Sarbjit Saini

BackgroundMany patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies.MethodsPEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The …

MethodsREMIX-1 and REMIX-2 are double-blind, placebo-controlled studies of patients≥ 18y with inadequately controlled CSU. Patients were randomized to remibrutinib 25 mg twice daily or placebo for 24 weeks and stratified by prior exposure to anti-IgE biologics (anti-IgE biologic–experienced vs anti-IgE biologic–naive) and region. Outcomes included CFB (least squares mean±SE) in UAS7 and rates of disease activity control (UAS7≤ 6) and complete absence of itch and hives (UAS7= 0) at week 12 by subgroup.ResultsAmong anti-IgE biologic–experienced (31.3%) and anti-IgE biologic–naive (68.7%) patients, CFB-UAS7 with remibrutinib was comparable for anti-IgE biologic–experienced (–19.75±0.92) and anti-IgE biologic–naive (–20.50±0.55) patients and was larger vs placebo (anti-IgE biologic–experienced:–12.98±1.29; anti-IgE biologic–naive:–13.25±0.76). A higher proportion of patients with …

IntroductionRemibrutinib (LOU064) is an oral, highly selective Bruton's Tyrosine Kinase (BTK) inhibitor that offers fast disease control in chronic spontaneous urticaria (CSU) patients who remain symptomatic despite H1-antihistamines. Remibrutinib showed high selectivity and potency in vitro, with the potential to minimize off-target effects. Here, we report the safety profile of remibrutinib from its completed Phase 2 clinical trials, including participants with long-term treatment.MethodsSafety data of remibrutinib from its completed Phase 2 studies across a range of immune-mediated conditions (CSU, Sjögren syndrome (SjS), asthma) were analyzed. Safety assessments comprised adverse events (AEs), including serious and AEs of special interest (AESI), vital signs, electrocardiograms, and laboratory parameters.ResultsAnalysis of safety data across completed Phase 2 clinical trials in CSU, SjS and asthma showed …

MethodsThis post-hoc analysis included data from 134 patients (age≥ 16; dupilumab: 67, placebo: 67) who answered the DLQI questionnaire in the LIBERTY-CSU CUPID Study A phase 3 trial (NCT04180488). The DLQI is a 10-item instrument with scores ranging from 0–30 (higher scores indicate greater QoL impairment). Proportion of patients per DLQI severity strata and item-level analyses at baseline and Week 24 were assessed.ResultsAt baseline, 92.5% of patients reported at least a moderate effect (DLQI≥ 6) on QoL, with 69.1% reporting a very/extremely large effect (DLQI≥ 11). The most affected QoL items (patients reporting" a lot/very much”) were" itchy, sore, painful, stinging"(91.0%)," embarrassed, self-conscious"(55.6%)," influenced the clothes you wear"(53.4%)," interfered with shopping, looking after home or garden"(51.9%), and" affected social, leisure activities"(51.1%). At Week 24, a significantly …

AH, antihistamine; BTK, Bruton’s tyrosine kinase; CSU, chronic spontaneous urticaria; FcεRI, high-affinity IgE receptor; H1, histamine-1; Ig, immunoglobulin; LYN, LCK/YES novel tyrosine kinase; SYK, spleen tyrosine kinase. 1. Guillen-Aguinaga S, et al. British J Derm. 2016; 175: 1153-1165. 2. ClinicalTrials. gov. NCT05030311. Accessed September 15, 2023. https://classic. clinicaltrials. gov/ct2/show/NCT05030311. 3. ClinicalTrials. gov. NCT05032157. Accessed September 15, 2023. https://classic. clinicaltrials. gov/ct2/show/NCT05032157

MethodsWe searched MEDLINE, Embase, CENTRAL, ICTRP, CBM, CNKI, VIP, and Wanfang to March 12 th, 2023 for randomized controlled trials (RCTs) evaluating LTRAs as an add-on to antihistamines in antihistamine refractory CU patients. We performed random effects meta-analyses addressing urticaria severity (UAS7; 0–42; lower better), health-related quality of life (DLQI; 0 to 30; lower better), adverse events (AEs), and serious adverse events (SAEs). We used the GRADE approach to evaluate the certainty of the evidence.ResultsWe identified 3,364 citations and ultimately included 7 RCTs representing 497 participants with median age of 43 years and median baseline UAS7 of 26.02 points. Compared to antihistamines alone, the addition of LTRAs improve urticaria severity (mean difference [MD]-5.99, 95% CI-9.88 to-2.10, 7 RCTs, high certainty) and may improve quality of life (MD-4.08, 95% CI-5.91 to-2 …

