Beyond the Skin: Assessing Itch in Atopic Dermatitis - Insights from UK Dermatologists. A Cross-Sectional Survey and Narrative Review.

Little is known about the validity of numeric rating scales (NRS) and verbal rating scales (VRS) for itch and itch frequency for assessing itch severity in atopic dermatitis (AD). We evaluated the Patient-Reported Outcomes Information System (PROMIS® ) Itch Questionnaire (PIQ) - itch severity assessment, including multiple NRS,VRS and frequency of itch assessments, in adults with AD and compared their performance. Self-administered questionnaires and skin examinations were performed in 410 patients with AD (aged 18-90 years) in a dermatology practice setting. PIQ NRS,VRS and frequency of itch had good content validity, strong correlations with one another (Spearman correlations P < 0·001) and weak-to-moderate correlations with patient-oriented eczema measure (POEM), Eczema Area and Severity Index (EASI), objective SCORing AD (SCORAD) and Dermatology Life Quality Index (DLQI) (P < 0·001) and very good discriminant validity. Changes from baseline in NRS,VRS and frequency of itch were moderately to strongly correlated with one another, and weakly to moderately correlated with other patient-reported (POEM,SCORAD itch, DLQI) and clinician-reported outcomes (EASI, objective SCORAD). NRS and VRS worst itch and average itch showed moderate-to-good test-retest reliability. There were no floor or ceiling effects for NRS or VRS itch, but there were ceiling effects for itch frequency. Each assessment was completed in < 1 min by all patients. NRS,VRS and frequency of itch items from PIQ - itch severity showed good content and construct validity, reliability, and/or responsiveness in adults with AD, and were feasible for use in clinical trials and practice. What is already known about this topic? Numeric rating scales (NRS), verbal rating scales (VRS) and frequency of itch have been used to assess the burden of itch. However, there have been limited results demonstrating their validity, responsiveness, interpretability and feasibility, particularly in atopic dermatitis (AD). What does this study add? This study demonstrated that NRS, VRS and frequency of itch items from the Patient-Reported Outcomes Information System (PROMIS® ) Itch Questionnaire (PIQ) - itch severity assessments had good construct validity, responsiveness, reliability and feasibility in the assessment of adult AD. PIQ NRS, VRS and frequency of itch all appear to have sufficient validity, reliability and feasibility for use as assessments of itch in adults with AD in clinical practice and trials. What are the clinical implications of this work? PIQ NRS and VRS are all simple, valid, reliable and feasible for use in clinical practice and trials to assess itch in adults with AD. Linked Comment: Oosterhaven. Br J Dermatol 2020; 183:802-803.

Introduction: Itch is a distressing atopic dermatitis (AD) symptom that impacts quality of life. With the emergence of multiple new agents for the treatment of AD, the ability and speed with which an agent reduces itch may factor in agent selection. Objective: In this study, the primary objective was to quantify the rate at which agents for AD provide itch reduction using the peak itch numerical rating scale (NRS) data from phase II and III clinical trials. Methods: A PubMed literature search was performed in February 2020 to find phase II and III randomized clinical trials for the treatment of AD published from 2014 to 2020. A TIMEACLIR-Itch value was calculated from NRS data to represent the time to meaningful itch reduction. Results: We find a shorter TIme to achieving a MEAningful CLInical Response for itch reduction (TIMEACLIR-Itch) for small molecule inhibitors when compared to biologic agents. We also observe that nemolizumab achieves TIMEACLIR-Itch more quickly than IL-4 or IL-4/13 agents. Conclusion: These findings support the role that IL-31 has in producing itch and the role Janus kinase inhibitors (JAKinibs) play in itch reduction. This comparison of TIMEACLIR-Itch for different treatments may help guide therapy and management for AD patients.

