In-person validation of the Ichthyosis Scoring System.

BACKGROUND: Ichthyoses are a heterogeneous group of skin disorders characterized by scaling and erythema. Recognizing the variability of scale and erythema by region and ichthyosis subtype, we developed the Ichthyosis Scoring System (ISS) to quantify severity. We previously found ISS to have high inter- and intrarater reliability in evaluating photographic images. To confirm ISS clinical utility, we examined its performance at the 2022 Foundation for Ichthyosis and Related Skin Types conference. METHODS: Sixty-five participants were evaluated by 3 of 9 medical professionals trained to score ichthyosis scale and erythema using ISS. Intrarater and interrater intraclass correlation coefficients (ICC) were analyzed using one-way and two-way random effects models, respectively. RESULTS: Intrarater reliability was excellent (ICC = 0.931, 95% CI, 0.921-0.940) for scale and good (ICC = 0.876, 95% CI, 0.853-0.899) for erythema scoring. Compared to photo validation with excellent intrarater reliability ratings for both scale (ICC = 0.956, 95% CI, 0.925-0.974) and erythema (ICC = 0.913, 95% CI, 0.855-0.949), ISS demonstrated equivalent reliability for live use. Overall interrater reliability for 10 body sites showed excellent (ICC >0.9) and good (ICC >0.75) agreement and consistency for both scale and erythema. Palms were an exception, demonstrating moderate (ICC >0.5) interrater agreement and consistency for erythema evaluation. CONCLUSIONS: ISS is a reliable measure of global and regional ichthyosis severity during in-person evaluations. Ease-of-use, accessibility, and content validity in both live and photographic evaluation endorse ISS as a standard for ichthyosis severity analysis.

When to expect scalp hair regrowth during treatment of severe alopecia areata with baricitinib: insights from trajectories analyses of patients enrolled in two phase III trials.

BACKGROUND: Baricitinib is approved for the treatment of adults with severe alopecia areata (AA). In the absence of robust data on the patterns of regrowth during treatment of severe AA, there is a gap in the knowledge regarding treatment expectations. OBJECTIVES: To examine whether different clinical response subgroups could be identified in baricitinib-treated patients with severe AA and factors that contribute to these subgroups. METHODS: The BRAVE-AA1 and BRAVE-AA2 phase III trials enrolled patients with severe AA [Severity of Alopecia Tool (SALT) score ≥ 50 (≥ 50% scalp hair loss)]. Patients randomized to baricitinib 4 mg or 2 mg retained their treatment allocation for 52 weeks. Based on patterns identified through growth mixture modelling (GMM), patients were categorized into responder subgroups according to when they first achieved ≥ 30% improvement from baseline in SALT score (SALT30). For each responder subgroup, trajectories of response (i.e. achievement of a SALT score ≤ 20, SALT score ≤ 10 and ≥ 50% change from baseline in SALT score) and baseline disease characteristics are reported. RESULTS: Respectively, 515 and 340 patients were randomized to once-daily baricitinib 4 mg and 2 mg at baseline; 69% and 51%, respectively, achieved SALT30 at least once by week 52. Based on GMM findings, we identified three responder subgroups: early (SALT30 by week 12), gradual (SALT30 after week 12-week 36) and late (SALT30 after week 36-week 52). The proportions of early, gradual and late responders and nonresponders were, respectively, 33%, 28%, 8% and 31% among patients treated with baricitinib 4 mg, and 20%, 23%, 9% and 49%, respectively, among those treated with baricitinib 2 mg. Early responders had a shorter trajectory to maximal clinical outcomes (e.g. > 78% achieved a SALT score ≤ 20 by week 36) vs. gradual or late responders. Early responders were more frequent among patients with baseline severe AA (SALT score 50 to < 95) vs. very severe AA (SALT score 95-100). Overall, responders (early to late) were more frequent in patients with short (< 4 years) episodes of hair loss. CONCLUSIONS: These analyses identified early, gradual and late responder subgroups for scalp hair regrowth in baricitinib-treated patients with severe AA, and that these subgroups are influenced by baseline characteristics. Findings from these analyses will help to inform treatment expectations for scalp hair regrowth.

Janus kinase inhibitors for alopecia areata.

Janus kinase (JAK) inhibitors have ushered in a new era in alopecia areata (AA). Historically, moderate-to-severe AA was refractory to treatment. JAK inhibitors have changed that; now, treatment of moderate-to-severe AA is possible. Here, we briefly review the history of and rationale for JAK inhibitor treatment of AA, phase 3 clinical trial data, and considerations regarding differences among JAK inhibitors, safety, and patient selection.

