Alopecia Areata: a Review

Journal of the Saudi Society of Dermatology & Dermatologic Surgery (2013) 17,37–45

King Saud University Journal of the Saudi Society of Dermatology & Dermatologic Surgery www.ksu.edu.sa www.jssdds.org www.sciencedirect.com

REVIEW ARTICLE Alopecia areata: A review

Syed Suhail Amin, Sandeep Sachdeva *

Department of Dermatology, JN Medical College, Aligarh Muslim University (AMU), Aligarh, India

Received 24 February 2013; revised 20 May 2013; accepted 25 May 2013 Available online 17 June 2013

KEYWORDS Abstract Alopecia areata (AA) is a nonscarring, autoimmune hair loss on the scalp, and/or body. Alopecia areata; Etiology and pathogenesis are still unknown. The most common site affected is the scalp in the form Etiology; of solitary or multiple patches of alopecia. Histopathology is characterized by an increased number Pathogenesis; of telogen follicles and presence of inﬂammatory lymphocytic inﬁltrate in the peribulbar region. Management Corticosteroids are the most popular drugs for the treatment of this disease. This review precisely outlines the etiologic and pathogenic mechanisms, clinical features, diagnosis and management of alopecia areata. ª 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University.

Contents

1. Introduction ...... 38 2. Dynamics of hair loss ...... 39 3. Etiopathogenesis ...... 39 3.1. Animal models in the understanding of pathogenesis...... 39 3.2. Psychological factors ...... 40 4. Clinical features ...... 40 4.1. Quantitating hair loss ...... 40 4.2. Gauging severity of disease ...... 41 5. Differential diagnosis...... 41 6. Histopathology ...... 41 7. Management...... 42 7.1. Glucocorticoids ...... 42 7.1.1. Intralesional corticosteroids ...... 42

* Corresponding author. Address: 3/115 A, Durgabadi, Marris Road, Aligarh, UP 202 002, India. Tel.: +91 9359507294. E-mail address: [email protected] (S. Sachdeva). Peer review under responsibility of King Saud University.

Production and hosting by Elsevier

2210-836X ª 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University. http://dx.doi.org/10.1016/j.jssdds.2013.05.004 38 S.S. Amin, S. Sachdeva

7.1.2 Topical corticosteroids ...... 42 7.1.3. Systemic corticosteroids ...... 42 7.1.4. Oral mini pulse sterpods...... 43 7.2. Minoxidil ...... 43 7.3. Anthralin...... 43 7.4. Topical immunomodulators ...... 43 7.5. PUVA...... 43 7.6. Cyclosporine A ...... 43 7.7. Tacrolimus ...... 43 7.8. Sulfasalazine ...... 44 7.9. Mesotherapy ...... 44 7.10. Biological theraphy...... 44 8. Conclusion ...... 44 References ...... 44

1. Introduction and Tazi-Ahnini, 2002; Hordinsky and Ericson, 2004). This view has been supported by the occurrence of AA in associa- Alopecia areata (AA) is a common cause of non scarring alo- tion with other autoimmune disorders like vitiligo, lichen pla- pecia that occurs in a patchy, conﬂuent or diffuse pattern. It nus, morphea, atopic dermatitis, Hashimoto’s thyroiditis, may involve loss of hair from some or all areas of the body, perinicious anemia and diabetes mellitus (Brenner, 1979). usually from the scalp (Odom, 2006). In 1–2% of cases, the More recently, it has been reported that there is a high preva- condition can spread to the entire scalp (Alopecia totalis) or lence of mood, adjustment, depressive and anxiety disorders in to the entire epidermis (Alopecia universalis). AA has a re- patients with AA (Ruiz-Doblado et al., 2003). This element of ported incidence of 0.1–0.2% with a lifetime risk of 1.7% with psychiatric morbidity has widely been purported to be both, a men and women being affected equally (Safavi et al., 1995). cause and effect of AA. A multipronged approach is therefore Sharma et al. in their decade long prospective study observed warranted in the management of such patients. Though corti- an incidence of 0.7% among new dermatology outpatients costeroids have been the mainstay in therapy, a wide array of (Sharma et al., 1996). The etiology of AA has eluded investiga- evidence based therapies have come into fore for management tors for years and therefore a multitude of associations have of AA. The present study attempts to systematically review the been proposed by researchers in the ﬁeld of trichology. One various aspects in the natural history of alopecia areata and of the strongest associations is with autoimmunity (McDonagh the pros and cons in the different treatment modalities.

