Biologic response modifiers: Indications, implications, and insights.

The field of biologic immune modulators is currently mushrooming at a dizzying pace. Although most of these biologics are tested and approved for one or a few indications, their unanticipated side effects and off-label use have contributed significantly to our understanding of basic immune mechanisms, the involvement of cytokines in several apparently nonimmunologic diseases, and the importance of compartmentalized immune responses. In this review we attempt to give a bird's-eye view of the major biologics and to highlight insights and implications derived from their secondary effects and adverse reactions.

Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis.

BACKGROUND: A key question in the allergy field is to understand how tissue-specific disease is manifested. Eosinophilic esophagitis (EoE) is an emerging tissue-specific allergic disease with an unclear pathogenesis. OBJECTIVE: Herein we tested the hypothesis that a defect in tissue-specific esophageal genes is an integral part of EoE pathogenesis. METHODS: We interrogated the pattern of expression of esophagus-specific signature genes derived from the Human Protein Atlas in the EoE transcriptome and in EPC2 esophageal epithelial cells. Western blotting and immunofluorescence were used for evaluating expression of esophageal proteins in biopsy specimens from control subjects and patients with active EoE. Whole-exome sequencing was performed to identify mutations in esophagus-specific genes. RESULTS: We found that approximately 39% of the esophagus-specific transcripts were altered in patients with EoE, with approximately 90% being downregulated. The majority of transcriptional changes observed in esophagus-specific genes were reproduced in vitro in esophageal epithelial cells differentiated in the presence of IL-13. Functional enrichment analysis revealed keratinization and differentiation as the most affected biological processes and identified IL-1 cytokines and serine peptidase inhibitors as the most dysregulated esophagus-specific protein families in patients with EoE. Accordingly, biopsy specimens from patients with EoE evidenced a profound loss of tissue differentiation, decreased expression of keratin 4 (KRT4) and cornulin (CRNN), and increased expression of KRT5 and KRT14. Whole-exome sequencing of 33 unrelated patients with EoE revealed 39 rare mutations in 18 esophagus-specific differentially expressed genes. CONCLUSIONS: A tissue-centered analysis has revealed a profound loss of esophageal tissue differentiation (identity) as an integral and specific part of the pathophysiology of EoE and implicated protease- and IL-1-related activities as putative central pathways in disease pathogenesis.

Toxic Epidermal Necrolysis after COVID-19 mRNA-1237 Vaccination.

This letter illustrates a case of toxic epidermal necrolysis (TEN) after COVID-19 mRNA-1273 vaccination, which corresponds with the existing published data and contributes detailed knowledge of TEN reaction after vaccination. Interestingly, the reaction started at the site of vaccination and the patient went on to tolerate a major excipient of the vaccine suggesting the reaction may be associated with the mRNA itself or is triggered by the immunostimulatory action of the vaccine.

Refractory Pediatric Fibrostenotic Eosinophilic Esophagitis Treated With Dupilumab.

Eosinophilic esophagitis (EoE) is a progressive inflammatory disease of the esophagus. Untreated or uncontrolled disease over time can lead to the development of fibrosis and formation of strictures. Once the patient develops strictures, it is difficult to treat with the available medical therapies and will often require esophageal dilations. The Food and Drug Administration recently approved dupilumab for the treatment of EoE in patients older than 12 years. The clinical trials excluded patients with esophageal strictures. We describe a case of EoE with fibrostenotic stricture who had stricture resolution while on dupilumab therapy.

A randomized, double-blind, parallel trial comparing capsaicin nasal spray with placebo in subjects with a significant component of nonallergic rhinitis.

OBJECTIVE: To investigate the efficacy and safety of ICX72 or Sinus Buster, a proprietary homeopathic preparation of Capsicum annum and Eucalyptol, versus placebo administered continuously over 2 weeks in subjects with a significant component of nonallergic rhinitis (NAR). METHODS: Forty-two consented subjects meeting inclusion/exclusion criteria were randomized to ICX72 (n = 20) or control (n = 22) administered twice daily over 2 weeks. The primary endpoint was change in total nasal symptom scores (TNSS) from baseline to end of study. Secondary endpoints included changes in individual symptom scores (ISS) over 2 weeks and average time to first relief. Mean TNSS and ISS were recorded after single dosing at different intervals over 60 minutes. Rhinitis quality-of-life, rescue medication, and safety endpoints were analyzed. RESULTS: ICX72 versus placebo subjects exhibited significant differences in changes from baseline to end of study for TNSS and each ISS (P < .01), had an average time to first relief of 52.6 seconds (P < .01), and improvement in nasal congestion, sinus pain, sinus pressure, and headache at 5, 10, 15, and 30 minutes, persisting at 60 minutes for nasal congestion and sinus pain (P < .05). No difference between groups in adverse events or rescue medication was observed. ICX72 versus placebo subjects experienced no rebound congestion or impaired olfaction at the end of the study. CONCLUSION: This is the first controlled trial demonstrating intranasal capsaicin, when used continuously over 2 weeks, rapidly and safely improves symptoms in rhinitis subjects with a significant NAR component.

