Influence of pathogenic filaggrin variants on dupilumab treatment in atopic dermatitis

Background: Pathogenic variants in filaggrin (FLG) are associated with an increased risk of atopic dermatitis (AD). Objective: We evaluated the influence of FLG variants on the effectiveness of dupilumab treatment in AD. Methods: This prospective observational study included adult AD patients treated with dupilumab from the BioDay registry. FLG was analyzed with single-molecule molecular inversion probe–targeted sequencing. Novel mutations were confirmed by Sanger sequencing. Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), numeric rating scale (NRS) pruritus, Dermatology Quality of Life Index (DLQI), and Patient-Oriented Eczema Measure (POEM) were assessed at baseline and at weeks 16 and 52. The study was registered at ClinicalTrials.gov as NCT03549416. Results: Genetic analysis of the 285 included patients showed biallelic pathogenic variants (FLG−/−) in 41 (14%), monoallelic pathogenic variants (FLG−/+) in 64 (23%), and wild-type alleles (FLG+/+) in 180 patients (63%). Three novel pathogenic variants were found. We observed no clinically relevant differences in EASI, IGA, NRS pruritus, DLQI, or total POEM scores for patients with and without pathogenic FLG variants at all time points. The FLG−/− group showed significantly higher POEM flaking and dryness scores at week 16 (P < .001 and P = .002, respectively) and week 52 (P < .001 and P = .016, respectively) compared to FLG+/+ as well as significant differences compared to FLG−/+, while differences in delta scores were nonsignificant. Conclusion: The effectiveness of dupilumab treatment in AD patients was not influenced by pathogenic FLG variants. However, patients with biallelic pathogenic FLG variants tended to have drier skin before and during dupilumab treatment compared to patients with monoallelic pathogenic variants or wild-type alleles

Alitretinoin as a treatment modality for ichthyosis in women of childbearing age - a case series and review of the literature

Background: Acitretin, a synthetic vitamin A derivative, is the most studied and widely used oral retinoid for ichthyoses. Its major disadvantage is the need for contraceptive measures during three years after discontinuation. An alternative is needed for women of childbearing age. With alitretinoin, another retinoid, pregnancy is considered safe one month after discontinuation. Objectives: To provide evidence for alitretinoin as an alternative for acitretin for ichthyosis in women of childbearing age. Our experience is shared in a case series combined with an overview of the current literature. Methods: Nine women of childbearing age (19-31 years, median 21) with different subtypes of ichthyosis (autosomal recessive congenital ichthyosis, (superficial) epidermolytic ichthyosis, erythrokeratoderma variabilis, and epidermolytic epidermal nevi, a mosaic form of epidermolytic ichthyosis) were included and treated with 30mg alitretinoin during 2-28 months. Severity was measured by Ichthyosis Area Severity Index (IASI) and Investigator Global Assessment (IGA). A literature search in Pubmed using the Mesh terms "alitretinoin", "skin diseases, genetic" and "ichthyosis" was performed.Results: Significant reduction in the mean scores of IGA, IASI-erythema, IASI-scaling and IASI-total was seen. Seven patients are still being treated, one patient stopped to become pregnant, one patient discontinued due to financial reasons. Observed side effects were reversible headache (n=6), asteatotic eczema (n=1), 'not feeling well' temporarily (n=1) and easier blistering of the feet (n=1). The literature search resulted in six case reports and case series about alitretinoin in ichthyosis and ichthyosis syndromes with in total 29 patients. The vast majority (21/29) reported significant improvement or even complete remission of skin symptoms. However, validated outcome measures to support these results were lacking. Side effects (n=16) were relatively mild, except for benign intracranial hypertension (n=1) and autoimmune hypothyroidism (n=1).Conclusion: Our study shows, with validated outcome measures, that alitretinoin is effective to mitigate the symptoms of ichthyosis in women of childbearing age and a suitable alternative to acitretin

Solving a new R2lox protein structure by microcrystal electron diffraction

Microcrystal electron diffraction (MicroED) has recently shown potential for structural biology. It enables the study of biomolecules from micrometer-sized 3D crystals that are too small to be studied by conventional x-ray crystallography. However, to date, MicroED has only been applied to redetermine protein structures that had already been solved previously by x-ray diffraction. Here, we present the first new protein structure—an R2lox enzyme—solved using MicroED. The structure was phased by molecular replacement using a search model of 35% sequence identity. The resulting electrostatic scattering potential map at 3.0-Å resolution was of sufficient quality to allow accurate model building and refinement. The dinuclear metal cofactor could be located in the map and was modeled as a heterodinuclear Mn/Fe center based on previous studies. Our results demonstrate that MicroED has the potential to become a widely applicable tool for revealing novel insights into protein structure and function