c. polymeropoulos, G. Birznieks & M. H. polymeropoulos the genetic background of Atopic Dermatitis (AD) with chronic pruritus is complex. Filaggrin (FLG) is an essential gene in the epidermal barrier formation s. Loss-of-function (Lof) variants in FLG associated with skin barrier dysfunction constitute the most well-known genetic risk factor for AD. in this study, we focused on the frequency and effect of FLG loss-of-function variants in association with self-reported age-of-onset of AD. The dataset consisted of 386 whole-genome sequencing (WGS) samples. We observe a significant association between FLG Lof status and age-of-onset, with earlier age of onset of AD observed in the FLG LOF carrier group (p-value 0.0003, Wilcoxon two-sample test). We first tested this on the two most prevalent FLG variants. Interestingly, the effect is even stronger when considering all detected FLG Lof variants. Having two or more FLG Lof variants associates with the onset of AD at 2 years of age. In this study, we have shown enrichment of rare variants in the EDC region in cases compared with controls. Age-of-onset analysis shows not only the effect of the FLG and likely eDc variants in terms of the heightened risk of AD, but foremost enables to predict early-onset, lending further credence to the penetrance and causative effect of the identified variants. Understanding the genetic background and risk of early-onset is suggestive of skin barrier dysfunction etiology of AD with chronic pruritus Atopic dermatitis (AD) is a chronic, inflammatory skin disease with an estimated prevalence of 7.3% in the US 1. The genetic background of chronic pruritus in AD is complex. The heritability of AD is estimated to be around 75% 2. Interestingly, when one or both parents have AD the risk of a child developing AD is higher than the risk of developing other atopic conditions, such as asthma and allergic rhinitis 3. This suggests that there are genetic factors specific to AD beyond those for general atopy 4. One of the main functions of the skin is to act as a barrier between the individual and the environment, preventing water loss and at the same time preventing pathogen and allergen entry 5. Skin barrier dysfunction is a key clinical feature of AD, as this facilitates penetration of allergens, immunological dysfunction, and consequently an increased risk of developing eczema 5,6. The skin barrier dysfunction has been associated with the etiology of the itch-scratch cycle. Genes encoding skin barrier proteins have been shown to play a role in the heritability of AD 7,8. FLG is the most studied gene in AD. Loss of function (LOF) variants resulting in aberrant FLG production, constitute the best-known AD gene-association and have been shown to predispose individuals to AD 5,8. FLG initially synthesizes profilaggrin, which is then transformed to FLG monomers which interact with intermediate filaments in the stratum corneum (SC), causing such to aggregate into dense parallel arrays of macrofilaments. This promotes cellular compaction and keratin cros...

The 5-HT(2A/2C) receptor antagonist, ritanserin, was reported to retard the acquisition of conditioned responses (CRs) during classical conditioning of the rabbit's nictitating membrane (NM) response. The present study compared the effects of ritanserin on acquisition of CRs to a tone conditioned stimulus (CS) with that of the 5-HT(2A/2C) receptor antagonist, LY-53,857 and the 5-HT2A selective antagonist, MDL-11,939. All three drugs were injected at equimolar doses of 0.067, 0.67 and 6.7 micromol/kg, SC, 1 h before behavioral testing. Ritanserin and MDL-11,939 retarded CR acquisition to a tone CS, while LY-53,857 had no effect. Control experiments demonstrated that ritanserin (1 micromol/kg), MDL-11,939 (1 micromol/kg) and LY-53,857 (2 micromol/kg) had no effect on baseline responding or non-associative responding to the CS. However, both ritanserin and MDL-11,939 impaired the performance of the unconditioned NM reflex, as measured by a decrease in UR amplitudes on US alone trials, while LY-53,857 had no effect. In previously trained animals, ritanserin robustly impaired the performance of CRs, as measured by a reduced ability of the CS to elicit CRs, while the effects of LY-53,857 and MDL-11,939 were marginal. The retardation of associative learning produced by ritanserin and MDL-11,939 may have been due, at least in part, to their impairment of the NM reflex arc. Since MDL-11,939 is a highly selective 5-HT2A antagonist, the retardation of learning and impairment of UR amplitudes produced by MDL-11,939 and ritanserin may have been due to blockade of the 5-HT2A receptor. The ability of ritanserin and MDL-11,939 to produce effects on learning and performance that were opposite to that of 5-HT(2A/2C) agonists suggests that they may be acting as inverse agonists at that receptor. These results stress the importance of the serotonergic system for optimal associative learning and motor function.

