Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks.

BACKGROUND: Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy. METHODS: In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours. RESULTS: A total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported. CONCLUSIONS: Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.).

Rheumatoid arthritis patients treated with Janus kinase inhibitors show reduced humoral immune responses following BNT162b2 vaccination.

OBJECTIVES: The mRNA-based COVID-19 vaccines are now employed globally and have shown high efficacy in preventing SARS-CoV-2 infection. However, less is known about the vaccine efficacy in immune-suppressed individuals. This study sought to explore whether humoral immunity to the COVID-19 vaccine BNT162b2 is altered in RA patients treated with Janus kinase inhibitors by analysing their antibodies titre, neutralization activity and B cell responses. METHODS: We collected plasma samples from 12 RA patients who were treated with Janus kinase inhibitors and received two doses of the BNT162b2 vaccine, as well as 26 healthy individuals who were vaccinated with the same vaccine. We analysed the quantity of the anti-spike IgG and IgA antibodies that were elicited following the BNT162b2 vaccination, the plasma neutralization capacity and the responsiveness of the B-lymphocytes. We used ELISA to quantify the antibody titres, and a plasma neutralization assay was used to determine the virus neutralization capacity. Alteration in expression of the genes that are associated with B cell activation and the germinal centre response were analysed by quantitative PCR. RESULTS: Reduced levels of anti-spike IgG antibodies and neutralization capacity were seen in the RA patients who were treated with JAK inhibitors in comparison with healthy individuals. Furthermore, B cell responsiveness to the SARS-CoV-2 spike protein was reduced in the RA patients. CONCLUSION: RA patients who are treated with JAK inhibitors show a suppressed humoral response following BNT162b2 vaccination, as revealed by the quantity and quality of the anti-spike antibodies.

The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria.

This update and revision of the international guideline for urticaria was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA²LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), the European Dermatology Forum (EDF; EuroGuiDerm), and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology with the participation of 64 delegates of 50 national and international societies and from 31 countries. The consensus conference was held on 3 December 2020. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease that presents with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous or inducible urticaria is disabling, impairs quality of life, and affects performance at work and school. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

Efficacy and safety of crisaborole in patients with mild-to-moderate atopic dermatitis and other atopic comorbidities.

Background: Crisaborole is a nonsteroidal anti-inflammatory phosphodiesterase 4 inhibitor that is approved for the treatment of patients with mild-to-moderate atopic dermatitis (AD); however, the efficacy and safety of crisaborole in patients with AD and other atopic comorbidities have not been investigated. Objective: This post hoc pooled analysis of the pivotal phase III studies (CrisADe CORE 1 and CORE 2) assessed the efficacy and safety of crisaborole versus vehicle in patients aged ≥ 2 years with mild-to-moderate AD and other atopic comorbidities. Methods: Patients with mild-to-moderate AD and a medical history of asthma, allergic rhinitis, or food allergies were identified. Efficacy assessments included the proportion of patients who achieved Investigator's Static Global Assessment (ISGA) success at day 29, ISGA clear or almost clear at day 29, and improvement in the Severity of Pruritus Scale score at week 4. Safety was assessed via treatment-emergent adverse events (TEAEs). Results: This analysis included 1522 patients (crisaborole, 1016; vehicle, 506); 26.2, 15.9, and 16.5% had a medical history of asthma, allergic rhinitis, and food allergies, respectively. The mean age was 12.2 years. A significantly greater proportion of patients treated with crisaborole achieved ISGA success at day 29 compared with patients treated with vehicle for most subgroups analyzed. Furthermore, a significantly greater proportion of patients treated with crisaborole achieved ISGA clear or almost clear at day 29 across all subgroups and demonstrated improvement in the Severity of Pruritus Scale score at week 4 versus patients treated with vehicle in most of the subgroups. Overall, most TEAEs were mild or moderate in severity; the most common treatment-related TEAE in patients with atopic comorbidities was application-site pain (crisaborole, 5.1%; vehicle, 1.7%). Conclusion: Crisaborole was efficacious and well tolerated in patients with mild-to-moderate AD and other atopic comorbidities, which suggested that crisaborole should be considered for the management of AD in this population. Clinical Trials NCT02118766 (CrisADe CORE 1) and NCT02118792 (CrisADe CORE 2), www.clinicaltrials.gov.

Sensory processing patterns affect headache severity among adolescents with migraine.

