Atopy and Response to Omalizumab Treatment in Chronic Spontaneous Urticaria.

INTRODUCTION: The possible influence of sensitization to aeroallergens on omalizumab response in chronic spontaneous urticaria (CSU) has been insufficiently investigated. This study's aim was to investigate atopy's influence on omalizumab response in CSU patients. METHOD: Retrospective study of CSU patients followed at a Portuguese Urticaria Center of Reference and Excellence (UCARE), treated with omalizumab for at least 6 months, between 2015 and 2022. At T0, all patients underwent quantification of specific immunoglobulin E (IgE) for total extract of most prevalent aeroallergens (ImmunoCAP Thermo Fisher Scientific®) and were divided in 2 groups, according to their response to omalizumab during the first 16 weeks of treatment: responders (R) (UAS7 <7) versus partial (PR) (UAS7 = 7-15) and nonresponders (UAS7 >15). R were further classified as fast (FR) (4-6 weeks) and slow responders (SR) (12-16 weeks). Total serum IgE, circulating eosinophil, and basophil counts were compared between groups at T0. p < 0.05 was considered statistically significant (SPSS® v25.0). RESULTS: Ninety-six patients (80% female) were studied, mean age 49 ± 14 years. Median CSU duration pre-omalizumab was 3 (0.6-20) years and mean omalizumab treatment duration was 3.7 ± 2.3 years. 38 (40%) had concomitant chronic inducible urticaria and 72 (75%) angioedema. Based on positive results of the specific IgE assay, 35 patients (36%) were considered atopic. Most patients (n = 30; 86%) were sensitized to house dust mites (HDM) (Dermatophagoides farinae = 28, Dermatophagoides pteronyssinus = 27, Blomia tropicalis = 19, Lepidoglyphus destructor = 17), followed by pollens (n = 12; 34%) (mixture of grasses = 10, Olea europaea = 7, Parietaria officinalis = 6), epithelia (n = 9; 26%) (dog = 8, cat = 7), and fungi (Alternaria alternata = 4; 11%). Eight patients (23%) were monosensitized to HDM and 4 (11%) to pollens. No significant association was found between aeroallergen sensitization and CSU duration, concomitant chronic inducible urticaria, or angioedema. Atopic patients featured significantly higher levels of baseline total serum IgE than nonatopic (469 vs. 94 U/mL, respectively; p = 0.0009). Mean baseline counts of eosinophils and basophils were not significantly different between atopic and non-atopic, respectively: eosinophils (128 vs. 121/mm3) and basophils (26 vs. 28/mm3). Regarding response to omalizumab, most patients (58; 60%) were responders: FR - 46 (79%); SR - 12 (21%). There was no significant association between aeroallergen sensitization and omalizumab response or speed of response. CONCLUSIONS: As far as we know, this is the first study exploring the influence of atopy sensitization pattern on omalizumab response in CSU. According to our results, presence of atopy/sensitization pattern does not influence omalizumab response in CSU patients.

The Role of Adjuvant Therapy in the Management of Chronic Urticaria. / [Artículo traducido] El papel de la terapia adyuvante en el tratamiento de la urticaria crónica espontánea.

Recent guideline on the management of urticaria recommends second-generation H1-antihistamine as the first-line therapy, with dose increases of up to fourfold if inadequately controlled. However, the treatment of chronic spontaneous urticaria (CSU) is often disappointing, so additional adjuvant therapies are needed to increase the effectiveness of first-line therapy, especially in patients who are refractory to the increase of antihistamine doses. Recent studies recommend various adjuvant therapy modalities for CSU, such as biological agents, immunosuppressants, leukotriene receptor antagonists, H2-antihistamine, sulfones, autologous serum therapy, phototherapy, vitaminD, antioxidants, and probiotics. This literature review was made to determine the effectiveness of various adjuvant therapies in managing CSU.

The Role of Adjuvant Therapy in the Management of Chronic Urticaria.

