Omalizumab for the Treatment of Multiple Food Allergies.

BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).

In-vitro and in-vivo anti-allergic effects of magnolol on allergic rhinitis via inhibition of ORAI1 and ANO1 channels.

ETHNOPHARMACOLOGICAL RELEVANCE: Flos Magnoliae (the dried flower buds of Magnolia biondii Pamp, FM) is a known herbal traditional medicine used for the symptomatic relief of nasal congestion and rhinorrhea caused by rhinitis and sinusitis. Magnolol, a neolignan from the magnolia family, is a secondary metabolite known to have anti-allergic and anti-inflammatory effects. However, the underlying mechanisms and therapeutic effect of magnolol in the treatment of allergic rhinitis (AR) remain elusive. AIMS OF THE STUDY: Anoctamin 1 (ANO1), a calcium-activated anion channel, mediates mucus and electrolyte secretion in nasal airway epithelial cells, whereas calcium release-activated calcium channel protein 1 (ORAI1) participates in the activation of T-lymphocytes and mast cells. The aim of our study is to understand the mechanisms of action of magnolol against AR, i.e., whether it acts through the modulation of ANO1 and ORAI1 channels that are expressed in nasal epithelial cells and T-lymphocytes, respectively. MATERIALS AND METHODS: Whole-cell patch clamp was used to record the activity of ORAI1 and ANO1 ion channels in ORAI1 or ANO1 overexpressed HEK293T cells, while the Ussing chamber apparatus was used to measure electrolyte transport via the epithelium, in Calu-3 cells cultured in an air-liquid interface. Additionally, calcium imaging of Jurkat T-lymphocytes was used to assess changes in the intracellular calcium concentration. Magnolol toxicity was assessed using the CCK-8 assay, and its effect on T-lymphocyte proliferation was measured by labeling human primary T-lymphocytes with carboxyfluorescein succinimidyl ester. Finally, OVA-induced Balb/c mice were employed to evaluate the effect of magnolol on nasal symptoms, as well as cytokine and eosinophil infiltration in AR. RESULTS: Magnolol inhibits ORAI1 and ANO1 channels in a concentration-dependent manner. Magnolol (30 µM) inhibits anti-CD3 induced cellular proliferation and production of IL-2 via ORAI1 channels in T-lymphocytes. Further, ATP-induced electrolyte transport mediated by ANO1 channels is significantly inhibited by magnolol in IL-4 sensitized Calu-3 cells. Notably, 300 µM magnolol significantly attenuates cytokine and eosinophil infiltration, thus alleviating AR symptoms in mice OVA-induced AR. CONCLUSION: Magnolol may be a promising therapeutic agent for the treatment and prevention of AR.

Alleviation effects of Rubus coreanus Miquel root extract on skin symptoms and inflammation in chronic atopic dermatitis.

Atopic dermatitis (AD) is an inflammatory skin disease characterized by chronic inflammatory dermatitis with immunological manifestations. The aim of this study was to investigate the effects of polyphenol-containing Rubus coreanus Miquel root extract on skin allergy and AD. The protective effects of R. coreanus root ethanol extract against AD were investigated using the human keratinocyte cell line HaCaT, human mast cell line HMC-1, and the 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin NC/Nga mouse model. Treatment with R. coreanus root ethanol extracts reduced ß-hexosaminidase and histamine release from HMC-1 cells stimulated with compound 48/80 compared to treatment with R. coreanus fruit ethanol extract. Furthermore, topical application of R. coreanus root ethanol extract dramatically reduced the severity of skin symptoms and the thickening and swelling of the dorsal skin and ear in DNCB-treated NC/Nga mice. The protein and mRNA expression of several cytokines (IL-4, IL-5, IL-12, IFN-γ, TNF-α, and TARC) and IgE was significantly lowered upon application of the R. coreanus root ethanol extract. The promising candidate for the active ingredient of R. coreanus root polyphenols was revealed to be ellagic acid. These findings clearly indicate that the R. coreanus root polyphenols show strong anti-allergic effects and suppress the symptoms of AD. Therefore, polyphenol-containing R. coreanus root ethanol extract could be a novel therapeutic candidate for the treatment of allergy and AD.

Chlorogenic Acid-Loaded Mesoporous Silica Nanoparticles Modified with Hexa-Histidine Peptides Reduce Skin Allergies by Capturing Nickel.

