Itch Scores Research Articles

Achievement of No-to-minimal Itch and Sleep Improvement with Tapinarof Cream 1% Once Daily in Two Pivotal Phase 3 Trials in Adults and Children Down to 2 Years of Age with Atopic Dermatitis

Introduction: Itch frequently causes sleep disturbance in patients with atopic dermatitis (AD). The gold-standard Peak Pruritus Numerical Rating Scale (PP-NRS) improvement from baseline is 4 points; however, more stringent outcomes include achieving no-to-minimal itch (PP-NRS ≤1). Tapinarof cream 1% once daily (QD) demonstrated superior efficacy, including itch reduction, versus vehicle and was well tolerated in adults and children down to 2 years of age with AD in the ADORING 1 and 2 pivotal phase 3 trials. Here we present highly stringent itch outcomes and sleep improvement with tapinarof from these trials. Methods: In ADORING 1 and 2, patients with a Validated Investigator Global Assessment for Atopic Dermatitis™ score ≥3 (moderate or severe), Eczema Area and Severity Index score ≥6, and body surface area involvement of 5–35% were randomized to tapinarof cream or vehicle QD for 8 weeks. Stringent PP-NRS assessments were analyzed post hoc and included achieving no‑to‑minimal itch (PP-NRS ≤1) or PP-NRS score <2. Mean weekly PP-NRS scores were assessed on an 11-point scale (0 indicates “no itch” and 10 is “worst imaginable itch”). The Patient Oriented Eczema Measure (POEM) question 2 evaluated sleep disturbance on a 5-point scale (0 indicates “no days” and 4 is “every day”); outcomes were pooled and stratified by age. Results: 407 and 406 patients were randomized in ADORING 1 and 2. Mean baseline scores were similar across ADORING 1 and 2 treatment groups: PP-NRS, 6.7 and 6.8; pooled POEM sleep disturbance scores, 2.0 (aged ≥12 years) and 2.4 (<12 years), respectively. Statistically significant achievement of no-to-minimal itch (PP-NRS ≤1), PP-NRS <2, and improvement in sleep were achieved with tapinarof versus vehicle as early as Week 1, the first assessment, and continued through Week 8. Stringent itch outcomes were achieved with tapinarof versus vehicle at Week 8: no-to-minimal itch, 31.4% versus 17.4% (P=0.0072) and 33.0% versus 14.0% (P=0.0003); and PP-NRS <2, 48.1% versus 28.4% (P=0.0006) and 46.8% versus 19.6% (P<0.0001) in ADORING 1 and 2, respectively. Sleep scores improved with tapinarof versus vehicle at Week 8: –1.4 versus –0.8 (≥12 years); –1.7 versus –1.0 (<12 years; both P<0.0001). Conclusion: Tapinarof cream 1% QD demonstrated early, significant, and meaningful achievement of no-to-minimal itch and improvement of sleep in adults and children down to 2 years of age with AD.

Persistent Inadequate Disease Control and Therapeutic Inertia in Moderate-to-Severe Atopic Dermatitis: A 12-month Longitudinal Analysis of Real-world Outcomes from the TARGET-DERM AD registry

Background: Therapeutic inertia refers to the delay or failure in treatment escalation in patients not achieving adequate disease control; it is a challenge in the management of moderate-to-severe atopic dermatitis (AD). Despite the availability of conventional (CST) and advanced systemic therapies (AST) utilized for the treatment of moderate to severe AD, many patients do not achieve treatment success. However, the extent of this inadequacy in real-world clinical practice remains underexplored. Objectives: This study evaluates the occurrence of therapeutic inertia and the proportion of patients with moderate-to-severe AD who continue to show inadequate response after receiving systemic therapies for a duration from 3 to 12 months Methods: We conducted a longitudinal analysis of patients with moderate-to-severe AD (vIGA-AD≥3) from the TARGET-DERM AD registry, including 3,457 participants from 39 centers in the U.S. and Canada. Eligible patients had documented outcomes at the initiation of systemic therapy and after 3 months up to 12 months of follow up. We assessed clinician- and patient-reported outcomes to identify the proportion of patients not meeting treatment targets based on expert consensus. An inadequate response was defined as not achieving a validated Investigator Global Assessment (vIGA-AD) score ≤2, a 50% improvement in Body Surface Area (BSA), and a ≥4-point reduction in the Worst Pruritus Numeric Rating Scale (WP-NRS). An optimal response was defined as a vIGA-AD score ≤1 (clear or almost clear skin), BSA ≤2%, and WP-NRS itch score of 0/1 (complete or almost complete skin resolution). Results: Out of 2,107 patients with moderate-to-severe AD, 445 met the inclusion criteria. The majority were adults (63.8%), female (62.0%), and Non-Hispanic White (45.4%), with an average age of 31 years. Most patients (88.8%) initiated treatment with AST, with dupilumab being the most common (86.5%). The mean vIGA-AD was 3.3 for AST and 3.6 for CST at initiation (P<0.01). At 6 months, 37% and 67% of AST-treated patients had inadequate responses in terms of skin clearance and itch outcomes, respectively, while 82% and 79% did not achieve optimal responses. At 12 months, these figures were approximately 30% and 66% for inadequate responses and 85% and 88% for not achieving optimal responses, respectively. CST-treated patients showed a similar trend. Conclusions: The study reveals that a significant portion of moderate-to-severe AD patients fail to achieve adequate disease control with systemic therapies over 12 months, indicating substantial presence of therapeutic inertia. These findings suggest a need for more proactive management strategies in AD treatment.