Mast cells are activated through a variety of different receptors to release preformed granules and mediators synthesized de novo. However, the physiology and function of mast cells are not fully understood. Traditional studies of mast cell activation in humans have utilized cultures of tissue-derived mast cells including CD34+ progenitor cells or well-characterized commercially available cell lines. One limitation of these methods is that mast cells are no longer in a natural state. Therefore, their applicability to human skin disorders may be limited. Human skin explant models have been utilized to investigate the short-term effects of cell mediators, drugs, and irritants on skin while avoiding the ethical concerns surrounding in vivo stimulation studies with non-approved agents. Nonetheless, few studies have utilized intact human tissue to study mast cell degranulation. This “Methods” paper describes the development and application of an intact skin explant model to study human mast cell activation. In this manuscript, we share our protocol for setting up ex vivo human skin explants and describe the results of stimulation experiments and techniques to minimize trauma-induced histamine release. Skin explants were generated using de-identified, full-thickness, non-diseased skin specimens from plastic and reconstructive surgeries. Results were reproducible and demonstrated FcɛRI- and MRGPRX2-induced mediator release which was inhibited with the use of a BTK inhibitor and QWF, respectively. Thus, this explant model provides a quick and accessible method of assessing human skin mast cell activation and inhibition.

MethodsLIBERTY-CSU CUPID Study A (NCT04180488) was a randomized, placebo-controlled, 24-week, phase 3 trial that evaluated dupilumab efficacy and safety in patients aged≥ 6 years with CSU who remained symptomatic despite H1-A1 treatment, and were omalizumab-naïve. Background therapy was study-defined H1-AH at up to 4-fold the approved dose. Endpoints included the proportion of patients with Urticaria Activity Score over 7 days (UAS7)≤ 6 and UAS7= 0 up to Week 36.ResultsIn patients with CSU inadequately controlled with H1-AH, dupilumab treatment resulted in a numerically greater proportion of patients achieving well-controlled urticaria (UAS7≤ 6) from Week 8 and urticaria-free (UAS7= 0) status from Week 14, vs placebo. At Week 24, 53.1% of dupilumab-treated patients achieved UAS7≤ 6 and 35.9% achieved UAS7= 0 (vs 34.0% and 18.9% with placebo; P= 0.0379 and P= 0.0411 …

BackgroundChronic spontaneous urticaria (CSU) is a chronic inflammatory disease characterized by recurrent pruritic wheals (hives) and/or angioedema. Patients with CSU could remain symptomatic despite standard-of-care H1-antihistamines (H1-AH) or anti-IgE (omalizumab) treatment. Dupilumab blocks IL-4/IL-13 signaling and is approved for multiple type 2/atopic indications.ObjectiveWe conducted two phase 3, randomized, placebo-controlled, double-blind trials comparing dupilumab to placebo in patients with CSU remaining symptomatic despite H1-AH.MethodsIn LIBERTY-CSU CUPID Study A, patients were omalizumab-naïve (n=138, age 6+). In Study B, patients were omalizumab-intolerant/incomplete responders (n=108, age 12+). The primary endpoint was either change from baseline over 7 days in the Urticaria Activity Score (UAS7) or Itch Severity Score (ISS7) at week 24, with the other as a key …

BackgroundShort courses of adjunctive systemic corticosteroids are commonly used to treat acute urticaria and chronic urticaria flares (both with or without mast cell-mediated angioedema), but their benefits and harms are unclear.ObjectiveTo evaluate the efficacy and safety of treating acute urticaria or chronic urticaria flares with versus without systemic corticosteroids.MethodsWe searched MEDLINE, EMBASE, CENTRAL, CNKI, VIP, Wanfang, and CBM databases from inception to July 8, 2023 for randomized controlled trials of treating urticaria with versus without systemic corticosteroids. Paired reviewers independently screened records, extracted data, and appraised risk of bias with the Cochrane 2.0 tool. We did random effects meta-analyses of urticaria activity, itch severity and adverse events. We assessed certainty of the evidence using the GRADE approach.ResultsWe identified 12 randomized trials enrolling …