Itch is the major symptom of atopic dermatitis (AD). Acupuncture has been shown to exhibit a significant effect on experimental itch in AD. Our study evaluated acupuncture and antihistamine itch therapy (cetirizine) on type I hypersensitivity itch and skin reaction in AD using a patient and examiner-blinded, randomized, placebo-controlled, crossover trial. Allergen-induced itch was evaluated in 20 patients with AD after several interventions in separate sessions: preventive (preceding) and abortive (concurrent) verum acupuncture (VAp and VAa), cetirizine (10mg, VC), corresponding placebo interventions (preventive, PAp, and abortive, PAa, placebo acupuncture; placebo cetirizine pill, PC) and a no-intervention control (NI). Itch was induced on the forearm and temperature modulated over 20min, using our validated model. Outcome parameters included itch intensity, wheal and flare size and the D2 attention test. Mean itch intensity (SE: 0.31 each) was significantly lower following VAa (31.9) compared with all other groups (PAa: 36.5; VC: 36.8; VAp: 37.6; PC: 39.8; PAp: 39.9; NI: 45.7; P<0.05). There was no significant difference between VAp and VC (P>0.1), although both therapies were significantly superior to their respective placebo interventions (P<0.05). Flare size following VAp was significantly smaller (P=0.034) than that following PAp. D2 attention test score was significantly lower following VC compared with all other groups (P<0.001). Both VA and cetirizine significantly reduced type I hypersensitivity itch in patients with AD, compared with both placebo and NI. Timing of acupuncture application was important, as VAa had the most significant effect on itch, potentially because of counter-irritation and/or distraction. Itch reduction following cetirizine coincided with reduced attention.

Background Itch is well-recognized as the universal and most burdensome symptom in atopic dermatitis (AD). Though, little is known about the heterogeneous characteristics of itch in AD. Objectives To examine the heterogeneous characteristics of itch and their associations in AD. Methods A prospective dermatology practice-based study of children and adults with AD (diagnosed by Hanifin-Rajka criteria) was performed using standardized, validated questionnaires and skin examinations. Severity of AD was assessed with Scoring AD (SCORAD), objective-SCORAD, Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), worst-itch verbal rating scale (VRS), average-itch VRS, Patient-reported Global Assessment (PtGA), hours spent itching, intensity of itch, and body surface area (BSA). Quality of life (QOL) was measured by the Dermatology Life Quality Index (DLQI). Latent class analysis (LCA) was used to identify dominant clinical patterns of itch-descriptors. The best-fitting model was selected by minimizing the Bayesian and Akaike information criteria. Multivariate logistic regression models were constructed to examine the relationship of latent class membership with AD severity (adjusting for age and gender) or DLQI scores (adjusting for age, gender, and SCORAD). Results Of 489 participants with AD, 307 (62.8%) reported ≥1 itch-descriptor, most commonly stinging (30.1%), painful (24.5%), burning (23.9%), tingling (23.1%), sensitive (21.7%), crawling (20.2%), warm (14.7%), pinprick (13.7%), tight (12.1%), throbbing (11.2%), sharp (9.6%), biting (9.2%), and/or shooting (3.5%). Participants who endorsed one or more of these itch-descriptors had more severe (verbal rating scales for average or worst itch), frequent and extensive itch, and worse overall AD severity (SCORAD, objective-SCORAD, EASI, IGA, PtGA) (all P ≤0.001). All of the itch-descriptors were more likely to be endorsed with increasing severity of itch and AD. LCA identified 3 distinct patterns of itch-descriptors: A) high conditional probabilities for nearly every itch-descriptor; B) intermediate probabilities for burning, crawling, painful, sensitive, stinging, and tingling; C) lowest probabilities for all itch-descriptors. Latent class membership was strongly associated with AD severity; Class A was associated with highest, class B with moderate, and class C with mildest severity of itch and AD (all P &amp;lt;0.0001). Class A (adjusted odds ratio [95% confidence interval]: 12.19 [2.14-231.29]) and B (4.02 [2.25-7.31]) were also associated with higher odds of moderate-severe impairments in DLQI scores compared to Class C, even after adjusting for AD severity. Conclusions Itch is a heterogeneous symptom of AD and can be experienced differently by AD patients. Many patients describe their itch as having qualities of pain (e.g., stinging, burning) and sensory disturbances (e.g., tingling, crawling), and not purely itch. Patients who described their itch using one or more these characteristics had more severe itch and AD and worse QOL. Clinicians caring for patients with AD should recognize the heterogeneous characteristics of itch and their burden on QOL. Future studies are needed to determine whether these distinct characteristics of itch have different underlying mechanisms or responses to therapy.

