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Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of the interleukin-4Rα-interleukin-13Rα1 heterodimer receptor signaling complex. We conducted two identically designed, 52-week, randomized, double-blind, placebo-controlled, phase 3 trials; both trials included a 16-week induction period and a 36-week maintenance period. Eligible patients with moderate-to-severe atopic dermatitis (adults [≥18 years of age] and adolescents [12 to <18 years of age, weighing ≥40 kg]) were randomly assigned in a 2:1 ratio to receive either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks. Outcomes for the induction period were assessed up to 16 weeks and are included in this report. The primary outcome was an Investigator's Global Assessment (IGA) score of 0 or 1 (indicating clear or almost clear skin; range, 0 to 4 [severe disease]) with a reduction (indicating improvement) of at least 2 points from baseline at week 16. Secondary outcomes included a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response) and assessments of itch and of itch interference with sleep. Safety was also assessed. In trial 1, the primary outcome was met in 43.1% of 283 patients in the lebrikizumab group and in 12.7% of 141 patients in the placebo group (P<0.001); an EASI-75 response occurred in 58.8% and 16.2%, respectively (P<0.001). In trial 2, the primary outcome was met in 33.2% of 281 patients in the lebrikizumab group and in 10.8% of 146 patients in the placebo group (P<0.001); an EASI-75 response occurred in 52.1% and 18.1%, respectively (P<0.001). Measures of itch and itch interference with sleep indicated improvement with lebrikizumab therapy. The incidence of conjunctivitis was higher among patients who received lebrikizumab than among those who received placebo. Most adverse events during the induction period were mild or moderate in severity and did not lead to trial discontinuation. In the induction period of two phase 3 trials, 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic dermatitis. (Funded by Dermira; ADvocate1 and ADvocate2 ClinicalTrials.gov numbers, NCT04146363 and NCT04178967, respectively.).

Key Points Itch—also referred to as pruritus—is an unpleasant sensation that elicits an urge to scratch Neuropathic pruritus is caused by neuronal or glial damage CNS disorders rarely trigger pruritus, but pruritus is commonly associated with peripheral neuropathies and disorders of mixed or undetermined aetiology with neurological involvement Treatment for neuropathic pruritus is similar to that for neuropathic pain, but μ opioids can induce itch and are, therefore, contraindicated Pruritus is a very common condition, with almost one-third of the global population experiencing itch in a given week. Its origin is not always in the skin: damage to neurons or glia can induce neuropathic pruritus, which is often associated with neuropathic pain. Neuropathic pruritus is often difficult to treat and—if chronic—can severely impair quality of life. Here, Laurent Misery and colleagues review the role of the nervous system and neuropathic syndromes in pruritus, summarize the currently available therapeutic options, and propose therapeutic strategies for managing neuropathic pruritus. Pruritus, also known as itch, is a very common, unpleasant sensation that elicits an urge to scratch. Its origin is not always in the skin, and neuropathic itch that is caused by neuronal or glial damage is common, but poorly understood by both dermatologists and neurologists. Although pruritus has not been considered as serious a symptom as pain, it is difficult to treat and—if chronic—can severely impair quality of life. Neuropathic itch is often associated with other clinical symptoms, most commonly neuropathic pain, and hypersensitization to stimuli is present in both pruritus and pain of neuropathic origin. The shared aetiology can aid in finding suitable treatment for itch in some cases, but more detailed knowledge of the mechanisms of itch, along with standardized, well-controlled trials, is needed. Pruritus research is an emerging but currently very active field, and our understanding of this sensation is rapidly increasing. Here, we review new discoveries regarding the role of the nervous system and the contribution of different pathways in pruritus, discuss the different aetiologies of neuropathic itch, and outline currently available and potential strategies for managing neuropathic pruritus.

