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1
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Messenger AG, Asfour L, Harries M. Frontal Fibrosing Alopecia: An Update. Am J Clin Dermatol 2025; 26:155-174. [PMID: 39699852 DOI: 10.1007/s40257-024-00912-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2024] [Indexed: 12/20/2024]
Abstract
In this review, we discuss recent developments in our understanding of frontal fibrosing alopecia, a disease that has become increasingly common and widespread since its first description in 1994. An inherited predisposition to frontal fibrosing alopecia, previously suspected from the occurrence of familial cases, has been confirmed through genetic studies. Nevertheless, the epidemiology continues to implicate environmental factors in the aetiology. The search has focussed mainly on personal skin care products such as facial moisturisers and UV filters, and there is also some evidence implicating exogenous oestrogens, but confirmation of direct causal links has so far proved elusive. The pathologic mechanisms underlying follicular deletion are being clarified, including the nature of the inflammatory component, the loss of follicular immune privilege in the bulge region and the role of epithelial-mesenchymal transition in the scarring process. Lichen planus pigmentosus, a common accompaniment to frontal fibrosing alopecia in those with darker skin, is probably a feature of the same pathology affecting interfollicular epidermis, rather than a co-morbidity, and may offer new clues to the aetiology. Treatment is still based largely on retrospective case series and variable endpoints. However, methods for assessing frontal fibrosing alopecia and monitoring treatment responses have been strengthened and randomised controlled trials with novel agents (e.g. Janus kinase inhibitors) are in progress. As the main aim of effective treatment is to prevent disease progression, early diagnosis will remain an important target, as will prevention in the longer term.
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Affiliation(s)
| | - Leila Asfour
- Chelsea and Westminster NHS Foundation Trust, London, SW10 9NH, UK
| | - Matthew Harries
- Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M6 8HD, UK
- Faculty of Biology, Medicine and Health, Centre for Dermatology Research, University of Manchester and NIHR Biomedical Research Centre, Manchester, UK
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2
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Popa A, Carsote M, Cretoiu D, Dumitrascu MC, Nistor CE, Sandru F. Study of the Thyroid Profile of Patients with Alopecia. J Clin Med 2023; 12:1115. [PMID: 36769763 PMCID: PMC9918246 DOI: 10.3390/jcm12031115] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/26/2023] [Accepted: 01/30/2023] [Indexed: 02/04/2023] Open
Abstract
Thyroid hormones are required for the physiological growth and maintenance of hair follicles. We aim to study the thyroid profile of patients with alopecia. This is a narrative review. PubMed literature was searched from 2013 to 2022. We followed different types of alopecia: alopecia areata (AA), androgenic alopecia in males and females, telogen effluvium (TE), frontal fibrosing alopecia (FFA), lichen planopilaris, and alopecia neoplastica (AN). AA shares a common autoimmune background with autoimmune thyroid diseases, either sporadic or belonging to autoimmune polyglandular syndromes. Some data suggested that AA is more severe if thyroid anomalies are confirmed, including subclinical dysfunction or positive antithyroid antibodies with normal hormone values. However, routine thyroid screening for patients with AA, if the patients are asymptomatic from a thyroid point of view and they have negative personal and family history of autoimmunity, remains controversial. TE, apart from the autoimmune type, associates thyroid anomalies of a hormonal assay (between 5.7% and 17%). FFA, mostly a postmenopausal entity (however, not exclusive), associates a higher prevalence of thyroid conditions (up to 50%) than the general population. However, these might have an age-dependent pattern, thus the association may be incidental since there are a limited number of studies. Overall, alopecia remains a very challenging condition for patients and physicians; a multidisciplinary team is required to improve the outcome and quality of life. The common autoimmune background is suggestive of some types of alopecia and thyroid disorders, yet, the underlying mechanisms are still a matter of debate. AA, TE, FFA, LPP, and, potentially, female pattern hair loss have been found to be connected with thyroid entities, thus a state of awareness from a dual perspective, of trichology and endocrinology, is helpful.
