BHNS Journal Club January 2020

By Dr L. Asfour (ST5)

Recent Publications on Hair:

Groundbreaking: Nature January 2020

It has been confirmed stress makes us grey!!!

Recent publication in Nature that has also been posted in mainstream media have demonstrated in mice how acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics, cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells. They found that it is independent of immune attack or adrenal stress hormones and instead is related to the activation of the sympathetic nerves that innervate the melanocyte stem-cell niche.

Zhang, B., Ma, S., Rachmin, I. et al. Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells. Nature 577, 676–681 (2020). https://doi.org/10.1038/s41586-020-1935-3

JAAD:

o   Complementary & Alternative Medicine for Alopecia Areata : A Systematic Review

o   Tkachenko, E., Okhovat, J.-P., Manjaly, P., Huang, K. P., Senna, M. M., & Mostaghimi, A. (2019). Complementary & Alternative Medicine for Alopecia Areata: A Systematic Review. Journal of the American Academy of Dermatology. (2020) 

·       Objective: To identify all Complementary and Alternative Medicine (CAM) for alopecia areata. Outcomes included disease course and psychological well-being.

·       A systematic review performed according to Preferred Reporting Items for systematic Reviews and Meta-analyses (PRISMA) guidelines

·       Studies published in English from 1950-2018

o   16 articles included:

§  5 Randomised controlled trials (RCTS)

§  5 prospective controlled cohorts

§  4 prospective non-controlled cohorts

§  1 retrospective cohort

§  1 case series

·       Limitations: small study sizes, variable quality of study design, variable disease severity and duration (in certain studies this was not reported)

·       Conclusions made with caution by authors:

§  CAM increasingly more popular particularly in dermatology and for hair loss with high utilization rates worldwide

§  Therapies with the highest quality and efficacy for hair growth in alopecia areata include essential oil aromatherapy, topical garlic, oral glucosides of peony with compound glycyrrhizin (an immunoregulatory plant extract used in psoriasis and vitiligo , thought to modulate Th17 differentiation).

§  Low quality studies reveal that hypnosis and mindfulness are effective for improving psychological outcomes and quality of life.

o   Trichoscopic findings of frontal fibrosing alopecia on the eyebrows: study of 151 cases

o   Anzai A, Pirmez R, Vincenzi C, Fabbrocini G, Romiti R, Tosti A, Trichoscopic findings of frontal fibrosing alopecia on the eyebrows: a study of 151 cases. Journal of the American Academy of Dermatology (2020)

·       Objective: To describe trichoscopic findings of FFA on the eyebrows. Eyebrow loss (madarosis) is thought to precede scalp alopecia in 39% of cases

·       Methods: Two independent evaluators analysed dermatoscopic images of 151 female patients with diagnosis of FFA between February 2015 and December 2018.

§  76 cases retrospectively

§  75 cases prospectively

§  FFA diagnosis confirmed from scalp biopsies

§  Exclusion criteria: if they had eyebrow plucking in the last month or eyebrow tattoo/microblading

·       Results:

§  Two categories patchy (23.8% of patients) and diffuse (76.1%)

§  Breakdown of madarosis & features from clinical photographs:

·       46 cases (30.4%) almost complete eyebrow loss  with >90%

·       49 cases (32.5%) with loss of 50-90%

·       57 cases (37.7%) with loss of <50%

·       13.9% showed diffuse erythema and 1.9% showed dyschromia

§   Trichoscopic signs included:

·       Yellow dots (92.7%)

·       Multiple pinpoint dots (79.5%)

·       Short thin hairs/vellus (76.2%)

·       Black dots (66.2%)

·       Dystrophic hairs (60.9%)

·       Tapering hairs in (13.9%)

§  Telangiectasia and pinpoint dots most frequent in those with loss of 50-90% and >90% (p-value 0.02 and 0.005)

§  Broken hairs and peripilar casts in those with loss <50% and 50-90% (p-value <0.0001 and 0.05)