Nickel-induced contact dermatitis is a severe allergic reaction to objects or environments that contain nickel. Many nanomaterials have been developed to reduce skin allergies by capturing nickel, but few agents are effective and safe. In this work, mesoporous silica nanoparticles (MSN) were synthesized and decorated with hexa-histidine peptides (denoted as MSN-His6), making it a strong nickel chelator. Subsequently, a dietary polyphenol, chlorogenic acid, was loaded into the mesopores of MSN (denoted as MSN-His6@CGA), realizing the potential of its anti-inflammatory properties. In vitro and in vivo experiments revealed that the synthesized MSN-His6@CGA nanoparticles exhibited more stable and stronger chelation, better biocompatibility, and ideal allergy-relieving ability, whether for environmental metal contamination or for allergic contact dermatitis caused by prolonged nickel exposure. Thus, the application of mesoporous silica-based nanoparticles may represent an ideal approach to alleviate skin allergies by capturing nickel, which would benefit people who suffer from metal-induced contact dermatitis.

Anti-Allergic Effect of 3,4-Dihydroxybenzaldehyde Isolated from Polysiphonia morrowii in IgE/BSA-Stimulated Mast Cells and a Passive Cutaneous Anaphylaxis Mouse Model.

In this study, we investigated the anti-allergic effects of 3,4-dihydroxybenzaldehyde (DHB) isolated from the marine red alga, Polysiphonia morrowii, in mouse bone-marrow-derived cultured mast cells (BMCMCs) and passive cutaneous anaphylaxis (PCA) in anti-dinitrophenyl (DNP) immunoglobulin E (IgE)-sensitized mice. DHB inhibited IgE/bovine serum albumin (BSA)-induced BMCMCs degranulation by reducing the release of ß-hexosaminidase without inducing cytotoxicity. Further, DHB dose-dependently decreased the IgE binding and high-affinity IgE receptor (FcεRI) expression and FcεRI-IgE binding on the surface of BMCMCs. Moreover, DHB suppressed the secretion and/or the expression of the allergic cytokines, interleukin (IL)-4, IL-5, IL-6, IL-13, and tumor necrosis factor (TNF)-α, and the chemokine, thymus activation-regulated chemokine (TARC), by regulating the phosphorylation of IκBα and the translocation of cytoplasmic NF-κB into the nucleus. Furthermore, DHB attenuated the passive cutaneous anaphylactic (PCA) reaction reducing the exuded Evans blue amount in the mouse ear stimulated by IgE/BSA. These results suggest that DHB is a potential therapeutic candidate for the prevention and treatment of type I allergic disorders.

Unintentional cetirizine overdose causing anticholinergic syndrome.

The incidence of anticholinergic syndrome due to second generation antihistamines is infrequently reported. Largely due to their decreased affinity for central nervous system (CNS) receptors, second generation antihistamines are rarely associated with anticholinergic symptoms, though toxicity is still possible particularly when taken in excess. We report a case of a six year old boy who presented with agitation, hallucinations, fixed and dilated pupils, tachycardia, and hyperthermia consistent with anticholinergic toxicity several hours after accidental overdose of a second generation antihistamine, cetirizine. Early identification of this rare phenomenon is important not only for appropriate emergency management but also for avoidance of potentially invasive and unnecessary tests which may further increase patient morbidity.

Juzentaihoto Exerts Anti-Allergic Effects by Inhibiting Effector T-Cell Activation and Inducing and/or Activating Regulatory T Cells in a Murine Model of Contact Hypersensitivity.

BACKGROUND: Juzentaihoto (JTT) is a Kampo prescription that has been used clinically for treating skin diseases such as atopic dermatitis in Japan. We have previously studied the anti-allergic effects of JTT on 2,4,6-trinitrochlorobenzene (TNCB)-induced contact hypersensitivity (CHS) in mice and demonstrated that it significantly suppresses ear swelling in a dose-dependent manner. However, the mechanism underlying the anti-allergic actions of JTT is obscure. METHODS: We investigated the mechanism underlying the anti-allergic effects of JTT using a TNCB-induced murine CHS model and adoptive cell transfer experiments. RESULTS: We showed that the anti-allergic effects of JTT are due to inhibition of effector T-cell activation and induction and/or activation of regulatory T cells. Furthermore, ex vivo experiments confirmed the effect of JTT on the activation of effector T cells and regulatory T cells, as interferon-γ production decreased, whereas interleukin (IL)-10 production increased, in the cultured lymphocytes obtained from 5% TNCB-sensitized mice treated with anti-CD3ε and anti-CD28 monoclonal antibodies. Flow cytometry showed that the CD4+CD25+Foxp3+, CD4+CD25+Foxp3-, and CD8+CD122+ cell population increased after oral administration of JTT. Finally, the anti-allergic effect of JTT by inducing and/or activating regulatory T cells (Tregs) was confirmed to be mediated by IL-10 through in vivo neutralization experiments with anti-IL-10 monoclonal antibodies. CONCLUSION: We suggested that JTT exerts anti-allergic effects by regulating the activation of effector T cells and Tregs involved in murine CHS model.