Pathophysiology of Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus associated with an atopic predisposition which appears to be increasing in prevalence over the last few decades. Symptoms stem from fibrosis, swelling, and smooth muscle dysfunction. In the past two decades, the etiology of EoE has been and is continuing to be revealed. This review provides an overview of the effects of genetics, environment, and immune function including discussions that touch on microbiome, the role of diet, food allergy, and aeroallergy. The review further concentrates on the pathophysiology of the disease with particular focus on the important concepts of the molecular etiology of EoE including barrier dysfunction and allergic hypersensitivity.

Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of ARC001, a Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial.

BACKGROUND: Peanut oral immunotherapy, using a variety of approaches, has been previously shown to induce desensitization in peanut-allergic subjects, but no products have been approved for clinical use by regulatory agencies. OBJECTIVE: We performed the first phase 2 multicentered study to assess the safety and efficacy of AR101, a novel oral biologic drug product. METHODS: A randomized, double-blind, placebo-controlled trial was conducted at 8 US centers. Eligible subjects were 4 to 26 years old, sensitized to peanut, and had dose-limiting symptoms to ≤143 mg of peanut protein in a screening double-blind, placebo-controlled food challenge (DBPCFC). Subjects were randomized 1:1 to daily AR101 or placebo and gradually up-dosed from 0.5 to 300 mg/day. The primary endpoint was the proportion of subjects in each arm able to tolerate ≥443 mg (cumulative peanut protein) at exit DBPCFC with no or mild symptoms. RESULTS: Fifty-five subjects (29 AR101, 26 placebo) were enrolled. In the intention-to-treat analysis, 23 of 29 (79%) and 18 of 29 (62%) AR101 subjects tolerated ≥443 mg and 1043 mg at exit DBPCFC, respectively, versus 5 of 26 (19%) and 0 of 26 (0%) placebo subjects (both P < .0001). Compared with placebo, AR101 significantly reduced symptom severity during exit DBPCFCs and modulated peanut-specific cellular and humoral immune responses. Gastrointestinal (GI) symptoms were the most common treatment-related adverse events (AEs) in both groups, with 6 AR101 subjects (21%) withdrawing, 4 of those due primarily to recurrent GI AEs. CONCLUSIONS: In this study, AR101 demonstrated an acceptable safety profile and demonstrated clinical activity as a potential immunomodulatory treatment option in peanut-allergic children over the age of 4, adolescents, and young adults.

Mechanisms of Disease of Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disease of the esophagus with clinical symptoms derived from esophageal dysfunction. The etiology of EoE is now being elucidated, and food hypersensitivity is emerging as the central cornerstone of disease pathogenesis. Herein, we present a thorough picture of the current clinical, pathologic, and molecular understanding of the disease with a focus on disease mechanisms.

Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment.

We recently identified a genome-wide genetic association of eosinophilic esophagitis (EoE) at 2p23 spanning the calpain 14 (CAPN14) gene, yet the causal mechanism has not been elucidated. We now show that recombinant CAPN14 cleaves a calpain-specific substrate and is inhibited by 4 classical calpain inhibitors: MDL-28170, acetyl-calpastatin, E-64, and PD151746. CAPN14 is specifically induced (>100-fold) in esophageal epithelium after IL-13 treatment. Epithelial cells overexpressing CAPN14 display impaired epithelial architecture, characterized by acantholysis, epidermal clefting, and epidermolysis. CAPN14 overexpression impairs epithelial barrier function, as demonstrated by decreased transepithelial resistance (2.1-fold) and increased FITC-dextran flux (2.6-fold). Epithelium with gene-silenced CAPN14 demonstrates increased dilated intercellular spaces (5.5-fold) and less organized basal cell layering (1.5-fold) following IL-13 treatment. Finally, CAPN14 overexpression results in loss of desmoglein 1 (DSG1) expression, whereas the IL-13-induced loss of DSG1 is normalized by CAPN14 gene silencing. Importantly, these findings were specific to CAPN14, as they were not observed with modulation of CAPN1 expression. These results, along with the potent induction of CAPN14 by IL-13 and genetic linkage of EoE to the CAPN14 gene locus, demonstrate a molecular and cellular pathway that contributes to T helper type 2 responses in mucosal epithelium.

Eosinophils and cancer.

Eosinophils have long been known to infiltrate tumors, and in most cases, this is associated with an improved prognosis. However, the reasons behind this infiltration and the mechanism of action of the eosinophil have remained elusive. In this article, we explore the biology of eosinophils and examine their function in homeostasis and disease states, specifically focusing on what is currently known about the association of the eosinophil with cancer.

Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in EoE cases of European ancestry and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replicating association of the 5q22 locus (meta-analysis P=1.9×10(-16)), we identified an association at 2p23 spanning CAPN14 (P=2.5×10(-10)). CAPN14 was specifically expressed in the esophagus, was dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to interleukin (IL)-13, and was located in an epigenetic hotspot modified by IL-13. Genes neighboring the top 208 EoE-associated sequence variants were enriched for esophageal expression, and multiple loci for allergic sensitization were associated with EoE susceptibility (4.8×10(-2)