Development of the alopecia areata scale for clinical use: Results of an academic-industry collaborative effort.

BACKGROUND: The current classification for alopecia areata (AA) does not provide a consistent assessment of disease severity. OBJECTIVE: To develop an AA severity scale based on expert experience. METHODS: A modified Delphi process was utilized. An advisory group of 22 AA clinical experts from the United States was formed to develop this AA scale. Representatives from the pharmaceutical industry provided feedback during its development. RESULTS: Survey responses were used to draft severity criteria, aspiring to develop a simple scale that may be easily applied in clinical practice. A consensus vote was held to determine the final AA severity statement, with all AA experts agreeing to adopt the proposed scale. LIMITATIONS: The scale is a static assessment intended to be used in clinical practice and not clinical trials. CONCLUSION: The final AA disease severity scale, anchored in the extent of hair loss, captures key features commonly used by AA experts in clinical practice. This scale will better aid clinicians in appropriately assessing severity in patients with this common disease.

A phase 2a randomized, placebo-controlled study to evaluate the efficacy and safety of the oral Janus kinase inhibitors ritlecitinib and brepocitinib in alopecia areata: 24-week results.

BACKGROUND: Alopecia areata (AA) is an autoimmune form of hair loss with limited treatments. OBJECTIVE: To evaluate the efficacy and safety of the Janus kinase inhibitors ritlecitinib and brepocitinib in patients who have AA with ≥ 50% scalp hair loss. METHODS: Patients were randomized to once-daily ritlecitinib, brepocitinib, or placebo. The primary efficacy endpoint was a 24-week change from baseline in the Severity of Alopecia Tool (SALT) score. The key secondary efficacy endpoint was the proportion of patients achieving 30% improvement in SALT score (SALT30). RESULTS: The ritlecitinib, brepocitinib, and placebo groups included 48, 47, and 47 patients, respectively. At week 24, least-squares mean difference from placebo in SALT score change from baseline was 31.1 (95% confidence interval [CI], 18.8-43.5) for ritlecitinib and 49.2 (95% CI, 36.6-61.7) for brepocitinib (P < .0001 for both comparisons with placebo). SALT30 was achieved by 50% (90% CI, 38%-62%) of patients receiving ritlecitinib, 64% (90% CI, 51%-75%) receiving brepocitinib, and 2% (90% CI, 0%-9%) receiving placebo. Two patients experienced a serious adverse event (rhabdomyolysis) in the brepocitinib group only. LIMITATIONS: Only a single-dosage regimen of each study drug was included. CONCLUSION: Treatment with ritlecitinib or brepocitinib for 24 weeks was efficacious and generally well tolerated.

The Alopecia Areata Consensus of Experts (ACE) study part II: Results of an international expert opinion on diagnosis and laboratory evaluation for alopecia areata.

BACKGROUND: We previously reported the Alopecia Areata Consensus of Experts study, which presented results of an international expert opinion on treatments for alopecia areata. OBJECTIVE: To report the results of the Alopecia Areata Consensus of Experts international expert opinion on diagnosis and laboratory evaluation for alopecia areata. METHODS: Fifty hair experts from 5 continents were invited to participate in a 3-round Delphi process. Consensus threshold was set at greater than or equal to 66%. RESULTS: Of 148 questions, expert consensus was achieved in 82 (55%). Round 1 consensus was achieved in 10 of 148 questions (7%). Round 2 achieved consensus in 47 of 77 questions (61%). The final face-to-face achieved consensus in 25 of 32 questions (78%). Consensus was greatest for laboratory evaluation (12 of 14 questions [86%]), followed by diagnosis (11 of 14 questions [79%]) of alopecia areata. Overall, etiopathogenesis achieved the least category consensus (31 of 68 questions [46%]). LIMITATIONS: The study had low representation from Africa, South America, and Asia. CONCLUSION: There is expert consensus on aspects of epidemiology, etiopathogenesis, clinical features, diagnosis, laboratory evaluation, and prognostic indicators of alopecia areata. The study also highlights areas where future clinical research could be directed to address unresolved hypotheses in alopecia areata patient care.

Consensus recommendations for the use of retinoids in ichthyosis and other disorders of cornification in children and adolescents.

Topical and systemic retinoids have long been used in the treatment of ichthyoses and other disorders of cornification. Due to the need for long-term use of retinoids for these disorders, often beginning in childhood, numerous clinical concerns must be considered. Systemic retinoids have known side effects involving bone and eye. Additionally, potential psychiatric and cardiovascular effects need to be considered. Contraceptive concerns, as well as the additive cardiovascular and bone effects of systemic retinoid use with hormonal contraception must also be deliberated for patients of childbearing potential. The Pediatric Dermatology Research Alliance (PeDRA) Use of Retinoids in Ichthyosis Work Group was formed to address these issues and to establish best practices regarding the use of retinoids in ichthyoses based on available evidence and expert opinion.

Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma.

The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

JAK Inhibitors for the Treatment of Pediatric Alopecia Areata.

Alopecia areata is a common autoimmune condition that disproportionately affects children and can significantly hinder quality of life. Few safe and effective therapies are available for the treatment of severely affected pediatric patients. JAK inhibitors have been recently established as an effective and well-tolerated therapy in adults, but there are limited data regarding the use of JAK inhibitors to treat alopecia areata in children. Here, we review the available literature regarding the use of JAK inhibitors in children in dermatology and across other medical disciplines.

The Alopecia Areata Consensus of Experts (ACE) study: Results of an international expert opinion on treatments for alopecia areata.

BACKGROUND: A systematic review failed to identify any systemic therapy used in alopecia areata (AA) where use is supported by robust evidence from high-quality randomized controlled trials. OBJECTIVE: To produce an international consensus statement on the use and utility of various treatments for AA. METHODS: Fifty hair experts from 5 continents were invited to participate in a 3-round Delphi process. Agreement of 66% or greater was considered consensus. RESULTS: In the first round, consensus was achieved in 22 of 423 (5%) questions. After a face-to-face meeting in round 3, overall, consensus was achieved for only 130 (33%) treatment-specific questions. There was greater consensus for intralesional treatment of AA (19 [68%]) followed by topical treatment (25 [43%]). Consensus was achieved in 45 (36%) questions pertaining to systemic therapies in AA. The categories with the least consensus were phototherapy and nonprescription therapies. LIMITATIONS: The study included a comprehensive list of systemic treatments for AA but not all treatments used. CONCLUSION: Despite divergent opinions among experts, consensus was achieved on a number of pertinent questions. The concluding statement also highlights areas where expert consensus is lacking and where an international patient registry could enable further research.

Histopathologic findings characteristic of CARD14-associated papulosquamous eruption.

BACKGROUND: Pathogenic mutations in caspase recruitment domain-containing protein 14 (CARD14) lead to CARD14-associated papulosquamous eruption, which shares clinicopathologic findings with psoriasis and pityriasis rubra pilaris. We aimed to describe distinguishing histopathologic features of CARD14-associated papulosquamous eruption. METHODS: This retrospective study examined the histopathologic features of specimens from patients with confirmed CARD14-associated papulosquamous eruption and adult patients with plaque psoriasis and pityriasis rubra pilaris. RESULTS: Lesional skin biopsies from patients with CARD14-associated papulosquamous eruption consistently showed alternating checkerboard parakeratosis and orthokeratosis, acanthosis without acantholysis, and dilated vessels in the dermal papillae, with some cases also showing follicular plugging. CONCLUSION: CARD14-associated papulosquamous eruption has a range of findings, with a predominance of features typically associated with pityriasis rubra pilaris.

Tofacitinib cream plus narrowband ultraviolet B phototherapy for segmental vitiligo in a child.

Segmental vitiligo often presents in childhood and tends to be more recalcitrant to therapy than generalized vitiligo. Recently, Janus kinase inhibitors have emerged as a promising treatment option, with some reports suggesting that concomitant ultraviolet light exposure may enhance therapeutic response. Here, we present a child with segmental vitiligo who responded rapidly and completely to treatment with tofacitinib cream plus phototherapy.

Cellular and Metabolic Basis for the Ichthyotic Phenotype in NIPAL4 (Ichthyin)-Deficient Canines.

Mutations in several lipid synthetic enzymes that block fatty acid and ceramide production produce autosomal recessive congenital ichthyoses (ARCIs) and associated abnormalities in permeability barrier homeostasis. However, the basis for the phenotype in patients with NIPAL4 (ichthyin) mutations (among the most prevalent ARCIs) remains unknown. Barrier function was abnormal in an index patient and in canines with homozygous NIPAL4 mutations, attributable to extensive membrane stripping, likely from detergent effects of nonesterified free fatty acid. Cytotoxicity compromised not only lamellar body secretion but also formation of the corneocyte lipid envelope (CLE) and attenuation of the cornified envelope (CE), consistent with a previously unrecognized, scaffold function of the CLE. Together, these abnormalities result in failure to form normal lamellar bilayers, accounting for the permeability barrier abnormality and clinical phenotype in NIPA-like domain-containing 4 (NIPAL4) deficiency. Thus, NIPAL4 deficiency represents another lipid synthetic ARCI that converges on the CLE (and CE), compromising their putative scaffold function. However, the clinical phenotype only partially improved after normalization of CLE and CE structure with topical ω-O-acylceramide because of ongoing accumulation of toxic metabolites, further evidence that proximal, cytotoxic metabolites contribute to disease pathogenesis.