26691 Rapid and concurrent improvements in the signs and symptoms of atopic dermatitis with baricitinib in the phase 3 study, BREEZE-AD5

To investigate the clinical efficacy and safety of dupilumab in the treatment of moderate to severe atopic dermatitis (AD) in China. A small sample self-controlled study before and after treatment was conducted to retrospective analysis patients with moderate to severe AD treated with dupilumab in the department of dermatology of the First Affiliated Hospital of Chongqing Medical University from July 2020 to March 2022. Dupilumab 600 mg was injected subcutaneously at week 0, and then 300 mg was injected subcutaneously every 2 weeks. The condition was evaluated by SCORAD(severity scoring of atopic dermatitis), NRS(numerical rating scale), DLQI(dermatology life quality index) and POEM(patient-oriented eczema measure). The improvement of SCORAD, NRS, DLQI and POEM was analyzed by paired t test and non-parametric paired Wilcoxon. The results showed that a total of 67 patients with moderate to severe AD received dupilumab treatment, of which 41 patients (the course of treatment was more than 6 weeks) had reduced the severity of skin lesions, improved quality of life and reduced pruritus. A total of 23 patients completed 16 weeks of treatment. At 4, 8, 12 and 16 weeks, SCORAD, NRS, DLQI and POEM decreased compared with the baseline, and the differences were statistically significant. SCORAD (50.13±15.19) at baseline, SCORAD (36.08±11.96)(t=6.049,P<0.001) at week 4,SCORAD (28.04±11.10)(t=10.471,P<0.001) at week 8, SCORAD (22.93±9.72)(t=12.428,P<0.001) at week 12, SCORAD (16.84±7.82)(t=14.609,P<0.001) at week 16, NRS 7(6,8) at baseline, NRS 4(3,5)(Z=-3.861,P<0.001) at week 4, NRS 2(1,4)(Z=-4.088,P<0.001) at week 8, NRS 1(0,2)(Z=-4.206,P<0.001) at week 12, NRS 2(0,2)(Z=-4.222,P<0.001) at week 16, DLQI (13.83±5.71) at baseline, DLQI (8.00±4.02)(t=6.325,P<0.001) at week 4, DLQI (5.61±3.50)(t=8.060,P<0.001) at week 8, DLQI (3.96±1.99)(t=8.717,P<0.001) at week 12, DLQI (2.70±1.89)(t=10.355,P<0.001) at week 16, POEM (18.04±6.41) at baseline, POEM (9.70±4.70)(t=7.031,P<0.001) at week 4, POEM (7.74±3.48)(t=8.806,P<0.001) at week 8, POEM (6.35±3.33)(t=10.474,P<0.001) at week 12, POEM (4.26±2.51)(t=11.996,P<0.001) at week 16. In the 16th week, 100%(23 patients), 91.3%(21 patients), 34.8%(8 patients) and 8.7%(2 patients) of 23 patients reached SCORAD30, SCORAD50, SCORAD70, and SCORAD90 statuses, respectively. There were 82.6%(19 patients), 95.7%(22 patients) and 95.7%(22 patients) of 23 patients with NRS, DLQI and POEM improved by≥4 points compared with baseline. Twelve patients with AD who continued to receive dupilumab after 16 weeks showed further improvement in skin lesions. The adverse events were conjunctivitis and injection site reaction. In conclusion, dupilumab is an effective and safe treatment for moderate and severe AD. However, the longer-term efficacy and safety require further studies involving larger sample sizes and a longer follow-up time.

