Bhargava K, Fenton D; Chambers J, Tomlinson J. Alopecia areata and its impact on young people. Dermatological Nursing, March 2015, Vol 14, No 1
Alopecia is defined as a partial or complete absence of hair from areas of the body where it normally grows. There are a variety of causes, which ultimately lead to hair loss, either with or without scarring at the level of the hair follicle. In the first part of this two-part article, Dr Kapil Bhargava and Dr David Fenton focus on alopecia areata (AA), which is one common non-scarring alopecia that frequently affects young people, having a lifetime risk of approximately 1.7% (Safavi et al, 1995). As many as 60% present with their first patch before the age of 20 years, and only 20% of patients are older than 40 years (Safavi et al,1995; Lu et al, 2006). While most patients are physically asymptomatic, hair loss may result in significant emotional and psychosocial distress. This is further explored in part 2 of the article, where Jennifer Chambers and Jackie Tomlinson discuss the young person’s experience of the condition. Full article is here.
Jagielska D, Redler S, Brockschmidt FF, Herold C, Pasternack SM, Garcia Bartels N, Hanneken S, Eigelshoven S, Refke M, Barth S, Giehl KA, Kruse R, Lutz G, Wolff H, Blaumeiser B, Böhm M, Blume-Peytavi U, Becker T, Nöthen MM, Betz RC. Follow-Up Study of the First Genome-Wide Association Scan in Alopecia Areata: IL13 and KIAA0350 as Susceptibility Loci Supported with Genome-Wide Significance. J Invest Dermatol. 2012 Apr 26
Recently, the first genome-wide association study (GWAS) of alopecia areata (AA) was conducted in a North-American sample, and this identified eight susceptibility loci surpassing genome-wide significance. The aim of the present follow-up association analysis was to confirm five of these eight loci (single-nucleotide polymorphisms (SNPs) from the CTLA4, IL-2RA, and HLA regions were not included due to previous own findings) and test 12 other loci from the GWAS, which did not surpass the threshold for genome-wide significance. Twenty-three SNPs from the 17 loci were investigated using a sample of 1,702 Central European AA patients and 1,723 controls. Of the five loci with previously reported genome-wide significance, association was confirmed for all of these: ULBP3/ULBP6, PRDX5, IL-2/IL-21, STX17, and IKZF4/ERBB3 (P-value <0.05). To detect robust evidence for association among the 12 other loci, a meta-analysis of the present association data and the data of the recent GWAS was performed. Genome-wide significant association was found for rs20541 (P(comb)=7.52 × 10(-10); odds ratio (OR)=1.30 (1.23-1.38)) and rs998592 (P(comb)=1.11 × 10(-11); OR=1.28 (1.21-1.36)), thus establishing IL-13 and KIAA0350/CLEC16A as susceptibility loci for AA. Interestingly, IL-13 and KIAA0350/CLEC16A are susceptibility loci for other autoimmune diseases, supporting the hypothesis of shared pathways of autoimmune susceptibility.
Ertugrul DT, Karadag AS, Takci Z, Bilgili SG, Ozkol HU, Tutal E, Akin KO. Serum holotranscobalamine, vitamin B12, folic acid and homocysteine levels in alopecia areata patients. Cutan Ocul Toxicol. 2012 May 17.
Alopecia areata has been associated with many autoimmune diseases. There is a common belief that the prevalance of pernicious anemia is increased in patients with alopecia areata. In this study, we sought to investigate vitamin B12, folate and homocysteine metabolism in alopecia areata. We measured holotranscobalamine (holoTC), vitamin B12, folate and homocysteine levels in 75 patients with alopecia areata and 54 controls. We did not find any significant differences in these parameters between these groups. We think that alopecia areata may not be associated with vitamin B12 deficiency. The co-occurence of pernicious anemia and alopecia areata in rare autoimmune syndromes, may not justify routine measurements of these parameters in alopecia areata patients.
van Zuuren EJ, Fedorowicz Z, Carter B, Andriolo RB, Schoones J. Interventions for female pattern hair loss. Cochrane Database Syst Rev. 2012 May 16;5:CD007628
BACKGROUND: Female pattern hair loss, or androgenic alopecia, is the most common type of hair loss affecting women. It is characterised by progressive shortening of the duration of the growth phase of the hair with successive hair cycles, and progressive follicular miniaturisation with conversion of terminal to vellus hair follicles (terminal hairs are thicker and longer, while vellus hairs are soft, fine, and short). The frontal hair line may or may not be preserved. Hair loss can have a serious psychological impact on people.