Pregabalin for Neuropathic Pain and Itch in Recessive Dystrophic Epidermolysis Bullosa

Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience neuropathic pain and itch. There is a lack of evidence on any treatment for these symptoms in patients with RDEB. To test the efficacy of pregabalin in the treatment of neuropathic pain and itch in patients with RDEB. A randomized, double-blinded, crossover trial of oral pregabalin (50-300 mg/d) vs placebo was conducted at 2 sites, Toronto (Canada) and Santiago (Chile) from January 1, 2019, to December 31, 2020. Patients eligible to participate were diagnosed with RDEB, aged 8 to 40 years, not pregnant or lactating (if female), and had evidence of probable neuropathic pain and itching defined as distal thermal sensory loss (confirmed by thermal roller), score of 4 or greater on the Douleur Neuropathique 4 questionnaire (DN4), and score greater than 4 on the 10-point visual analog scale [VAS]). Patients with a clinically important or poorly controlled medical or psychiatric condition or pregabalin intolerance or allergy were excluded. Of 41 patients screened, 3 were not eligible and 28 declined enrollment. Data analyses were performed in 2021 through 2023. Participants received both pregabalin and matched placebo (titrated to a maximum-tolerated dose of 300 mg/day) in a randomized sequence so that comparisons could be made within participants and between groups. Difference in the mean pain and itch scores between pregabalin and placebo treatment (measured using VAS) before and after intervention. In all, 10 participants were randomized to 2 groups, 6 patients (mean [SD] age, 26.7 [8.1] years; 3 females [50%]) in group 1, and 4 patients (mean [SD] age, 26.5 [7.8] years, 2 females [50%]) in group 2. Group 1 received a sequence of pregabalin-placebo while group 2 received placebo-pregabalin. Pregabalin significantly reduced mean (SD) pain scores by 1.9 (1.5) points when controlling for sequence and treatment period vs baseline, while placebo had 0.1 (2.0) points of reduction. The effect of pregabalin was a mild but significant reduction in itch compared to baseline (mean [SD] points, 0.9 [2.2]), whereas the placebo produced no reduction (0.1 [2.5]). The mean pregabalin dose was generally well tolerated. The results of this randomized crossover trial indicate that pregabalin significantly reduced pain and itch scores from baseline compared to placebo in patients with RDEB. This feasibility study provided preliminary data on the efficacy of pregabalin in managing pain and itch in RDEB and gathered essential data to inform the design of a larger cohort trial. ClinicalTrials.gov Identifier: NCT03928093.

Safety and efficacy of a novel 0.5% epinastine topical eyelid cream in allergic conjunctivitis: a phase 3 trial.

The high prevalence of allergic conjunctivitis in Japan necessitates novel, easy-to-use treatment options for prophylactic use. We evaluated the safety and efficacy of a newly-developed 0.5% epinastine topical eyelid cream to prevent the development of allergic conjunctivitis. This was a phase 3, single-centre, double-masked, intra-patient randomised trial in asymptomatic adults (aged 20-65 years) with seasonal allergic conjunctivitis in Japan. The left and right eyes of eligible patients were randomised to receive a topical application of either 0.5% epinastine cream (~ 30mg per dose) to one eye or placebo cream to the other (on the outer skin of the upper and lower eyelids) after a conjunctival antigen challenge (CAC) test. Symptom severity was assessed up to 24h post-treatment. Primary efficacy endpoints were mean ocular itching and conjunctival hyperaemia severity scores in each eye; safety endpoints included adverse events (AEs) and adverse drug reaction (ADRs). In total, 30 patients (60 eyes) were included in the study. The 0.5% epinastine topical eyelid cream reduced mean ocular itching scores (difference in least squares means ± standard error, - 1.12 ± 0.214; p < 0.0001) and mean conjunctival hyperaemia scores (- 0.54 ± 0.197; p = 0.0097) 24h after treatment versus placebo. The 0.5% epinastine topical eyelid cream was well tolerated, with no AEs or ADRs reported. With its novel route of administration, 0.5% epinastine topical eyelid cream may be considered a unique, easy-to-use, once-daily treatment option to prevent the onset of seasonal allergic conjunctivitis.

Short-term effect of a moderate-potency topical corticosteroid on epidermal biophysical parameters in patients with mild-to-moderate atopic dermatitis: A randomised controlled study.