§  Focal area of follicular loss in those with >90%

§  Trichoscopic signs most commonly seen in patchy alopecia: black dots (88%), dystrophic hairs (86.1%), peripilar casts (66.6%) and eyebrow regrowth in different directions

§  Yellow dots seen in both patchy and diffuse but most common in diffuse pattern

§  Trichoscopic characteristics correlated to skin types: as expected Fitzpatrick skin type I-III (versus FST IV-VI) more commonly noted to have telangiectasia, red dots, perifollicular erythema and follicular plugs

·       Limitations: No comparison to normal controls or individuals with other hair disorders, lack of histological correlation to trichoscopic findings

·       Conclusions by authors:

§  Most frequent signs yellow dots, multiple pinpoint dots, short thin hairs/vellus. 

§  Trichoscopy findings of the eyebrows does not correlate with that of the scalp in FFA

§  Tapered hairs can be present leading to a misdiagnosis of Alopecia areata

o   Fibrosing alopecia in a pattern distribution (FAPD)

o   Griggs J., Trueb RM, Reis Gavazzoni Dias MF, Hordinsky M, Tosti A, Fibrosing alopecia in pattern distribution, Journal of American Academy of Dermatology (2020)

·       Objective:

§  FAPD was described in 2000. It is a form of scarring alopecia characterized by patterned hair loss similar to Androgenetic alopecia (AGA) but with trichoscopic and histopathologic signs of both lichen planopilaris (LPP) and AGA.

§  To review epidemiology, pathogenesis, clinical features, diagnosis, and treatment of (FAPD)

·       Methods:

§  Using Pubmed and Scopus searches to identify all articles discussing FAPD

§  Total of 15 articles between 2000- 2019 (with total of 188 patients- 164 female: 24 male, average age 53.8)

·       Results:

§  In a multicenter retrospective study of >2000 patients seen in 22 specialist hair clinics across 4 continents a total of 57 patients (2%) were diagnosed with FAPD

§  FAPD was 4^th most frequent subtype of cicatricial alopecia

§  FAPD affects androgen dependent scalp and is typically associated with hair follicle miniaturization. Rarely reported to affect eyebrows, and not known to affect eyelashes or other body hair.

§  Other skin findings rarely reported include reticulated pattern of pruritic red dots on the chest and facial papules.

§  There are several hypotheses for FAPD pathogenesis. FAPD may represent an exaggerated inflammatory response to damaged hair follicles triggered by AGA, 37% of patients with AGA may have moderate to severe perifollicular inflammation or fibrosis on biopsy.

§  Treatment options aim to decrease inflammation and reverse miniaturization. A singe case report discusses the use of autologous hair transplantation; however, LPP has been reported to occur after hair transplantation suggesting that FAPD may not be the best candidates.

·       Limitations: 120 patients had biopsy data reported. Data on treatments is limited to small retrospective studies and case reports with poor follow up.

·       Conclusions by authors:

§  FAPD and FFA share similar histopathology

§  FAPD does not affect androgen independent occipital and body hair

§  FAPD present with symptomatic scalp and poor response to treatment

§  Further studies are needed before recommendations can be made regarding a specific treatment

BJD:

o   Alopecia areata is characterized by dysregulation in systemic type 17 and type 2 cytokines, which may contribute to disease associated psychological morbidity

o   Bain K.A, McDonald E., Moffat F, Tutino M, Castelino M, Barton A, Cavanagh J, Ijaz U.Z, Siebert S, McInnes I.B, Astrand A, Holmes S and Milling SWF. Br J Derm 2020; 182: 130-137

·       Objectives: To provide detailed insight into the systemic cytokine signature associated with AA and the association between cytokines and depression

·       Methods:

§  Multiplex analysis of plasma cytokines from patients with AA, Psoriatic arthritis and healthy controls

§  The use of Hospital Anxiety and depression Scale (HADS) to assess depression and anxiety

§  AA volunteers did not have any other inflammatory condition such as IBD, Rheumatoid arthritis, psoriatic arthritis, psoriasis or ankylosing spondylitis. However 20 out of the 39 AA patients had known atopic dermatitis.

