It Remains Unknown Whether Filaggrin Gene Mutations Evolved to Increase Cutaneous Synthesis of Vitamin D

About 8-10% of normal Northern Europeans are heterozygous carriers of common FLG mutations, while only 1-4% of southern Europeans display these mutations, and only very rarely are mutations detected in African populations. Although mutations are found in Asians, they are different from those encountered in Northern Europeans. Importantly, FLG mutation carriers have 10% increased serum vitamin D concentrations compared to controls. Based on these observations, we have proposed that this latitude-dependent gradient of FLG mutations across Europe, Asia and Africa could have provided an evolutionary advantage for heterozygous FLG mutation carriers, residing at northern latitudes, depletion of the FLG downstream product, trans-urocanic acid, would facilitate the intracutaneous synthesis of vitamin D3 by allowing increased transcutaneous absorption of UVB photons. Such loss-of-function FLG mutations would have provided an evolutionary advantage for modern humans, living in the far North of Europe, where little UV-B penetrates the atomosphere. In a recent article, it was concluded not only that the UVB-Vitamin D3 hypothesis is invalid, but also that FLG genetic variations, including loss-of-function variants, provide little or no impact on the fitness of modern humans. While we welcome studies that reassess our hypothesis, their conclusions are not valid for reasons explained in this letter

Skin disorders in Parkinson's disease:potential biomarkers and risk factors

Astrid-Helene Ravn, Jacob P Thyssen, Alexander Egeberg Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark Abstract: Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, characterized by a symptom triad comprising resting tremor, rigidity, and akinesia. In addition, non-motor symptoms of PD are well recognized and often precede the overt motor manifestations. Cutaneous manifestations as markers of PD have long been discussed, and cumulative evidence shows an increased prevalence of certain dermatological disorders in PD. Seborrheic dermatitis is considered to occur as a premotor feature of PD referable to dysregulation of the autonomic nervous system. Also, an increased risk of melanoma has been observed in PD. Light hair color is a known risk factor for melanoma, and interestingly the risk of PD is found to be significantly higher in individuals with light hair color and particularly with red hair. Furthermore, several studies have reported a high prevalence of PD in patients with bullous pemphigoid. Moreover, a 2-fold increase in risk of new-onset PD has been observed in patients with rosacea. Besides the association between PD and various dermatological disorders, the skin may be useful in the diagnosis of PD. Early PD pathology is found not only in the brain but also in extra-neuronal tissues. Thus, the protein α-synuclein, which is genetically associated with PD, is present not only in the CNS but also in the skin. Hence, higher values of α-synuclein have been observed in the skin of patients with PD. Furthermore, an increased risk of PD has been found in the Cys/Cys genotype, which is associated with red hair color. In this review, we summarize the current evidence of the association between PD and dermatological disorders, the cutaneous adverse effects of neurological medications, and describe the potential of skin protein expression and biomarkers in identification of risk and diagnosis of PD. Keywords: Parkinson’s disease, melanoma, rosacea, seborrheic dermatitis, bullous pemphigoi

A detailed look at the European Medicines Agency's recommendations for use of Janus kinase inhibitors in patients with atopic dermatitis

Background Oral Janus kinase inhibitors (JAKi) have been approved for the treatment of several chronic inflammatory conditions, including rheumatoid arthritis (RA) and atopic dermatitis (AD). Prompted by new evidence, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recently reassessed the benefit–risk balance of oral JAKi. The PRAC recommended that oral JAKi should be used only if no suitable alternatives are available in patients ≥65 years of age, or who have a history of atherosclerotic cardiovascular (CV) disease, other CV risk factors (e.g. history of long-term smoking) or have malignancy risk factors, and used with caution in patients at risk of pulmonary embolism or deep vein thrombosis. The European Commission's final decision was issued in March 2023. Objectives Our goal was to highlight the PRAC recommendations, especially in the context of oral JAKi use in AD. Methods Authors summarized the PRAC recommendations, the new clinical evidence on oral JAKi safety and key differences between patients with RA and AD. Results Risk of developing adverse events of special interest (e.g. cardiovascular events, malignancy) is higher in patients with RA than in patients with AD, because of the higher prevalence of the underlying risk factors. Conclusions The benefit–risk profile of JAKi approved for AD remains favourable, including use as first-line systemic therapy for patients with AD <65 years of age and without CV or malignancy risk factors