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Affiliation(s)
- Adelina Popa
- Department of Dermatovenerology, “Carol Davila University” of Medicine and Pharmacy & “Elias” University Emergency Hospital, 011461 Bucharest, Romania
| | - Mara Carsote
- Department of Endocrinology, “Carol Davila” University of Medicine and Pharmacy & “C.I. Parhon” National Institute of Endocrinology, 011461 Bucharest, Romania
| | - Dragos Cretoiu
- Department of Cellular and Molecular Biology, and Histology, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy & National Institute for Mother and Child Health Alessandrescu-Rusescu, 011461 Bucharest, Romania
| | - Mihai Cristian Dumitrascu
- Department of Obstetrics and Gynaecology, “Carol Davila” University of Medicine and Pharmacy & University Emergency Hospital, 011461 Bucharest, Romania
| | - Claudiu-Eduard Nistor
- Department 4–Cardio-Thoracic Pathology, Thoracic Surgery II Discipline, “Carol Davila” University of Medicine and Pharmacy & Thoracic Surgery Department, “Carol Davila” Central Emergency University Military Hospital, 011461 Bucharest, Romania
| | - Florica Sandru
- Department of Dermatovenerology, “Carol Davila University” of Medicine and Pharmacy & “Elias” University Emergency Hospital, 011461 Bucharest, Romania
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3
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Ramírez-Marín HA, Tosti A. Examining the autoimmune aspects of frontal fibrosing alopecia. Expert Rev Clin Immunol 2022; 18:1091-1094. [PMID: 35904171 DOI: 10.1080/1744666x.2022.2106971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
| | - Antonella Tosti
- Dr. Philip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida.
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4
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Miao YJ, Jing J, Du XF, Mao MQ, Yang XS, Lv ZF. Frontal fibrosing alopecia: A review of disease pathogenesis. Front Med (Lausanne) 2022; 9:911944. [PMID: 35957858 PMCID: PMC9357920 DOI: 10.3389/fmed.2022.911944] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 07/05/2022] [Indexed: 11/13/2022] Open
Abstract
Frontal fibrosing alopecia (FFA) is a primary patterned cicatricial alopecia that mostly affects postmenopausal women and causes frontotemporal hairline regression and eyebrow loss. Although the incidence of FFA has increased worldwide over the last decade, its etiology and pathology are still unclear. We cover the latest findings on its pathophysiology, including immunomodulation, neurogenic inflammation, and genetic regulation, to provide more alternatives for current clinical treatment. A persistent inflammatory response and immune privilege (IP) collapse develop and lead to epithelial hair follicle stem cells (eHFSCs) destruction and epithelial-mesenchymal transition (EMT) in the bulge area, which is the key process in FFA pathogenesis. Eventually, fibrous tissue replaces normal epithelial tissue and fills the entire hair follicle (HF). In addition, some familial reports and genome-wide association studies suggest a genetic susceptibility or epigenetic mechanism for the onset of FFA. The incidence of FFA increases sharply in postmenopausal women, and many FFA patients also suffer from female pattern hair loss in clinical observation, which suggests a potential association between FFA and steroid hormones. Sun exposure and topical allergens may also be triggers of FFA, but this conjecture has not been proven. More evidence and cohort studies are needed to help us understand the pathogenesis of this disease.