Recent guideline on the management of urticaria recommends second-generation H1-antihistamine as the first-line therapy, with dose increases of up to fourfold if inadequately controlled. However, the treatment of chronic spontaneous urticaria (CSU) is often disappointing, so additional adjuvant therapies are needed to increase the effectiveness of first-line therapy, especially in patients who are refractory to the increase of antihistamine doses. Recent studies recommend various adjuvant therapy modalities for CSU, such as biological agents, immunosuppressants, leukotriene receptor antagonists, H2-antihistamine, sulfones, autologous serum therapy, phototherapy, vitamin D, antioxidants, and probiotics. This literature review was made to determine the effectiveness of various adjuvant therapies in managing CSU.

Myricetin alleviated immunologic contact urticaria and mast cell degranulation via the PI3K/Akt/NF-κB pathway.

Immunologic contact urticaria (ICU) is characterized by the wheal and flare reaction from direct contact with a chemical or protein agent, which involves a type I hypersensitivity mediated by allergen-specific immunoglobulin E (sIgE). Myricetin (Myr), a bioactive flavonoid, exhibits antiinflammatory activities. Our results showed that treatment with Myr could alleviate ICU symptoms, including a decrease in the number of wheals and scratching, and inhibit ear swelling in the IgE/DNFB-induced mice. The serum level of IgE, histamine, interleukin (IL)-4, TNF-α, and MCP-1 were reduced in Myr-treated mice. Myr also attenuated mast cells (MCs) degranulation and H-PGDS, TSLP, IL-33, PI3K, Akt, and NF-κB mRNA levels in ICU model. The IgE-mediated anaphylaxis mouse models demonstrated anti-allergic effects of Myr. In vitro analysis showed that Myr reduced IgE-induced calcium (Ca2+ ) influx, suppressed degranulation, and chemokine release in LAD2 cells (human primary mast cells). Myr can significantly inhibited PLCγ1, Akt, NF-κB, and p38 phosphorylation. In conclusion, the study demonstrated that Myr alleviate ICU symptoms and inhibit mast cell activation via PI3K/Akt/NF-κB signal pathway.

Dietary strategies for chronic spontaneous urticaria: an evidence-based review.

Although the relationship between diet and chronic spontaneous urticaria (CSU) remains elusive, several patients seek dietary modifications as they are easy and cost-effective. Adequate patient education and counseling are crucial as modified diets may be beneficial for a subset of antihistamine refractory CSU patients, and no modality currently exists to identify these patients. Elimination of food items based exclusively on patient history may lead to unnecessary restrictions in most cases resulting in nutritional deficiencies and impaired quality of life. Several dietary strategies have been tried till date with varying rates of success and evidence. This review highlights the various dietary strategies along with their levels of evidence, which may help the treating dermatologists and physicians to counsel CSU patients and make evidence-based treatment decisions. There is grade A recommendation for the elimination of food additives (artificial pseudoallergens), personalized diets, vitamin D supplementation, Diamine oxidase supplementation and probiotics (in children), grade B recommendation for dietary elimination of red meat, fish and their products, natural pseudoallergens (fruits, vegetables, and spices), and low-histamine diet, while dietary elimination of gluten (with concomitant celiac disease) has grade C recommendation. Notably, elimination diets should be continued for at least 3 consecutive weeks to assess their effectiveness.

The effect of vitamin D add-on therapy on the improvement of quality of life and clinical symptoms of patients with chronic spontaneous urticaria.

BACKGROUND: Chronic urticaria is a common distressing allergic skin disorder. Immune dysregulation, histamine release and mast cell degranulation are suggested as its underlying mechanisms. OBJECTIVE: Add-on therapy of vitamin D was evaluated in patients with chronic spontaneous urticaria to determine the quality of life and urticaria severity score. METHODS: In a prospective, double-blinded study, 80 participants with chronic spontaneous urticaria were randomized to low (4200 IU/week, group 1) and high (28,000 IU/week, group 2) vitamin D3 supplementation groups for 12 weeks. Demographic data; quality of life, urticaria severity and medication scores; 25-hydroxyvitamin D and anti-thyroid peroxidase antibody levels; and autologous serum skin test data were collected. RESULTS: Both groups showed significantly reduced total urticaria severity score; decrement in group 2 score was significant compared to group 1 at week 6 (P = 0.010). Quality of life score was also significantly reduced; decrement in group 2 score was significant compared to group 1 at both weeks 6 (P = 0.005) and 12 (P = 0.007). 25-hydroxyvitamin D levels were elevated significantly over the course of 12 weeks in both groups; however, the elevation in group 2 was significantly higher than group 1 at week 12 (P = 0.002). Medication score was significantly reduced, with no significant difference between groups. No association was observed between positive autologous serum skin test, angioedema and high level of Anti thyroperoxidase antibody with positive response to vitamin D. CONCLUSIONS: Add-on therapy with vitamin D (28,000 IU/week) can be considered as a safe and potentially beneficial treatment in patients with chronic spontaneous urticaria.

