What We Know About AA
The best answer is…..NOT ENOUGH!
Alopecia Areata is a poorly understood recurrent nonscarring type of hair loss that can affect any hair-bearing area.
Clinically, alopecia areata can manifest in many different patterns. Although medically non-life threatening, alopecia areata is associated with other illnesses and can cause tremendous emotional and psychosocial distress in affected patients and their families.
The exact pathophysiology of alopecia areata remains unknown. The most widely accepted hypothesis is that alopecia areata is a T-cell–mediated autoimmune condition that is most likely to occur in genetically predisposed individuals.
Much evidence supports the hypothesis that alopecia areata is an autoimmune condition. The process appears to be T-cell mediated, but antibodies directed to hair follicle structures also have been found with increased frequency in alopecia areata patients compared with control subjects. Using immunofluorescence, antibodies to anagen-phase hair follicles were found in as many as 90% of patients with alopecia areata compared with less than 37% of control subjects. The autoantibody response is heterogeneous and targets multiple structures of the anagen-phase hair follicle. The outer root sheath is the structure targeted most frequently, followed by the inner root sheath, the matrix, and the hair shaft. Whether these antibodies play a direct role in the pathogenesis or whether they are an epiphenomenon is not known.
Histologically, lesional biopsy findings of alopecia areata show a perifollicular lymphocytic infiltrate around anagen-phase hair follicles. The infiltrate consists mostly of T-helper cells and, to a lesser extent, T-suppressor cells. CD4 and CD8 lymphocytes likely play a prominent role because the depletion of these T-cell subtypes results in complete or partial regrowth of hair in the Dundee experimental bald rat (DEBR) model of alopecia areata. The animals subsequently lose hair again once the T-cell population is replete. The fact that not all animals experience complete regrowth suggests that other mechanisms likely are involved. Total numbers of circulating T lymphocytes have been reported at both decreased and normal levels.
Studies in humans also reinforce the hypothesis of autoimmunity. Studies have shown that hair regrows when affected scalp is transplanted onto SCID (severe combined immunodeficiency) mice that are devoid of immune cells. Autologous T lymphocytes isolated from an affected scalp were cultured with hair follicle homogenates and autologous antigen-presenting cells. Following initial regrowth, injection of the T lymphocytes into the grafts resulted in loss of regrown hairs. Injections of autologous T lymphocytes that were not cultured with follicle homogenates did not trigger hair loss.
A similar experiment on nude (congenitally athymic) mice failed to trigger hair loss in regrown patches of alopecia areata after serum from affected patients was injected intravenously into the mice. However, the same study showed that mice injected with alopecia areata serum showed an increased deposition of immunoglobulin and complement in hair follicles of both grafted and nongrafted skin compared with mice injected with control serum, which showed no deposition.
In addition, research has shown that alopecia areata can be induced using transfer of grafts from alopecia areata–affected mice onto normal mice. Transfer of grafts from normal mice to alopecia areata–affected mice similarly resulted in hair loss in the grafts.
Clinical evidence favoring autoimmunity suggests that alopecia areata is associated with other autoimmune conditions, the most significant of which are thyroid diseases and vitiligo.
In conclusion, the beneficial effect of T-cell subtype depletion on hair growth, the detection of autoantibodies, the ability to transfer alopecia areata from affected animals to nonaffected animals, and the induction of remission by grafting affected areas onto immunosuppressed animals are evidence in favor of an autoimmune phenomenon. Certain factors within the hair follicles, and possibly in the surrounding milieu, trigger an autoimmune reaction. Some evidence suggests a melanocytic target within the hair follicle. Adding or subtracting immunologic factors profoundly modifies the outcome of hair growth.
Many factors favor a genetic predisposition for alopecia areata. The frequency of positive family history for alopecia areata in affected patients has been estimated to be 10-20% compared with 1.7% in control subjects. The incidence is higher in patients with more severe disease (16-18%) compared with patients with localized alopecia areata (7-13%). Reports of alopecia areata occurring in twins also are of interest. No correlation has been found between the degree of involvement of alopecia areata and the type of alopecia areata seen in relatives. Alopecia areata has been reported to occur concurrently or sequentially in both identical and fraternal twins. The concordance rate or genetic effect in alopecia areata is believed to be 55 per cent, which means environmental factors have the potential to also play a significant role in this hair disease.