OBJECTIVE: To evaluate the relationship between pain catastrophizing level, sensory processing patterns, and headache severity among adolescents with episodic migraine. BACKGROUND: Catastrophizing about pain is a critical variable in how we understand adjustment to pain and has a unique contribution in predicting pain intensity. Recent reports found that migraine is also related to enhanced sensory sensitivity. However, the relationship between pain severity, pain catastrophizing level and sensory sensitivity requires greater study especially among adolescents. METHODS: Participants were 92 adolescents aged 13-18 years, 40 with episodic migraine and 52 healthy controls. The migraine patients were prospectively recruited from outpatient pediatric neurology clinics. All participants completed the Adolescent/Adult Sensory Profile (AASP), and the Pain Catastrophizing Scale for children (PCS-ch). The migraine groups also completed the PedMIDAS, which measures Headache related disability. RESULTS: Adolescents with migraine had significantly lower tendency to seek sensory input than healthy controls. Elevated rumination and helplessness correlated with higher migraine pain severity. Tendency to avoid sensory input predicted the migraine related disability level. They also significantly higher pain catastrophizing level than healthy controls, as seen in enhanced rumination (p ≤ 0.001) and helplessness (p ≤ 0.05). CONCLUSIONS: Sensory processing difficulties are common among adolescents with episodic migraine. Sensory avoidance may be related to pain experience, and pain catastrophizing and disability level. TRIAL REGISTRATION: ISRCTN ISRCTN73824458. Registered 28 September 2014. retrospectively registered.

Recombinant human C1 esterase inhibitor treatment for hereditary angioedema attacks in children.

BACKGROUND: Attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1-INH-HAE) usually begin during childhood or adolescence. However, limited data are available regarding indications and modalities of treatment of children. This study evaluated recombinant human C1-INH (rhC1-INH) for HAE attacks in children. METHODS: This open-label, phase 2 study included children aged 2-13 years with C1-INH-HAE. Eligible HAE attacks were treated intravenously with rhC1-INH 50 IU/kg body weight (maximum, 4200 IU). The primary end-point was time to beginning of symptom relief (TOSR; ≥20 mm decrease from baseline in visual analog scale [VAS] score, persisting for two consecutive assessments); secondary end-point was time to minimal symptoms (TTMS; <20 mm VAS score for all anatomic locations). RESULTS: Twenty children (aged 5-14 years; 73 HAE attacks) were treated with rhC1-INH. Seventy (95.9%) of the attacks were treated with a single dose of rhC1-INH. Seven (35.0%) children were treated for four or more attacks. Overall, median TOSR was 60.0 minutes (95% confidence interval [CI], 60.0-65.0); data were consistent across attacks. Median TTMS was 122.5 minutes (95% CI, 120.0-126.0); data were consistent across attacks. No children withdrew from the study due to adverse events. No treatment-related serious adverse events or hypersensitivity reactions were reported; no neutralizing antibodies were detected. CONCLUSIONS: Recombinant human C1-INH was efficacious, safe, and well tolerated in children. Data support use of the same dosing regimen for HAE attacks in children (50 IU/kg; up to 4200 IU, followed by an additional dose, if needed) as is currently recommended for adolescents and adults.

The association between semaphorin 3A levels and gluten-free diet in patients with celiac disease.

Celiac disease (CD) is an inflammatory disease affecting the small intestine. We aim to assess serum level and expression of semaphorin 3A (Sema3A) on T regulatory (Treg) cells in CD patients. Twenty-six newly diagnosed celiac patients, 13 celiac patients on a gluten-free diet and 16 healthy controls included in the study. Sema3A protein level in the serum of celiac patients was significantly higher compared to healthy group (7.17±1.8ng/ml vs. 5.67±1.5ng/ml, p=0.012). Sema3A expression on Treg cells was statistically lower in celiac patients compared to healthy subjects (p=0.009) and significantly lower in celiac patients compared to celiac patients on gluten free diet (p=0.04). Negative correlation was found between Sema3A on Teg cells and the level of IgA anti-tTG antibodies (r=-0.346, p<0.01) and anti-DGP (r=-0.448, p<0.01). This study suggests involvement of the Sema3A in the pathogenesis of CD.

Health-related quality of life among children with hereditary angioedema.