Atopic dermatitis (AD) is a multifaceted inflammatory skin disease characterized by chronic itch and acute itch flare (AIF), with basophils playing pivotal roles in both. VAMP7 mediates immune responses; however, its function in basophils remains undefined. We sought to elucidate the role of VAMP7 in basophil-mediated chronic itch and AIF in AD. Basophil-specific VAMP7 knockout (Ba-V7KO) and control V7fl/fl mice were used to model chronic itch and AIF in AD. The role of basophil-VAMP7 was assessed through RNA sequencing, fluorescence-activated cell sorting, quantitative RT-PCR, ELISA, and pharmacological inhibition. Ba-V7KO mice exhibited impaired chronic itch but normal AIF, accompanied by reduced skin levels of MCPT8, histamine, CCL24, and CCR3 across both models, whereas OSM was reduced only in the AIF model. After fluorescence-activated cell sorting, VAMP7 knockout basophils exhibited reduced activity, with OSM downregulated in AIF and CCR3 reduced in both models. VAMP7 knockout also decreased IL-4 and LTC4 release from basophils. Additionally, OSM downregulated barrier proteins and upregulated pruriceptors in keratinocytes; however, these effects were reversed by SC144, which restored skin barrier function in AIF without affecting itch response in either model. In the chronic model, CCR3 inhibition alleviated pruritus, correlating with the downregulation of itch-related transcripts. VAMP7 is essential for basophil-driven chronic itch and AIF in AD by maintaining basophil activity, regulating skin barrier damage in AIF via the OSM pathway, and modulating chronic itch through the CCL24/CCR3 axis. Targeting basophil-VAMP7 offers a potential strategy to restore skin barrier function in AIF and alleviate chronic itch in AD.

IntroductionAtopic dermatitis is a complex, chronic, inflammatory skin disease that requires long-term control of symptoms like itch and sleep loss and improvement in quality of life, in addition to reduction of clinical signs. Lebrikizumab is a selective interleukin-13 inhibitor approved in the European Union, United Kingdom, United Arab Emirates, Canada, and Japan for treatment of moderate-to-severe atopic dermatitis in adults and adolescents. Here, we assess the magnitude of changes across signs and symptoms of atopic dermatitis with lebrikizumab monotherapy over the 16-week induction period in two phase 3 studies, ADvocate1 and ADvocate2.MethodsEligible adults (aged ≥ 18 years) and adolescents (aged 12 to < 18 years and weighing ≥ 40 kg) with moderate-to-severe atopic dermatitis were randomized to receive either 250 mg of lebrikizumab or placebo subcutaneously every two weeks. Least squares mean percentage change from baseline through week 16 was compared between lebrikizumab and placebo using mixed model repeated measure analysis for the following endpoints: Eczema Area and Severity Index (EASI), Pruritus Numeric Rating Scale (NRS), Sleep-Loss Scale, Patient-Oriented Eczema Measure (POEM), and Dermatology Life Quality Index (DLQI).ResultsIn both trials, significant (P < 0.05) improvements were observed for lebrikizumab treatment compared with placebo at each 2-week timepoint for EASI, Pruritus NRS, Sleep-Loss Scale, and POEM, and at each 4-week timepoint for DLQI, through week 16. Statistically significant (P < 0.001) improvements were observed at 16 weeks for lebrikizumab treatment versus placebo in ADvocate1/ADvocate2 for EASI (71.9%/75.0% vs. 35.6%/43.3%), Pruritus NRS (53.3%/46.3% vs. 21.4%/18.0%), Sleep-Loss Scale (57.7%/55.6% vs. 23.9%/25.5%), POEM (54.4%/45.8% vs. 18.8%/16.9%), and DLQI (64.2%/60.5% vs. 28.5%/32.2%). Patient photos show improvements in skin appearance when disease measures improve.ConclusionsLebrikizumab monotherapy resulted in significant and fast improvements in multiple dimensions of disease (clinical signs, symptoms, and quality of life) over 16 weeks in patients with moderate-to-severe atopic dermatitis.Trial RegistrationClinicalTrials.gov identifiers, NCT04146363; NCT04178967.