Asian herbal medicine and chronic urticaria: which are the therapeutic perspectives?

Chronic urticaria (CU) is a pathologic condition marked by the emergence of wheals, angioedema, or both for more than six weeks. The improper activation and degranulation of mast cells is the triggering event, which results in the production of various mediators such as histamine, leukotrienes, PAF, chemokines, and cytokines. Antihistamines are currently the most common pharmacological treatment for urticaria, but corticosteroids and monoclonal antibodies can also be employed. Patients who have been taking antihistamines for a long time are often looking for alternatives. Whole plants, portions of plants, or single extracted active compounds are all used in phytomedicine. Plant elements are frequently combined to create formulations that can be utilized to treat a variety of pathological disorders. Anti-inflammatory and/or anti-allergic properties are found in several herbs regularly used in herbal formulations. Antioxidant properties are also present in some of the constituents. Exogenous antioxidants have been shown to improve the progression of autoimmune disorders in numerous studies. The aim of this review is to identify the most common herbs used to treat chronic urticaria, and to characterize their efficacy, mechanisms of action, and risk/benefit ratio in comparison to western treatment, and also to find less often used formulations and assess their therapeutic efficacy, safety profile, and potential for wider use.[Figure: see text].

[Proteomic study of Jingfang Mixture on urticaria based on label-free quantitative proteomics technology].

This study aims to explore the effect of Jingfang Mixture on the protein expression of urticaria in mice and explain the mechanism of Jingfang Mixture in the treatment of urticaria. Twenty-seven male Kunming mice were randomly divided into a normal group, a model group and a Jingfang Mixture group according to body weight. Except for the normal group, mice in the model group and the Jingfang Mixture group were injected with the mixture of ovalbumin and Al(OH)_3 gel for the first immunization, and the second immunization was performed on the 10 th day to induce the urticaria model. Mice in the Jingfang Mixture group started to be administered on the 6 th day after the initial immunization, and was administered continuously for 21 days. The normal group and the model group were replaced with the same amount of purified water. Twenty-four hours after the last administration, an appropriate amount of skin was taken, and label-free quantitative proteomics technology was used to detect the differences in protein expression in skin tissue. The signaling pathways involved in the differential proteins was further analyzed. The results of proteomics indicated that seventy-six proteins were involved in the intervention of Jingfang Mixture on mice with urticaria, and the differential proteins were mainly enriched in biological process(BP), molecular function(MF), and cellular component(CC). Kyoto Encyclopedia of Genes and Genomes(KEGG) analysis showed that the signaling pathways regulated by Jingfang Mixture mainly involved carbon metabolism, metabolic pathways, glucagon signaling pathway, glycolysis/gluconeogenesis, pentose phosphate pathway, hypoxia inducible factor-1(HIF-1) signaling pathway, purine metabolism, adherens junction, calcium signaling pathway, leukocyte transendothelial migration, and inflammatory mediator regulation of transient receptor potential(TRP) channels, which were involved in skin tissue energy metabolism and immune regulation. The findings of this study showed that the protective effect of Jingfang Mixture on mice with urticaria was closely related to the regulation of immune disorders, and the regulatory effect on immune system may be achieved through the regulation of energy metabolism by Jingfang Mixture.

Factors Related to Omalizumab Drug Survival and Treatment Responses in Chronic Urticaria.

