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This alopecia affects younger patients between the ages of 15-40 years. It usually presents with a sudden onset of non-scarring hair loss. Exclamation mark hairs can be found at the advancing border. Nail changes may also be present. There may be remissions, exacerbations, or progression of the disease. If the entire scalp is affected, it is termed alopecia totalis. If the hair loss involves the entire body, alopecia universalis. In these latter patients, there is an association with HLA DR11 and DQ7. A familial history is present in 10-25% of all patients.

Most investigators favor an autoimmune etiology for this disease. Associations with other autoimmune disorders including Addison's disease, vitiligo, Hashimoto's thyroiditis, and lupus erythematosus are common. Some patients have circulating antibodies to hair follicle antigens. Initially, there is attack of the hair follicle by CD4 positive T cells associated with dendritic cells. Cell deletion by apoptosis follows.


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Mediation of alopecia areata by cooperation between CD4+ and CD8+ T lymphocytes: transfer to human scalp explants on Prkdc(scid) mice.

Gilhar A, Landau M, Assy B, Shalaginov R, Serafimovich S, Kalish RS.

Research Laboratories, Flieman Medical Center and B. Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel.

Arch Dermatol 2002 Jul;138(7):916-22 Abstract quote

OBJECTIVE: To determine the role of CD4+ and CD8+ T lymphocytes in the pathogenesis of alopecia areata.

DESIGN: Relapse of alopecia areata was induced in autologous human scalp grafts on Prkdc(scid) mice by injection of activated T lymphocytes derived from lesional skin. CD4+ and CD8+ T cells were separated by magnetic beads before injection.

SETTING: University-based dermatology practice.

PARTICIPANTS: Eleven patients with either alopecia totalis or severe alopecia areata.

MAIN OUTCOME MEASURES: Hair regrowth, hair loss, and immunohistochemical findings of scalp explants.

INTERVENTION: Transfer of scalp T cells to autologous lesional scalp explants on Prkdc(scid) mice.

RESULTS: Injection of unseparated T cells and mixed CD4+ plus CD8+ T cells resulted in significant hair loss (P<.01) in 5 of 5 experiments. However, injection of purified CD4+ or CD8+ T cells alone did not result in reproducible hair loss. CD4+ and CD8+ T cells induced follicular expression of intercellular adhesion molecule 1 (CD54), HLA-DR, and HLA-A, HLA-B, and HLA-C after injection into scalp grafts.

CONCLUSIONS: CD4+ and CD8+ T cells have a role in the pathogenesis of alopecia areata. It is hypothesized that CD8+ T cells act as the effector cells, with CD4+ T cell help. It is now necessary to look for HLA-A, HLA-B, and HLA-C associations with alopecia areata. Therapeutic manipulations that interfere with CD8+ activity should be examined.



Alopecia areata update: part I. Clinical picture, histopathology, and pathogenesis.
Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J.

Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.

J Am Acad Dermatol. 2010 Feb;62(2):177-88, quiz 189-90. Abstract quote

Alopecia areata (AA) is an autoimmune disease that presents as nonscarring hair loss, although the exact pathogenesis of the disease remains to be clarified. Disease prevalence rates from 0.1% to 0.2% have been estimated for the United States. AA can affect any hair-bearing area. It often presents as well demarcated patches of nonscarring alopecia on skin of overtly normal appearance. Recently, newer clinical variants have been described. The presence of AA is associated with a higher frequency of other autoimmune diseases. Controversially, there may also be increased psychiatric morbidity in patients with AA. Although some AA features are known poor prognostic signs, the course of the disease is unpredictable and the response to treatment can be variable. Part one of this two-part series on AA describes the clinical presentation and the associated histopathologic picture. It also proposes a hypothesis for AA development based on the most recent knowledge of disease pathogenesis.