A patient-oriented approach to long-term use of omalizumab in chronic spontaneous urticaria.

BACKGROUND: Omalizumab is an effective and safe treatment for antihistamine resistant chronic spontaneous urticaria (CSU), however, long-term efficacy and safety remains unclear. OBJECTIVE: To evaluate the efficacy and safety of omalizumab in CSU patients treated for long term and to identify long-term management strategies. METHODS: We retrospectively analyzed demographic characteristics, clinical features, laboratory parameters and treatment outcomes of 41 CSU patients who received omalizumab for at least 3 years. Treatment responses were evaluated with urticaria control test (UCT). Treatment safety was evaluated by comparing laboratory findings before and three years after omalizumab initiation as well as considering patients' adverse event reports. RESULTS: The patients (mean age 40.46 years; 63.4% women) received omalizumab for an average of 41.93 months (mean 31.68 injections/patient). The mean baseline UCT score was 5.56 and average number of injections to reach UCT score ≥12 was 3.3. Nine patients (22%) responded insufficiently to 300 mg/4 weeks omalizumab and required updosing. Thirty-eight patients (92.7%) could tolerate longer dose intervals (>4 weeks) and the dose interval was increased after a mean of 11.53 injections. There was no loss of efficacy of omalizumab. Sixteen patients (39%) had been retreated with omalizumab after a mean discontinuation time of 24 weeks. Five patients (12.2%) reported mild and transient adverse effects. Liver and renal function tests as well as full blood count before and after omalizumab were in normal ranges. CONCLUSION: For the long-term management of CSU, omalizumab is a safe and effective treatment which can be tailored according to patients' disease activity.

MP-AzeFlu in Moderate-to-Severe Allergic Rhinitis: A Literature Review.

Allergic rhinitis (AR) is prevalent, and many patients present with moderate-to-severe symptomatic disease. The majority of patients are not satisfied with their AR treatment, despite the use of concurrent medications. These gaps underscore the need for treatment with more effective options for moderate-to-severe AR. The authors' objective was to review systematically the efficacy and safety of MP-AzeFlu for the treatment of AR. The primary outcomes studied were nasal, ocular, and total symptoms. Other outcomes included time to onset and of AR control, quality of life, and safety. Searches of PubMed and Cochrane databases were conducted on May 14, 2020, with no date restrictions, to identify publications reporting data on MP-AzeFlu. Clinical studies of any phase were included. Studies were excluded if they were not in English, were review articles, did not discuss the safety and efficacy of MP-AzeFlu for AR symptoms. Treatment of AR with MP-AzeFlu results in effective, sustained relief of nasal and ocular symptoms, and faster onset and time to control compared with intranasal azelastine or fluticasone propionate. Long-term use of MP-AzeFlu was safe, with benefits in children, adults, and adults aged ≥65 years. Other treatment options, including fluticasone propionate and azelastine alone or the combination of intranasal corticosteroids and oral antihistamine, do not provide the same level of efficacy as MP-AzeFlu in terms of rapid and sustained relief of the entire AR symptom complex. Furthermore, MP-AzeFlu significantly improves patient quality of life. MP-AzeFlu is a currently available combination that may satisfy all these patient needs and expectations.

Anti-allergic actions of a Chinese patent medicine, huoxiangzhengqi oral liquid, in RBL-2H3 cells and in mice.