Figure 1 Phases of hair growth. Alopecia areata: A review 39

McDonagh and Tazi-Ahnini, 2002). An association between AA and human leukocyte antigen (HLA) has been demonstrated. Kavak et al. reported patients with AA had HLA- A1, HLA-B62, HLA-DQ1, and HLADQ3 (Ay Se et al., 2000). Recently, in the United States, Barahmani et al. demonstrated that a non-HLA molecule including the major histocompatibility complex class I chain-related gene A (MICA) is associated with AA. It could be a potential candidate gene and part of an extended HLA haplotype that may contribute to susceptibility and severity of this entity (Barahmani et al., 2006). HLA class I molecules are expressed on virtually all nucleated cells and platelets and present antigens to CD8+ T cells. HLA class II molecules have three main subclasses (DR, DQ, and DP); they are found on specific immune cells, including B cells, activated T cells, macrophages, keratino- cytes, and dendritic cell and present peptides to CD4+ T cells. Because class II molecules are associated with antigen presentation, many studies have focused on this area of the HLA molecule (Mari, 2004). These associations with HLA-DR and HLA-DQ suggest a Figure 2 Multifactorial etiology of alopecia areata. role for T cells in this disease as well as autoimmunity. Patients with AA have an increased frequency of autoantibodies to follic- 2. Dynamics of hair loss ular structures; however, there is little consistency in which follicular structures are labeled by the antibodies (Gilhar and Kalish, Hair follicle growth occurs in cycles (Fig. 1). Each cycle consists 2006). Other diseases that are reported to be associated with AA of a long growing phase (anagen), a short transitional phase are at higher rate than the normal population. They are atopic (catagen) and a short resting phase (telogen). At the end of dermatitis, vitiligo, thyroid disease, and Down’s syndrome the resting phase, the hair falls out (exogen) and a new hair (Tan et al., 2002). Most of the research in the field of AA thus starts growing in the follicle beginning the cycle again. There demonstrates a strong case for the implication of autoimmunity are considerable variations in the length of the three phases, in the etiopathogenesis. Other potential offenders proposed in with the duration of the anagen determining the type of hair the causation of AA are psychologic stress, anemia, parasitic produced, particularly its length. Normally about 100 strands infestations, hypothyroidism, hyperthyroidism and diabetes. of hair reach the end of their resting phase each day and fallout (Trueb, 2010). Hair loss in non scarring alopecias, including 3.1. Animal models in the understanding of pathogenesis alopecia areata essentially represents a disorder of hair follicle cycling (Paus, 1996). It is believed that in AA, an as yet uniden- The Dundee experimental bald rat (DEBR) and the C3H/HeJ tified trigger stimulates an autoimmune lymphocytic attack on mouse are well-established animal models for alopecia areata the hair bulb. This inflammation is specific for anagen hairs and can be used for the study of genetic aspects, pathogenesis and causes anagen arrest. A disruption of the growing phase, and therapy of the disease. In C3H/HeJ mice alopecia areata that is anagen arrest, causes abnormal loss of anagen hairs (ana- can be experimentally induced by grafting lesional skin from gen effluvium), clinically recognized as dystrophic anagen hair an affected mouse to a histocompatible recipient which offers with tapered proximal ends and lack of root sheaths. A related the possibility to study the influence of various factors on the but distinct entity observed very frequently in women is ‘telogen development of the disease. Studies on the C3H/HeJ mouse effluvium’. This is an umbrella term inclusive of conditions and the DEBR have corroborated the concept that alopecia wherein the affected hairs undergo an abrupt conversion from areata is a T-cell mediated autoimmune disease and various anagen to telogen (anagen release), clinically seen as localized steps and aspects of the pathogenesis have been elucidated. shedding of hair in the telogen and morphologically identified as hair with a depigmented bulb (Wasserman et al., 2007).