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Affiliation(s)
- Yu-Jie Miao
- Department of Dermatology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jing Jing
- Department of Dermatology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Jing Jing,
| | - Xu-Feng Du
- Department of Dermatology, Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China
| | - Mei-Qi Mao
- Department of Dermatology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiao-Shuang Yang
- Department of Dermatology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhong-Fa Lv
- Department of Dermatology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Zhong-Fa Lv,
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Dubin C, Glickman JW, Del Duca E, Chennareddy S, Han J, Dahabreh D, Estrada YD, Zhang N, Kimmel GW, Singer G, Chowdhury M, Zheng AY, Angelov M, Gay-Mimbrera J, Ruano Ruiz J, Krueger JG, Pavel AB, Guttman-Yassky E. Scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement. J Am Acad Dermatol 2021; 86:551-562. [PMID: 34044102 DOI: 10.1016/j.jaad.2021.05.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 05/11/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Frontal fibrosing alopecia (FFA) is a progressive, scarring alopecia of the frontotemporal scalp that poses a substantial burden on quality of life. Large-scale global profiling of FFA is lacking, preventing the development of effective therapeutics. OBJECTIVE To characterize FFA compared to normal and alopecia areata using broad molecular profiling and to identify biomarkers linked to disease severity. METHODS This cross-sectional study assessed 33,118 genes in scalp using RNA sequencing and 350 proteins in serum using OLINK high-throughput proteomics. Disease biomarkers were also correlated with clinical severity and a fibrosis gene set. RESULTS Genes differentially expressed in lesional FFA included markers related to Th1 (IFNγ/CXCL9/CXCL10), T-cell activation (CD2/CD3/CCL19/ICOS), fibrosis (CXCR3/FGF14/FGF22/VIM/FN1), T-regulatory (FOXP3/TGFB1/TGFB3), and Janus kinase/JAK (JAK3/STAT1/STAT4) (Fold changes [FCH]>1.5, FDR<.05 for all). Only one protein, ADM, was differentially expressed in FFA serum compared to normal (FCH>1.3, FDR<.05). Significant correlations were found between scalp biomarkers (IL-36RN/IL-25) and FFA severity, as well as between JAK/STAT and fibrosis gene-sets (r>.6; P <.05). LIMITATIONS This study was limited by a small sample size and predominantly female FFA patients. CONCLUSION Our data characterize FFA as an inflammatory condition limited to scalp, involving Th1/JAK skewing, with associated fibrosis and elevated T-regulatory markers, suggesting the potential for disease reversibility with JAK/STAT inhibition.
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Affiliation(s)
- Celina Dubin
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jacob W Glickman
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ester Del Duca
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Dermatology, University of Magna Graecia, Catanzaro, Italy
| | - Sumanth Chennareddy
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Joseph Han
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Dante Dahabreh
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Yeriel D Estrada
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ning Zhang
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Grace W Kimmel
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Giselle Singer
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Mashkura Chowdhury
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Andrew Y Zheng
- Macaulay Honors College at City University of New York (CUNY) Hunter College, New York, New York
| | - Michael Angelov
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jesús Gay-Mimbrera
- Immune-Mediated Inflammatory Skin Diseases Research Group, IMIBIC/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain
| | - Juan Ruano Ruiz
- Department of Dermatology, Reina Sofia University Hospital, Cordoba, Spain
| | - James G Krueger
- Laboratory of Investigative Dermatology, Rockefeller University, New York, New York
| | - Ana B Pavel
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Biomedical Engineering, The University of Mississippi, Oxford, Mississippi.
| | - Emma Guttman-Yassky
- Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York; Laboratory of Investigative Dermatology, Rockefeller University, New York, New York.