BACKGROUND: The clinical expressions of hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) and its related burden may negatively affect patient quality of life. This study aimed to assess health-related quality of life (HRQoL) in children with C1-INH-HAE. METHODS: Children (N = 98: 34 C1-INH-HAE patients, 64 healthy controls) aged 3-18 years were recruited in Israel and Hungary. All individuals completed a demographic questionnaire, a disease activity and site questionnaire, and the Pediatric Quality of Life Inventory (PedsQL™) 4.0 Generic Core Scales (child self-report and maternal proxy report) to assess HRQoL. RESULTS: Among C1-INH-HAE patients, nine (26.5%) had 1-5 attacks/year, six (17.6%) had 6-18 attacks/year, eight (23.5%) had 25-60 attacks/year, and 11 (32.4%) were asymptomatic over the previous year. Children with C1-INH-HAE attacks demonstrated lower HRQoL than healthy control children across the total score, school, and psychosocial dimensions of the PedsQL™. The number of C1-INH-HAE attacks negatively correlated with the total HRQoL score (r = -0.48, p = 0.008), school-related HRQoL (r = -0.39, p = 0.02), and psychosocial HRQoL (r = -0.43, p = 0.01). Patients with multisite laryngeal, abdominal, and peripheral C1-INH-HAE attacks had a lower HRQoL compared with those who experienced solely peripheral attacks across the total score (p = 0.04), physical (p = 0.04), and school (p = 0.02) domains. There was no significant difference between asymptomatic C1-INH-HAE patients and healthy controls. CONCLUSIONS: Children with symptomatic C1-INH-HAE demonstrate impaired HRQoL compared with healthy controls. HRQoL was affected by the frequency and site of C1-INH-HAE attacks and mostly in the school and physical domains.

The relationship between anxiety and quality of life in children with hereditary angioedema.

BACKGROUND: The severe life-threatening characteristics of hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) can affect anxiety levels among pediatric patients. This emotional burden together with the physical restrictions of C1-INH-HAE may decrease children's health-related quality of life (HRQoL). OBJECTIVES: (i) To compare anxiety state and trait between children with C1-INH-HAE and healthy controls; (ii) to examine the relationship between the level of anxiety of children with C1-INH-HAE, their disease activity/affected sites and their HRQoL; and (iii) to predict the HRQoL of children with C1-INH-HAE based on their anxiety level and disease activity/affected sites METHODS: Thirty-three children with C1-INH-HAE (aged 5-18 years) and 52 healthy controls were recruited from Israel and Hungary. All children completed the State-Trait Anxiety Inventory for Children (STAIC), the Pediatric Quality of Life Inventory (Peds-QL) demographic questionnaire and a disease activity and site questionnaire . Disease activity was defined as the number of attacks in last year. RESULTS: Both anxiety state and trait were significantly higher among children with C1-INH-HAE as compared to the controls (44.74±10.56 vs 38.76±10.67, P<.01, 29.21±5.16 vs 25.23±4.09, P<.001 in comparison). Significant differences were found between C1-INH-HAE patients with HAE attacks, asymptomatic C1-INH-HAE patients, and healthy controls in both anxiety state (F56,2 =4.69, P=.001) and trait (F56,2 =9.06, P<.0001). A higher anxiety trait was correlated with the number of angioedema-affected sites (r=.52, P=.003). The presence of HAE attacks and higher anxiety trait predicted a lower HRQoL in children with C1-INH-HAE. CONCLUSIONS: C1-INH-HAE children have higher anxiety trait and state, which correlate with reduced HRQoL domains.

A high and equal prevalence of the Q703K variant in NLRP3 patients with autoinflammatory symptoms and ethnically matched controls.

OBJECTIVES: Cryopyrin associated periodic syndromes (CAPS) comprise a spectrum of autoinflammatory disorders of varying severity caused by mutations in the NLRP3 gene. The NLRP3-Q703K allele has been reported both as a functional polymorphism and as a low penetrance mutation. METHODS: To describe the clinical phenotype of subjects with the Q703K allele and to report the frequency of this allele among patients with autoinflammatory symptoms and healthy controls. To this end, a cohort of 10 ethnically-matched controls per each Q703K-carrying patient, was composed. RESULTS: Ninety patients suspected of harboring a systemic autoinflammatory disease (SAID), exclusive of FMF, were referred to our center for genotyping between 2012 and 2015. Fourteen of them (15.5%) were found to carry the Q703K allele, compared to 22 of 130 (16.9%) healthy, ethnically matched controls. CONCLUSIONS: The similar carrier rate of the NLRP3-Q703K allele among patients with manifestations of a SAID and an ethnically matched control group suggest that this variant, does not determine the clinical phenotype. This reiterates the importance of testing a control group to avoid erroneously attributing a causative role to a gene polymorphism.