§  18/ 39 had patchy AA, 17/39 had severe disease and 4/39 were in remission

§  17/39 were on treatment (Intralesional steroids 8; DPC 8; Methotrexate 1)

·       Results:

§  AA patients had increased plasma levels of Type 2 cytokines IL-33, IL-31 and IL-17E (IL-25) in addition to the type 17 cytokines IL-17A, IL-21, IL-23 and IL-17F

§  IL-8 was significantly reduced in AA cohort compared to healthy controls (P<0.05)

§  Despite previous reports, there was no difference in levels of IFN-γ between AA cohort and healthy controls

§  IL-17E levels were higher in those with severe hair loss (SALT score >95%)

§  Patients with severe hair loss (AT/AU) experienced depression and anxiety less frequently

§  Patients with patchy AA scored 17% mild depression, 6% moderate and 11% severe depression. 55% experienced anxiety.

§  Patients with patchy AA with disease onset <10years demonstrated the highest burden of depression/ anxiety

§  Liner regression model was used to assess association between circulating cytokines and depression/anxiety. IL-22 significantly and positively predicted depression score across 10-fold subset validations (P<0.01) and IL-17E also significantly predicted depression score in 6 of 10-fold cross validations.

·       Conclusions:

§  Dysregulation of type 17 and type 2 immune pathways may also be implicated in the underlying immunological mechanism of AA. Providing insight to other potential immune pathways beyond CD8+ NKG2D+ T-cells.

§  IL-17E amd IL-22 positively predict depression score. IL-17E is expressed in neural cells during inflammation. IL-22 receptor has been detected on brain endothelial cells and implicated in neuroinflammatory disorders such as Multiple sclerosis. However, the study is not able to determine whether there is a direct or indirect relationship between cytokines and depression or whether it is related to similar extrinsic factors. 

o   Does skewing of cytokine production link alopecia areata and depression? Commentry.

·       Linked article Bain et al. Br J Dermatol

·       Ohyama M. Br J Dermatol 2020; 182: 15-16

§  Past investigations have demonstrated activation of T-helper  Th1, Th 2, Th 17 cytokines and IL-23 in AA and concurrent diseases such as atopic dermatitis (AD) and psoriasis

§  Ohyama raises the question of whether the positive correlation between IL-17E/ 25 and IL-22 and depression may be in view of the high incidence of AD in an AA cohort (20 of 39 cases). IL-17E and IL-22 are reported to be implicated in the pathophysiology of AD.

§  Further work is needed to assess whether there is a direct link between cytokines and depression. Nonetheless, the novel work reported by Bain and colleagues will enable further dissection of the cytokine profiles in AA and the possible role in the development psychological comorbidities.  

o   Apremilast and tofacitinib exert differential effects in the humanized mouse model of alopecia areata

o   Research letter

o   Britva R. L, Keren A. Paus R. Gilhar A. Br J Dermatol (2020) 182: 227-228

·       Objective:

§  To appreciate the efficacy of Phosphodiesterase PDE 4 inhibitor (Apremilast) and Janus Kinase JAK inhibitor (Tofacitinib) using the humanized mouse model of AA

·       Methods:

§  3-mm xenotranplants of hair bearing scalp skin from 3 healthy male volunteers who had undergone cosmetic procedures were grafted onto mice

§  Each treated group was represented by the three volunteers

§  AA lesions were induced by intradermal injection of autologous healthy donor preactivated peripheral blood mononuclear cells.

§  Three treated groups: Methylcellulose (vehicle), Apremilast and Tofacitinib

§  Analysis was performed using Kruskal- Wallis test followed by Mann- Whitney U-test.