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A Cell Membrane-Level Approach to Cicatricial Alopecia Management: Is Caveolin-1 a Viable Therapeutic Target in Frontal Fibrosing Alopecia? Biomedicines 2021; 9:biomedicines9050572. [PMID: 34069454 PMCID: PMC8159142 DOI: 10.3390/biomedicines9050572] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/05/2021] [Accepted: 05/17/2021] [Indexed: 12/12/2022] Open
Abstract
Irreversible destruction of the hair follicle (HF) in primary cicatricial alopecia and its most common variant, frontal fibrosing alopecia (FFA), results from apoptosis and pathological epithelial-mesenchymal transition (EMT) of epithelial HF stem cells (eHFSCs), in conjunction with the collapse of bulge immune privilege (IP) and interferon-gamma-mediated chronic inflammation. The scaffolding protein caveolin-1 (Cav1) is a key component of specialized cell membrane microdomains (caveolae) that regulates multiple signaling events, and even though Cav1 is most prominently expressed in the bulge area of human scalp HFs, it has not been investigated in any cicatricial alopecia context. Interestingly, in mice, Cav1 is involved in the regulation of (1) key HF IP guardians (TGF-β and α-MSH signaling), (2) IP collapse inducers/markers (IFNγ, substance P and MICA), and (3) EMT. Therefore, we hypothesize that Cav1 may be an unrecognized, important player in the pathobiology of cicatricial alopecias, and particularly, in FFA, which is currently considered as the most common type of primary lymphocytic scarring alopecia in the world. We envision that localized therapeutic inhibition of Cav1 in management of FFA (by cholesterol depleting agents, i.e., cyclodextrins/statins), could inhibit and potentially reverse bulge IP collapse and pathological EMT. Moreover, manipulation of HF Cav1 expression/localization would not only be relevant for management of cicatricial alopecia, but FFA could also serve as a model disease for elucidating the role of Cav1 in other stem cell- and/or IP collapse-related pathologies.
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7
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Frontal Fibrosing Alopecia: A Review. J Clin Med 2021; 10:jcm10091805. [PMID: 33919069 PMCID: PMC8122646 DOI: 10.3390/jcm10091805] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/14/2021] [Accepted: 04/17/2021] [Indexed: 12/19/2022] Open
Abstract
Frontal fibrosing alopecia is a scarring alopecia, the prevalence of which is increasing worldwide since its first description in 1994. The reason for this emerging epidemic may be a higher exposure to an unknown trigger, although its aethiology and pathogenesis still remain enigmatic. Clinical, trichoscopic, sonographic, and histopathologic findings are allowing clinicians to understand more aspects about this type of cicatricial alopecia. Several treatments have been used in frontal fibrosing alopecia, although the 5-alpha reductase inhibitors seem to be the most promising. The aim of this report is to provide a compilation about the published data regarding frontal fibrosing alopecia in a narrative review.
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Adipose Infiltration of the Dermis, Involving the Arrector Pili Muscle, and Dermal Displacement of Eccrine Sweat Coils: New Histologic Observations in Frontal Fibrosing Alopecia. Am J Dermatopathol 2019; 41:492-497. [PMID: 30624243 DOI: 10.1097/dad.0000000000001349] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Frontal fibrosing alopecia (FFA) is an irreversible scarring alopecia, and its incidence has reached epidemic size. Immune privilege collapse of the bulge and epithelial mesenchymal transition play a role in the pathogenesis. We have noted adipose tissue in the dermis in several specimens from FFA. OBJECTIVE Our primary objective was to verify the presence of adipose tissue at the isthmus level in biopsies from FFA. Additional objectives included the presence of deep inflammation and position of the sweat coils. METHODS Eighty-three histologic specimens of FFA diagnosed at the Dermatopathology Laboratory at the Department of Dermatology, University of Miami, within 3 years were evaluated retrospectively. All biopsies were bisected horizontally and assessed at several levels. Sixty biopsies from androgenetic alopecia served as controls. Statistical analysis was performed using the χ test. A P value of 0.05 or less was considered significant. RESULTS Sixty specimens met the inclusion criteria for optimal quality and classic diagnostic features. Seventy percent demonstrated fat tissue infiltration at the isthmus level as clusters of cells or small globules versus 23% of the controls. The fat infiltration in the arrector pili muscle (APM) was present in 55% versus 15% of the controls, and the sweat coils were positioned in the reticular dermis in 43% versus 1.7% of the controls. All results were statistically significant (P < 0.0001). When accounting for the simultaneous presence of any of these 3 variables, 30% of the FFA cases had triple positivity, 61.7% had double positivity, and 75% had at least 1 positive variable versus 0%, 15%, and 10%, respectively, of the controls. CONCLUSION New histologic findings in FFA involve the presence of adipose tissue in the dermis. We believe that the close interaction of the hair follicles and the APM with the adipose tissue may play a role in APM degeneration and in epithelial mesenchymal transition.