[RECOMMENDATION FOR EVALUATION AND TREATMENT OF CHRONIC URTICARIA - THE ISRAELI ASSOCIATION FOR ALLERGY AND CLINICAL IMMUNOLOGY].

INTRODUCTION: Chronic urticaria is a disease manifested by a pruritic rash lasting longer than 6 weeks that may severely affect quality of life and daily function. Chronic urticaria can be further divided into chronic spontaneous urticaria which appears without a trigger and chronic inducible urticaria which evolves following distinct physical triggers. These two clinical manifestations could coexist in the same patient. The pathogenesis of chronic urticaria is not fully elucidated, although it is considered an autoimmune disease in at least 50% patients that produce auto- IgG antibodies targeted against the high affinity Fc receptor and to a lesser extent against IgE itself. Auto-antibodies associated with different autoimmune diseases can be detected such as those directed at thyroid proteins. Urticaria tends to spontaneously resolve in 50% of patients within the first year while others will suffer from it for a much longer period of time. The treatment of chronic urticaria has dramatically progressed in the last decade, enabling reduction of systemic corticosteroid use which has been the cornerstone of treatment in the past. The recommended treatment for chronic urticaria is currently based on a stepwise approach that enables achieving disease control with a reasonably good quality of life. The first step of the treatment ladder consists of selective, new generation, anti-H1 histamine blockers, which do not cross the blood brain barrier, starting from the recommended dose (first line) and increasing up to four-fold (second line). The third line of treatment is the addition of immune modulators such as leukotriene receptor blockers (Singulair), anti-IgE biological therapy (Xolair), or cyclosporine. In this review we present the updates and considerations arising during evaluation and treatment of chronic urticaria. The need for specific tests, immunologist/allergologist evaluation, as well as treatment modalities taking into consideration the large body of evidence that has accumulated in the last few years, the new international guidelines as well as their application in Israel have been addressed.

Seasonal Exacerbation of Asthma Is Frequently Associated with Recurrent Episodes of Acute Urticaria.

BACKGROUND: Asthma and urticaria are both partially mediated by an increased release of histamine from highly activated mast cells. They are pathophysiologically different, as mast cell degranulation in these 2 disorders results from different mechanisms. OBJECTIVE: To assess the incidence of urticaria in patients with asthma, and of asthma in patients with chronic spontaneous urticaria (CSU). PATIENTS AND METHODS: Over 1 year of follow-up, asthma patients (n = 110) were assessed for the incidence and characteristics of urticaria, and a link, if it existed, to seasonal exacerbations and the severity of asthma was traced. We also prospectively assessed CSU patients (n = 95) during the same period of time for the incidence of asthma. Healthy individuals (n = 100), serving as a control group, were also assessed. RESULTS: Episodes of urticaria occurred in 26/110 asthma patients (23.6%), but in only 2/100 healthy control subjects (2%) (p < 0.0001). During the 1-year observation period, episodes of urticaria were significantly more frequent in asthma patients with positive skin-prick test reactions (mainly seasonal pollens), and consequently occurred mostly during seasonal asthma exacerbation, i.e. during acute episodes of urticaria. The incidence of asthma in CSU patients was recorded in 10.5% of the group, similar to that in the healthy control population. DISCUSSION: Our study demonstrates, for the first time, that asthma patients frequently develop acute urticaria, mainly during seasonal exacerbations. In contrast, CSU patients do not show an increased incidence of asthma.

Adaptation and Validation of the Israeli Version of the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL).