Maralixibat (MRX) is an ileal bile acid transporter inhibitor (IBATi) recently approved by the Food and Drug Administration for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) 1 year of age and older. Recent data suggest that MRX is associated with improved event-free survival in this population suggesting that the drug may potentially improve liver disease outcomes beyond pruritus control in ALGS. Patients with ALGS clearly have impaired growth and therefore we evaluated the impact of long-term MRX treatment on the nutritional status of these patients.Height and weight Z-scores were evaluated in patients who participated in 3 clinical trials of MRX and their long-term, open-label extensions for treatment of cholestatic pruritus in ALGS; only patients for whom we had height and weight data at baseline and week 204 follow-up were included. T-tests and Pearson correlation coefficients were used to evaluate the association between height with other parameters known to correlate with growth.Data were available for 34 patients with baseline mean (SD) age of 6.7 (3.8) years, height Z-score of -1.66 (1.17) and weight Z-score of -1.46 (0.95). Overall, mean height Z-score increased to -1.29 (1.03) at week 204 (change from baseline: 0.37; p=0.0004). The greatest catch-up height gain was observed among those within the lowest baseline quartile height Z-scores, increasing from -3.1 (0.71) at baseline to -2.38 (0.82) at week 204 (change from baseline: 0.72; p=0.018), and there was a significant correlation between change in height and baseline height (r=-0.48; p=0.004). Similarly, greater catch-up weight gain was observed with lower baseline weight Z-scores, with a significant correlation between change in weight and baseline weight (r=-0.39; p=0.02). The change in height Z-scores correlated with the change in weight Z-scores such that greater catch-up linear growth was observed in patients with greater catch-up weight gain (r=0.73; p<0.0001). There was no clear change in vitamin D levels or albumin throughout treatment. Among patients with sBA <200 µmol/L at week 48, height Z-score increased from -1.58 (1.23) at baseline to -1.16 (1.00) at week 204 (change from baseline: 0.42; p=0.001), whereas there was no significant change in height Z-score among patients with sBA ≥200 µmol/L.Catch-up height and weight are observed in patients with ALGS treated with MRX, and importantly patients with the greatest height disadvantage at baseline had the greatest catch-up in height. Increased catch-up height was also seen in patients that achieved lower sBA with MRX, suggesting an improvement in bile acid homeostasis may be a factor. Further analyses are needed comparing growth trajectories in MRX-treated patients to a natural history cohort of patients with ALGS to fully understand the attributability of MRX.

Real-world evidence (RWE) analytics continue to advance natural history comparisons in rare diseases. The Global Alagille Alliance (GALA) is the largest global clinical research database for Alagille syndrome (ALGS). Maralixibat (MRX) is an ileal bile acid transporter inhibitor approved by the FDA for the treatment of cholestatic pruritus in patients with ALGS ≥1 year of age. A pre-specified analysis plan applied novel analytical techniques to compare RWE from GALA with a MRX cohort with the aim to compare event-free survival (EFS) in patients with ALGS.GALA contains retrospective data for clinical parameters, biochemistries and outcomes. The MRX database comprises of 84 ALGS patients with up to 6 years of data. EFS was defined as the time to first event of hepatic decompensation (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplantation (LT), or death. GALA was filtered to align key MRX eligibility criteria. The index time was determined via maximum likelihood estimation. Balance among baseline (BL) variables was assessed. Selection of patients and index time was blinded to clinical outcomes. Sensitivity and subgroup analyses, and adjustments for covariates, were applied. Missing outcomes data were censored at last contact.Of 1,438 patients in GALA, 469 were eligible. Age, total bilirubin (TB), gamma glutamyltransferase (GGT) and alanine aminotransferase (ALT) were well balanced between groups and no statistical differences were observed for age, mutation, region, TB, GGT and ALT. Median BL serum bile acids (sBA) was significantly higher in the MRX cohort (p=0.003); 85% of sBA data was not available in GALA. EFS rates in the MRX cohort were significantly better than those reported in the GALA control, (crude 6-year EFS: 73% and 50%, respectively, and adjusted for age, sex, TB, ALT: HR=0.305; 95% CI: 0.189–0.491; p<0.0001). Varied index times, weighted inverse probability of treatment weights, average treatment effect in the treated, LT and death only, regions, sBA sub-group, pruning events to 12 months were consistent with the primary result. Limitations include no standardised measure of pruritus and limited sBA data in GALA, and inherent bias for patients who enter a clinical trial.This 6-year analysis suggests the potential for improved EFS with MRX in patients with ALGS. This RWE analysis provides a potential method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible. Limitations will always be present given lack of prospective conduct and inherent biases, though sensitivity analyses can help mitigate and aid interpretation.