INTRODUCTION: This study aimed to evaluate factors affecting drug survival and treatment response in patients with chronic urticaria treated with omalizumab in clinical practice. METHODS: This study included 386 patients with chronic urticaria. Demographic characteristics, clinical features, laboratory parameters, and omalizumab treatment data were analyzed retrospectively. The 7-day urticaria activity score (UAS7) and urticaria control test (UCT) were used to assess disease severity and treatment responses. RESULTS: Well-controlled disease (UAS7 ≤6) was achieved in 59.3% of patients at a median of 2 months. Complete response was significantly higher in patients treated with omalizumab for ≥12 months (p < 0.001). Family history of asthma (p = 0.01) was less frequent, and disease duration (p = 0.041) was shorter in patients with well-controlled disease. Total treatment duration was longer in patients with relapse (p < 0.001) and serum Helicobacter pylori IgA positivity (p = 0.029). DISCUSSION/CONCLUSION: Treatment response is better in patients treated with omalizumab for ≥12 months. However, prolonged treatment does not prevent relapse. Our findings suggest that continuous or intermittent therapy is an appropriate alternative treatment option in patients with severe chronic urticaria; however, continuous therapy can be preferred to maintain the patient's quality of life.

Severe chronic spontaneous urticaria in children - treatment options according to the guidelines and beyond - a 10 years review.

This is a retrospective study of 18 children with chronic spontaneous urticaria (CSU), where standard therapies, including up-dosing of antihistamines and omalizumab, were unable to cure the disease and where alternative strategies with experimental and off-label medication had to be used. MATERIALS: Being aware that our questionnaire is validated only for elder children or adults, we utilized the UAS7 to monitor disease control with the help of the parents. RESULTS: The UAS7 score decreased from a mean of 25 to an average of 13 after 8 weeks of therapy in 13 patients. Five patients had no significant reduction of UAS7 by week 8. In two of five patients, where periodic improvement was seen, omalizumab therapy was continued and showed complete response after 1-2 years. In three children, alternative treatments with cyclosporine and dupilumab, approved by the ethics committee, showed symptom improvement from a mean UAS7 of 29 to a mean value of 6. CONCLUSIONS: When omalizumab therapy including up-dosing strategies or shortened interval shows no symptom improvement, alternative therapies, sometimes off-label have to be considered in time.

Efficacy and safety of active vitamin D supplementation in chronic spontaneous urticaria patients.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a common skin disorder affecting negatively patients' lives. Vitamin D deficiency has been reported to be associated to many allergic skin disorders. OBJECTIVE: This study aimed to evaluate the association between the serum level of 25 hydroxy vitamin D and CSU and to assess the efficacy and safety of active vitamin D in management of CSU. METHODS: The study was conducted on 77 patients with CSU and 67 healthy controls, then the 77 CSU patients were randomized to either the study group that received 0.25 µg alfacalcidol daily or the placebo group that received oral placebo for 12 weeks. RESULTS: Serum 25(OH) D was significantly lower in CSU as compared to healthy controls and was negatively correlated to the urticarial severity. After alfacalcidol administration, the study group showed significant higher level of 25(OH) D compared to the placebo group. In addition, the mean serum level of IL6, hsCRP and TNFα significantly decreased in the study group in comparison to the placebo group and as compared to their baseline results. CONCLUSION: Vitamin D deficiency is more common in CSU patients as compared to healthy people and hence, alfacalcidol might have a beneficial role as add on therapy in CSU management with no reported side effects.

What's New in the Treatment of Urticaria and Angioedema.

Chronic urticaria and angioedema are diseases often managed by Allergy and Immunology specialists. Recent international guidelines have outlined a stepwise approach to management of patients using dose escalation of second-generation antihistamines followed by use of omalizumab and finally cyclosporine in more refractory cases. In select patients (those with refractory chronic urticaria), nonbiologic alternative medications with anti-inflammatory or immunosuppressant activity may be considered. Angioedema without wheals may have several different pathophysiologic mechanisms. Optimal management of mast cell-mediated angioedema is less clear but is often managed similar to chronic spontaneous urticaria. Drug-induced angioedema due to angiotensin-converting enzyme inhibitors is a common cause of angioedema in the emergency department. Although bradykinin is thought to be a primary mediator for this type of angioedema, studies of targeted therapies have been generally disappointing. In contrast, several targeted therapies have been proven successful using acute and preventive approaches for management of hereditary angioedema. Further developments, including novel biologics, novel oral therapies, and gene therapy approaches, may hopefully continue to broaden therapeutic options to ensure optimal individual management of patients with hereditary angioedema.

Effects of Serum Vitamin D Levels and Vitamin D Supplementation on Urticaria: A Systematic Review and Meta-Analysis.