CONTEXT: Huoxiangzhengqi oral liquid (HXZQ-OL), a traditional Chinese medicine formula, has antibacterial, anti-inflammation and gastrointestinal motility regulation effects. OBJECTIVE: The study investigates the anti-allergic activity and underlying mechanism of HXZQ-OL. MATERIALS AND METHODS: IgE/Ag-mediated RBL-2H3 cells were used to evaluate the anti-allergic activity of HXZQ-OL (43.97, 439.7 and 4397 µg/mL) in vitro. The release of cytokines and eicosanoids were quantified using ELISA. RT-qPCR was used to measure the gene expression of cytokines. The level of intracellular Ca2+ was measured with Fluo 3/AM. Immunoblotting analysis was performed to investigate the mechanism of HXZQ-OL. In the passive cutaneous anaphylaxis (PCA), BALB/c mice (5 mice/group) were orally administrated with HXZQ-OL (263.8, 527.6 and 1055 mg/kg/d) or dexamethasone (5 mg/kg/d, positive control) for seven consecutive days. RESULTS: HXZQ-OL not only inhibited degranulation of mast cells (IC50, 123 µg/mL), but also inhibited the generation and secretion of IL-4 (IC50, 171.4 µg/mL), TNF-α (IC50, 88.4 µg/mL), LTC4 (IC50, 52.9 µg/mL) and PGD2 (IC50, 195.8 µg/mL). Moreover, HXZQ-OL suppressed the expression of IL-4 and TNF-α mRNA, as well as the phosphorylation of Fyn, Lyn and multiple downstream signalling proteins including MAPK and PI3K/NF-κB pathways. In addition, HXZQ-OL (527.5 mg/kg) attenuated the IgE-mediated PCA with 55% suppression of Evans blue exudation in mice. CONCLUSIONS: HXZQ-OL attenuated the activation of mast cell and PCA. Therefore, HXZQ-OL might be used as an alternative treatment for allergic diseases.

Sodium R-lipoate and enzymatically-modified isoquercitrin suppressed IgE-independent anaphylactic reactions and stress-induced gastric ulceration in mice.

Anaphylaxis is a life-threatening allergic reaction, for which the worldwide prevalence is rapidly increasing. The currently used synthetic antiallergic drugs have a high tendency to cause adverse effects, like gastric ulcers, in long-term use. Therefore, a great deal of attention has been given to develop new safer and more effective antiallergic agents from natural compounds that are chemically/enzymatically-modified. Here, we evaluated/compared the efficacy of two different doses (50 and 100 mg/kg body weight "b.w", given orally) of sodium R-lipoate (NaRLA) and enzymatically-modified isoquercitrin (EMIQ) in alleviating both local/systemic non-immunological anaphylactic reactions and stress-induced gastric ulceration in mice, in comparison with sulfasalazine (SSZ) as a reference drug. The results indicated that the pre-treatment of animals with NaRLA or EMIQ (especially at 100 mg/kg b.w) completely succeeded, as SSZ, in alleviating the hind paw edema induced by either histamine or compound 48/80 (Cpd 48/80). Furthermore, NaRLA and EMIQ prevented the mast cell degranulation and anaphylactic shock caused by Cpd 48/80 (in a dose-dependent manner) and reduced significantly (P < 0.001) the histamine release from the mouse peritoneal mast cells, like SSZ. Moreover, their use was associated with alleviating both gastric histopathological and biochemical alterations in the water-restraint stress (WRS) mice model towards the control values. They also decreased the percentage of degranulated mesenteric mast cells in the WRS mice model. In conclusion, our findings provide possibility that both NaRLA and EMIQ may serve as an effective therapeutic agents for mast cells-dependent anaphylactic reactions without risks of inducing gastric ulcers.

Comparative nasal airflow with loratadine-pseudoephedrine and fluticasone nasal spray for allergic rhinitis.