Several genes have been studied and a large amount of research has focused on human leukocyte antigen. Two studies demonstrated that human leukocyte antigen DQ3 (DQB1*03) was found in more than 80% of patients with alopecia areata, which suggests that it can be a marker for general susceptibility to alopecia areata. The studies also found that human leukocyte antigen DQ7 (DQB1*0301) and human leukocyte antigen DR4 (DRB1*0401) were present significantly more in patients with alopecia totalis and alopecia universalis.
Another gene of interest is the interleukin 1 receptor antagonist gene, which may correlate with disease severity. Finally, the high association of Down syndrome with alopecia areata suggests involvement of a gene located on chromosome 21. Current data also suggest there are differences in a major locus on chromosome 6 between patients with long-standing extensive alopecia areata and those with limited, patchy disease of short duration.
In summary, genetic factors likely play an important role in determining susceptibility and disease severity. Alopecia areata is likely to be the result of polygenic defects rather than a single gene defect. The role of environmental factors in initiating or triggering the condition is suspected but yet to be determined.
Interleukin 1 and tumor necrosis factor were shown to be potent inhibitors of hair growth in vitro. Subsequent microscopic examination of these cultured hair follicles showed morphologic changes similar to those seen in alopecia areata.
Innervation and Vasculature
Another area of interest concerns the modification of perifollicular nerves. The fact that patients with alopecia areata occasionally report itching or pain on affected areas raises the possibility of alterations in the peripheral nervous system. Circulating levels of the neuropeptide calcitonin gene-related peptide (CGRP) were decreased in 3 patients with alopecia areata compared with control subjects. CGRP has multiple effects on the immune system, including chemotaxis and inhibition of Langerhans cell antigen presentation and inhibition of mitogen-stimulated T-lymphocyte proliferation.
CGRP also increases vasodilatation and endothelial proliferation. Similar findings were reported in another study, in which decreased cutaneous levels of substance P and of CGRP but not of vasoactive intestinal polypeptide were found in scalp biopsy specimens. The study also noted a lower basal blood flow and greater vasodilatation following intradermal CGRP injection in patients with alopecia areata compared with control subjects. More studies are needed to shed light on the significance of these findings.
Other hypotheses have been proposed to explain the pathophysiology of alopecia areata, but more evidence is needed to support them. Alopecia areata was believed to possibly have an infectious origin, but no microbial agent has been isolated consistently in patients. Many efforts have been made to isolate cytomegalovirus, but most studies have been negative.
Frequency in the United States
Prevalence in the general population is 0.1-0.2%. The lifetime risk of developing alopecia areata is estimated to be 1.7%. Alopecia areata is responsible for 0.7-3% of patients seen by dermatologists.
Worldwide prevalence of alopecia areata is the same as that in the United States.
Alopecia areata by itself is not associated with higher rates of mortality. Statistically increased prevalence of other auto-immune disorders in affected individuals makes its effect on morbidity undetermined. It can cause emotional and psychosocial distress in affected individuals. Self-consciousness concerning personal appearance can become important. Addressing these issues with patients is important in helping them cope with the condition.
All races are affected equally by alopecia areata; no increase in prevalence has been found in a particular ethnic group.
Data concerning the sex ratio for alopecia areata vary slightly in the literature. In one study including 736 patients, a male-to-female ratio of 1:1 was reported.In another study on a smaller number of patients, a slight female preponderance was seen.
Alopecia areata can occur at any age from birth to the late decades of life. Congenital cases have been reported. Peak incidence appears to occur from age 15-29 years. As many as 44% of people with alopecia areata have onset at younger than 20 years. Onset in patients older than 40 years is seen in less than 30% of patients with alopecia areata.
The natural history of alopecia areata is unpredictable. Extreme variations in duration and extent of the disease occur from patient to patient. Alopecia areata most often is asymptomatic, but some patients (14%) experience a burning sensation or pruritus in the affected area. The condition usually is localized when it first appears. Of patients with alopecia areata, 80% have only a single patch, 12.5% have 2 patches, and 7.7% have multiple patches. No correlation exists between the number of patches at onset and subsequent severity. Alopecia areata most often affects the scalp (66.8-95%); however, it can affect any hair-bearing area. The beard is affected in 28% (males; see first image below), eyebrows in 3.8%, and extremities in 1.3% of patients (see second image below). More than one area can be affected at once.