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9
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Abstract
Frontal fibrosing alopecia (FFA) is an irreversible scarring alopecia with unknown etiology and no cure. The goal is to establish the diagnosis in the early stage, before developing a hairless band of atrophy involving the frontal, temporal scalp and sideburns. Pathology is rarely needed once the disease is clinically apparent. The classic histologic features include follicular dropout with the absence or atrophy of the sebaceous glands and lichenoid lymphohistiocytic infiltrate with concentric layered fibrosis at the upper follicular level. We describe a common pattern that was repeatedly seen in 6 horizontally sectioned scalp biopsies from patients with early presentation of FFA suspected on trichoscopy by the focal presence of peripilar casts around terminal hairs. All biopsies revealed overall preserved follicular architecture with average number of 11 vellus follicles, atrophy of the sebaceous glands, and perifollicular lymphohistiocytic infiltrate involving the outer root sheath of the vellus follicles (n = 5). There was no perifollicular fibrosis of the vellus follicles and no lichenoid inflammation and perifollicular fibrosis of the terminal follicles. This new pattern of "inflammatory vellus involvement" most likely corresponds to an early onset of the disease. The absence of the classic features in such biopsies from early FFA can lead to misdiagnosis.
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10
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Tavakolpour S, Mahmoudi H, Abedini R, Kamyab Hesari K, Kiani A, Daneshpazhooh M. Frontal fibrosing alopecia: An update on the hypothesis of pathogenesis and treatment. Int J Womens Dermatol 2019; 5:116-123. [PMID: 30997385 PMCID: PMC6451751 DOI: 10.1016/j.ijwd.2018.11.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 10/12/2018] [Accepted: 11/07/2018] [Indexed: 01/10/2023] Open
Abstract
Frontal fibrosing alopecia (FFA) is a relatively new scarring alopecia that is considered a variant of lichen planopilaris (LPP) with no recognized promising treatments. In this study, we tried to clarify the underlying signaling pathways and their roles in the pathogenesis and progression of FFA. Because of several differences in clinical manifestations, response to treatments, and pathological findings, these two conditions could be differentiated from each other. Taking into account the already discussed signaling pathways and involved players such as T cells, mast cells, and sebaceous glands, different possible therapeutic options could be suggested. In addition to treatments supported by clinical evidence, such as 5 alpha-reductase inhibitors, topical calcineurin inhibitors, hydroxychloroquine, peroxisome proliferator-activated receptor gamma agonists, and oral retinoid agents, various other treatment strategies and drugs, such as phototherapy, Janus kinase inhibitors, dehydroepiandrosterone, sirolimus, cetirizine, and rituximab, could be suggested to mitigate disease progression. Of course, such lines of treatment need further evaluation in clinical trials.
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Affiliation(s)
- Soheil Tavakolpour
- Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - HamidReza Mahmoudi
- Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Robabeh Abedini
- Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Kambiz Kamyab Hesari
- Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amin Kiani
- Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Daneshpazhooh
- Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
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11
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Subash J, Alexander T, Beamer V, McMichael A. A proposed mechanism for central centrifugal cicatricial alopecia. Exp Dermatol 2018; 29:190-195. [PMID: 29660185 DOI: 10.1111/exd.13664] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2018] [Indexed: 12/19/2022]
Abstract
Central centrifugal cicatricial alopecia (CCCA) has an unknown mechanism. Analyzing other scarring diseases (lichen planopilaris, fibrotic kidney disease and scleroderma) may help to clarify the mechanism of scarring in CCCA. These diseases were chosen for comparison due to either their location of disease (skin or scalp specifically), or prominence in patients of African descent. Genetics, possible triggers, an autoimmune lymphocytic response, and epithelial to mesenchymal transition are potentially involved. Possible common pathways in scarring diseases and a better understanding of the CCCA mechanism will lead to further research into the pathogenesis and potential treatments of CCCA.