MethodsDe-identified, non-diseased skin specimens were obtained from plastic surgeries for this IRB-exempt study. Specimens were biopsied using a 2.5 mm punch. We measured spontaneous, stimulated, and residual histamine (RH) of biopsy pairs using an fluorometric autoanalyzer. Spontaneous histamine release (HR) was assessed following incubation in media alone for 1 hour at 37 o C. Stimulated HR was determined for various concentrations of MC stimuli±their respective inhibitors at various time points at 37 o C. RH content was extracted by incubating biopsies overnight at 4 o C in 1.6% perchloric acid. Total skin histamine content (TSHC) was calculated by adding HR and RH content for each biopsy pair. All results were expressed as a percentage of TSHC.ResultsSpontaneous HR was correlated with TSHC (r s= 0.4913, p= 0.0032). Stimulated HR varied depending on the reagent, dose, duration of …

MethodsThis post-hoc analysis included data from 138 patients (dupilumab: 70; placebo: 68) of the LIBERTY-CSU CUPID Study A phase 3 trial (NCT04180488). The CU-Q2oL is a 23-item questionnaire scored on a 5-point Likert scale with scores ranging from 0–100; higher scores indicate greater impairment. Proportion of patients reporting the two worst (very much/extremely) and two best (not at all/a little) responses for each item was analyzed at baseline and Week-24, respectively.ResultsAt baseline, the mean (SD) CU-Q2oL total score was 41.0 (17.3) and 46.7 (20.3) in the dupilumab and placebo arms, respectively. The top two “very much/extremely” bothered items were “itching”(dupilumab: 86%; placebo: 84%) and “hives”(dupilumab: 81%; placebo: 77%). At Week-24, a significantly greater proportion of dupilumab-treated patients reported “not at all/a little” bothered by itching (60%) and hives (69 …

Objective:To report the integrated safety profile of remibrutinib using pooled data from completed phase 2 clinical trials in chronic spontaneous urticaria (CSU), Sjögren syndrome (SjS), and asthma, including long-term treatment up to 52 weeks.Background:Remibrutinib, a potent, highly selective, covalent, oral Bruton’s tyrosine kinase inhibitor, is currently being investigated in 2 phase 3 trials for the treatment of relapsing multiple sclerosis (NCT05147220/NCT05156281). The high selectivity of remibrutinib has the potential to result in a favorable safety profile by minimizing off-target effects.Design/Methods:Pooled data from completed phase 2 studies of CSU (including the 52-week open-label extension), SjS, and asthma were analyzed. Safety assessments included adverse events (AEs), serious AEs (SAEs), and AEs of special interest (AESIs). Analyses were conducted for patients receiving any remibrutinib dose …

Background: Prurigo nodularis (PN) is characterized by the presence of itchy nodules on the trunk/extremities, often accompanied by skin pain and sleep disruption. Psychometric validation and within-patient meaningful change thresholds for 3 patient-reported outcome instruments have been assessed in patients with PN: Worst Itch Numerical Rating Scale (WI-NRS), Skin Pain-NRS, and Sleep-NRS. The proportion of patients achieving clinically meaningful improvement in these scores was investigated in 2 pooled randomized, double-blind, placebo-controlled, phase 3 trials of dupilumab in adults with PN uncontrolled on topical therapies, LIBERTY-PN PRIME (NCT04183335) and PRIME2 (NCT04202679).Methods: Adults with PN inadequately controlled on topical prescription therapies or when those therapies are not advisable were randomized 1: 1 to dupilumab 300 mg every 2 weeks or matched placebo …

Chronic spontaneous urticaria (CSU) is a common skin disease without an etiology in the vast majority of cases. The similarity of symptoms and pathology to allergen-induced skin reactions supports that skin mast cell IgE receptor activation is also involved in CSU. Accumulating evidence also supports a role for blood basophils in disease expression. Blood basopenia is noted in active CSU disease with the recruitment of blood basophils to skin lesion sites. Blood basophils further display altered IgE receptor mediated degranulation patterns in two phenotypes that improve in remission. In active CSU subjects, changes in IgE receptor signaling molecule expression levels accompany the altered degranulation function in blood basophils. The success of therapies targeting IgE in CSU patients have also shown that altered blood basophil phenotypes and enumeration have potential use as a disease biomarker.© 2023 Japanese Society of Allergology. Published by Elsevier BV This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).