BACKGROUND: Chronic urticaria (CU) is a common disabling disorder. The CU-Q2oL (Chronic Urticaria Quality of Life Questionnaire) is a specific questionnaire for evaluating quality of life in CU patients. It consists of 23 items divided into six quality-of-life dimensions. It was initially developed in Italy and later validated in other countries. OBJECTIVES: To validate and adapt the CU-Q2oL to the Hebrew language in order to make it suitable for use in Israel. METHODS: The CU-Q2oL questionnaire was translated to Hebrew. A group of 119 CU patients were asked to complete this version, in addition to the Dermatology Life Quality Index (DLQI) and Urticaria Activity Score (UAS) questionnaires. A factorial analysis was performed to identify CU-Q2oL subscales, internal consistency and convergent validity assessment, as well as factors determining quality-of-life scores. RESULTS: The factor analysis identified six scales of the Israeli CU-Q2oL: (i) sleep and concentration, (ii) function and mental status, (iii) embarrassment and clothing limitations, (iv) itching, (v) eating behavior and medication side effects, and (vi) swelling, which accounted for 77% of the data variance. Five scales showed good internal consistency over 0.81. The mean ± SD score of CU-Q2oL in our patients with CIU was 41 ± 21.7. We found a strong positive correlation between the overall scores of CU-Q2oL and DLQI questionnaires (r = 0.8, P < 0.01). Additionally, we found a positive correlation between UAS and both CU-Q2oL and DLQI (r = 0.62, P < 0.01, and r = 0.53, P < 0.01, respectively). CONCLUSIONS: This study demonstrates that the Israeli CU-Q2oL questionnaire is suitable for both clinical use and research in Israel.

[KIDNEY DISEASES IN NORTH ISRAEL ACCORDING TO KIDNEY BIOPSIES - BNAI-ZION MEDICAL CENTER 14 YEARS' EXPERIENCE].

INTRODUCTION: Little is known about the prevalence of kidney diseases according to renal biopsy in Israel. Since updated literature worldwide emphasizes changing etiologies of chronic kidney disease, it is crucial to research and define the epidemiology and pathology of kidney disease in Israel. Hereby, we introduce an original review of the prevalence of kidney diseases in our study population, which we believe reflects the prevalence of kidney diseases in the population of Israel. AIMS: To investigate the prevalence of kidney diseases diagnosed by renal biopsy, according to age, gender, race and clinical symptoms. METHODS: A total of 155 kidney biopsies were conducted in the years 2000-2014 in Bnai-Zion Medical Center in Haifa, according to formal accepted indications. Most of the biopsies (65%) were needle aspirations in a retroperitoneal approach, in which 90% were ultrasound guided and the rest computed tomography guided, while the other 35% of biopsies involved laparoscopic approaches. RESULTS: The most common indications for kidney biopsy were nephrotic syndrome, nephritic syndrome and proteinuria (37.4%, 25.8% and 24.5%, respectively). Average glomeruli number per biopsy was 17.5 vs. 82.2 for needle aspiration and laparoscopic approach, respectively (statistically significant). The most common diagnosis was focal segmental glomerulosclerosis (FSGS), followed by chronic glomerulonephritis, IgA nephropathy, lupus nephritis, minimal change disease (MCD), membranous nephropathy and tubulointerstitial disease (20%, 11.5%, 11.5%, 10.1%, 9.5%, 8.1% and 6.1%, respectively). CONCLUSIONS: FSGS was the most common diagnosis in patients presented with nephrotic syndrome or proteinuria, men, and patients above 60 years of age. Patients below 30 years of age were mainly diagnosed with IgA nephropathy. DISCUSSION: In recent years, FSGS is becoming more prevalent compared with other chronic kidney disease especially in the older population. IgA nephropathy is still the most common diagnosis in young patients and in patients presented with hematuria. To the best of our knowledge, no data exists on the prevalence of kidney diseases in Israel, and our study is an important contribution to the epidemiological and clinical knowledge on the subject.

The Decline of Pertussis-Specific Antibodies After Tetanus, Diphtheria, and Acellular Pertussis Immunization in Late Pregnancy.

We prospectively measured pertussis-specific antibodies 9-15 months after delivery in women immunized with tetanus, diphtheria, and acellular pertussis (Tdap) after the 20th week of their recent pregnancy. The Tdap-immunized women (n = 38) exhibited a decline in geometric mean concentrations between their peripartum and follow-up levels for immunoglobulin G to pertussis toxin (21.48 [95% confidence interval, 12.51-36.89] vs 11.72 [7.09-19.37] IU/mL];); filamentous hemagglutinin (185.95 [157.93-218.94] vs 140.33 IU/mL [113.46-173.57] IU/mL); and pertactin (171.52 [120.73-243.67] vs 83.74 [60.58-115.75] IU/mL) (all P < .001). For women immunized with Tdap during late pregnancy, pertussis-specific immunoglobulin G levels decreased significantly 9-15 months after delivery.