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Affiliation(s)
- Jacob Subash
- Department of Dermatology, Wake Forest University, Winston-Salem, NC, USA
| | | | - Victoria Beamer
- Department of Dermatology, Wake Forest University, Winston-Salem, NC, USA
| | - Amy McMichael
- Department of Dermatology, Wake Forest University, Winston-Salem, NC, USA
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12
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Harries MJ, Jimenez F, Izeta A, Hardman J, Panicker SP, Poblet E, Paus R. Lichen Planopilaris and Frontal Fibrosing Alopecia as Model Epithelial Stem Cell Diseases. Trends Mol Med 2018; 24:435-448. [DOI: 10.1016/j.molmed.2018.03.007] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 03/14/2018] [Accepted: 03/14/2018] [Indexed: 01/06/2023]
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13
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Imanishi H, Ansell DM, Chéret J, Harries M, Bertolini M, Sepp N, Bíró T, Poblet E, Jimenez F, Hardman J, Panicker SP, Ward CM, Paus R. Epithelial-to-Mesenchymal Stem Cell Transition in a Human Organ: Lessons from Lichen Planopilaris. J Invest Dermatol 2017; 138:511-519. [PMID: 29106928 DOI: 10.1016/j.jid.2017.09.047] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 09/15/2017] [Accepted: 09/16/2017] [Indexed: 12/15/2022]
Abstract
Epithelial-to-mesenchymal transition (EMT) is critical for embryonic development and wound healing, and occurs in fibrotic disease and carcinoma. Here, we show that EMT also occurs within the bulge, the epithelial stem cell (eSC) niche of human scalp hair follicles, during the inflammatory permanent alopecia, lichen planopilaris. We show that a molecular EMT signature can be experimentally induced in healthy human eSCs in situ by antagonizing E-cadherin, combined with transforming growth factor-β1, epidermal growth factor, and IFN-γ administration, which to our knowledge has not been reported previously. Moreover, induction of EMT within primary human eSCs can be prevented and even partially reversed ex vivo by peroxisome proliferator-activated receptor-γ agonists, likely through suppression of the transforming growth factor-β signaling pathway. Furthermore, we show that peroxisome proliferator-activated receptor-γ agonists also attenuates the EMT signature even in lesional lichen planopilaris hair follicles ex vivo. We introduce lichen planopilaris as a model disease for pathological EMT in human adult eSCs, report a preclinical assay for therapeutically manipulating eSC EMT within a healthy human (mini-)organ, and show that peroxisome proliferator-activated receptor-γ agonists are promising agents for suppressing and partially reversing EMT in human hair follicles eSCs ex vivo, including in lichen planopilaris.
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Affiliation(s)
- Hisayoshi Imanishi
- Centre for Dermatology Research, University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Biomedical Research Centre, Manchester, UK; Department of Dermatology, Osaka City University Graduate School of Medicine, Japan
| | - David M Ansell
- Centre for Dermatology Research, University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Biomedical Research Centre, Manchester, UK
| | | | - Matthew Harries
- Centre for Dermatology Research, University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Biomedical Research Centre, Manchester, UK; Dermatology Centre, University of Manchester, Salford Royal NHS Foundation Trust, Salford, UK
| | - Marta Bertolini
- Monasterium Laboratory, Münster, Germany; Department of Dermatology, University of Münster, Münster, Germany
| | - Norbert Sepp
- Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria
| | - Tamás Bíró
- Departments of Immunology and Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Enrique Poblet
- Department of Pathology, University General Hospital of Murcia, Murcia, Spain
| | - Francisco Jimenez
- Mediteknia Dermatology Clinic, Medical Pathology Group, Instituto de Investigación Biosanitaria, Universidad de Las Palmas de Gran Canaria, Gran Canaria, Canary Islands, Spain
| | - Jonathan Hardman
- Centre for Dermatology Research, University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Biomedical Research Centre, Manchester, UK
| | | | | | - Ralf Paus
- Centre for Dermatology Research, University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Biomedical Research Centre, Manchester, UK.
