical, and the treated area should be protected from the sun [59].

#### **10.6. Photochemotherapy**

No controlled studies of oral or topical psoralen plus ultraviolet A (PUVA) therapy in alopecia areata have been reported [59]. The reports about the efficacy of PUVA therapy are conflicting. Several studies have shown low response rates of PUVA therapy [60, 61], while others have shown good response rates [62, 63]. PUVA therapy is thought to eradicate the mononuclear cell infiltrate, surrounding the hair follicle responsible for the disease [16]. Uncertainty about efficacy and concerns about PUVA-induced skin carcinogenesis make this therapy option a rarely chosen one [59].

#### **10.7. Systemic glucocorticosteroids**

Systemic corticosteroids have been used since 1952 in the treatment of alopecia areata; however, relapse rates are high upon dose reductions [64].

Long-term daily treatment with oral corticosteroids will produce favorable results in a part of the patients [33]. It was reported that 12–28% of patients with 1–99% scalp alopecia areata regrew 50% or more of their hair after a 6-week tapering course of prednisone therapy, starting at 40 mg daily. 2% minoxidil therapy may be useful for prolonging the response to the treatment after prednisone cessation [65]. However, oral corticosteroids are no longer used for chronic therapy of alopecia areata because of their side effects [33]. Side effects of oral steroids include avascular necrosis, weight gain, hypertension, diabetes, sleep alteration, mood changes, weakness, acneiform eruptions, irregular menses, and striae [52].

High-dose intravenous corticosteroid pulse therapy can be considered in patients with multifocal or ophiasis-type alopecia areata if treatment with topical sensitizers or highly potent topical corticosteroids during 6 months have failed. In more extensive involvement, such as alopecia totalis and universalis, treatment efficacy was shown to be diminished [64].

#### **10.8. Immunosuppressive treatment**

Immunosuppressive agents namely sulfasalazine, methotrexate, and cyclosporine can be used in the treatment of alopecia areata.

Sulfasalazine therapy can be an alternative treatment option in persistent alopecia areata cases. Studies have shown favorable treatment response, but a high relapse rate. The most common side effects include nausea, vomiting, headache, fever, and rash; less commonly hematologic abnormalities and hepatotoxicity can develop [66, 67].

Severe forms of alopecia areata resistant to conventional topical and/or systemic treatments may respond to methotrexate. In a retrospective study, weekly 15–25 mg methotrexate with or without 10–20 mg prednisolone daily was reported to be effective in 64% of cases [68].

Cyclosporine has been used alone or in conjunction with corticosteroids variable response rates [47]. Use of cyclosporine is limited because of side effects and high relapse rate. Side effects include nephrotoxicity, immune suppression, hypertension, and hypertrichosis of body hair [59].

#### **10.9. Other therapies**

#### *10.9.1. Excimer laser*

Anthralin 1% cream is applied daily for 15 or 20 min initially and then washed. The contact time is increased by 5 min weekly up to 1 h or to the time required to cause a low-grade dermatitis. Once the contact time sufficient to produce the mild dermatitis is found, subsequent therapy is continued daily for the established period of time. Anthralin should be applied at least 3 months before evaluating the response to treatment. Side effects include severe irritation, folliculitis, regional lymphadenopathy, and staining of skin, clothes and fair hair. Patients should avoid eye

No controlled studies of oral or topical psoralen plus ultraviolet A (PUVA) therapy in alopecia areata have been reported [59]. The reports about the efficacy of PUVA therapy are conflicting. Several studies have shown low response rates of PUVA therapy [60, 61], while others have shown good response rates [62, 63]. PUVA therapy is thought to eradicate the mononuclear cell infiltrate, surrounding the hair follicle responsible for the disease [16]. Uncertainty about efficacy and concerns about PUVA-induced skin carcinogenesis make this therapy option a

Systemic corticosteroids have been used since 1952 in the treatment of alopecia areata; how-