OBJECTIVES: To determine the effectiveness and safety of the available options for the treatment of female pattern hair loss in women.
SEARCH METHODS: We searched the following databases up to October 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2011, Issue 4), MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1806), AMED (from 1985), LILACS (from 1982), PubMed (from 1947), Web of Science (from 1945), and reference lists of articles. We also searched several online trials registries for ongoing trials.
SELECTION CRITERIA: Randomised controlled trials that assessed the effectiveness of interventions for female pattern hair loss in women.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data.
MAIN RESULTS: Twenty two trials, comprising 2349 participants, were included. A wide range of interventions were evaluated, with 10 studies investigating the different concentrations of minoxidil. Pooled data from 4 studies indicated that a greater proportion of participants (121/488) treated with minoxidil reported a moderate increase in their hair regrowth when compared with placebo (64/476) (risk ratio (RR) = 1.86, 95% confidence interval (CI) 1.42 to 2.43). In 7 studies, there was an important increase of 13.28 in total hair count per cm² in the minoxidil group compared to the placebo group (95% CI 10.89 to 15.68). There was no difference in the number of adverse events in the twice daily minoxidil and placebo intervention groups, with the exception of a reported increase of adverse events (additional hair growth on areas other than the scalp) with minoxidil (5%) twice daily. Most of the other comparisons consisted of single studies. These were assessed as high risk of bias: They did not address our prespecified outcomes and provided limited evidence of either the efficacy or safety of these interventions.
AUTHORS' CONCLUSIONS: Although more than half of the included studies were assessed as being at high risk of bias, and the rest at unclear, there was evidence to support the effectiveness and safety of topical minoxidil in the treatment of female pattern hair loss. Further direct comparison studies of minoxidil 5% applied once a day, which could improve adherence when compared to minoxidil 2% twice daily, are still required. Consideration should also be given to conducting additional well-designed, adequately-powered randomised controlled trials investigating several of the other treatment options.
Macdonald A, Clark C, Holmes S. Frontal fibrosing alopecia: A review of 60 cases. J Am Acad Dermatol. 2012 Apr 13.
BACKGROUND: Frontal fibrosing alopecia (FFA) is a variant of lichen planopilaris primarily affecting postmenopausal women, with a predilection for the frontotemporal hairline.
OBJECTIVES: We sought to examine possible causal associations and review the clinical features, natural history, and response to treatment of patients with FFA attending a specialist hair clinic.
METHODS: This was a case note review of 60 patients with FFA.
RESULTS: The number of patients with FFA seen has increased over the last decade. All were Caucasian women, with significantly above-average affluence scores and were less likely to be smokers. The mean age at presentation was 64 years and average disease duration was 3.4 years (range: 6 months-30 years). Three patients were premenopausal. All patients had frontotemporal involvement, with follicular hyperkeratosis, scarring, and variable perifollicular erythema. Several patients had more unusual patterns: 8 had extensive parietal involvement, 4 had occipital involvement, 1 had asymmetric frontal involvement, and 5 had typical FFA associated with diffuse scalp lichen planopilaris. Eyebrow loss was documented in 73%, eyelash loss in 3%, and body hair loss in 25%. Almost all patients had been treated with superpotent topical steroids. Other treatments included topical calcineurin inhibitors; intralesional triamcinolone acetate; phototherapy; hydroxychloroquine; lymecycline; and prednisolone. Although some treatments may reduce inflammation, their efficacy in controlling the progress of the alopecia was uncertain.
CONCLUSIONS: FFA is a clinically distinctive condition, the prevalence of which appears to be increasing. It has a generally poor response to treatment. The origin remains uncertain.