3. Etiopathogenesis

The etiology of AA has experienced considerable drift over the years and different schools of thought have assigned varied eti- ologies to the condition (Fig. 2). A viral etiology was proposed in the late 1970s but subsequent articles have demonstrated no connection (Tosti et al., 1996). A genetic study by Yang et al. found that 8.4% of the patients had a positive family history of AA, suggesting a polygenic additive mode of inheritance (Yang et al., 2004). It has now been widely postulated that AA is an organ-speciﬁc autoimmune disease with genetic pre- disposition and an environmental trigger (McMichael, 1997; Figure 3 Localised patch of alopecia areata on scalp. 40 S.S. Amin, S. Sachdeva

Based on this knowledge new therapeutic options may be mal hair demarcates the periphery of the lesion (Fig. 3). The developed such as inhibition of lymphocyte-homing by an scalp is the most common site affected by AA (90%) Tan et anti-CD44v10 antibody, or inhibition of costimulation by al. (2002) and Camacho (1997). Scalp and body hair such as eye- monoclonal antibodies (Freyschmidt-Paul et al., 2004). brows, eyelashes, beard, underarm hair, and pubic hair may be Animal models have also suggested a role of vitamin A in affected (Alopecia Totalis), as well as the entire body (Alopecia the regulation of both the hair cycle and immune response to Universalis). The ophiasis pattern refers to a severe form of AA alter the progression of AA. Gene array in graft-induced extending along the posterior occipital and temporal scalp mar- C3H/HeJ mice revealed that genes involved in retinoic acid gins. The affected skin appears normal with no grossly evident (RA) synthesis were increased, whereas RA degradation genes epidermal alterations such as scaling or follicular abnormalities were decreased in AA compared with sham controls. RA levels (Diana Draelos, 2007). In all forms ‘‘exclamation point hairs’’ were also increased in C3H/HeJ mice with AA. C3H/HeJ mice are found, that become narrower along the length of the strand were fed a puriﬁed diet containing one of the four levels of die- closer to the base may be seen within or around the areas of alo- tary vitamin A or an unpuriﬁed diet 2 weeks before grafting pecia (Cline, 1988). Upon regrowth, hair often initially lack pig- and disease progression followed. High vitamin A accelerated ment resulting in blonde or white hair (Finner, 2011). Nail AA, whereas mice that were not fed vitamin A had more severe changes can be seen in a portion of patients (10–66%) of AA. disease by the end of the study. More hair follicles were in ana- Small shallow pits (30%) up to trachyonychia (sandpaper nails; gen in mice fed with high vitamin A. Both the number and 10%) are typical, rarely other changes can also be seen. A red- localization of granzyme B-positive cells were altered by vita- spotted lunula and periungual erythema have been postulated min A. IFNc was the lowest and IL13 highest in mice fed with as a sign of acute nail involvement (Olsen, 2003). high vitamin A. Other cytokines were reduced and chemokines increased as the disease progressed (Duncan et al., 2013). 4.1. Quantitating hair loss