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Atopic dermatitis (AD) is a relapsing and remitting disease characterized by intense pruritus that can lead to scratching and eczematous lesions that vary in extent and severity. 1 Over 60% of AD cases are mild, characterized by slight erythema, induration and lichenification. 2,3 Chronic pruritus, pruritus lasting more than 6 weeks, has been reported by 91% of AD patients. 4,5 The pathophysiology of AD is driven by a combination of skin barrier dysfunction, neuroinflammation and immune system dysregulation. 6,7 Elevated substance P (SP) is found in both serum and lesional skin of patients with AD. 5,8,9 SP, a neuropeptide released from the activation of sensory neurons, preferentially binds to the neurokinin-1 (NK-1) receptor and is a known itch mediator. 5 Tradipitant (VLY-686), a novel NK-1 receptor antagonist, has the potential to reduce itch related to AD through inhibition of SP-mediated itch signalling. We examined the efficacy and safety of tradipitant, in reduction of chronic pruritus in adults with mild to severe AD.EPIONE was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted at 74 US centres. Altogether 375 patients [mean (SD): age, 41.8 (15.0) years; sex, 243 (64.8%) female] were randomly assigned to tradipitant (n = 188) or placebo (n = 187). Although there was a numerical benefit in the tradipitant group over placebo, EPIONE did not meet its primary endpoint of reduction in pruritus [Least Squares (LS) Mean difference (95% CI), À0.2 (À0.8 to 0.4), P = 0.567]. However, robust antipruritic effect was observed in patients with mild lesion severity [rated 1 or 2 by the validated Investigator Global Assessment for Atopic Dermatitis at baseline À1.6 (À2.9 to À0.3), P = 0.015; Figs 1 and 2a]. This result was confirmed by daily diary [À2.09 (À3.31 to À0.87), P = 0.001] and observed after one full day of treatment [Fig. 2b, À0.61 (À1.21 to À0.01), P = 0.0457]. Improvement in nighttime sleep was also observed in mild AD [À1.46 (À2.60 to À0.32) P = 0.013].The most frequent treatment-emergent adverse events (TEAEs) were mild to moderate. There were no common TEAEs identified in the treatment arm, defined by >5% incidence.Tradipitant treatment resulted in a clinically meaningful reduction in patient-reported worst itch and sleep disturbance Figure 1 Worst Itch-Numeric Rating Scale (WI-NRS) change by week. Mild atopic dermatitis (AD) patients have greater improvement in worst itch after tradipitant treatment. Forest plots of the analysis of intent-to-treat and IGA 1,2 WI-NRS change by week. Plotted as least squares mean difference and 95% CI after tradipitant or placebo treatment.

This study examined the role of the serotonin 5-HT2 receptor in motor function by examining the effect of antagonists on the motor performance of a cranial nerve reflex, the nictitating membrane (NM) reflex of the rabbit. The NM reflex was elicited by varying intensities of a tactile stimulus and the magnitudes of the elicited responses were measured at each intensity. Dose-response curves were obtained for the effects of several 5-HT2 receptor antagonists on response magnitude. d-Bro-molysergic acid diethylamide (BOL), LY-53,857 and ketanserin had no significant effect on the magnitude of the NM reflex, indicating that they are neutral antagonists. However, the 5-HT2 receptor antagonists ritanserin, MDL-11,939 and mianserin produced a significant reduction in response magnitude with no significant effects on response frequency, suggesting that they were acting as inverse agonists at the 5-HT2 receptor. The reduction in reflex magnitude produced by mianserin (10 micromol/kg) was fully blocked by BOL (5.8 micromol/kg), supporting the conclusion that mianserin was producing a reduction in reflex magnitude through an effect at the 5-HT2 receptor. The occurrence of inverse agonism suggests the possible existence of constitutive activity in vivo. We conclude that the 5-HT2 receptor (either 2A or 2C) plays an important role in motor function, perhaps by providing a tonic influence on motor systems.