Rossi A, Cantisani C, Melis L, Iorio A, Scali E, Calvieri S. Minoxidil use in dermatology, side effects and recent patents. Recent Pat Inflamm Allergy Drug Discov. 2012 May;6(2):130-6
Minoxidil, a vasodilator medication known for its ability to slow or stop hair loss and promote hair regrowth, was first introduced, exclusively as an oral drug, to treat high blood pressure. It was however discovered to have the important side-effect of increasing growth or darkening of fine body hairs; this led to the development of a topical formulation as a 2% concentration solution for the treatment of female androgenic alopecia or 5% for treating male androgenic alopecia. Measurable changes disappear within months after discontinuation of treatment. The mechanism by which it promotes hair growth is not fully understood. Minoxidil is a potassium channel opener, causing hyperpolarization of cell membranes and it is also a vasodilator, it is speculated that, by widening blood vessels and opening potassium channels, it allows more oxygen, blood and nutrients to the follicle. This can also cause follicles in the telogen phase to shed, usually soon to be replaced by new, thicker hairs in a new anagen phase. It needs to be applied regularly, once or twice daily, for hair gained to be maintained, and side effects are common. The most common adverse reactions of the topical formulation are limited to irritant and allergic contact dermatitis on the scalp. There have been cases of allergic reactions to the nonactive ingredient propylene glycol, which is found in some topical solution especially if they are galenic. Increased hair loss which can occur during Minoxidil use, is due to the synchronization of the hair cycle that the treatment induces. In this review, we described its mechanism of action, use in dermatology and some patents related to alternative treatment of allergic reactions due to its use.
Forstbauer LM, Brockschmidt FF, Moskvina V, Herold C, Redler S, Herzog A, Hillmer AM, Meesters C, Heilmann S, Albert F, Alblas M, Hanneken S, Eigelshoven S, Giehl KA, Jagielska D, Blume-Peytavi U, Garcia Bartels N, Kuhn J, Hennies HC, Goebeler M, Jung A, Peitsch WK, Kortüm AK, Moll I, Kruse R, Lutz G, Wolff H, Blaumeiser B, Böhm M, Kirov G, Becker T, Nöthen MM, Betz RC. Genome-wide pooling approach identifies SPATA5 as a new susceptibility locus for alopecia areata. Eur J Hum Genet. 2012 Mar;20(3)
Alopecia areata (AA) is a common hair loss disorder, which is thought to be a tissue-specific autoimmune disease. Previous research has identified a few AA susceptibility genes, most of which are implicated in autoimmunity. To identify new genetic variants and further elucidate the genetic basis of AA, we performed a genome-wide association study using the strategy of pooled DNA genotyping (729 cases, 656 controls). The strongest association was for variants in the HLA region, which confirms the validity of the pooling strategy. The selected top 61 single-nucleotide polymorphisms (SNPs) were analyzed in an independent replication sample (454 cases, 1364 controls). Only one SNP outside of the HLA region (rs304650) showed significant association. This SNP was then analyzed in a second independent replication sample (537 cases, 657 controls). The finding was not replicated on a significant level, but showed the same tendency. A combined analysis of the two replication samples was then performed, and the SNP rs304650 showed significant association with P=3.43 × 10(-4) (OR=1.24 (1.10-1.39)). This SNP maps to an intronic region of the SPATA5 (spermatogenesis-associated protein 5) gene on chromosome 4. The results therefore suggest the SPATA5 locus is a new susceptibility locus for AA.
Yoshida R, Tanaka K, Amagai M, Ohyama M. Involvement of the bulge region with decreased expression of hair follicle stem cell markers in senile female cases of alopecia areata. J Eur Acad Dermatol Venereol. 2011 Nov;25(11):1346-50
BACKGROUND: Alopecia areata (AA) is a common hair loss disorder characterized by cellular autoimmune reaction predominantly involving the bulbar portion of anagen hair follicles. In most cases of AA, the bulge stem cell area remains intact. Recently, a couple of molecules, such as keratin15 (K15) and CD200, have been identified as biomarkers of human bulge cells. Of note, an immunosuppressive molecule, CD200 is speculated to provide an immune privilege for bulge stem cells.
OBJECTIVE: To investigate expression levels of stem cell markers, especially CD200, in two senile female cases of AA with unusual lymphocytic cell infiltrates surrounding both the bulge and the bulbar regions. Then, compare them with those in common AA cases without the bulge involvement.