3.2. Psychological factors Hair pull tests conducted at the periphery of the lesion may be correlated with disease activity and also assist in determining Some studies have suggested that emotional stress contributes the etiology of alopecia. A few clinical tests are presented to the appearance of alopecia areata, given the observation below: that emotional trauma precedes the process (Baker, 1987) to- The pull test: this test helps to evaluate diffuse scalp hair loss. gether with the high prevalence of psychological disorders Gentle traction is exerted on a group of hair (about 40–60) on occurring in these patients (Colon et al., 1991). While, on the three different areas of the scalp. The number of extracted contrary, other studies have demonstrated that there is no par- hairs is counted and examined under a microscope. Nor- ticipation of emotional phenomena in the development of alo- mally, <3 hairs per area should come out with each pull. If pecia areata (van der Steen et al., 1992). >10 hairs are obtained, the pull test is considered positive. A possible explanation of the pathogenic mechanisms pro- The pluck test: In this test, the individual pulls hair out ‘‘by voked by emotional conditions lies in the production of neu- the roots.’’ The root of the plucked hair is examined under a romediators capable of interfering in the immunity. Some microscope to determine the phase of growth and used to studies have revealed a decrease in the expression of calcitonin diagnose a defect of telogen, anagen, or systemic disease. gene related peptide (CGRP) and substance P in the scalp of Telogen hairs are hairs that have tiny bulbs without sheaths alopecia areata patients (Hordinsky et al., 1995a,b). CGRP at their roots. Telogen effluvium shows an increased per- has an anti-inflammatory action, (Raud et al., 1991) and its de- centage of hairs upon examination. Anagen hairs are hairs crease in alopecia areata could favor the characteristic follicu- that have sheaths attached to their roots. Anagen effluvium lar inflammatory phenomena. Substance P is capable of shows a decrease in telogen-phase hairs and an increased inducing hair growth in mice (Paus et al., 1994) and its de- number of broken hairs. crease in alopecia areata could be a contributing factor to Scalp biopsy: This test is done when alopecia is present, but the reduced proliferation of pilar follicles. the diagnosis is unsure. The biopsy allows for differing between scarring and nonscarring forms in case there is clin- 4. Clinical features ical distinction is difficult. Hair samples are taken from areas of inflammation, usually around the border of the bald patch. The diagnosis of AA is essentially made on clinical grounds. Daily hair counts: This is normally done when the pull test is Age at onset, duration and progression of disease, personal negative. It is done by counting the number of hairs lost. The and family history of atopy, family history of similar disease hair that should be counted are the hairs from the first morn- with special reference to autoimmune disease and other sys- ing combing or during washing. The hair is collected in a clear temic complaints are noted in detail. Routine investigations like plastic bag for 14 days. The strands are recorded. If the hair complete hemogram, anemia panel, erythrocyte sedimentation count is >100/day, it is considered abnormal except after rate, thyroid function tests, serum calcium, serum proteins, shampooing, where hair counts will be up 250 and be normal. etc. should be carried out to arrive at a specific diagnosis. Skin Trichoscopy: Trichoscopy is a non-invasive method of hair biopsy and autoimmune panel may be performed in selected and scalp evaluation. The test may be performed with the cases. Alopecia areata most commonly manifests as a sudden use of a hadheld dermoscope or a videodermoscope. In alo- loss of hair in localized areas. The lesion is usually a round or pecia areata trichoscopy shows regularly distributed ‘‘yel- oval patch of alopecia and may be solitary (Alopecia Areata low dots’’ (hyperkeratotic plugs), micro-eclamation mark monolocularis) or numerous (Alopecia Areata multilocularis). hairs, and ‘‘black dots’’ (destroyed hairs in the hair follicle The patch of alopecia usually has a distinct border where nor- opening. Alopecia areata: A review 41