BACKGROUND: Although it is known that oral antihistamine-pseudoephedrine combination tablets have a faster onset than intranasal corticosteroid sprays in the treatment of allergic rhinitis after the first dose, the magnitude of change has not been measured in a comparative manner. Furthermore, the sensation of sprayed liquid in the nose may lead patients to mistakenly believe that intranasal steroid sprays work instantly. OBJECTIVE: To evaluate, numerically, nasal airflow changes provided by a single dose of loratadine-pseudoephedrine tablet (LP) and fluticasone propionate nasal spray (FP) in participants experiencing allergic rhinitis symptoms, including nasal congestion. METHODS: This single-center, double-blinded, placebo-controlled, crossover study evaluated objective nasal airflow changes in patients with a documented sensitivity to ragweed pollen. Participants were randomized to receive 1 of 4 treatment sequences, and their peak nasal inspiratory flow (PNIF) was measured in a span of 4 hours after pollen exposure in an environmental exposure unit. RESULTS: Average change in PNIF was 31% with LP in the course of the study, significantly greater than with placebo and FP (12% and 15%, respectively; P < .001). Nevertheless, FP did not produce a significant change compared with its placebo. At hour one post-dose, LP had a clinically significant 31% increase in PNIF, whereas FP only yielded an 8.6% increase (P < .001). Measurable nasal airflow improvements are associated with the opening of nasal passages, allowing congested patients to breathe more freely. CONCLUSION: A single dose of LP quickly and significantly (P < .001) improved nasal airflow after ragweed pollen challenge in an environmental exposure unit. Comparatively, FP did not display this same benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03443843.

Cytarabine-Induced Corneal Toxicity: Clinical Features and Relief of Symptoms with Loteprednol Etabonate 0.5% in Two Patients

We report two patients who developed toxic keratopathy following high-dose cytarabine chemotherapy and whose symptoms resolved following topical loteprednol etabonate 0.5% treatment. A 25-year-old woman and a 26-year-old man with acute myeloid leukemia were referred to our department with symptoms of ocular discomfort, photophobia, and blurred vision after consolidation chemotherapy. Central corneal epithelial microcysts were observed bilaterally in both patients, and in vivo confocal microscopy showed highly reflective disseminated granular and irregular intraepithelial opacities, mainly in the basal epithelial layers. Loteprednol etabonate 0.5% relieved both patients' symptoms in less than a week, and the microcysts disappeared in 2 to 3 weeks of treatment. Although there is no standardized treatment protocol for cytarabine-induced corneal toxicity, dexamethasone 0.1% and prednisolone phosphate 1.0% were reported to be effective in the resolution of discomfort and symptoms. In the two patients we report herein, loteprednol etabonate 0.5% four times daily was also effective in suppressing the symptoms.

Case Report: Omalizumab for Chronic Spontaneous Urticaria in Pregnancy.

Most chronic spontaneous urticaria (CSU) patients are female, and pregnancy can aggravate the disease activity of patients, but little is known about the efficacy and safety of omalizumab in pregnant CSU patients. We report two pregnant CSU patients treated with omalizumab and review the published information on omalizumab treatment during 11 pregnancies. The outcomes reported on patients with known pregnancies showed they had normal pregnancies and healthy babies as well as complete control of their CSU. The two new cases we reported support the view that omalizumab could be an effective and safe treatment option for pregnant and breastfeeding CSU patients. Further high-quality studies need to be carried out in order to obtain more information on the long-term efficacy and safety of the use of omalizumab during pregnancy in patients with chronic urticaria, including CSU.

Clinical Characteristics, Management, and Natural History of Chronic Inducible Urticaria in a Pediatric Cohort.

BACKGROUND: Some forms of chronic urticaria (CU) can be specifically attributed to a response to a definite trigger, referred to as chronic inducible urticaria (CIndU). We aimed to assess the demographics, clinical characteristics, comorbidities, natural history, and management of pediatric patients with CIndU. METHODS: Over a 6-year period, children presenting to the allergy clinic at the Montreal Children's Hospital (MCH) with CIndU were prospectively recruited. CU was defined as the presence of wheals and/or angioedema, occurring for at least 6 weeks. A standardized diagnostic test was used to establish the presence of a specific form of urticaria. Resolution was defined as the absence of hives for 1 year without treatment. RESULTS: Sixty-four patients presented with CIndU, of which 51.6% were male, with a median age of 12.5 (interquartile range 7.3, 15.9) years. Cold CU and cholinergic CU were the most common subtypes (60.3 and 41.3%, respectively). Basophil counts were undetectable in 48.4% of the cases, and C-reactive protein levels were elevated in 7.8% of patients. Of all cases, 71.4% were controlled with second-generation antihistamines. The resolution rate was of 45.3% (95% confidence interval 33.1-57.5%), based on per-protocol population within the 6-year course of the study. Resolution was more likely in patients who presented with well-controlled urticaria control test scores and elevated CD63 counts and in those suffering from thyroid comorbidity. CONCLUSION: The natural history of CIndU resolution in pediatric patients was relatively low and was associated with elevated CD63 levels, as well as thyroid comorbidity.