Long-term daily treatment with oral corticosteroids will produce favorable results in a part of the patients [33]. It was reported that 12–28% of patients with 1–99% scalp alopecia areata regrew 50% or more of their hair after a 6-week tapering course of prednisone therapy, starting at 40 mg daily. 2% minoxidil therapy may be useful for prolonging the response to the treatment after prednisone cessation [65]. However, oral corticosteroids are no longer used for chronic therapy of alopecia areata because of their side effects [33]. Side effects of oral steroids include avascular necrosis, weight gain, hypertension, diabetes, sleep alteration, mood

High-dose intravenous corticosteroid pulse therapy can be considered in patients with multifocal or ophiasis-type alopecia areata if treatment with topical sensitizers or highly potent topical corticosteroids during 6 months have failed. In more extensive involvement, such as

Immunosuppressive agents namely sulfasalazine, methotrexate, and cyclosporine can be

Sulfasalazine therapy can be an alternative treatment option in persistent alopecia areata cases. Studies have shown favorable treatment response, but a high relapse rate. The most common side effects include nausea, vomiting, headache, fever, and rash; less commonly

alopecia totalis and universalis, treatment efficacy was shown to be diminished [64].

changes, weakness, acneiform eruptions, irregular menses, and striae [52].

hematologic abnormalities and hepatotoxicity can develop [66, 67].

contact with this chemical, and the treated area should be protected from the sun [59].

**10.6. Photochemotherapy**

116 Hair and Scalp Disorders

rarely chosen one [59].

**10.7. Systemic glucocorticosteroids**

**10.8. Immunosuppressive treatment**

used in the treatment of alopecia areata.

ever, relapse rates are high upon dose reductions [64].

Mechanism of action of excimer laser in alopecia areata is thought to depend on induction of T cell apoptosis as proven in in vitro studies [69]. In a treatment of 18 patients with 42 alopecia areata patches with the 308 nm excimer laser, hair regrowth was observed in 41.5% of treated areas. Lesions on the extremities, patients with alopecia totalis, or alopecia universalis were resistant to the treatment [70].

#### *10.9.2. Low-dose recombinant interleukin 2*

Low-dose interleukin 2 (IL-2) is essential to proliferate Treg cells, which play a key role in alopecia areata [71]. A prospective study in 5 patients with extensive, treatment-resistant alopecia areata, 1.5 million IU/d subcutaneous interleukin 2 was administered during 5 days, followed by three 5-day courses of 3 million IU/d at weeks 3, 6, and 9. It was reported that 4 of the 5 patients attained considerable hair regrowth. Treatment adverse events were mild to moderate and included asthenia, arthralgia, urticaria, and injection site reactions [72].

#### *10.9.3. Janus kinase inhibitors*

Tofacitinib citrate is a small-molecule selective Janus kinase 1/3 (JAK 1/3) inhibitor that was approved by FDA, in late 2012, for the treatment of moderate-to-severe rheumatoid arthritis. A patient with longstanding alopecia universalis, treated with tofacitinib for psoriasis had hair regrowth, being the first documented case of alopecia areata responding to tofacitinib. After eight months of tofacitinib treatment (5 mg twice daily for 2 months followed by 10 mg in the morning and 5 mg at night thereafter), the patient had full regrowth of hair at all body sites [73]. There have been other case reports showing efficacy of tofacitinib treatment [74, 75]. Adverse effects of tofacitinib use include increased risk of severe infections including tuberculosis, anemia, neutropenia, headache, and mild nausea [74].

Another JAK inhibitor, ruxolitinib applied topically twice daily for 12 weeks in a patient with refractory alopecia universalis induced almost full eyebrow regrowth and approximately 10% regrowth of scalp hair [76].

#### *10.9.4. Simvastatin/ezetimibe*

Simvastatin 40 mg and ezetimibe 10 mg daily treatment for alopecia totalis and alopecia universalis was documented to have favorable responses in case reports [77]. In a prospective uncontrolled study, simvastatin/ezetimibe 40 mg/10 mg daily for 24 weeks was shown to be an effective treatment option for alopecia areata [78].