Atopic dermatitis (AD) is a common inflammatory chronic skin disease typically associated with atopic comorbidities and other non-atopic conditions such as sleep disturbances, and mood/anxiety disorders. A growing literature proposed a crucial role of sleep disturbances in the development of mental health problems in AD. We tested this assumption by mediation model analyses in adult AD patients.A total of 57 patients (mean age ± std. dev., 34.28 ± 13.07 years; 27 males; range 18–67 years) diagnosed with AD participated in a cross-sectional study. We evaluated self-perceived severity of AD, insomnia, depression, and anxiety symptoms using validated questionnaires: the Patient-Oriented Eczema Measure (POEM), the Insomnia Severity Index (ISI), the Beck Depression Inventory-second edition (BDI-II), and the Generalized Anxiety Disorder-7 scale (GAD-7), respectively. Two mediation models were performed, testing the mediation effect of insomnia symptoms on the relationship between AD severity and depression (model 1) and anxiety (model 2). AD symptoms, as expressed by POEM, were positively associated with insomnia, depression, and anxiety severity. Insomnia fully mediated the effect of AD severity on depression and anxiety. Specifically, insomnia accounted for 81.64% of the relationship between atopic eczema severity and depression, and for 81.84% of the effect of AD severity on anxiety symptoms. The present study proposed a critical role of insomnia in predisposing adult AD patients to experience depression and anxiety. Early interventions focused on treating sleep disturbances could indirectly be beneficial on mental health of patients with AD, counteracting the onset and exacerbation of anxiety and depression disorders.

Disease characteristics, comorbidities, treatment patterns and quality of life impact in children <12 years old with atopic dermatitis: Interim results from the PEDISTAD Real-World Registry

Structured patient-reported outcomes of atopic dermatitis (AD) severity are not standardized in clinical practice. To determine the construct validity, internal consistency, cross-cultural validity and floor or ceiling effects of multiple AD severity assessments. This is a cross-sectional, population-based study of 2893 adults, including 602 adults who met a modified set of U.K. diagnostic criteria for AD. AD severity was assessed using self-reported global AD severity, Patient-Oriented Eczema Measure (POEM), Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD) and its objective and subjective components, and numerical rating scale (NRS)-itch. Quality of life was assessed using Short-Form (SF)-12 mental and physical health scores, Short-Form Six Dimensions (SF-6D) health utility scores and Dermatology Life Quality Index (DLQI). Mental health was assessed with the Hospital Anxiety and Depression Scale (HADS). PO-SCORAD, PO-SCORAD objective and subjective subscores, NRS-itch and POEM all had moderate-to-strong correlations with each other and DLQI, fair-to-moderate correlations with HADS-anxiety and HADS-depression, and inverse correlations with SF-12 mental component score and SF-6D (Pearson correlations, P < 0·001). All scores showed good criterion validity as judged by anova and receiver operator characteristics. PO-SCORAD, PO-SCORAD objective subscore and POEM had similarly good internal consistency (Cronbach's alpha = 0·84, 0·82 and 0·86); the PO-SCORAD subjective subscore was less internally consistent (alpha = 0·57). All scores showed potentially poor cross-cultural validity as demonstrated by uniform and nonuniform differential item functioning by age, sex and/or race/ethnicity for multiple items. There were floor effects for POEM, but not for the other assessments. PO-SCORAD, PO-SCORAD objective and subjective subscores, NRS-itch and POEM appear to be valid for assessing AD severity in clinical practice. What's already known about this topic? Few studies have demonstrated the validity of the atopic dermatitis severity assessments Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD), PO-SCORAD subscores, numerical rating scale (NRS)-itch and Patient-Oriented Eczema Measure (POEM). What does this study add? This study demonstrates that PO-SCORAD, PO-SCORAD subscores, NRS-itch and POEM all had good construct validity in the assessment of atopic dermatitis severity in adults. Only POEM demonstrated floor effects. What are the clinical implications of this work? PO-SCORAD, PO-SCORAD subscores, NRS-itch and POEM all appear to have sufficient validity to be used as assessments of atopic dermatitis severity in clinical practice.