Introduction Tyrosine kinase 2 (TYK2) is an intracellular enzyme that mediates signaling of cytokines (eg, IL-23, Type I interferons) involved in psoriasis pathogenesis. Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved in the US, EU, and other countries for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was significantly more efficacious than placebo or apremilast and was well tolerated in the phase 3 POETYK PSO-1 and PSO-2 trials. We evaluated changes in lipid parameters in these trials. Methods PSO-1 (NCT03624127) and PSO-2 (NCT03611751) were 52-week, double-blind trials conducted globally. Patients with moderate to severe plaque psoriasis (PASI≥ 12, sPGA≥ 3, BSA involvement≥ 10%) were randomized 1: 2: 1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. This …

IntroductionCT-P39 is being developed as a biosimilar of reference omalizumab (ref-omalizumab). This is a double-blind, randomized, active-controlled, phase-3 study in patients with chronic spontaneous urticaria to compare efficacy and safety of CT-P39 to ref-omalizumab.MethodsTo demonstrate therapeutic equivalence between CT-P39 and ref-omalizumab, the patients were randomly assigned in a 1:1 ratio to receive 300 mg of CT-P39 (n=204) or ref-omalizumab (n=205) every 4 weeks up to Week 12. Primary endpoint was mean change from baseline in weekly itch severity score (ISS7) at Week 12 between CT-P39 300 mg and ref-omalizumab 300 mg groups.ResultsFor the primary efficacy evaluation, 95% confidence interval of treatment difference in terms of mean changes from baseline in ISS7 at Week 12 was entirely within the predefined equivalence margin of [−2.0, 2.0] (Table 1). Secondary efficacy …

Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for >6 weeks. Mast cells (MCs) and basophils are the key pathogenic drivers of CSU; their activation results in histamine and cytokine release with subsequent dermal inflammation. Two overlapping mechanisms of MC and basophil activation have been proposed in CSU: type I autoimmunity, also called autoallergy, mediated via IgE against various autoallergens, and type IIb autoimmunity, mediated predominantly via IgG directed against the IgE receptor FcεRI or FcεRI-bound IgE. Both mechanisms involve cross-linking of FcεRI and activation of downstream signaling pathways and may co-occur in the same patient. In addition, B-cell receptor (BCR) signaling has been postulated to play a key role in CSU by generating autoreactive B cells and autoantibody production. A cornerstone of FcεRI …

A 56-year-old man with well-controlled human immunodeficiency virus, anxiety, depression, and hypercholesterolemia developed acute urticaria, lip angioedema, and respiratory distress after consumption of a cheeseburger, French fries, lemonade, mid ibuprofen. He was evaluated in the emergency department and, during admission, developed asystole, diaphoresis, pallor, and a brief episode of posturing that was treated with two doses of epinephrine. Results of the initial workup with electrocardiogram, troponin, complete blood cell count, and comprehensive metabolic panel were normal. He was subsequently evaluated by an allergist for further recommendations.

Background:Chronic urticaria (CU) is a common chronic inflammatory disease. Vaccination against viral infections including COVID-19 can induce increased CU disease activity. As of now, it is unclear how often CU exacerbations occur after COVID-19 vaccination. Method (s) COVAC-CU is an international, multicenter, observational, cross-sectional study of the global network of urticaria centers of reference and excellence (UCAREs). COVAC-CU evaluates the effects of COVID-19 vaccination in patients with CU including rates and risk factors of CU exacerbation. Here, we analyzed 1857 patients with CU who had received at least one COVID-19 vaccination. Data were collected via a questionnaire and retrieved from patient charts. Result (s) Of 1857 patients with CU (median age 42 years; range 18-91 years), 72.1% were female and 71.2%, 14.4% and 14.4% had chronic spontaneous urticaria, chronic inducible urticaria, or both, respectively. Most patients had received two doses of COVID-19 vaccine (79.1%), compared to one (9.7%), three (11%), or four (0.3%). Vaccine type included BTN162b2 (58.4%; BioNTech/Pfizer), ChAdOx1 nCOV-19 (13.8%; AstraZeneca), BBIBP-CorV (8.2%; Sinopharm), Gam-COVID-Vac (8%; Sputnik), mRNA-1273 (5.3%; Moderna), and Ad26. COV 2.5 (4.7%; Janssen/J&J). Less than 10% of patients used premedication, and less than half of patients (44.4%) reported one or more adverse reactions after vaccination. The most common adverse reactions were local injection site reactions (29.6%), fatigue (19.7%), fever (19%), muscle pain (17.9%), headache (14%), and exacerbation of CU (15%). Severe allergic …