RATIONALE: Recently we reported that Benralizumab was effective in treating chronic spontaneous urticaria (CSU) unresponsive to H1-antihistamines. However, the mechanism of action(s) that explain why an IL-5Ralpha antagonist improves CSU symptoms is not entirely understood. This study investigated transcriptomic pathways in skin biopsies and blood in H1-antihistamine unresponsive CSU patients collected before and after treatment with Benralizumab. METHODS: A single-blinded, single-center, repeated-measures study enrolled 12 CSU patients aged 18-75 years, unresponsive to high doses of H1-antihistamines. Subjects were treated with a single-dose placebo followed by benralizumab 30mg s.c. every 4 weeks 312 weeks. Clinical improvement was assessed using the Urticaria Activity Score over 7 days (UAS7) and Eos% in peripheral blood. RNA-sequencing followed by geneset enrichment analysis (GSEA) of differentially expressed genes (DEGs) was performed on blood and lesional vs. non-lesional skin biopsies obtained from CSU subjects post-placebo and post-Benralizumab treatment; similar biological samples were obtained from six non-CIU subjects as controls. RESULTS: UAS7 improved significantly in 7/9 subjects who completed the study. In blood samples, 109 DEGs (78 under-expressed, 31 overexpressed) were identified post-Benralizumab vs. controls, and 31 DEGs were identified (all under-expressed) post-Benralizumab vs. post-placebo. Normalized expression levels of several DEGs were significantly correlated with improvements in UAS7 (p<0.05) and Eos% (p<0.001). GSEA suggests Benralizumab-mediated control of autoimmune inflammation by limiting excess tryptophan catabolism, SIGLEC-8 expression on Eos/mast cells, and IL4-/IL5-mediated inflammation. CONCLUSIONS: We present newly available genomic analysis data demonstrating that Benralizumab normalizes gene expression in CSU patients through several novel biologic pathways which may explain its clinical effect.
RATIONALE: Cow's milk protein (CMP) allergy is a common food allergy in infants. Information regarding the best timing to first introduce CMP is controversial. There are data suggesting that avoidance of CMP for at least the first three days of life has a protective effect for CMP allergy (CMA). Others suggest that introduction of CMP after the first 15-30 days of life, raises the risk for CMA. The current ongoing study assesses the effect of early and continuous exposure to cow's milk formula (CMF) on the development of CMA. METHODS: Newborns were prospectively recruited shortly before birth and divided to groups according to parents' preference: exclusive breastfeeding; breastfeeding with at least one daily meal of CMF, and feeding with CMF only. Infants were followed monthly until the age of 12 months. RESULTS: To date 1,560 infants were recruited: 1,160 (74.35%) were followed for six months or more, and 635 (40.7%) completed 12 months of follow up. Five hundred and seven infants (51.4%) were exclusively breastfed untill 2 months of age, 318 (32.2%) combined breastfeeding and CMF, and 162 (16.4%) ate only CMF. Immediate reaction proven by skin test developed in 9 infants (0.91%), all were exclusivly breastfed. Within this group, the prevalence of CMAwas 1.77% compared to zero in the other groups (RR51.96, CI 95% 1.23-1.96, p50.004). CONCLUSIONS: It appears that early and contineous exposure to CMF since birth has a protective effect against the development of IgE mediated CMA. A larger cohort is needed in order to validate these results.
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