Skin barrier dysfunction is an important component of atopic dermatitis (AD) pathophysiology. Topical corticosteroids (TCSs) are the mainstay therapy, but steroid phobia is emerging due to potential side effects. We aimed to determine the short-term effect of clobetasone butyrate on patients with AD. This investigator-blinded, randomised, moisturiser-controlled study evaluated patients with stable mild-to-moderate AD. Clobetasone butyrate ointment plus aqueous cream (Aq) or Aq alone was applied on randomised sites twice daily for 6 weeks. The itch score, modified Eczema Area and Severity Index (M-EASI) and epidermal biophysical parameters were assessed at baseline and 1 h, 3 h, 2 weeks and 6 weeks after application. Sixteen patients, among whom 14 (87.5%) were women and two (12.5%) were men, participated in the study. There were no significant differences in pH, transepidermal water loss (TEWL) and hydration between TCS + Aq and Aq from 1 h to 6 weeks. A non-significant trend of pH increment was observed with TCS + Aq from baseline to 6 weeks. TEWL and hydration improved at 6 weeks for both treatment arms. The difference in TEWL from baseline was significant with Aq (P=0.01). The M-EASI at 6 weeks was comparable between the two arms. TCS + Aq improved itch and erythema better than Aq (P=0.02). No cutaneous adverse effects were observed at both sites. Short-term application of clobetasone butyrate with Aq is safe with no significant changes in epidermal biophysical parameters while controlling the symptoms and signs of eczema faster than Aq alone.

Treatment of Brachioradial Pruritus: A Tertiary Center Retrospective Analysis.

This retrospective study investigates the efficacy of 2 treatment regimens, pregabalin alone versus pregabalin combined with ketamine, amitriptyline, and lidocaine cream, in reducing itch in patients with brachioradial pruritus at a tertiary care center. Electronic medical records of 64 brachioradial pruritus patients seen at the University of Miami Itch Center were analyzed. A significant reduction in itch scores was seen with both treatments, with no significant difference between the groups. A small number of patients experienced adverse effects, including drowsiness and weight gain with pregabalin and skin irritation with ketamine, amitriptyline, and lidocaine cream. Ultimately, our findings underscore the potential of utilizing combined therapy for difficult-to-treat brachioradial pruritus cases and implementing individualized approaches for managing neuropathic pruritus. Further controlled clinical trials are needed to establish optimal treatment protocols.

Clinical Characteristics of Cutaneous Pain in Psoriasis.

Background: Psoriasis is a common inflammatory disease that is often associated with itch and pain. This study aimed to evaluate the clinical characteristics of skin pain among patients with psoriasis. Materials: A total of 106 patients diagnosed with psoriasis were included in the study (34% female; mean age 42.1 ± 13.0 years). Disease severity was assessed using the Psoriasis Area and Severity Index (PASI). Itch severity was evaluated using the numeric rating scale (NRS) and 4-Item Itch Score (4IIS). The intensity of skin pain was measured through the NRS, short-form McGill pain questionnaire (SF-MPQ), visual analog scale (VAS), and Douleur Neuropathique-4 questionnaire (DN4). Results: In the past week, 84.9% of psoriasis patients reported itch, while 50% of them reported skin pain. The average NRS for itch was 4.52 ± 2.88 points, and the 4IIS yielded a mean score of 6.79 ± 4.37 points. In terms of the intensity of cutaneous pain, the mean NRS was 2.42 ± 2.96 points; the SF-MPQ score averaged 4.84 ± 7.51 points; and the VAS score was 1.92 ± 2.65 points. Furthermore, 17% of adult psoriasis patients reported neuropathic pain. In 84.9% of the participants, skin pain was concurrent with areas affected by itch, while 18.9% of patients exhibited cutaneous pain encompassing all itchy areas. The pain NRS demonstrated significant correlations with the SF-MPQ (r = 0.531, p < 0.001), VAS (r = 0.779, p < 0.001), itch NRS (r = 0.551, p < 0.001), and 4IIS (r = 0.569, p < 0.001). No association was found between the pain NRS and PASI or disease duration. Conclusions: Skin pain of mild intensity and itch of moderate intensity are prevalent symptoms in psoriasis patients. Strong correlations between skin pain and itch can be explained by the process of neurogenic inflammation.

Relationship between pruritus and sleep in participants with primary biliary cholangitis in the Phase 2b GLIMMER trial

BackgroundCholestatic pruritus and fatigue are debilitating conditions associated with primary biliary cholangitis (PBC) and can significantly impact patients’ quality of life. Pruritus in PBC often worsens at night and patients frequently report sleep disturbance, which contributes to cognitive symptoms and fatigue. Linerixibat is an ileal bile acid transporter inhibitor in clinical development for the treatment of pruritus associated with PBC and was recently assessed versus placebo in the Phase 2b GLIMMER trial. This post-hoc analysis assesses the relationship between pruritus severity and sleep disturbance in participants of GLIMMER regardless of treatment group.MethodsGLIMMER (NCT02966834), a multicenter, double-blind, randomized, placebo-controlled trial, recruited 147 patients with PBC and moderate-to-severe pruritus. Following 4 weeks single-blind placebo, patients (randomized 3:1) received linerixibat or placebo for 12 weeks (to Week 16). Participants graded their itch (twice daily) and its interference with sleep (once daily) in an electronic diary using a 0–10 numerical rating scale (NRS). Weekly and monthly itch scores were calculated as the mean of the worst daily itch score over the respective time period. At study visits, participants completed the 5-D itch scale and the PBC-40 quality of life questionnaire, both of which contain an item specific to itch-related sleep disturbance. The impact of pruritus on sleep was assessed post hoc through correlations between the changes in NRS, 5-D itch, and PBC-40.ResultsStrong correlations were found between change from baseline in weekly itch and sleep NRS scores (r = 0.88 [95% confidence interval (CI): 0.83; 0.91]) at the end of treatment (Week 16), as well as in monthly itch and sleep NRS scores (r = 0.84 [95% CI: 0.80; 0.87]). Patients with improved weekly pruritus score severity category demonstrated reduced perceived sleep interference on average. Itch responders (≥2-point improvement in weekly itch score from baseline) displayed larger improvements in weekly sleep NRS score, 5-D itch, and PBC-40 sleep items, than itch non-responders (<2-point improvement).ConclusionsA strong correlation exists between changes in pruritus severity and sleep interference in patients with PBC; pruritus reduction could generate concomitant improvement in sleep.

