Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the ...aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.
Uncombable hair syndrome (UHS), also known as “spun glass hair syndrome,” “pili trianguli et canaliculi,” or “cheveux incoiffables” is a rare anomaly of the hair shaft that occurs in children and ...improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. Elucidation of the molecular outcomes of the disease-causing mutations by cell culture experiments and tridimensional protein models demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins. Scanning electron microscopy observations revealed morphological alterations in hair coat of Padi3 knockout mice. All together, these findings elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology in general.
Introduction
Alopecia areata (AA) can negatively affect quality of life (QoL) and is associated with increased prevalence of anxiety and depression (vs people without AA). This study compared ...physician-assessed and patient self-rated severity of AA in a European sample and described the patient-reported burden of AA stratified by physician-assessed severity.
Methods
Real-world data were collected from the Adelphi Real World AA Disease Specific Programme™, a retrospective point-in-time cross-sectional survey of dermatologists and their adult patients with AA in five European countries (France, Germany, Italy, Spain, UK). Physicians provided clinical data and an AA severity assessment, according to their own definition of ‘mild’, ‘moderate’ and ‘severe’. Patients were invited to provide their perception of AA severity and completed patient-reported outcome (PRO) questionnaires, including Skindex-16 for AA (Skindex-16 AA), EuroQol-5-dimension questionnaire 5-level (EQ-5D-5L), Hospital Anxiety and Depression Scale and the Work Productivity and Activity Impairment Questionnaire.
Results
Data for 2083 patients were collected by 239 physicians; 561 of these patients completed PRO questionnaires. In 78.5% of cases with available data (
N
= 549), there was alignment between patient and physician-rated AA severity (severity was rated higher by physicians in 15.7% of cases, by patients in 5.8% of cases). Data from all PRO instruments showed an increase in patient-reported burden and work and activity impairment with increasing physician-rated AA severity. For the Skindex-16 AA, the Emotions scale had the worst scores; anxiety/depression was the EQ-5D-5L dimension with the highest percentages of patients reporting any perceived problem.
Conclusions
These data highlight the significant impact that AA can have beyond hair loss, especially for patients with severe AA. There was substantial physician–patient alignment on severity assessment. Higher physician-rated AA severity was associated with higher levels of patient-reported disease burden, including anxiety and depression, and work and activity impairment. These data may help inform appropriate treatment strategies.
Plain Language Summary
Alopecia areata (AA) can negatively affect quality of life and is associated with increased prevalence of anxiety and depression (vs people without AA). This study used surveys of adult patients with AA in Europe and their dermatologists to compare how doctors and patients assess AA severity. We also looked at how patients rate the overall burden and broader effects of AA (not just hair loss) according to whether their doctor classed their AA as ‘mild’, ‘moderate’ or ‘severe’. Data for 2083 patients were collected by 239 doctors; 561 patients completed questionnaires about their AA and its potential effects on their quality of life, mental health and ability to work or perform other activities. In 78.5% of cases (from 549 patients with both patient and doctor-rated severity), patients and their doctors agreed on the same AA severity category (mild, moderate or severe). However, in 15.7% of cases, doctors rated AA severity as being higher than reported by the patient, and in 5.8% of cases the patient classed their AA as being more severe than reported by the doctor. Data from patient questionnaires showed that the burden associated with AA was higher in patients with more severe AA (as per their doctor’s own definition of severity); anxiety/depression was the most commonly reported problem related to quality of life. This study highlights the significant impact that AA can have beyond hair loss, especially for patients with severe AA. Information from this study may help to inform appropriate treatment strategies for people with AA.
Abstract
We present data from a UK cohort of patients with alopecia areata (AA) who have sought Janus kinase inhibitor (JAKi) treatments prior to National Health Service funding. We have explored ...referral methods, access to consultations, and shared care in monitoring and acquisition of medication both from the UK and abroad. We have looked at the drugs and dosage, adjuvant therapies and response to treatment, and report data on side-effects and reasons for changing drugs or stopping treatment. Thirty-four patients (25 adults and nine children) self-referred to a UK-based private hair clinic for JAKi treatment over a period of 36 months. The median age of patients was 40 years (interquartile range 18–50). The patients sought treatment from a wide geographical area in the UK, with one patient living 400 miles from the clinic. Seventeen (50%) and 14 (41%) patients were prescribed baricitinib and tofacitanib, respectively, with three (9%) patients prescribed both. Nineteen (56%) patients had severe alopecia with > 95% hair loss. Social media, in particular a closed Facebook group, was an important source of referral and information on sourcing medication from abroad. Nine per cent of consultations were virtual (telephone/video). The cost of treatment varied from £100 per month to £1400, with a large difference between UK-sourced medication and that from abroad. Eight (24%) patients showed no scalp regrowth response to first-line treatment, despite dose escalation, with one subsequently experiencing total hair regrowth on swapping to a different JAKi class. One patient had to stop treatment after developing breast cancer. JAKi are an exciting and emerging treatment for AA that are yet to be widely prescribed by UK practitioners. However, the response to JAKi is not universal. Owing to the cost of private prescription, patients are choosing to source JAKi from abroad. Our study presents data on how the alopecia community has helped inform patients about treatment access.