METHODS: Transverse sections containing the bulge levels were prepared from unaffected and affected lesions, respectively, from each AA group and immunohistochemical investigation using anti-K15 and CD200 antibodies was performed. Importantly, an approach to detect CD200 in paraffin sections was newly developed. Immunoreactivities of individual antibodies were compared between corresponding lesions in each patient group.
RESULTS: In unaffected bulge lesions, K15 immunoreactivity was not different between bulge-involving AA and common AA groups, whilst that of CD200 was decreased in the former group. Both K15 and CD200 immunoreactivities were decreased in affected bulge lesions of bulge-involving AA compared to the bulge of common AA cases.
CONCLUSION: Selective downregulation of CD200 in the bulge area could contribute to the collapse of immune privilege with resultant unusual bulge involvement in a subset of AA
Kemp EH, Sandhu HK, Weetman AP, McDonagh AJ. Demonstration of autoantibodies against tyrosine hydroxylase in patients with alopecia areata. Br J Dermatol. 2011 Dec;165(6):1236-43
BACKGROUND: There is strong evidence to suggest that alopecia areata (AA) is a tissue-specific, T cell-mediated autoimmune disease, which is usually characterized by patchy areas of hair loss on the scalp. Tyrosine hydroxylase (TH) is a known B-cell autoantigen in patients with autoimmune polyendocrine syndrome type 1 (APS1) associated with the presence of AA. In addition, melanocyte-specific proteins, gp100 and MelanA, are putative T-cell autoantigens in AA and so may also represent targets of the humoral immune response.
OBJECTIVE: To analyse the sera of patients with AA for the presence of antibodies against TH and the melanocyte-specific proteins tyrosinase, tyrosinase-related protein (TRP)-1, TRP-2, gp100 and MelanA.
METHODS: Radioimmunoassays were used to detect the relevant antibodies in sera from patients with AA (n = 32) and in sera from healthy individuals (n = 28).
RESULTS: Of 32 patients with AA, six (19%) were positive for TH antibodies. A significant increase in the frequency of TH antibodies in the AA patient group was evident when compared with controls (P = 0·03). Only three of 32 (9%) patients exhibited antibody responses to tyrosinase, TRP-1, TRP-2 and gp100. No immunoreactivity against MelanA was detected in any patient with AA.
CONCLUSION: Antibodies against TH can be present in patients with AA unrelated to APS1. Humoral immune responses against tyrosinase, TRP-1, TRP-2, gp100 and MelanA are not prevalent in patients with AA. Overall, a dominant melanocyte-specific B-cell autoantigen in AA has yet to be identified.
Ahn KJ, Choi EA, Kim J, Lee JH, Lee KH, Bang D, Cho SB. Increased retinol-binding protein (RBP) 4 and anti-RBP4 antibody in alopecia areata. Br J Dermatol. 2011 Oct;165(4):837-44.
BACKGROUND: Neither the underlying pathogenesis of alopecia areata (AA) nor the molecular mechanisms leading to hair loss have been fully elucidated.
OBJECTIVES: To compare the protein profiles of sera obtained from patients with AA with those from healthy controls.
METHODS: Protein profiles of sera obtained from subjects with AA and healthy controls were compared using proteomics techniques. Serum levels of the identified protein were quantified by specific enzyme-linked immunosorbent assay (ELISA). The relative serum reactivities of the recombinant human protein were compared between patients with AA and healthy controls using Western blots and double indirect immunofluorescence
RESULTS: The upregulated expression of retinol-binding protein (RBP) 4 was identified, and RBP4 ELISA demonstrated significantly increased serum levels of RBP4 among subjects with AA when compared with healthy controls. Western blots using recombinant human RBP4 and the sera from both groups presented serum reactivity of antihuman recombinant RBP4 IgG antibodies in 10/15 subjects with AA (67%) and 2/15 healthy controls (13%). Double indirect immunofluorescence demonstrated merged fluorescence signals of serum anti-RBP4 IgG antibodies and monoclonal antibodies to RBP4 in subjects with AA on the outer root sheath and companion layer.
CONCLUSIONS: Our data demonstrate that AA is associated with increased serum levels of RBP4 and positive IgG immunoreactivity against recombinant human RBP4. These results suggest that the major components for the retinoic acid biosynthesis pathway may be crucially involved in the pathogenic process of AA.