LEARNING OBJECTIVES: After completing this learning activity, participants should be familiar with the most recent advances in AA pathogenesis, recognize the rare and recently described variants of AA, and be able to distinguish between different histopathologic stages of AA

Familial aggregation of alopecia areata.

Blaumeiser B, van der Goot I, Fimmers R, Hanneken S, Ritzmann S, Seymons K, Betz RC, Ruzicka T, Wienker TF, De Weert J, Lambert J, Kruse R, Nothen MM.

Department of Medical Genetics, University Hospital of Antwerp, Antwerp, Belgium.
J Am Acad Dermatol. 2006 Apr;54(4):627-32. Epub 2006 Jan 23. Abstract quote  

BACKGROUND: Familial aggregation of alopecia areata (AA) has been previously described, but systematic studies with information obtained directly from family members have yet to be undertaken.

OBJECTIVE: We sought to study the pattern of familial aggregation of AA by assessing the affection status of patients' relatives. The study included 206 index patients with a total of 1029 first-degree and 2625 second-degree relatives.

METHODS: First-degree relatives were directly interviewed, whereas information on second-degree relatives was obtained by interviewing the index patients and their first-degree relatives.

RESULTS: Estimated lifetime risks were 7.1% in siblings, 7.8% in parents, and 5.7% in offspring. The risk in second-degree relatives was slightly higher than the reported population risk. Age at onset in index patients and first-degree relatives was significantly correlated.

LIMITATIONS: Using patients drawn from specialized hair clinics may have produced results showing a higher proportion of early onset and severe cases.

CONCLUSION: The familial aggregation of AA supports the role of genetic factors in the development of the disease. In addition, our data indicate genetic factors might contribute to the age at onset of AA.


The histopathology varies with the stage of the disease

It is classified as a disorder of premature telogen hair with anagen arrest

In fully developed lesions, there are telogen hair follicles with small anagen follicles. Overall, there is reduction of follicle density. There may be a mild peribulbar inflammatory cell infiltrate around small anagen follicles. Fibrous tracts or fibrous streamers are present, extending along the site of previous follicles

No scarring is observed. At the expanding edge, most of the follicles are in late catagen and telogen. Larger anagen follicles have a peribulbar lymphocytic infiltrate (called swarm of bees) with occasional macrophages and plasma cells. There is marked reduction in size of the anagen follicle epithelial matrix when compared to the dermal papillae.

Histopathological pictures of the initial changes of the hair bulbs in alopecia areata.

Ihm CW, Hong SS, Mun JH, Kim HU.

Department of Dermatology, Chonbuk University Medical School and Institute for Medical Sciences, Chonju, South Korea.
Am J Dermatopathol. 2004 Jun;26(3):249-53. Abstract quote  

A biopsy of the seemingly normal scalp of a patient who had just begun to develop alopecia areata showed distinctive changes in bulbar morphology, in addition to peribulbar lymphocytic infiltrates.

One of these changes was a loss of structural integrity of the centrally located supramatrical upper bulbar region.

The other was the shrinkage of hair bulbs in the direction of club shape. Uninvolved intact anagen follicles were also present among these involved follicles.

Histopathologic features of alopecia areata: a new look.

Whiting DA.

Baylor Hair Research and Treatment Center, Dallas, TX 75246, USA.
Arch Dermatol. 2003 Dec;139(12):1555-9. Abstract quote  

BACKGROUND: A peribulbar lymphocytic infiltrate is the expected histologic feature of alopecia areata, but it is absent in many scalp biopsy specimens. Other diagnostic criteria are needed.

OBJECTIVE: To establish the histologic features of alopecia areata in scalp biopsy specimens taken from different types of alopecia areata, using follicular counts to relate biopsy findings to stages of the disease.

METHODS: Fifty consecutive new patients with alopecia areata were studied. Four-millimeter punch biopsy specimens were taken from the scalp in areas of recent, active hair loss; old, inactive hair loss; or recent hair regrowth. Specimens were sectioned horizontally. Terminal and vellus-like hairs were counted. Inflammation and fibrosis around lower and upper follicles were rated.