Episodes of localized (< 50% involvement) patchy alopecia areata usually are self limited; spontaneous regrowth occurs in most patients within a few months, with or without treatment.
Extensive alopecia areata: Extensive (>50% involvement) forms of alopecia areata are less common. Alopecia totalis or alopecia universalis are reported to occur at some point in 7% of patients; alopecia areata involving more than 40% hair loss is seen in 11%. The proportion of patients with alopecia totalis appears to decrease with every decade of life.
- In 30% of patients with alopecia totalis, complete hair loss occurred within 6 months after onset of disease. Sharma et al reported a mean progression period to alopecia totalis of 4 months after onset. The natural evolution of alopecia totalis is unpredictable, but recurrences of alopecia areata (not necessarily alopecia totalis) are expected.
- In a study involving 736 patients,the relapse rate was 90% over 5 years. One percent of children and 10% of adults can experience long-lasting regrowth. Forty-four percent of children and 34% of adults experience a significant period of normal or near-normal hair growth. Twenty-two percent of children and 34% of adults do not experience regrowth.
Associated conditions: Because some of the entities associated with alopecia areata occur uncommonly in the general population, a large number of patients with alopecia areata need to be examined to confirm whether an increased prevalence of these conditions exists among patients with alopecia areata. Unfortunately, most studies are performed on small groups; therefore, the data should be interpreted carefully.Precipitating factors: A precipitating factor can be found in 15.1% of patients with alopecia areata. Major life events, febrile illnesses, drugs, pregnancy, trauma, and many other events have been reported, but no clear conclusions can be drawn. Despite these findings, most patients with alopecia areata do not report a triggering factor preceding episodes of hair loss.
- Atopic dermiatitis is seen in 9-26% of patients with alopecia areata. In the general population, the prevalence of atopic dermatitis in children in temperate developed countries varies from 5-20%. In adults, the prevalence decreases to 2-10%. Some authors have found atopy to be a poor prognostic factor for alopecia areata.
- Vitiligo is seen with an incidence varying from 1.8-3% compared with 0.3% in control subject.
- Clinically evident thyroid disease was found in 0.85% of 1700 patients with alopecia areata.The prevalence of thyroid disease determined on a clinical or laboratory basis varies among studies from 0.85-14.7%. The incidence of thyroid disease in control subjects is estimated to be 0.17-2%. The presence of microsomal antibodies is found in 3.3-16% of patients. Antibodies can be found with or without signs or symptoms of thyroid disease, but patients with positive autoantibodies have a higher incidence of functional abnormalities found on thyroid-releasing hormone tests (26% vs 2.8%). The incidence of thyroid microsomal and thyroglobulin antibodies in control subjects is 7%. Other studies have not supported these results. A study in 100 patients with alopecia areata failed to find an increased incidence of circulating autoantibodies, including mitochondrial and thyroglobulin antibodies.
- Collagen-vascular diseases have been found in 0.6-2% of patients with alopecia areata, while the incidence in control subjects is 0.17%. The incidence of alopecia areata in 39 patients with lupus erythematous was 10% in a study by Werth et al,in contrast to 0.42% of general dermatologic patients.
- Diabetes mellitus was found to be more common in control subjects (1.4%) than in patients with alopecia areata (0.4%).The occurrence of alopecia areata may protect against the appearance of type I diabetes mellitus. However, the incidence of type I diabetes mellitus was significantly higher in relatives of patients with alopecia areata compared with the general population.
- Alopecia areata is seen in 6-8.8% of patients with Down syndrome, but only 0.1% of patients with alopecia areata have Down syndrome. The high frequency of alopecia areata in patients with Down syndrome suggests that a genetic linkage for alopecia areata may exist on chromosome 21.
- Anxiety, personality disorders, depression, and paranoid disorders are seen with increased prevalence varying from 17-22% of patients, and the lifetime prevalence of psychiatric disorders is estimated to be 74% in patients with alopecia areata. Psychiatric problems are seen in both children and adults. No association has been made between the severity of the psychiatric disorder and that of alopecia areata.
- Stressful life events within the 6-month period preceding episodes of alopecia areata were significantly higher in patients with alopecia areata compared with patients with androgenetic alopecia or tinea capitis. Major stress factors (eg, death in family) were reported in 12% of patients.