§  CD-8 positive cells and Terminal deoxynucleotidyl transferase TDT-mediated dUTP-biotin nick end labeling (TUNEL) and Ki6 were counted

·       Results:

§  There were more responder xenotransplants seen in the Tofacitinib treated mice (8/15; 53%) versus Apremilast (3/12; 25%) and these had higher mean number of hairs per graft

§  Histology and immunohistochemistry confirmed the macroscopic findings. Apremilast did no substantially restore the collapsed hair-follicle immunoprivilege or substantially reduce the degree of ahir follicle dystrophy. This contrasted the strong therapeutic effect of tofacitinib which echoes the effectiveness demonstrated in clinical trials.

§  The long-term systemic use raises the risk of underestimated and potentially significant adverse effects due to undesired cytokine blockade such as IL-10.

·       Conclusions by the authors:

§  The humanized mouse model of AA can enable us to explore systematically the long-term consequences of JAK/STAT inhibition

§  The use of humanized mouse model of AA is well suited to generate clinically relevant, predictive in vivo data in the context of preclinical drug screening for pharmacological interventions in AA

Case Reports:

JAAD:

o   Hair regrowth in 2 patients with recalcitrant central centrifugal cicatricial alopecia after use of topical metformin

o   Araoye, E. F., Thomas, J. A. L., & Aguh, C. U. (2020). Hair regrowth in 2 patients with recalcitrant central centrifugal cicatricial alopecia after use of topical metformin. JAAD Case Reports, 6(2), 106–108.

·       Metformin has shown efficacy in improving fibrosis in a mouse model of fibroproliferative disorders (such as uterine fibroids, systemic sclerosis, keloids) through the mediation of adenosine monophosphoate-activated protein kinase (AMPK). In a mouse model of idiopathic pulmonary fibrosis metformin reversed and accelerated resolution of the fibrotic process via deactivation and apoptosis of myofibroblasts. Adverse effects of systemic metformin include nausea, bloating, diarrhea, rarely lactic acidosis and hypoglycaemia. No systemic adverse effects reported with topical use. 10% metformin cream was chosen based on pharmacist recommendation to minimize systemic absorption

·       Both cases females with Type VI skin (69years old and 54 years old) biopsy proven stage 4a CCCA

§  Case 1:

§  Previous treatments: intralesional triamcinolone, topical clobetasol 0.05%, minoxidil 5% foam and Viviscal.

§  After 5 years of standard therapy discontinued all and started monotherapy topical 10% Metformin cream x3/week and then once daily. Substantial regrowth seen at 6 months

§  Case 2:

§  Previous treatments: intralesional triamcinolone, topical clobetasol 0.05%, minoxidil 5% foam and ketoconazole 2% cream. Used for 9 months with marginal improvement

§  Combination therapy of minoxidil topical, intralesional steroids and topical 10% metformin cream once daily used. Notable improvement seen after 4 months.

·       Limitation:

§  Trichoscopy was not performed to assess conversion of vellus to terminal follicles

§  Unclear how authors quantified improvement

·       Conclusions:

§  Large randomized controlled trials are needed to further assess the potential benefit of topical metformin

Other Case Reports worth looking at:

JAAD:

o   Albendazole-induced anagen effluvium

o   Ghias, M. H., Amin, B. D., & Kutner, A. J. (2020). Albendazole-induced anagen effluvium. JAAD (2020) Case Reports, 6(1), 54–56.

BJD:  Research Letters Jan 2020

o   Olmsted syndrome with alopecia universalis caused by heterozygous mutation in PERP (242)

o   S. Dai, Z. Sun, M. Lee, H. Wang, Y. Yang and Z. Lin

o   Detailed hair shaft analysis in a man with delayed-onset Chediak-Higashi syndrome (223)

o   O. Veraitch, L.Allison, G. Vizcay- Barreena, R. A. Fleck, A. Price, D. A. Fenton, J. A. McGrath and C. M Stefanato.