RESULTS: The histopathologic features of alopecia areata were not significantly affected by the sex, age, and race of the patient or by the type, percentage of hair loss, total duration, or regression of alopecia areata. The major factor affecting the histopathologic features was the duration of the current episode of alopecia areata. In the acute stage, bulbar lymphocytes surrounded terminal hairs in early episodes and miniaturized hairs in repeated episodes. In the subacute stage, decreased anagen and increased catagen and telogen hairs were characteristic. In the chronic stage, decreased terminal and increased miniaturized hairs were found, with variable inflammation. During recovery, increasing numbers of terminal anagen hairs from regrowth of miniaturized hairs and a lack of inflammation were noted.

CONCLUSIONS: The histopathologic features of alopecia areata depend on the stage of the current episode. Alopecia areata should be suspected when high percentages of telogen hairs or miniaturized hairs are present, even in the absence of a peribulbar lymphocytic infiltrate.


Direct immunofluorescence (DIF) C3 and IgG and IgM along the basement membrane of the inferior segement of the hair follicles



Atrichia with papular lesions resulting from compound heterozygous mutations in the hairless gene: A lesson for differential diagnosis of alopecia universalis.

Henn W, Zlotogorski A, Lam H, Martinez-Mir A, Zaun H, Christiano AM.

Institute of Human Genetics, Saarland University, Homburg/Saar, Germany.

J Am Acad Dermatol 2002 Oct;47(4):519-23 Abstract quote

BACKGROUND: Atrichia with papular lesions (APL) is a rare, autosomal recessive form of total alopecia in which mutations in the hairless (HR) gene have been shown to underlie the phenotype.

OBJECTIVE: We suspect that APL is actually much more common than previously believed. We sought to investigate whether APL might also be found among patients in small families, particularly those giving a history of (1) normal hair at birth, which was shed and never regrew, and (2) "alopecia universalis" that is recalcitrant to any treatment.

METHODS: We identified a small family of German origin in which 2 of 4 siblings were affected and gave this clinical history. Direct sequence analysis of the HR gene in the nuclear family was performed.

RESULTS: Mutation analysis revealed distinct mutations on each allele of the HR gene. This is the first demonstration of compound heterozygous mutations underlying APL.

CONCLUSION: These findings support the hypothesis that APL can exist in small nonconsanguineous families and may be masquerading clinically as alopecia universalis. Accurate discrimination between APL and alopecia universalis should prevent unnecessary treatment of patients affected with APL.


Alopecia areata: a long term follow-up study of 191 patients.

Department of Dermatology, University of Bologna, Italy.

J Am Acad Dermatol. 2006 Sep;55(3):438-41. Abstract quote

BACKGROUND: The prognosis of alopecia areata (AA) is difficult to predict. Few studies report long-term follow-up of AA patients.

OBJECTIVE: The purpose of this study is to better assess the long-term evolution of AA and the possible relationship between disease severity and treatment response with long-term prognosis.

METHODS: One hundred ninety-one patients with AA who presented with a new diagnosis of AA between 1983 and 1990 were subsequently contacted by phone. Patients were queried regarding current disease status, treatments, and disease course.

RESULTS: Severity of AA at first consultation ranged from mild (128 patients) to severe (63 patients). Fifty-five of 191 patients were affected by concomitant autoimmune or related inflammatory disease. Sixty-six of 191 patients were presently disease free (follow-up duration, 15-22 years; mean 17.74 years). These include 41 of 60 patients with S1 disease (68.3%), 22 of 68 patients with S2 disease (32.3%), 1 of 11 patients with S3 disease (9%), 1 of 14 patients with S4 disease (7.1%), and 1 of 11 patients with alopecia totalis (AT) (9.1%). Sixty-nine of 191 patients (36-1%) were presently affected by AT or alopecia universalis. There was a statistically significant tendency of severe patterns of AA to worsen over time. In children, 18 of 39 (13 with < or =S2 disease and 5 with > or =S3 disease) with AA had developed AT or alopecia universalis at long-term follow-up. In children, however, this trend was not statistically significant. Patients with severe AA who responded to topical immunotherapy seem to have a better prognosis than nonresponders.