#1151 The prevalence and disease burden of CKD associated pruritus in Danish dialysis patients and current treatment practices—preliminary results

Abstract Background and Aims Chronic kidney disease associated pruritus (CKD-aP) is rarely assessed by health care providers and potentially under-reported by patients despite the potential negative impact on health-related quality of life (HRQoL). Our aim was to investigate the prevalence of CKD-aP in a large cohort of Danish dialysis patients based on validated patient-reported outcome (PRO) instruments. A secondary aim was to investigate CKD-aP awareness among renal physicians including current treatment practices. Method The study was designed as a non-interventional, cross-sectional multicentre study. Chronic dialysis patients from four different regions in Denmark were invited to participate. CKD-aP was assessed with a one-page questionnaire containing Danish versions of two validated PRO instruments. The worst itch numeric rating scale (WI-NRS) was used for itch severity within the previous 24 hours (ranging from 0-10 with CKD-aP defined as WI-NRS score &amp;gt;4 which equals moderate to severe CKD-aP). The 5-D itch scale was used as a multidimensional measure of itching and HRQoL. The five dimensions of the 5-D itch scale (degree, duration, direction, disability, and distribution) were summed together to obtain total score ranging from 5 (no pruritus) to 25 (most severe). CKD-aP awareness and treatment practices among doctors and nurses were investigated with a simple self-invented questionnaire. Results We recruited 500 chronic dialysis patients of which 87% were treated with in-center haemodialysis (HD), 10% with peritoneal dialysis (PD) and 3% with home HD (HHD). Mean age ± SD was 65 ± 14 years and 64% were males. Fig. 1 shows WI-NRS and total 5-D itch score distribution according to dialysis modality. CKD-aP prevalence (based on WI-NRS score &amp;gt;4) was 19% (all patients regardless of dialysis modality) but tended to be higher among PD patients (29%) in comparison with HD (18%) and HHD (23%) as shown in Fig. 1. Odds ratio (OR) with logistic regression for CKD-aP based on WI-NRS score as a binary dependent variable (≤4 or &amp;gt;4) and dialysis modality yielded: OR (PD vs. HD): 1.83 (0.96-3.49) and OR (HHD vs. HD): 1.35 (0.36-5.03). No pruritus (WI-NRS score = 0) was found in 61% of patients and 20% had mild pruritus (WI-NRS score ≤4). WI-NRS score correlated significantly with total 5-D itch score (Spearman's rank correlation coefficient (all patients): ρ = 0.80; P &amp;lt; .001). Median total 5-D itch score (IQR) was 5 (5-10) based on all patients regardless of dialysis modality. Itch intensity over the past 2 weeks was rated moderate to unbearable by 23% and not present in 54% of patients. Itch duration was less than 6 hours in 91% of patients and 29% of patients had no change in itching over the past 2 weeks. Overall, the impact of CKD-aP on daily activities (leisure/social, housework/errands and work/school) was minimal in most patients but sleep disability (score &amp;gt;1) was found in 18%. Sleep disability was significantly associated with higher WI-NRS score. Perceived CKD-aP prevalence (based on 28 questionnaires) was 20-40% according to most physicians (54%), 25% estimated it to be lower and 21% expected it to be higher. Topical therapy with fatty cream was the preferred treatment by most physicians followed by increased dialysis and non-sedating antihistamines. Conclusion Roughly one out of five patients on chronic dialysis treatment suffers from moderate to severe CKD-aP. HRQoL is negatively affected by CKD-aP primarily manifested as sleep disturbance. Most physicians tend to overestimate CKD-aP prevalence and prescribe fatty cream as their preferred treatment.

Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat.

Total serum bile acid (TSBA) levels are elevated in patients with primary biliary cholangitis (PBC) and may mediate cholestatic pruritus. Linerixibat, an ileal bile acid transporter inhibitor, improved pruritus in patients with PBC. We explored the relationship between linerixibat dose, TSBA concentration, and pruritus. Data from Phase 1/2 trials were used to develop a population kinetic-pharmacodynamic model to characterize the linerixibat dose-TSBA relationship. Individual Bayesian parameter estimates for participants in the GLIMMER study were used to derive the area under the TSBA concentration curve over 24 h (AUC0-24). Time-matched post hoc estimates of AUC0-24 were correlated with pruritus reported on a 0-10 numerical rating scale. Baseline TSBA concentration was correlated with change from baseline (ΔBL) in monthly itch score (MIS). ΔBL in model-estimated TSBA AUC0-24 was correlated with time-matched ΔBL in weekly itch score (WIS) or MIS. Linerixibat dose dependently reduced TSBA AUC0-24, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC0-24 correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC0-24, 60% were pruritus responders (≥2-point improvement in WIS from baseline). Linerixibat treatment leads to rapid, dose-dependent TSBA reductions. Baseline TSBA levels do not correlate with on-treatment pruritus change, suggesting they do not predict linerixibat response. Change in TSBA AUC0-24 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.