Nails as described earlier, show changes in the form of pit- ring alopecias have loss of follicular ostia, or atrophy. Clinical ting or trachyonychia (Olsen et al., 2004). Stigmata of organ inflammation is frequently, but not always, present. Histologic specific autoimmunity may be present on systemic inflammation may be present. Ultimately, histologic confirma- examination. tion is the best method to confirm the presence of a fibrosing/ scarring process with loss of hair follicles. A few entities in 4.2. Gauging severity of disease scarring alopecias are Lichen planopilaris, Central centrifugal cicatricial alopecia, Pseudopelade, Discoid lupus and Traction alopecia. The main confounders in diagnosis are the other Researchers have devised a clinical scale in order to assess the varieties of non scarring alopecias. They are: severity of AA (Ay Se et al., 2000), presented as follows: Trichotillomania: this condition probably causes most con- 1 Mild: Three or less patches of alopecia with a widest diam- fusion and it is possible that it coexists with alopecia areata eter of <3 cm or disease limited to eyelashes and eyebrows. in some cases. The incomplete nature of the hair loss in 2 Moderate: Existence of more than three patches of alopecia trichotillomania and the fact that the broken hairs are or a patch greater than 3 cm at the widest diameter without firmly anchored in the scalp (i.e. they remain in the growing alopecia totalis or universalis. phase, anagen, unlike exclamation mark hairs) are distin- 3 Severe: Alopecia totalis or alopecia universalis. guishing features. 4 Ophiasis: Severe form in which loss of hair occurs in the Tinea capitis: the scalp is inflamed in tinea capitis and there shape of a wave at the circumference of the head (described is often scaling but the signs may be subtle. above). Early scarring alopecia. Telogen effluvium. The National Alopecia Areata Foundation working com- Anagen effluvium (drug-induced) may mimic diffuse alope- mittee has devised ‘‘Severity of Alopecia Tool score’’ (SALT cia areata. score) Price and Gummer, 1989. Scalp is divided into four areas Systemic lupus erythematosus. namely, Vertex – 40% (0.4) of scalp surface area; right profile of Secondary syphilis. scalp – 18% (0.18) of scalp surface area; left profile of scalp – Loose anagen hair syndrome: This is a disorder of abnormal 18% (0.18) of scalp surface area; Posterior aspect of scalp – anagen hair anchorage. It is commonly found in children 24% (0.24) of scalp surface area. Percentage of hair loss in and has an autosomal dominant inheritance (Lew, 2009). any of these areas is percentage of hair loss multiplied by per- ADTA: Acute diffuse and total alopecia (ADTA) is a new cent surface area of the scalp in that area. SALT score is the subtype of alopecia areata with favorable prognosis. ADTA sum of percentage of hair loss in all above mentioned areas. has been reported to have a short clinical course ranging from acute hair loss to total baldness, followed by rapid 5. Differential diagnosis recovery, sometimes even without treatment (Garcia-Her- nandez, 2000). Though alopecia areata is a form of non scarring alopecia, it is SISAPHO: This is an unusual form of Alopecia, in which a sometimes confused with different varieties of scarring alope- band-like pattern is found on the frontal hairline. This can cia as well. This is also because many alopecia types are bipha- be clinically confused with frontal fibrosing alopecia. The sic in their natural history. The first step, therefore is to opposite of ophiasis type, where hairs are lost centrally distinguish between scarring and non scarring alopecias. Scar- and spared at the margins of the scalp, is called sisiapho. It may mimic androgenetic alopecia (Ragunatha et al., 2008). Raunatha et al. in their case report have demonstrated infantile scurvy also, as a cause of diffuse non scarring alopecia of the scalp (Whiting, 2003).

6. Histopathology

The histopathologic features of alopecia areata depend on the stage of the current episode and do not vary with the age, sex or race of the patient (Igarashi et al., 1981). In the acute stage, terminal hairs are surrounded by bulbar lym- phocytes (‘swarm of bees’) (Fig. 4). In the subacute stage, decreased anagen and increased catagen and telogen hairs are characteristically found. In the chronic stage, decreased terminal and increased miniaturized hairs are found, with vari- able inflammation. Immunofluorescence studies have shown deposits of C3, IgG, and IgM along the basement membrane of the inferior part of the hair follicle (Shimmer and Parker, Figure 4 Swarm of bees’ appearance of the inflammatory 2001). During recovery, increasing numbers of terminal ana- infiltrate around terminal hair follicles in alopecia areata. (H&E gen hairs from regrowth of miniaturized hairs and a lack of stain). inflammation are noted. Alopecia areata should histologically 42 S.S. Amin, S. Sachdeva