LIMITATIONS: Follow-up was only performed by phone.

CONCLUSIONS: Severity of AA at time of first consultation is an important prognostic factor. Response to therapy (topical immunotherapy) may be associated with better prognosis. In children, the prognosis is worse; our study found that AA worsens over time.

Alopecia areata update: part II. Treatment.

Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J.

Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.

J Am Acad Dermatol. 2010 Feb;62(2):191-202 Abstract quote

Various therapeutic agents have been described for the treatment of alopecia areata (AA), but none are curative or preventive. The aim of AA treatment is to suppress the activity of the disease. The high rate of spontaneous remission and the paucity of randomized, double-blind, placebo-controlled studies make the evidence-based assessment of these therapies difficult. The second part of this two-part series on AA discusses treatment options in detail and suggests treatment plans according to specific disease presentation. It also reviews recently reported experimental treatment options and potential directions for future disease management.

LEARNING OBJECTIVES: After completing this learning activity, participants should be able to compare the efficacy and safety of various treatment options, formulate a treatment plan tailored to individual patients, and recognize recently described treatments and potential therapeutic approaches.

Etanercept does not effectively treat moderate to severe alopecia areata: an open-label study.

Strober BE, Siu K, Alexis AF, Kim G, Washenik K, Sinha A, Shupack JL.

The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA.
J Am Acad Dermatol. 2005 Jun;52(6):1082-4. Abstract quote  

In this prospective, open-label pilot study, we evaluated the safety and efficacy of etanercept, a TNF-alpha inhibitor, in the treatment of moderate to severe alopecia areata, alopecia totalis, or alopecia universalis. Seventeen otherwise healthy adults with moderate to severe alopecia areata were enrolled.

The primary outcome measure was the extent of hair regrowth during and after the end of treatment as evaluated by the Severity of Alopecia Tool (the SALT score). After between 8 and 24 weeks of continuous treatment with etanercept 50 mg given subcutaneously twice weekly, significant regrowth of hair was not shown in any of the subjects treated.

Based on these results, etanercept appears to be ineffective in treating subjects with treatment-refractory, moderate to severe alopecia areata, alopecia totalis, or alopecia universalis.

Topical minoxidil in extensive alopecia areata, including 3-year follow-up.

Price VH.

Kaiser Permanente Medical Center, San Francisco, Calif.

Dermatologica 1987;175 Suppl 2:36-41 Abstract quote

Perhaps the most intriguing aspect of topical minoxidil is the fact that this drug can promote hair growth in two unrelated conditions: alopecia areata (AA) and androgenetic alopecia. The two conditions have quite different underlying mechanisms. In AA, hair follicles respond to some signal or cell injury by entering a state of aborted cyclical activity; this state can reverse itself spontaneously, or it can be temporarily circumvented with nonspecific immunomodulating agents. In androgenetic alopecia, genetically marked hair follicles undergo progressive, androgen-mediated miniaturization; antiandrogens have been conventionally sought to intercept this process.

It is not known how minoxidil promotes hair growth except that living follicles capable of stimulation and hypertrophy are required. It may be that minoxidil influences some fundamental signal to the follicular apparatus, irrespective of the pathophysiology involved.

We have used topical minoxidil solution in 90 patients, aged 7-63 years, with extensive AA affecting 25-100% of the scalp. One study was double-blind, and placebo-controlled for an entire year. Minoxidil-treated patients responded better than placebo-treated patients. Both 3 and 5% topical minoxidil solutions have been used, and treatment with the 3% solution has continued for up to 3 years. The results of these studies will be discussed. While topical minoxidil is not very effective for those with 100% scalp hair loss, it is an effective, easy and safe treatment for those with AA affecting 25-99% of the scalp.