Our patient is a 75-year-old man who presented after his pet dog licked persistently at an asymptomatic lesion behind his right ear. Examination revealed a nodular lesion in the postauricular sulcus. ...Histology confirmed malignant melanoma, which was subsequently excised. Canine olfactory detection of human malignancy is a well-documented phenomenon. Advanced olfaction is hypothesised to explain canine detection of bladder, breast, colorectal, lung, ovarian, prostate and skin cancers. Further research in this area may facilitate the development of a highly accurate aid to diagnosis for many malignancies, including melanoma.
Global and trichoscopic photography are fundamental in the clinical assessment of hair loss. Standardised protocols in this respect are lacking.BACKGROUNDGlobal and trichoscopic photography are ...fundamental in the clinical assessment of hair loss. Standardised protocols in this respect are lacking.To create novel, pragmatic and flexible standardised photography protocols for hair loss, which are practical to use for clinicians and medical photographers alike.OBJECTIVESTo create novel, pragmatic and flexible standardised photography protocols for hair loss, which are practical to use for clinicians and medical photographers alike.Published disease severity scales for a variety of hair loss conditions were utilised to create standardised photography protocols. There were reviewed and refined by a national clinical working group of consultant dermatologists specialising in hair loss.METHODSPublished disease severity scales for a variety of hair loss conditions were utilised to create standardised photography protocols. There were reviewed and refined by a national clinical working group of consultant dermatologists specialising in hair loss.Three main presentation-based protocols are presented, defined by the type of hair loss a patient may present with; including pattern loss, frontal fibrosing alopecia/traction alopecia and alopecia areata and other patchy hair loss disorders. Additional supplementary protocols facilitate further specific views for a variety of individualised clinical scenarios, based on user discretion.RESULTSThree main presentation-based protocols are presented, defined by the type of hair loss a patient may present with; including pattern loss, frontal fibrosing alopecia/traction alopecia and alopecia areata and other patchy hair loss disorders. Additional supplementary protocols facilitate further specific views for a variety of individualised clinical scenarios, based on user discretion.We present novel, pragmatic, standardised photography protocols for hair loss disorders. These can be used by clinicians even where formal medical photography units are unavailable. Standardisation allows high-quality, informative images for objective assessment and monitoring of hair loss in clinical practice, as well as in research settings.CONCLUSIONSWe present novel, pragmatic, standardised photography protocols for hair loss disorders. These can be used by clinicians even where formal medical photography units are unavailable. Standardisation allows high-quality, informative images for objective assessment and monitoring of hair loss in clinical practice, as well as in research settings.
Abstract
Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, demonstrated efficacy in adults with severe alopecia areata (AA) over 36 weeks in two phase III, randomized, double-blind, ...placebo-controlled trials, BRAVE-AA1 (NCT03570749) and BRAVE-AA2 (NCT03899259). Using integrated data from the long-term extension periods of both trials, we report treatment response to baricitinib by the AA severity subgroup based on the Severity of Alopecia Tool (SALT) score over 52 weeks. Patients randomized to baricitinib at baseline (n = 855) retained their treatment allocation (2 mg/4 mg) through to week 52 in both trials and were included in week 52 analyses; placebo nonresponders were rescued at week 36. Severity of AA at baseline was defined as severe (SALT score 50–94) or very severe (SALT score 95–100). Key inclusion criteria were SALT score ≥ 50, current AA episode lasting > 6 months to < 8 years without spontaneous improvement within 6 months prior to screening, and no previous inadequate response to oral JAK inhibitors. Efficacy endpoints included the proportion of patients achieving a SALT score ≤ 20 and the proportion of patients achieving Clinician-Reported Outcome (ClinRO) Measure for Eyebrow/Eyelash Hair Loss™ 0,1 (no, minimal gaps) with ≥ 2-point improvement from baseline among patients with baseline scores 2,3 (significant gaps, no notable eyebrows/eyelashes). Analyses were presented descriptively for each subgroup up to week 52. Nonresponder imputation was used for missing data. Data collected after permanent study drug discontinuation or at remote visits due to the COVID-19 pandemic were excluded. In total, 1200 patients were enrolled (BRAVE-AA1, n = 654; BRAVE-AA2, n = 546). At baseline, the overall mean (SD) age was 37.5 (12.9) years; 60.7% were female and 46.8% and 53.2% of patients had severe and very severe AA, respectively. At week 52, a SALT score ≤ 20 was achieved by 36.1% and 51.2% of patients on baricitinib 2 mg and baricitinib 4 mg, respectively, with severe AA and 12.4% and 27.7% of patients on baricitinib 2 mg and baricitinib 4 mg, respectively, with very severe AA. Eyebrow/Eyelash Hair Loss™ scores 0,1 with ≥ 2-point improvement from baseline at week 52 were achieved by 19.4% and 26.0% (baricitinib 2 mg) and 37.5% and 38.5% (baricitinib 4 mg) of patients with severe AA and 24.3% and 25.3% (baricitinib 2 mg) and 47.6% and 48.1% (baricitinib 4 mg) of patients with very severe AA. Following 52 weeks of treatment with both baricitinib doses, clinical responses of SALT score ≤ 20 were observed both in patients with severe and very severe AA. Proportions of patients achieving full coverage or minimal gaps in eyebrows and eyelashes were similar at week 52, regardless of scalp hair-loss severity.
Funding sources: Eli Lilly and Company.
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