Figure 5 Algorithm for management of Alopecia areata in different age groups. (*Adapted with permission from the Editor, J. Am. Acad. Dermatol. 2010;62:191–202). be suspected when high percentages of telogen hair or minia- treatment are often seen in 1–2 months. Additional treatments turized hair are present, even in the absence of a peribulbar are repeated every 4–6 weeks. lymphocytic infiltrate. The histopathology of the lesion in ADTA reveals infiltration of mononuclear cells around the 7.1.2. Topical corticosteroids hair follicles and prominent pigment incontinence (Garcia- Several forms of topical corticosteroids have been reported to Hernandez, 2000). exhibit varying levels of efficacy in AA. Some of the topical therapies have included fluocinolone acetonide cream, fluocin- 7. Management olone scalp gel, betamethasone valerate lotion and clobetasol propionate ointment (Tosti et al., 2003; Camacho, 1997). They Management of patients with alopecia areata is a challenging remain a very good option in children because of their painless task as a number of risk factors have been implicated in its eti- application and wide safety margin. ology. No definitive cure has been established, and treatment has focused mainly on containing disease activity. 7.1.3. Systemic corticosteroids Systemic corticosteroids do not constitute the first line treat- 7.1. Glucocorticoids ment for alopecia areata because of their extensive side effect profile. The dosages necessary to maintain hair regrowth in Topical and intralesional steroids have been the mainstay of AA are between 30 and 150 mg daily (Burton and Shuster, therapy, and have been used as first line agents for the manage- 1975). Treatment course can range from 1 to 6 months, but ment of the same. Glucocorticoids have been harnessed for prolonged courses should be avoided secondary to the numer- their overarching anti-inflammatory effects for AA (Ross ous side effects of these drugs especially when children are trea- and Shapiro, 2005). ted. Systemic steroids are thus not preferred in the treatment of alopecia areata except for some cases as a short course only. Its 7.1.1. Intralesional corticosteroids side effect profile in conjunction with the long-term treatment For circumscribed AA involving less than 50% of the scalp, requirements and high relapse rates make systemic corticoste- intralesional corticosteroids are the first-line approach (Mada- roids a more limited option. Friedli et al. (1998) have also re- ni and Shapiro, 2000). Triamcinolone acetonide in a concen- ported successful therapy with pulsed methylprednisolone tration of 10 mg/ml is administered using a 0.5-inch long 30- (250 mg IV twice daily for three consecutive days) in patchy gauge needle in multiple 0.1 mL injections approximately AA. Contraindications and side effects should however be dis- 1 cm apart (Pascher et al., 1970). Initial results of intralesional cussed at length with patients considered for this therapy. Alopecia areata: A review 43