Leung MC, Sutton CW, Fenton DA, Tobin DJ. Trichohyalin is a potential major autoantigen in human alopecia areata. J Proteome Res. 2010 Oct 1;9(10):5153-63
Several lines of evidence support an autoimmune basis for alopecia areata (AA), a common putative autoimmune hair loss disorder. However, definitive support is lacking largely because the identity of hair follicle (HF) autoantigen(s) involved in its pathogenesis remains unknown. Here, we isolated AA-reactive HF-specific antigens from normal human scalp anagen HF extracts by immunoprecipitation using serum antibodies from 10 AA patients. Samples were analyzed by LC-MALDI-TOF/TOF mass spectrometry, which indicated strong reactivity to the hair growth phase-specific structural protein trichohyalin in all AA sera. Keratin 16 (K16) was also identified as another potential AA-relevant target HF antigen. Double immunofluorescence studies using AA (and control sera) together with a monoclonal antibody to trichohyalin revealed that AA sera contained immunoreactivity that colocalized with trichohyalin in the growth phase-specific inner root sheath of HF. Furthermore, a partial colocalization of AA serum reactivity with anti-K16 antibody was observed in the outer root sheath of the HF. In summary, this study supports the involvement of an immune response to anagen-specific HFs antigens in AA and specifically suggests that an immune response to trichohyalin and K16 may have a role in the pathogenesis of the enigmatic disorder.
Ito T. Hair follicle is a target of stress hormone and autoimmune reactions. J Dermatol Sci. 2010 Nov;60(2):67-73
Interest in the hair follicle (HF) has recently increased, yet the detailed mechanisms of HF function and immune privilege (IP) have not yet been elucidated. This review discusses the critical points of immunobiology and hormonal aspects of HFs. The HF is a unique mini-organ because it has its own immune system and hormonal milieu. In addition, the HF immune and hormonal systems may greatly affect skin immunobiology. Therefore, knowledge of HF immunobiology and hormonal aspects will lead to a better understanding of skin biology. The HF has a unique hair cycle (anagen, catagen and telogen) and contains stem cells in the bulge area. The HF is closely related to sebaceous glands and the nervous system. This article reviews the interaction between the endocrine/immune system and HFs, including the pathogenesis of alopecia areata associated with stress.
Petukhova L, Duvic M, Hordinsky M, Norris D, Price V, Shimomura Y, Kim H, Singh P, Lee A, Chen WV, Meyer KC, Paus R, Jahoda CA, Amos CI, Gregersen PK, Christiano AM. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature. 2010 Jul 1;466(7302):113-7
Alopecia areata (AA) is among the most highly prevalent human autoimmune diseases, leading to disfiguring hair loss due to the collapse of immune privilege of the hair follicle and subsequent autoimmune attack. The genetic basis of AA is largely unknown. We undertook a genome-wide association study (GWAS) in a sample of 1,054 cases and 3,278 controls and identified 139 single nucleotide polymorphisms that are significantly associated with AA (P <or= 5 x 10(-7)). Here we show an association with genomic regions containing several genes controlling the activation and proliferation of regulatory T cells (T(reg) cells), cytotoxic T lymphocyte-associated antigen 4 (CTLA4), interleukin (IL)-2/IL-21, IL-2 receptor A (IL-2RA; CD25) and Eos (also known as Ikaros family zinc finger 4; IKZF4), as well as the human leukocyte antigen (HLA) region. We also find association evidence for regions containing genes expressed in the hair follicle itself (PRDX5 and STX17). A region of strong association resides within the ULBP (cytomegalovirus UL16-binding protein) gene cluster on chromosome 6q25.1, encoding activating ligands of the natural killer cell receptor NKG2D that have not previously been implicated in an autoimmune disease. By probing the role of ULBP3 in disease pathogenesis, we also show that its expression in lesional scalp from patients with AA is markedly upregulated in the hair follicle dermal sheath during active disease. This study provides evidence for the involvement of both innate and acquired immunity in the pathogenesis of AA. We have defined the genetic underpinnings of AA, placing it within the context of shared pathways among autoimmune diseases, and implicating a novel disease mechanism, the upregulation of ULBP ligands, in triggering autoimmunity.