Topical nitrogen mustard in the treatment of alopecia areata: a bilateral comparison study.

Bernardo O, Tang L, Lui H, Shapiro J.

University of British Columbia hair Research and Treatment Centre, Division of Dermatology, Vancouver General Hospital, Vancouver, Canada.

J Am Acad Dermatol. 2003 Aug;49(2):291-4. Abstract quote

Topical nitrogen mustard is an alkylating agent. Its efficacy in treating alopecia areata was reported in an uncontrolled study.

We present a preliminary, half-head, controlled 16-week study showing that topical nitrogen mustard was of benefit in 1 of 6 patients treated with 50% to 100% scalp involvement. Another 4 patients did not complete the trial.

PUVA Arch Dermatol 1983;119:975-8.
The PUVA-turban as a new option of applying a dilute psoralen solution selectively to the scalp of patients with alopecia areata

J Am Acad Dermatol 2001;44:248-52

Treated 9 patients with severe, rapidly progressing, treatment-resistant alopecia areata with PUVA-turban treatment as a modification of bath-PUVA therapy. At each treatment session a cotton towel was soaked with a 0.0001% 8-MOP solution (1 mg/L) at 37°C, wrung gently to remove excess water, and wrapped around the patient's head in a turban fashion for 20 minutes. This was directly followed by UVA radiation

Treatment sessions were initially performed 3 to 4 times per week

Cumulative UVA doses given over treatment periods of up to 24 weeks were 60.9 to 178.2 J/cm2, with single doses ranging from 0.3 to 8.0 J/cm2. After up to 10 weeks of treatment, hair regrowth could be noticed in 6 of 9 patients. Two patients did not respond to the treatment, and one patient showed only vellus hair regrowth.

May be considered a useful method of administering a dilute psoralen solution selectively to the scalp of patients
Well-tolerated and, in some patients, efficient therapeutic alternative in the treatment of alopecia areata

Predictive Model for Immunotherapy of Alopecia Areata With Diphencyprone

Marni C. Wiseman, MD, FRCPC; Jerry Shapiro, MD, FRCPC; Nina MacDonald, RN, BScN; Harvey Lui, MD, FRCPC

Arch Dermatol. 2001;137:1063-1068 Abstract quote

Background Immunotherapy with diphencyprone (diphenylcyclopropenone) is used in the treatment of alopecia areata (AA). Response rates have varied in the literature.

Objectives To determine the efficacy of diphencyprone therapy for AA in the largest reported cohort of patients; to identify patient and treatment factors predictive of therapeutic success; and to develop a practical model for predicting patient response.

Methods The medical records of 148 consecutive patients treated with diphencyprone were reviewed. A clinically significant response to diphencyprone therapy was defined as a cosmetically acceptable response or greater than 75% terminal hair regrowth. Survival analyses using the Kaplan-Meier method and the Cox proportional hazards model were performed to determine significant factors predictive of regrowth and relapse.

Results Using a survival analysis model, the cumulative patient response at 32 months was 77.9% (95% confidence interval, 56.8%-98.9%). Variables independently associated with clinically significant regrowth were age at onset of disease and baseline extent of AA. Older age at onset of AA portended a better prognosis. A cosmetically acceptable end point was obtained in 17.4% of patients with alopecia totalis/universalis, 60.3% with 75% to 99% AA, 88.1% with 50% to 74% AA, and 100% with 25% to 49% AA. A lag of 3 months was present between initiation of therapy and development of significant hair regrowth in the first responders. Relapse after achieving significant regrowth developed in 62.6% of patients.

Conclusions Response to diphencyprone treatment in AA is affected by baseline extent of AA and age at disease onset. A prolonged treatment course might be necessary. A predictive model has been developed to assist with patient prognostication and counseling.