- Others associations in some studies include pernicious anemia, myasthenia gravis, ulcerative colitis, lichen planus, and Candida endocrinopathy syndrome.
The presence of smooth, slightly erythematous (peach color) or normal-colored alopecic patches is characteristic. The presence of exclamation point hairs (ie, hairs tapered near proximal end) is pathognomonic but is not always found. A positive result from the pull test at the periphery of a plaque usually indicates that the disease is active, and further hair loss can be expected. Additionally, hair loss on other hair-bearing areas also favors the diagnosis. The most common presentation is the appearance of one or many round-to-oval denuded patches. No epidermal changes are associated with the hair loss.
Alopecia areata can be classified according to its pattern. Hair loss most often is localized and patchy (see image below).
A reticular pattern occurs when hair loss is more extensive and the patches coalesce. An ophiasis pattern occurs when the hair loss is localized to the sides and lower back of the scalp (see image below).
Conversely, sisaipho (ophiasis spelled backwards) pattern occurs when hair loss spares the sides and back of the head (see image below).
Alopecia Totalis occurs with 100% hair loss on the scalp (see image below).
Alopecia universalis occurs with complete loss of hair on all hair-bearing areas. Alopecia areata usually is focal; however, it can be diffuse, thereby mimicking telogen effluvium (TE) or the type of androgenetic alopecia seen in women (see image below).
- Dermoscopic findings have been reported to be helpful in the diagnosis of difficult cases of alopecia areata.
- The presence of yellow dots seems to be a specific feature of alopecia areata and has been reported to be present in 95% of patients, regardless of their disease stages. Following histopathological correlation, these yellow dots represent degenerated follicular keratinocytes and sebum contained within the ostium of hair follicles. Although occasionally seen in advanced male-pattern hair loss, yellow dots are not seen in cases of female-pattern hair loss, scaring alopecia, or telogen effluvium.
- Other dermoscopic signs reported include black dots, tapering hairs, broken hairs, and clustered short vellus hairs.
- Nail involvement is found in 6.8-49.4% of patients and most commonly is seen in patients with severe forms of alopecia areata.
- Pitting is the most common finding.
- Several other abnormalities have been reported (eg, trachyonychia, Beau lines, onychorrhexis, onychomadesis, koilonychia, leukonychia, red lunulae).
- Fingernails predominantly are affected.
Therapy for alopecia areata must be considered against the background of the normal course of the disease. Ninety percent of patients with limited (<25%) scalp involvement with alopecia areata experience spontaneous regrowth within 2 years. This group also generally responds favorably to a variety of treatments. On the other hand, the presence of severe nail abnormalities, atopy (asthma, allergic rhinnitis, and atopic dermatitis), and onset less than 5 years old with extensive hair loss, have all been implicated as negative prognostic factors. Alopecia totalis or universalis which lasts for > 2 years is believed to have a particularly low chance of spontaneous regrowth and is less responsive to therapy.
The most commonly prescribed medications for limited patch stage alopecia areata include anti-inflammatory medications, including topical or intralesional steroid injections. Topical 2% or 5% minoxidil may also be prescribed to promote hair growth. Unlike its use in male or female pattern baldness where one has to keep using the drug to maintain hair growth, topical minoxidil need only be used for as long as it is needed in the management of alopecia areata ie discontinuation of the drug after full regrowth is not commonly associated with renewed hair shedding.
The management of extensive alopecia areata is more challenging as patients may or may not respond to therapy. Different treatment options include the aforementioned medications as well as oral corticosteroids or psoralen plus ultraviolet A light (PUVA). Topical immunotherapy with diphencyprone and squaric acid dibutylester is used extensively in some parts of the world: these are not drugs per se but rather chemicals and thus there are not FDA approved preparations. For this reason, many dermatologists in the US do not feel comfortable using them.
Many alternative therapies have been suggested for Alopecia Areata but their effectiveness remains inconclusive due to lack of study. RLT Microbiotic Therapy is currently under study by Immune Research Center for effectiveness in reversing Alopecia Areata, Totalis, and Universalis.
The true cause of alopecia areata remains unknown. The exact role of possible factors needs to be clarified.
- No known risk factors exist for alopecia areata, except a positive family history.
- The exact role of stressful events remains unclear, but they most likely trigger a condition already present in susceptible individuals, rather than acting as the true primary cause.