#1419 A single, easy-to-use question to assess pruritus intensity in daily dialysis practice

Abstract Background and Aims Chronic kidney disease-associated pruritus (CKD-aP) has been shown to negatively impact certain clinical outcomes and quality of life (QoL) in patients with kidney failure. However, regular screening for CKD-aP is not yet routine dialysis practice and no consensus on the preferred instrument exists. To facilitate implementation of regular screening for CKD-aP we assessed the performance of two different instruments validated in patients with CKD-aP. Method The Worst Itching Intensity Numerical Rating Scale (WI-NRS) asks patients to indicate the worst itch intensity in the past 24 hours (range 0 [no itch] to 10 [worst itch imaginable]). The 5-D Itch scale assesses itch-related QoL (range 5-25 where higher values indicate worse QoL) and includes one question on itch intensity over the past 2 weeks (5-D ‘degree’ domain, range 1 [not present] to 5 [unbearable]). Both instruments were included in two phase-3 clinical trials, KALM-1 and KALM-2, that established the favourable benefit-risk profile of difelikefalin over placebo in patients on haemodialysis with moderate to severe CKD-aP. WI-NRS was collected daily during the trial and 5-D Itch at the first dialysis visit in weeks 5, 9, 11 and 13. We assessed the correlations between both the 5-D total score and degree domain and a) the single WI-NRS measurement collected on the same day and b) the average of daily WI-NRS scores collected over the previous 2 weeks in all patients independent of treatment exposure. Results The two instruments demonstrated moderate to strong correlations (range 0.5635-0.7039, p &amp;lt; 0.0001) independent of whether the total 5-D Itch score or the 5-D itch degree question were compared with a single, same-day WI-NRS measurement or with the mean WI-NRS scores over the 2-week recall period of the 5-D Itch (Table). In addition, correlations remained consistent over time, supporting the reliability of the findings. Conclusion Using the WI-NRS to ask patients about their worst itch in the past 24 hours is a simple and swift approach for reliably identifying those with bothersome pruritus that also affects their itch-related QoL.

Real-World Long-Term Effectiveness of Risankizumab Among Patients with Moderate-to-Severe Psoriasis: Analysis from an International Medical Chart Review (RAPID) Study.

Real-world data on the efficacy of risankizumab (RZB) in clinical moderate-to-severe plaque psoriasis (PsO) are limited. The RAPID study assessed real-world clinical and patient-reported outcomes in RZB-treated PsO patients using data collected from dermatologists in Canada, the Czech Republic, Germany, Japan, and Poland. This ongoing, retrospective chart review collected data from medical records of RZB-treated adults with moderate-to-severe PsO (09/2022-06/2023). Eligible patients received RZB, had ≥ 12months of medical records after RZB initiation (index date), and had Psoriasis Area and Severity Index (PASI), Investigator Global Assessment (IGA), or static Physician's Global Assessment (sPGA) scores ≥ 3months before and up to 18months after the index date. The proportion of patients achieving a clear/almost clear PsO (IGA/sPGA = 0/1), PASI ≤ 1, Dermatology Life Quality Index (DLQI) = 0/1, and a 90%/100% improvement from baseline in PASI as well as the mean changes in PASI, DLQI, itch, and skin pain scores at 12 and 18 months were reported for patients with non-missing assessments at baseline and 12months. Most patients (66.4%) were male, 74.0% were biologic naïve, and 73.0% had scalp PsO. Mean baseline IGA/sPGA was 3.7 ± 0.5, with a mean PASI of 23.3 ± 11.8. After 12months, 86.1% of patients reported IGA/sPGA ≤ 1, and 75.7% achieved PASI90; these further increased to 91.1% and 80.5% at 18months. DLQI, itch, and skin pain scores improved over time. These data demonstrated the durable, real-world effectiveness of RZB in patients with moderate-to-severe PsO through continued improvement in disease and symptom severity over 18months, with most of the patients reporting clear/almost clear skin.

Efficacy and safety of difelikefalin in the treatment of hemodialysis patients with pruritus: A meta-analysis and systematic review.

The incidence of pruritus associated with hemodialysis (HD) patients can be as high as 70%, and ~40% of patients suffer from moderate to severe systemic pruritus. Difelikefalin (CR845), a peripheral restrictor κ-opioid receptor agonist, activates opioid receptors on peripheral neurons and immune cells to relieve pruritus in patients. However, the clinical effect of difelikefalin on HD-related pruritus is unclear. Therefore, the purpose of this meta-analysis and systematic review was to investigate the safety and efficacy of difelikefalin in the treatment of HD-associated pruritus. This study explored the efficacy and safety of difelikefalin in the treatment of pruritus in HD patients by systematic review and meta-analysis. Randomized controlled trials on difelikefalin in the treatment of pruritus in HD patients were retrieved from PubMed, Embase, Cochrane Library, and Web of Science electronic databases. The retrieval deadline was January 1, 2023. Stata 15.0 software was used for data analysis of the included studies. A total of 4 randomized controlled trials were included, totaling 1,268 patients (736 patients in the experimental group and 532 patients in the control group). Results of the meta-analysis showed that, compared with the control group, difelikefalin could significantly improve the Worst Itch Numeric Rating Scale score (improvement &gt; 3; risk ratio (RR)=1.28, 95% confidence interval (CI) (1.07, 1.53)), decrease the 5-D itch score (standardized mean difference=-0.43, 95% CI (-0.55, -0.30)), and significantly improve adverse events (RR=1.33, 95% CI (1.13, 1.56)). Although difelikefalin can improve itching symptoms in HD patients, it can also increase adverse reactions based on the current literature. Therefore, more studies are needed to further explore the safety and efficacy of difelikefalin treatment.