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14
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Tziotzios C, Stefanato CM, Fenton DA, Simpson MA, McGrath JA. Frontal fibrosing alopecia: reflections and hypotheses on aetiology and pathogenesis. Exp Dermatol 2016; 25:847-852. [DOI: 10.1111/exd.13071] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2016] [Indexed: 02/06/2023]
Affiliation(s)
- Christos Tziotzios
- St John's Institute of Dermatology; King's College London (Guy's Campus); London UK
| | | | - David A. Fenton
- St John's Institute of Dermatology; King's College London (Guy's Campus); London UK
| | - Michael A. Simpson
- Division of Genetics and Molecular Medicine; King's College London; Guy's Hospital; London UK
| | - John A. McGrath
- St John's Institute of Dermatology; King's College London (Guy's Campus); London UK
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Aldoori N, Dobson K, Holden C, McDonagh A, Harries M, Messenger A. Frontal fibrosing alopecia: possible association with leave-on facial skin care products and sunscreens; a questionnaire study. Br J Dermatol 2016; 175:762-7. [DOI: 10.1111/bjd.14535] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2016] [Indexed: 12/19/2022]
Affiliation(s)
- N. Aldoori
- Department of Dermatology; Royal Hallamshire Hospital; Sheffield S10 2JF U.K
| | - K. Dobson
- Department of Dermatology; Royal Hallamshire Hospital; Sheffield S10 2JF U.K
| | - C.R. Holden
- Department of Dermatology; Royal Hallamshire Hospital; Sheffield S10 2JF U.K
| | - A.J. McDonagh
- Department of Dermatology; Royal Hallamshire Hospital; Sheffield S10 2JF U.K
| | - M. Harries
- The Dermatology Centre; Manchester University; Salford Royal NHS Foundation Trust; Salford M6 8HD U.K
| | - A.G. Messenger
- Department of Dermatology; Royal Hallamshire Hospital; Sheffield S10 2JF U.K
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16
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17
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Snail1-driven plasticity of epithelial and mesenchymal cells sustains cancer malignancy. Biochim Biophys Acta Rev Cancer 2015; 1856:55-61. [PMID: 26050961 DOI: 10.1016/j.bbcan.2015.05.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 05/20/2015] [Accepted: 05/24/2015] [Indexed: 12/19/2022]
Abstract
The transcription factor Snail1 induces epithelial-to-mesenchymal transition (EMT) in tumor epithelial cells, a process associated with the emergence of stemness, invasion and cancer malignancy. Here, we review recent reports indicating that Snail1 also regulates mesenchymal plasticity and paracrine signaling and propose that Snail1 orchestrates the generation of cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs). Our view supports the current models for tumorigenesis that consider stemness and tumor microenvironment as retroactive actors for metastasis formation, revealing Snail1 as a regulator of these metastatic forces. This view offers new perspectives for understanding and targeting metastasis.
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18
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Lyakhovitsky A, Barzilai A, Amichai B. Frontal fibrosing alopecia update. World J Dermatol 2015; 4:33-43. [DOI: 10.5314/wjd.v4.i1.33] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Revised: 12/01/2014] [Accepted: 12/19/2014] [Indexed: 02/06/2023] Open
Abstract
Frontal fibrosing alopecia (FFA) is a recently described form of primary cicatricial alopecia, characterized by progressive recession of the frontotemporal hairline and eyebrow loss, occurring predominantly in postmenopausal women. The incidence of FFA has increased significantly during the last decade and we may be facing an epidemic of the disease. Because this condition causes permanent hair loss, prompt diagnosis and treatment are essential for obtaining optimal outcome. This article reviews existing knowledge on epidemiology, etiopathogenesis, clinico-histological features, diagnosis, and treatment modalities of FFA.