7.1.4. Oral mini pulse steroids satisfactory results (Galbraith, 1984). Adverse effects of topical To avoid the side effects of daily steroids, pulse therapy was immunotherapy include pruritus, mild erythema, scaling, and conceived.In a study conducted by Pasricha et al., betametha- postauricular lymphadenopathy. Reported undesired side ef- sone oral mini-pulse therapy is a convenient and fairly effective fects include contact urticaria, postinflammatory hyper- and treatment modality for extensive alopecia areata (Pasricha and hypo-pigmentation, erythema mutliforme, facial or eyelid ede- Kumrah, 1996). However, it is proposed that randomized con- ma, fever, flulike symptoms, anaphylaxis,‘‘dyschromia in controlled trials with standard therapies on a larger number of pa- fetti,’’ and vitiligo. tients are required to give more insight into the efficacy and safety of oral mini-pulse therapy for extensive alopecia areata. 7.5. PUVA Oral mini-pulse therapy (OMP) with corticosteroids has been successfully used for the treatment of alopecia areata with min- The use of PUVA (psoralen plus ultraviolet light A) is based imal side effects. Persistent hiccups is a rare complication of on the concept that the mononuclear cells and Langerhans oral and intravenous corticosteroid therapy (Dickerman and cells that surround the affected hair follicles may play a direct Jaikumar, 2001). pathogenic role and that PUVA therapy can eradicate this inflammatory cell infiltrate. Recently, Whitmont did a study 7.2. Minoxidil with 8-methoxypsoralen (8-MOP) (oral dose-0.5 mg/ kg) plus UVA radiation at 1 J per square cm (J/cm2) and have demon- First introduced as an antihypertensive agent, its side effect of strated complete hair regrowth in patients with AA totalis hypertrichosis led to its use as treatment for various forms of (53%) and AA universalis (55%) and a low relapse rate among alopecia. Minoxidil directly affects follicles by stimulating pro- these patients (21%) within a long period of follow up (means liferation at the base of the bulb and differentiation above the 5.2 years) Whitmont and Cooper, 2003. In 2005, Mohamed dermal papilla, independent of its vascular influences (Fiedler et al. did a large study (124 patients with AA and 25 patients et al., 1990). Minoxidil has shown considerable results in the with AA totalis or universalis) (Mohamed et al., 2005). They management of AA and it is believed that patients resistant used topical 8-MOP plus UVA radiancy at higher doses (8– 2 to minoxidil treatment often suffer from severe AA, AT or 42 J/cm ) and they found that 85% of patients from the AA AU (Buhl, 1991; Fransway and Muller, 1988). Combination group had good or excellent response to the treatment, and therapy of minoxidil 5% lotion and anthralin have been docu- 14 patients from AA U group had 50% hair regrowth. Side ef- mented to show better results by few authors (Price, 1987). fects included slight erythema and painful burning in patients who did not protect their scalp from sunlight after PUVA 7.3. Anthralin exposure. Recurrence of hair loss was noted in eight cases after a period of 10 months to 2 years of treatment. Anthralin exerts its effect through its irritant contact proper- The relatively simple procedure of PUVASOL therapy (Lo- ties. It also acts through its immunosuppressive and anti- cal and systemic) because of good availability of solar radia- inflammatory properties via the generation of free radicals tion, negligible side effects, encouraging results and non- (Madani and Shapiro, 2000). Patients are instructed to apply availability of various other procedures and frequent treatment 0.5–1% anthralin cream to bare areas for 20–30 min daily over failures with these treatment schedules makes this procedure 2 weeks, gradually increasing daily exposure until low-grade better suited in the tropics. (Sharma et al., 1990) erythema and pruritus develops, which when once achieved is continued for 3–6 months (Ross and Shapiro, 2005). It is be- 7.6. Cyclosporine A (CsA) lieved to be a suitable agent for children under 10 years of age (Thappa and Vijayikumar, 2001). Adverse effects include scal- Cyclosporine A is a common antimetabolite drug used in post- ing, staining of treated skin and fabrics, folliculitis, and regio- transplantation patients which exerts its effect via inhibition of nal lymphadenopathy. T-cell activation. A common cutaneous side effect is hypertrichosis, which occurs in approximately 80% of patients, possi- 7.4. Topical immunomodulators bly as a result of prolongation of the anagen phase of the hair cycle. It also decreases the perifollicular lymphocytic infil- Topical immunotherapy relies on inciting an allergic contact trates, particularly the mean number of helper T cells (Taylor dermatitis (ACD) by applying potent contact allergens to the et al., 1993) Successful use of systemic CsA in patients with AA affected skin. It is believed that contact sensitizers act through has been conflicting as it is a nephrotoxic, hepatotoxic drug, it immunomodulation of the skin and its appendages at several also causes gingival hyperplasia, headaches, tremors, and different points. Dinitrochlorobenzene (DNCB) was the first hyperlipidemia (Gupta et al., 1990). sensitizer used for the treatment of AA (Rosenberg and Drake, 1976). Other contact sensitizers used in alopecia areata are di- 7.7. Tacrolimus phenyl-cyclo-propenone (DPCP) and squaric acid dibutyl ester (SADBE). The only disadvantage of DNCB is its mutagenicity Tacrolimus is a topical calcineurin inhibitor that inhibits tran- by Ames test. DNCB was however found to be non-carcino- scription following T-cell activation of several cytokines genic when fed in large doses in rats, mice, guinea pigs and including interleukin-2, interferon-and tumor necrosis factor man. Happle and Echternacht (1977), had a good response (Lawrence, 1998). Yamamoto et al. reported in their findings with DNCB. Inosiplex, a synthetic drug that acts as an immu- that tacrolimus stimulated hair growth in mice (Yamamoto nomodulating agent was used recently in cases of alopecia to- et al., 1994) although subsequent studies showed conflicting re- talis and cell mediated immunodeficiency states with sults (Jiang et al., 1995). 44 S.S. Amin, S. Sachdeva