Deucravacitinib, an Oral, Selective, Allosteric Tyrosine Kinase 2 Inhibitor, in the Phase 3 Clinical Trials in Psoriasis, POETYK PSO-1 and PSO-2: Time to Meaningful Improvements in Itch as Assessed by the Psoriasis Symptoms and Signs Diary

Introduction: In the phase 3 POETYK PSO-1 and PSO-2 trials in psoriasis, patients completed the Psoriasis Symptoms and Signs Diary (PSSD) daily, recording the average severity of psoriasis symptoms and signs, including itch, over the past 24 hours. Patients receiving deucravacitinib experienced greater improvement in PSSD scores than patients receiving placebo or apremilast, as previously reported. In this analysis, we evaluate the time to improvement in itch in patients treated with deucravacitinib vs placebo in both POETYK trials. Methods: In each trial, adults with moderate to severe plaque psoriasis were randomized 1:2:1 to placebo, deucravacitinib 6 mg once daily, and apremilast 30 mg twice daily; at Week 16, patients receiving placebo crossed over to receive deucravacitinib. Adjusted mean score change from baseline for the PSSD itch item was modeled for deucravacitinib vs placebo using an analysis of covariance model with factors for geographic region, body weight, and prior biologic use, and the baseline value as a covariate. Improvements of ≥2 points on individual PSSD items have been established earlier as meaningful to patients. Time to ≥2-, ≥3-, and ≥4-point improvements from baseline to Week 16 on the PSSD itch item was estimated with Kaplan-Meier methods. Cox models estimated hazard ratios (HRs) for these improvements. Missing data for each analysis were imputed using modified baseline observation carried forward methods. Results: In each trial, significantly greater improvement from baseline in itch score was observed within 2 weeks with deucravacitinib vs placebo. Across both trials, the median (95% confidence interval [CI]) time to ≥2-point and ≥3-point improvements was 6.0 (5.0– 7.0) and 9.0 (8.0–11.0) weeks, respectively, for patients receiving deucravacitinib and not reached for patients receiving placebo (censored at Week 16). Patients receiving deucravacitinib were 3 times more likely to achieve a ≥2-point meaningful improvement in itch score than patients receiving placebo (HR [95% CI]: 3.0 [2.1–4.1] and 3.4 [2.6–4.5] in POETYK PSO-1 and PSO-2, respectively). HRs in favor of deucravacitinib increased as the threshold for improvement increased: at ≥3 points, HRs (95% CI) were 4.0 (2.6–6.1) and 4.9 (3.4–6.9), and at ≥4 points, HRs (95% CI) were 6.5 (3.4–12.4) and 8.8 (5.1–15.2), in POETYK PSO-1 and PSO-2, respectively. Conclusion: Patients receiving deucravacitinib vs placebo experienced improvement in their itch within 2 weeks of treatment. About half of patients receiving deucravacitinib experienced meaningful improvement in itch within 6 weeks. Sponsored by: Bristol Myers Squibb.

Dominant dystrophic epidermolysis bullosa is associated with glycolytically active GATA3+ T helper 2 cells which may contribute to pruritus in lesional skin.

Dominant dystrophic epidermolysis bullosa (DDEB) is characterized by trauma-induced blisters and, in some individuals, intense pruritus. Precisely what causes itch in DDEB and optimal ways to reduce it have not been fully determined. To characterize DDEB skin transcriptomes to identify therapeutic targets to reduce pruritus in patients. Using bulk RNA sequencing, we evaluated affected and unaffected skin biopsy samples from six patients with DDEB (all with the very itchy pruriginosa subtype) and four healthy individuals. Single-cell transcriptomes of affected (n = 2) and unaffected (n = 1) DDEB skin and healthy skin (n = 2) were obtained. Dupilumab treatment was provided for three patients. The skin bulk transcriptome showed significant enrichment of T helper (Th)1/2 and Th17 pathways in affected DDEB skin compared with nonlesional DDEB skin and healthy skin. Single-cell transcriptomics showed an association of glycolytically active GATA3+ Th2 cells in affected DDEB skin. Treatment with dupilumab in three people with DDEB led to significantly reduced visual analogue scale (VAS) itch scores after 12 weeks (mean VAS 3.83) compared with pretreatment (mean VAS 7.83). Bulk RNAseq and quantitative polymerase chain reaction showed that healthy skin and dupilumab-treated epidermolysis bullosa (EB) pruriginosa skin have similar transcriptomic profiles and reduced Th1/Th2 and Th17 pathway enrichment. Single-cell RNAseq helps define an enhanced DDEB-associated Th2 profile and rationalizes drug repurposing of anti-Th2 drugs in treating DDEB pruritus.

Histamine- and pruritogen-induced itch is inhibited byaTRPM8 agonist: a randomized vehicle-controlled human trial.