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Jouanique C, Reygagne P. [Frontal fibrosing alopecia]. Ann Dermatol Venereol 2014; 141:272-8. [PMID: 24703641 DOI: 10.1016/j.annder.2014.01.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Revised: 12/03/2013] [Accepted: 01/09/2014] [Indexed: 01/06/2023]
Abstract
Frontal fibrosing alopecia (FFA) was first described in 1994. It is characterized by scarring alopecia in bands involving the anterior area of the scalp. Alopecia of the eyebrows is frequently associated, as are pubic, facial and body hair alopecia. The clinical and histologic features are evocative of lichen planopilaris (LPP), and AFF is in fact regarded as a special pattern of LPP. Histology reveals a lymphocytic infiltrate located around the isthmus and follicular infundibulum associated with a decrease in the number of follicles, which are supplanted by fibrous tract. AFF most commonly affects post-menopausal women, but instances have been described in men and in young women. This orphan disease has increased in recent years, with more than 37 articles dedicated to this condition since it was first described in 1994. The pathophysiology remains unknown. The condition develops slowly with spontaneous stabilization over several years but it is impossible to predict the degree of expression prior to stabilization. In this article we review the various treatments proposed, for none of which formal proof of efficacy has been provided to date.
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Affiliation(s)
- C Jouanique
- Service de dermatologie, hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France; Centre Sabouraud, hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France
| | - P Reygagne
- Centre Sabouraud, hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France.
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21
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Abstract
Primary cicatricial alopecias (PCA) are a rare group of disorders, in which the hair follicle is the main target of destructive inflammation resulting in irreversible hair loss with scarring of affected lesions. The most typical clinical manifestation of PCA is the loss of visible follicular ostia. The histopathological hallmark of a fully developed lesion is the replacement of the hair follicle structure by fibrous tissue. PCA could share similar clinical manifestations and eventually lead to "burn-out" alopecia. Some subsets are hardly distinguishable histopathologically and the mechanisms that elicit such a destructive reaction have not been fully elucidated. Thus, the management of PCA represents one of the most challenging clinical problems for dermatologists. The aim of this review is to provide a concise and comprehensive summary of recent advances in PCA management, especially focusing on novel methodologies to aid diagnosis, and updates on our understanding of the etiopathogenesis. Dermoscopy, a new pathological preparation technique and direct immunofluorescence analysis enable more accurate clinicopathological diagnosis of PCA. Microarray analysis may be beneficial to distinguish PCA subtypes. Currently suggested mechanisms underlying PCA include loss of immune protection of stem cells, impaired stem cell self-maintenance, enhanced autoimmunity by pro-inflammatory cytokines and environmental/genetic predispositions. Interestingly, recent data indicates the association between lipid metabolism dysregulation and PCA development, implying an important role of the sebaceous gland dysfunction in the etiopathogenesis. Based on that hypothesis and observations, novel therapeutic approaches have been proposed, including the use of peroxisome proliferator-activated receptor-γ agonist for lichen planopilaris.
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Affiliation(s)
- Manabu Ohyama
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
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Nakamura M, Sugita K, Tokura Y. Expression of Snail1 in the vimentin-expressing squamous cell carcinoma mimicking atypical fibroxanthoma: possible involvement of an epithelial-mesenchymal transition. J Eur Acad Dermatol Venereol 2011; 24:1365-6. [PMID: 20384675 DOI: 10.1111/j.1468-3083.2010.03659.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Nakamura M, Tokura Y. Expression of SNAI1 and TWIST1 in the eccrine glands of patients with systemic sclerosis: possible involvement of epithelial-mesenchymal transition in the pathogenesis. Br J Dermatol 2010; 164:204-5. [PMID: 21054330 DOI: 10.1111/j.1365-2133.2010.10021.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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