7.8. Sulfasalazine Source of funding

Sulfasalazine is believed to be a good alternative treatment for None. alopecia areata because of its good efficacy, good adverse event profile and steroid sparing nature. The drug has immu- References nosuppressive and immunomodulatory effects, including the inhibition of inflammatory cell chemotaxis, and cytokine and AU Rashidi, T., Mahd, A.A., 2008. SO Treatment of persistent antibody production and similar to cyclosporine, sulfasalazine alopecia areata with sulfasalazine. Int. J. Dermatol. 47 (8), 850. has been shown to inhibit the release of interleukin 2 (Ellis Ay Se, Kavak, Can, Baykal, Guzin, Ozarmagan, et al, 2000. HLA in et al., 2002). In a study on treatment of persistent alopecia are- alopecia areata. Int. J. Dermatol. 39, 598. ata with sulfasalazine. thirty-nine patients with persistent alo- Baker, G.H.B., 1987. Psychological factors and immunity. J. Psycho- pecia areata received 3 g of oral sulfasalazine for months, and som. Res. 31, 1–10 [Links]. terminal hair regrowth was quantified as no response, moder- Barahmani, N., de Andrade, M., Slusser, J.P., et al, 2006. Major ate response, or good response. A good response occurred in histocompatibility complex class I chain-related gene A polymor- phisms and extended haplotypes are associated with familial 10 of the 39 patients (25.6%), a moderate response in 12 alopecia areata. J. Invest. Dermatol. 126, 74–78. (30.7%), and a poor or no response in 17 (43.5%) AU Rashidi Brenner, R., 1979. Coincidences of alopecia areata, vitiligo, onycho- and Mahd, 2008. dystrophy, localized scleroderma and lichen planus. Dermatologica 159, 356–358. 7.9. Mesotherapy Buhl, A.E., 1991. Minoxidil’s action in hair follicles. J. Invest. Dermatol. 96, 73–74, 73S–74S. Mesotherapy employs multiple injections of pharmaceutical Burton, J.L., Shuster, S., 1975. Large doses of glucocorticoid in the treatment of alopecia areata. Acta Derm. Venereol. 55, 493–496. and homeopathic medications, plant extracts, vitamins, and Camacho, F., 1997. Alopecia areata. Clinical characteristics and other ingredients into the target tissue. However, this is expen- dermatopathology. In: Trichology: Diseases of the Pilosebaceous sive and not effective, thereby precluding its widespread use. Follicle. Aula Medical Group S. A, Madrid, pp. 440–471. Camacho, F., 1997. Alopecia areata. Clinical characteristics and 7.10. Biological therapy dermatopathology. In: Trichology: Diseases of the Pilosebaceous Follicle. Aula Medical Group, S. A, Madrid, pp. 440–471. These medications synthesized from recombinant proteins re- Cline, D.J., 1988. Changes in hair color. Dermatol. Clin. 6, 295–303. Colon, E.A., Popkin, M.K., Callies, A.L., Dessert, N.J., Hordinsky, duce the pathogenic T cells, inhibit T-cell activation and inhi- M.K., 1991. 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