Alopecia areata or hair loss occurs in one in 1,000 people. If medical reasons for the hair loss are ruled out, opinion and hypothesis point towards autoimmunity and stress as possible causes. Dealing with the gradual or sudden loss of head hair, eyebrows, eyelashes, nasal, ear and body hair poses unique challenges for those it affects. Autoimmune-associated alopecia areata has no age boundaries and affects children, men and women equally. The dramatic change in appearance can result in psychological trauma, loss in confidence, bullying, low self-esteem and relationship difficulties.
Gilhar A. Collapse of immune privilege in alopecia areata: coincidental or substantial? J Invest Dermatol. 2010 Nov;130(11):2535-7
Only indirect evidence supports the concept that a collapse of immune privilege (IP) in hair follicles leads to the development of alopecia areata (AA). In this issue, Kang et al. provide further evidence to support this theory, demonstrating downregulation of the expression of several genes important for the immunosuppressive environment in lesional and perilesional areas of AA.
Skurkovich, S., Korotky, N. G., Sharova, N. M. & Skurkovich, B.(2005) Treatment of Alopecia Areata with Anti-Interferon-γ Antibodies. Journal of Investigative Dermatology Symposium Proceedings 10 (3), 283-284.
This study examined anticytokine therapy to treat autoimmune diseases such as alopecia. There is evidence that alopecia areata may be a cell-mediated autoimmune disorder of the hair follicle. Sixteen alopecia areata patients with varying degrees of hair loss were treated with anti-IFN (interferon) twice daily for 5 successful days. Most were then observed monthly for up to 6 months after completion of the therapy. The results showed that 8 of the 9 patients with patchy progressive hair loss stabilised and showed no additional hair loss. After 4-6 months these patients (except one) showed partial or full hair regrowth. Only one showed recurrence. Of the five patients with total hair loss three had some limited growth. The other two showed only vellus hair or no response. Of the two patients with stable patchy hair loss, one grew complete eyebrows and eyelashes, but neither showed scalp growth.
The problem with this study is that it is uncontrolled, and so these patients may have shown hair regrowth without treatment.
Palkina, T. N., Sharov, A. A., Sharova, T. Y. & Botchkarev, Vladimir A. (2005) Neurotrophins in Autoimmune Diseases: Possible Implications for Alopecia Areata. Journal of Investigative Dermatology Symposium Proceedings 10 (3), 282-282.
Neurotrophins are a family of related polypeptides (chains of amino acids) which, according to the evidence, play an important role during the development of autoimmune disorders. The mechanisms are unknown. Neurotrophins are present in skin affected by alopecia areata and promote hair follicle regression in normal non-affected skin. The authors suggest that neurotrophins may, because of this, play a role in alopecia areata pathogenesis. By studying mice, the authors show that neurotrophin-stimulated apoptis (programmed cell-death) in CD8 cells (immune cells involved in the cellular immune response which detect and kill cells infected by foreign organisms) may play a role as part of the protective response mechanisms limiting the development of alopecia areata. They also suggest that p75NTR agonists (a type of neurotrophin receptor) could be used as a therapeutic intervention to arrest the development of alopecia areata.
Martinez-Mir, Amalia, Zlotogorski, Abraham & Christiano, Angela M. (2005) Search for Susceptibility Genes in Alopecia Areata. Journal of Investigative Dermatology Symposium Proceedings 10 (3), 281-282.
The prognosis of alopecia areata is unpredictable and there is no definite treatment. Evidence suggests that alopecia areata is polygenetic, but genetic studies have been limited to analyses of association. The authors searched for susceptibility genes by performing a genome-wide scan across a number of families containing several people who had alopecia areata. They collected DNA from a total of 22 families, comprising 69 unaffected and 78 affected family members. Because of the complexity of traits, the authors expected to find a number of genetic components will contribute to the final presentation of the phenotype. They used a variety of statistical techniques, leading to several chromosomal regions yielding suggestive scores, including the HLA region on chromosome 6. Further research is currently being conducted with a larger group of families, with the hope that these studies will lead to the identification of alopecia areata susceptibility genes, and provide a foundation for understanding how the genes interact with each other, and with variables such as the immune system and environmental factors.