Review of genodermatoses with characteristic histopathology and potential diagnostic delay.

Advances in human genetics have enabled discovery of new genes for inherited skin diseases and cutaneous malformations as well as refined categorization of genodermatoses. Careful phenotyping has been central to genetic discoveries, and it provides critical clues for clinical diagnoses, particularly when the skin disorder is not congenital. This article will review several lesser-known genodermatoses that often present after infancy with recognizable histopathologic features.

Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome.

Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin.

CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris.

BACKGROUND: Heterozygous mutations in caspase recruitment domain family member 14 gene (CARD14) have been shown to be associated with psoriasis and familial pityriasis rubra pilaris (PRP). Many subjects with CARD14 mutations display features of both disorders, which can result in diagnostic uncertainty. In addition, these eruptions are often recalcitrant to conventional psoriasis therapies such as methotrexate, oral retinoids, and tumor necrosis factor-α inhibitors. OBJECTIVE: We sought to describe the clinical characteristics, family history, and response to therapy in subjects with papulosquamous eruptions due to mutations in CARD14. METHODS: Subjects were referred for genetic testing as part of a registry of subjects with inherited disorders of keratinization. DNA was isolated from blood or saliva, and multiplex targeted sequencing or whole exome sequencing was performed. Clinical histories of subjects with CARD14 mutations were reviewed. RESULTS: We identified 15 kindreds with CARD14-associated papulosquamous eruption (CAPE). Characteristic features of CAPE include early age of onset; prominent involvement of the cheeks, chin, and ears; family history of psoriasis or PRP; minimal response to conventional topical and systemic psoriasis therapies; and improvement with ustekinumab. LIMITATIONS: Relatively small sample size. CONCLUSIONS: Many subjects with CARD14 mutations display characteristics of both psoriasis and PRP. We propose the term CARD14-associated papulosquamous eruption to describe this spectrum of disease. Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab.

Tofacitinib for the treatment of alopecia areata and variants in adolescents.

BACKGROUND: There are no reliably effective therapies for alopecia areata (AA). OBJECTIVE: We sought to evaluate the benefit and adverse effects of the Janus kinase 1/3 inhibitor, tofacitinib, in a series of adolescent patients with AA. METHODS: We reviewed the records of 13 adolescent patients with AA treated with tofacitinib. Severity of disease was assessed using the Severity of Alopecia Tool (SALT). Adverse events were evaluated by laboratory monitoring, physical examinations, and review of systems. RESULTS: Thirteen patients, aged 12 to 17 years, with AA were treated with tofacitinib. Nine patients experienced clinically significant hair regrowth. Median percent change in SALT score was 93% (mean 61%; 1%-100%) at an average of 6.5 months of treatment. Adverse events were mild. LIMITATIONS: Limitations include the retrospective nature of the data, small sample size, and lack of a control group. CONCLUSION: Tofacitinib is a promising therapy for AA in adolescents. The use of tofacitinib and other Janus kinase inhibitors for the treatment of AA in this age group should be further evaluated in prospective clinical trials.

Tofacitinib for the treatment of severe alopecia areata and variants: A study of 90 patients.

BACKGROUND: Alopecia areata (AA) is a common autoimmune disorder. There are no reliably effective therapies for AA. OBJECTIVE: We sought to evaluate the safety and efficacy of the Janus kinase 1/3 inhibitor, tofacitinib, in a series of patients over an extended period of time. METHODS: This is a retrospective study of patients age 18 years or older with AA with at least 40% scalp hair loss treated with tofacitinib. The primary end point was the percent change in Severity of Alopecia Tool (SALT) score during treatment. RESULTS: Ninety patients met inclusion criteria. Of 65 potential responders to therapy, defined as those with alopecia totalis or alopecia universalis with duration of current episode of disease of 10 years or less or alopecia areata, 77% achieved a clinical response, with 58% of patients achieving greater than 50% change in SALT score over 4 to 18 months of treatment. Patients with AA experienced a higher percent change in SALT score than did patients with alopecia totalis or alopecia universalis (81.9% vs 59.0%). Tofacitinib was well tolerated, and there were no serious adverse events. LIMITATIONS: The retrospective nature of the data, the relatively small number of patients, and lack of a control group are limitations. CONCLUSION: Tofacitinib should be considered for the treatment of severe AA, alopecia totalis, and alopecia universalis; tofacitinib dose response will be better defined by randomized controlled trials.