Atopic dermatitis (AD) is predominantly characterized by intense itching, but concomitant skin pain is experienced by more than 40% of patients. Patients with AD display considerable somatosensory aberrations including increased nerve sensitivity to itch stimuli (hyperknesis), perception of itch from innocuous stimuli (alloknesis), or perception of pain from innocuous stimuli (allodynia). This review summarizes the current understanding of the similarities and differences in the peripheral mechanisms underlying itch and pain in atopic dermatitis. These distinct yet reciprocal sensations share many similarities in the peripheral nervous system including common mediators (such as serotonin [5-HT], endothelin-1 [ET-1], interleukin-33 [IL-33], and thymic stromal lymphopoietin [TSLP]), receptors (such as members of the G protein-coupled receptor [GCPR] family and toll-like receptors [TLRs]), and ion channels for signal transduction (such as certain members of the transient receptor potential [TRP] cation channels). Itch-responding neurons are also sensitive to pain stimuli. However, there are distinct differences between itch and pain signaling. For example, specific immune responses are associated with pain (type 1 and/or type 3 cytokines and certain chemokine C–C [CCL2, CCL5] and C–X–C motif ligands [CXCL]) and itch (type 2 cytokines, including IL-31, and periostin). The TRP melastatin channels TRPM2 and TRPM3 have a role in pain but no known role in itch. Activation of mu-opioid receptors is known to alleviate pain but exacerbate itch. Understanding the connection between itch and pain mechanisms may offer new insights into the treatment of chronic pain and itch in atopic dermatitis.

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), −0.2 (−0.8 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 −1.6 (−2.9 to −0.3), P = 0.015; Figs 1 and 2a]. This result was confirmed by daily diary [−2.09 (−3.31 to −0.87), P = 0.001] and observed after one full day of treatment [Fig. 2b, −0.61 (−1.21 to −0.01), P = 0.0457]. Improvement in nighttime sleep was also observed in mild AD [−1.46 (−2.60 to −0.32) 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 in the mild AD study population. Statistically significant improvement was seen after one day of treatment for itch and two days for sleep. It is possible that the immediate and robust improvements observed in the mild AD subgroup were seen not only because of different levels of cutaneous inflammation between AD severities but also because of distinct AD endotypes including different clinical manifestations, molecular levels and genetic associations.10 The concept of different endotypes in AD underlines the need for targeted therapeutics in different AD disease types.11 Itch related to nerve hypersensitivity causes increased scratching which worsens eczema and induces excoriations. Suppression of itch in mild AD can thus prevent worsening of atopic dermatitis. In our study, we saw no significant Eczema Area and Severity Index or SCORing Atopic Dermatitis (SCORAD) index improvement in early weeks; however, we did not expect improvement of acute lesions but rather of excoriations in the long term. Improvement in excoriations of mild patients was largest at Week 2 (P = 0.0374). We observed numerical improvement across all time-points studied in terms of lesion severity (excoriations). Tradipitant may represent a new oral systemic option for mild AD patients based on the well-tolerated safety profile and immediate robust improvement in itch and sleep. Future studies are needed to confirm these efficacy results and refine treatment recommendations for AD patients who despite having mild lesions, experience significant pruritus. SEW is a former employee of Vanda and a stockholder. CX is an employee of Vanda and a stockholder. ARK is an employee of Vanda and a stockholder. JLB is an employee of Vanda and a stockholder. MAM is an employee of Vanda and a stockholder. JW is an employee of Vanda and a stockholder. SPS is an employee of Vanda and a stockholder. BP is an employee of Vanda and a stockholder. SS is an investigator for Dermasence, Galderma, Kiniksa Pharmaceuticals, Menlo Therapeutics, Trevi Therapeutics, Novartis, Sanofi, and Vanda Pharmaceuticals Inc.; and is a consultant and/or member of the advisory board for Almirall, Bayer, Beiersdorf, Bellus Health, Bionorica, Cara Therapeutics, Celgene, Clexio Biosciences, DS Biopharma, Galderma, Menlo Therapeutics, Novartis, Perrigo, and Trevi Therapeutics. CP is an employee of Vanda and a stockholder. GB is an employee of Vanda and a stockholder. MHP is Chief Executive Officer of Vanda. Vanda Pharmaceuticals Inc. The sponsor designed the study. All authors, including those representing the sponsor, contributed to data interpretation and writing of the report. All authors had final responsibility for the decision to submit for publication. Vanda shares data related to this trial in peer-reviewed journals, medical conferences and Clinicaltrials.gov. Individual patient data are not publically available.