Placebo-controlled oral pulse prednisolone therapy in alopecia areata.

Kar BR, Handa S, Dogra S, Kumar B.

Department of Dermatology, Venereology, and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
J Am Acad Dermatol. 2005 Feb;52(2):287-90. Abstract quote

BACKGROUND: Systemic corticosteroids administered as pulse therapy have been found helpful in a wide array of diseases including alopecia areata (AA). None of the studies published so far regarding their use in AA have been randomized or placebo-controlled.

OBJECTIVE: We sought to compare the efficacy of weekly oral prednisolone pulse therapy in a placebo-controlled trial for patients with extensive AA.

METHODS: A total of 43 patients were randomly divided into two groups. Patients in group A (23 patients) were treated with oral prednisolone (200 mg once weekly, 5 40-mg tablets) and patients in group B (20 patients) were given placebo tablets on an identical schedule. The total study period was 6 months, consisting of 3 months of active therapy followed by another 3 months of observation.

RESULTS: Significant hair regrowth was obtained in 8 patients in the prednisolone-treated group. Two of the responders experienced a relapse during the observation period of 3 months. In the placebo group, none of the patients had significant hair regrowth at the end of the study.

CONCLUSION: Oral prednisolone pulse therapy is useful in AA. Placebo-controlled studies with varying dosage schedules are required to standardize the dose of prednisolone used in pulse therapy, optimize the therapeutic efficacy, and minimize side effects.

Clobetasol propionate 0.05% under occlusion in the treatment of alopecia totalis/universalis.

Tosti A, Piraccini BM, Pazzaglia M, Vincenzi C.

Department of Dermatology, University of Bologna, Italy.

J Am Acad Dermatol. 2003 Jul;49(1):96-8 Abstract quote

BACKGROUND: Efficacy of topical steroids in alopecia areata is still discussed.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of clobetasol propionate 0.05% ointment under occlusion in 28 patients with alopecia areata totalis (AT) or AT/alopecia universalis.

METHODS: A total of 28 patients were instructed to apply 2.5 g of clobetasol propionate to the right side of the scalp every night under occlusion with a plastic film. Treatment was performed 6 days a week for 6 months. When regrowth of terminal hair occurred, treatment was extended over the entire scalp. All patients were followed up for another 6 months.

RESULTS: Of the 28 patients included in the study, 8 were treated successfully (28.5%). Regrowth of terminal hair began on the treated side 6 to 14 weeks after the start of treatment. Of these 8 patients, 3 had a relapse and were not able to maintain hair regrowth.

CONCLUSION: Our study shows that clobetasol propionate 0.05% under occlusion is effective in inducing hair regrowth in patients with AT or AT/alopecia universalis. Occurrence of hair regrowth only on the treated half of the scalp clearly shows that efficacy of treatment is a result of a local and not systemic effect of the drug. Although only 17.8% of patients had long-term benefit by treatment, our results were obtained in a population of patients with severe and refractory forms of the disease.


Sulfasalazine for alopecia areata.

Ellis CN, Brown MF, Voorhees JJ.

Department of Dermatology, University of Michigan Medical School and Dermatology Service, Department of Veterans Affairs Ann Arbor Healthcare System.

J Am Acad Dermatol 2002 Apr;46(4):541-4 Abstract quote

Sulfasalazine is used as a therapy for various autoimmune conditions, including psoriasis; its effectiveness is presumed to be the result of its immunomodulatory effects.

We have treated patients with severe alopecia areata with sulfasalazine as part of our dermatology practice and have noticed cosmetically acceptable regrowth in 23% of patients in whom a response could be determined. In view of its good safety profile, sulfasalazine may be considered for systemic treatment of severe alopecia areata.

Commonly Used Terms

Exclamation mark hairs-Characteristic gross morphologic change of hairs found at the advancing margins. These represent hairs in late catagen or telogen.

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Last Updated February 17, 2010

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