Skin is among the first and most heavily damaged organs upon sulphur mustard (SM) exposure. Pruritus is the most common chronic skin complication of SM, which adversely affects the quality of life (QoL). However, current therapies for the management of SM-induced pruritus are very limited and associated with side effects. The present trial investigated the efficacy of curcumin in the alleviation of SM-induced chronic pruritic symptoms. A total of ninety-six male Iranian veterans (age 37–59 years) were randomised to receive either curcumin (1 g/d, n 46) or placebo (n 50) for 4 weeks. Serum concentrations of substance P and activities of antioxidant enzymes were measured at baseline and at the end of the trial. Assessment of pruritus severity was performed using the pruritus score, visual analogue scale (VAS) and scoring atopic dermatitis (SCORAD) index. QoL was evaluated using the Dermatology Life Quality Index (DLQI) questionnaire. Serum concentrations of substance P (P < 0·001) as well as activities of superoxide dismutase (P = 0·02), glutathione peroxidase (P = 0·006) and catalase (P < 0·001) were significantly reduced in the curcumin group, while no significant change was observed in the placebo group. Curcumin supplementation was also associated with significant reductions in measures of pruritus severity including the pruritus score (P < 0·001), VAS score (P < 0·001), overall (P < 0·001) and objective SCORAD (P = 0·009), and DLQI's first question (P < 0·001). None of these measures was significantly changed in the placebo group. As for the QoL, although DLQI scores decreased in both groups (P < 0·001 and P = 0·003 in the curcumin and placebo groups, respectively), the magnitude of reduction was significantly greater in the curcumin group (P < 0·001). In conclusion, curcumin may be regarded as a natural, safe, widely available and inexpensive treatment for the management of SM-induced chronic pruritus.

Chronic spontaneous urticaria is an idiopathic syndrome defined by recurring itch, hives, or angioedema (or a combination of these symptoms) for more than 6 weeks. Remibrutinib, an oral, highly selective Bruton's tyrosine kinase inhibitor, showed efficacy and favorable safety in phase 2b trials. Data from phase 3 trials are needed. In the identical, multicenter, double-blind, randomized, placebo-controlled REMIX-1 and REMIX-2 trials, we evaluated the efficacy and safety of remibrutinib in patients with symptomatic chronic spontaneous urticaria after treatment with second-generation H -antihistamines. Patients were randomly assigned in a 2:1 ratio to receive oral remibrutinib at a dose of 25 mg twice daily or placebo. The primary end point was the change from baseline to week 12 in the urticaria activity score during a 7-day period (UAS7), which comprises severity scores for itch and hives during 1 week (scores range from 0 to 42, with higher scores indicating greater severity). Key secondary end points included adverse events and a UAS7 of 6 or lower at weeks 2 and 12 and a UAS7 of 0 at week 12. A total of 470 patients in REMIX-1 and 455 in REMIX-2 were randomly assigned to receive either remibrutinib (313 and 300 patients, respectively) or placebo (157 and 155 patients, respectively). The remibrutinib group had a significantly greater decrease in the UAS7 at week 12 than the placebo group (least-squares mean [±SE] change, -20.0±0.7 vs. -13.8±1.0 [P<0.001] in REMIX-1 and -19.4±0.7 vs. -11.7±0.9 [P<0.001] in REMIX-2), which appeared to be sustained through week 24. At week 12, significantly more patients in the remibrutinib group than in the placebo group had a UAS7 of 6 or lower (REMIX-1, 49.8% vs. 24.8% [P<0.001]; REMIX-2, 46.8% vs. 19.6% [P<0.001]) and a UAS7 of 0 (REMIX-1, 31.1% vs. 10.5% [P<0.001]; REMIX-2, 27.9% vs. 6.5% [P<0.001]). The percentages of patients with any adverse event and with serious adverse events were similar in the remibrutinib group and the placebo group, although a higher percentage of patients in the remibrutinib group than in the placebo group had petechiae (3.8% vs. 0.3% in the combined groups). Treatment with oral remibrutinib resulted in a significant improvement in a composite measure of itching and hives at week 12. (Funded by Novartis Pharmaceuticals; REMIX-1 and REMIX-2 ClinicalTrials.gov numbers, NCT05030311 and NCT05032157, respectively.).

In a double-blind, placebo-controlled, phase 3 trial, patients undergoing hemodialysis who had moderate-to-severe pruritus were randomly assigned to receive the selective kappa opioid receptor agonist difelikefalin or placebo for 12 weeks. Difelikefalin significantly reduced itch intensity and improved quality of life as compared with placebo.