Background Itch, skin pain, and sleep disturbance are burdensome symptoms in atopic dermatitis (AD) that negatively influence a patient’s quality of life (QoL). Objective To evaluate the impact of baricitinib on patient-reported outcomes (PROs) in adult patients with moderate-to-severe AD, and explore the association between improvement in key signs and symptoms of AD with improvements in QoL and patient’s assessment of disease severity. Methods Data were analyzed from two phase III monotherapy trials (BREEZE-AD1/BREEZE-AD2) in which patients were randomized 2:1:1:1 to once-daily placebo, baricitinib 1-mg, 2-mg, or 4-mg for 16 weeks and assessed using PRO measures. Results At week 16, baricitinib 4-mg and 2-mg significantly reduced itch severity (Itch Numeric Rating Scale (NRS) (BREEZE-AD1: percent change from baseline −36.6% and −29.4% vs. placebo (–12.0%), p≤.001 and p≤.05; BREEZE-AD2: −47.2% and −46.9% vs. placebo (–16.6%), p≤.001). Baricitinib significantly reduced SCORing AD (SCORAD) pruritus (4-mg in BREEZE-AD1 and 2-mg in BREEZE-AD2) and Patient Oriented Eczema Measure (POEM) itch (both doses). Improvements in skin pain severity and sleep disturbance were also observed. Improvements in AD symptoms showed higher correlations with patients’ assessment of AD severity and QoL than improvements in skin inflammation. Conclusions Baricitinib significantly improved symptoms in patients with moderate-to-severe AD. ClinicalTrials.gov identifiers NCT03334396 (BREEZE-AD1) and NCT03334422 (BREEZE-AD2).

Chronic itch is a debilitating symptom of atopic dermatitis (AD). Current therapeutic approaches for managing this condition include topical and systemic pharmacological agents with inconsistent efficacy and potential adverse effects. Sophocarpine (SPC) is a quinolizidine alkaloid derived from Sophora flavescens and has a wide range of bioactive activities, including anticancer, anti-inflammatory, antiviral, and analgesic effects. Recent research has shown that SPC exerts anti-inflammatory, anti-pruritic, and analgesic effects primarily through the inhibition of TRPA1 and TRPV1 channels. In this study, we investigated the antipruritic effects of SPC in an AD mouse model of chronic itch. AD-like chronic itch was induced in mice by topical application of MC903 solution (2 nmol in ethanol) on the shaved nape skin once daily for 14 consecutive days. Spontaneous scratching behaviors were recorded on D8, D10, D12, and D14. AD mice were administered SPC (1, 5, 10, and 20mg·kg-1·d-1, i.p.) from D8 to D14. SPC (500 ng/10 μL) was also intrathecally injected once a day for 7 days. We showed that SPC treatment dose-dependently mitigated scratching behavior and suppressed spinal astrocyte reactivity in AD mice. Histological and imaging analyses revealed that SPC treatment reversed epidermal thickening and attenuated dermal vasodilation. In LPS-stimulated astrocytes in vitro, SPC (20, 80 μM) dose-dependently downregulated the mRNA levels of the proinflammatory factors Tnf, Cxcl1, Ccl2, Il1b, Il6, and Lcn2. In IP3R2 knockout mice, disruption of spinal astrocytic calcium signaling also reduced chronic itch, thereby supporting the involvement of astroglial pathways. Collectively, these results demonstrate that SPC effectively alleviates chronic itch in the AD mouse model by suppressing astrocyte reactivity, likely through modulation of neuroinflammatory and calcium signaling pathways, supporting its potential as a promising therapeutic candidate for the treatment of AD-associated chronic itch. Schematic summary of the main findings illustrating that SPC alleviates chronic itch in AD by inhibiting spinal astrocyte reactivity and pro-inflammatory signaling. Specifically, SPC suppresses the activation of spinal astrocytes in the dorsal horn, reduces the expression of pro-inflammatory mediators, and thereby decreases scratching behavior in AD mice.