Allergies often present challenges in managing itch and the effects of histamine. Cooling agents that act via transient receptor potential melastatin 8 (TRPM8) agonism have shown potential in itch management. However, animal studies on itch have limitations, as animals cannot communicate subjective events and their fur-coated skin differs from that of humans. Human studies offer more direct and reliable information. To investigate the effects of a specific TRPM8 agonist gel (cryosim-1) on itch induced by various pruritogens in human skin. Calcium imaging experiments determined the binding of cryosim-1 and histamine to their respective receptors. Thirty healthy volunteers underwent skin prick tests with pruritogens and a control vehicle. Itch and pain intensity were measured using a numerical rating scale (NRS) across 10 min. Participants were randomly assigned to pretreatments with vehicle or TRPM8 agonist gel. Tests were repeated at a later date, and skin moisture, transepidermal water loss and mechanical sensitivity were measured. The in vitro study confirmed that histamine is not a TRPM8 agonist and cryosim-1 does not act as an agonist or antagonist on the human histamine 1 receptor. The TRPM8 agonist gel significantly reduced the itch intensity for all pruritogens compared with the vehicle-only gel. It also reduced itch NRS and the integrated itch score. Mechanical sensitivity was also reduced. The specific TRPM8 agonist gel effectively suppressed human skin itch induced by various pruritogens. These versatile actions suggest that cooling agents may be promising treatments for multiple forms of itch stimuli.

529 - Worsening of itch before flaring in patients with moderate-to-severe atopic dermatitis treated with abrocitinib: a post hoc analysis of the phase 3 JADE REGIMEN trial

Abstract Background Patients with atopic dermatitis (AD) often experience a disease course that fluctuates in severity over time, with periods of remission interrupted by flares. Abrocitinib, an oral, once-daily Janus kinase-1 selective inhibitor is approved for the treatment of patients with moderate-to-severe AD. In the phase 3 JADE REGIMEN (NCT03627767) trial, patients achieved an initial response with abrocitinib 200 mg, which was maintained with continued treatment with abrocitinib 200 mg, reduced-dose treatment with abrocitinib 100 mg, or placebo (treatment withdrawal). Following an initial efficacy response, over the 40-week maintenance period some patients across all treatment groups, but predominantly those who switched to placebo, experienced flares, defined as ≥50% loss of Eczema Area and Severity Index response at week 12 and Investigator’s Global Assessment score ≥2, and received rescue therapy. The utility of itch response as a predictor of an upcoming flare in these patients has not yet been determined. Objective To assess itch response before flaring in patients treated with abrocitinib who experienced a flare during the maintenance period of JADE REGIMEN. Methods In JADE REGIMEN, patients aged ≥12 years with moderate-to-severe AD who responded to abrocitinib 200 mg during open-label induction for 12 weeks were randomly assigned 1:1:1 to receive abrocitinib 200 mg, abrocitinib 100 mg, or placebo for up to 40 weeks (maintenance period). Patients who experienced a flare during maintenance received rescue treatment with abrocitinib 200 mg plus topical medicated therapy in an open-label 12-week period. This post hoc analysis evaluated mean itch scores in subsets of patients who did or did not experience flares during the maintenance period. Itch was assessed using the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD; © 2016 Pfizer Inc. All rights reserved.) itch numerical rating scale (NRS) item which asked patients, “How itchy was your skin over the past 24 hours?” on a scale from 0 (not itchy) to 10 (extremely itchy). PSAAD scores were collected daily via an e-diary during the screening period and from day 1 through the end of study. Daily itch scores were analyzed at baseline (day of randomization to maintenance treatment groups), from 14 days prior to flaring (from day –14 to day –1), and on the day of flare (day 0) in patients who experienced a flare, and at baseline through 274 days post-randomization in patients who did not experience a flare. Results Of 1233 patients treated with abrocitinib 200 mg in the open-label induction period, 798 (65%) achieved response at week 12 and were randomized to abrocitinib 200 mg (n=266), abrocitinib 100 mg (n=265), or placebo (n=267) in the maintenance period. Across all treatment groups, 442 (55%) patients did not experience a flare and 356 (45%) patients experienced a flare during maintenance. Among patients who did not experience a flare, mean PSAAD itch NRS score remained consistently around 2, with a mean score of 1.5 on day 1 of randomization and 2.1 on day 274 post-randomization. Among patients who experienced a flare, mean PSAAD itch NRS score at baseline was 1.8, which increased to 4.4 on day –14 (14 days before flaring) and continued to increase up to the day of flare (day 0 mean score: 6.4). Conclusions After a successful initial response with abrocitinib, mean itch scores remained stable over time among patients who did not flare. Patients who experienced a flare had worsening of itch from 2 weeks before until the onset of flare. Monitoring of itch may predict onset of flares in patients with moderate-to-severe AD and help inform treatment management or optimization to achieve disease control.

568 - Persistent inadequate disease control and therapeutic inertia in moderate-to-severe atopic dermatitis: a 12-month longitudinal analysis of real-world outcomes from TARGET-DERM registry

Abstract Background Therapeutic inertia refers to the delay or failure to escalate treatment in patients who are not achieving adequate disease control and poses a challenge in the management of moderate-to-severe atopic dermatitis (AD). Despite the availability of conventional (CST) and advanced systemic therapies (AST) currently utilized for the treatment of moderate to severe AD, many patients do not achieve treatment success. However, the extent of this inadequacy in real-world clinical practice remains underexplored. Objectives This study aims to evaluate the occurrence therapeutic inertia (assessed as non-escalation of therapy despite limited disease control) and the proportion of patients with moderate-to-severe AD who continue to show an inadequate response after receiving systemic therapies for a duration ranging from 3 to 12 months. Methods We conducted a longitudinal analysis of patients with moderate-to-severe AD (vIGA-AD≥3) from the TARGET-DERM AD registry, including 3,457 participants from 39 centers in the U.S. and Canada. Eligible patients had documented outcomes at the initiation of systemic therapy and after 3 months up to 12 months of follow up. We assessed clinician- and patient-reported outcomes to identify the proportion of patients not meeting pre-defined targets based on expert consensus. An inadequate response was defined as not achieving a validated Investigator Global Assessment (vIGA-AD) score ≤2, a 50% improvement in Body Surface Area (BSA), and a ≥4-point reduction in the Worst Pruritus Numeric Rating Scale (WP-NRS). An optimal response was defined as a vIGA-AD score ≤1 (clear or almost clear skin), BSA ≤2%, and WP-NRS itch score of 0/1 (complete or almost complete skin resolution). Results Out of 2,107 patients with moderate-to-severe AD, 445 met the inclusion criteria. The majority were adults (63.8%), female (62.0%), and Non-Hispanic White (45.4%), with an average age of 31 years. Most patients (88.8%) initiated treatment with AST, with dupilumab being the most common (86.5%). The mean vIGA-AD was 3.3 for AST and 3.6 for CST at initiation (P&amp;lt;0.01). At 6 months, 37% and 67% of AST-treated patients had inadequate responses in terms of skin clearance and itch outcomes, respectively, while 82% and 79% did not achieve optimal responses. At 12 months, these figures were approximately 30% and 66% for inadequate responses and 85% and 88% for not achieving optimal responses, respectively. CST-treated patients showed a similar trend. Conclusions The study reveals a significant portion of moderate-to-severe AD patients fail to achieve adequate disease control with systemic therapies over 12 months, indicating a substantial presence of therapeutic inertia. These findings suggest a need for more proactive management strategies in AD treatment.

Functional brain alterations in symptomatic dermographism patients-An exploratory magnetoencephalography study.

Symptomatic dermographism (SD) is a common form of urticaria, which is triggered by stroking the skin. Brain involvement in its aetiology was investigated by means of magnetoencephalography (MEG) after provocation with histamine and dermography. Wheals were induced by histamine skin prick test and dermography in twelve SD patients and fourteen controls. Itch severity was scored on a Visual Analogue Scale (VAS). Relative power and functional connectivity (FC) were measured using a 306-channel whole-head MEG system at baseline and 10 min after histamine and dermography, and contrasted between groups and conditions. Furthermore, wheal diameter and itch scores after these procedures were correlated with the MEG values. SD patients had higher itch scores after histamine and dermography. No significant group-differences were observed in relative power or FC for any condition. In both groups, power decreases were mostly observed in the beta band, and power increases in the alpha bands, after provocation, with more regions involved in patients compared to controls. Increased FC was seen after histamine in patients, and after dermography in controls. In patients only, dermography and histamine wheal size correlated with the alpha2 power in the regions of interest that showed significant condition effects after these procedures. Our findings may be cautiously interpreted as aberrant itch processing, and suggest involvement of the central nervous system in the aetiology of SD.

Efficacy and Safety of Cannabis Transdermal Patch for Alleviating Psoriasis Symptoms: Protocol for a Randomized Controlled Trial (CanPatch).

Current topical treatments for psoriasis offer limited efficacy and are associated with long-term adverse effects in a subset of patients, highlighting the need for new therapeutic options. Cannabidiol (CBD), a non-psychoactive cannabinoid derived from Cannabis sativa L., has shown potential in reversing psoriasis pathology through its action on skin receptors in preclinical studies. Given the promising properties of CBD, transdermal patches containing this compound represent a novel approach to psoriasis treatment. However, comprehensive data on their efficacy and safety remain scarce. We outline a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of CBD transdermal patches with minimal tetrahydrocannabinol (THC) in 60 patients with mild to moderate plaque-type psoriasis at a university hospital in Thailand (n = 60). This study aims to evaluate the changes in the local psoriasis severity index (LPSI), itch score via a visual analog scale, and occurrence of adverse events on day 0, 30, 60, and 90 of the study. Additionally, we will examine the alteration in the skin, gut, and oral microbiome in a subset of participants to explore potential correlations with treatment outcomes. The primary outcome will focus on the difference in LPSI scores at the end of the study period, employing an intention-to-treat analysis. Multivariate logistic regression will be used to identify baseline clinical and microbiological predictors of treatment response. This study aims to investigate the efficacy and safety of CBD transdermal patches in alleviating the symptoms of psoriasis. The results of this study may highlight a novel topical treatment option that reduces suffering in patients with psoriasis. We also designed to provide a holistic evaluation by considering both clinical outcomes and the underlying biological mechanisms, including the interaction with the human microbiome. Through this trial, we aim to contribute valuable insights into personalized psoriasis management strategies.