(1) Backgrounds: Several studies have shown that the level of 25-hydroxyvitamin D (25(OH)D) could affect urticaria. The association of Vitamin D (VitD) with urticaria has not been well established. (2) Methods: The up-to-date meta-analysis was performed to synthesize the new findings. We performed a systematic search in PubMed, EMBASE, Web of Science, and Cochrane Database. We included the observational studies with the comparisons of 25(OH)D between urticarial populations and controls and clinical studies with the clinical severity of urticaria records. (3) Results: A meta-analysis of seventeen studies of urticaria group vs. controls revealed a mean difference of -9.35 ng/mL (95% CI -12.27 to -6.44). There was also an association of urticaria with VitD deficiency. In the subgroup analysis of age and disease type, significant effects of 25(OH)D were found among adult and chronic urticarial populations. Six VitD supplementation trials showed a significant reduction in clinical urticarial score on intervention with VitD with the standard mean difference of -3.63 and -1.54 among randomized control studies and repeated measure trials, respectively. (4) Conclusions: The urticarial population, especially the adult chronic urticarial patients, may be associated with a high risk for lower serum 25(OH)D. VitD supplementations could result in a reduction of urticarial clinical symptoms.

Hyperthyroidism treatment by alternative therapies based on cupping and dietary-herbal supplementation: a case report.

OBJECTIVES: Hyperthyroidism is characterized by increasing production of thyroid hormone (TH) and decreasing of thyroid stimulation hormone (TSH) secretion. The treatment of hyperthyroidism includes such as anti-thyroid drugs, radioiodine, and thyroidectomy have many side effects without complete curing results. We described a successful treatment of hyperthyroidism patient with dietary-herbal supplementation with wet cupping without any medicine. CASE PRESENTATION: A 29-years female, blood analysis showed that she had low TSH (0.012 mlU/mL), and normal levels of T3 and T4. After completing 16 weeks on Carbimazole, TSH value still low (0.024 mlU/mL) and urticaria was appeared. She decided to stop Carbimazole and try alternative therapy choices. She received wet cupping and dietary-herbal supplementations (including royal jelly, green barley grass and Taraxaf®) for two months. Notably, TSH values was increased during-after intervention and urticaria was disappeared. CONCLUSIONS: Alternative therapy could be a beneficial choice for hyperthyroidism treatment without any side effects or complications under physician supervision.

Compound glycyrrhizin combined with antihistamines for chronic urticaria: A protocol for systematic review and meta analysis.

BACKGROUND: To investigate the efficacy and safety of compound glycyrrhizin (CG) combined with antihistamines in the treatment of chronic urticaria (CU). METHODS: We will use computers to search all databases including Medline, Embase, Pubmed, Web of Science and Cochrane Central Register of Controlled Trials and China's 4 databases: China National Knowledge Infrastructure Database, China Biomedical Literature Database, China Science Journal Database, and Wanfang Database. Find data from creation date to July 2020. In addition, we will manually search the list of medical journals as a supplement. The scope of the search included randomized controlled clinical studies related to CG combined with antihistamines for CU. The primary outcome is the disease activity control. Secondary outcomes include response rate, adverse events, and recurrence rates. The Cochrane RevMan V5.3 Deviation Assessment Tool will be used to assess bias assessment risk, data integration risk, meta-analysis risk, and subgroup analysis risk (if conditions are met). The average difference, standard mean difference, and binary data will be used to represent continuous results. RESULTS: This study will comprehensively review the existing evidence on CG combined with antihistamines for CU. CONCLUSION: This systematic review will provide a basis for judging the effectiveness and safety of CG combined with antihistamines in the treatment of CU. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42020156153.

Phototherapy May be a Useful Adjuvant Therapy for Retractable Chronic Spontaneous Urticaria: A Systematic Review.

The recent guideline on the management of urticaria recommends second-generation H1 antihistamine as the first-line therapy, with dose increases of up to fourfold and the addition of omalizumab or cyclosporine if inadequately controlled. However, the treatment of chronic spontaneous urticaria (CSU) is often disappointing. Therefore, a safe and effective treatment option is needed for refractory CSU. To evaluate whether phototherapy can relieve urticarial symptoms and serve as an additional treatment for CSU uncontrolled with antihistamine, we performed a qualitative systematic review. Our result suggests that NBUVB could be an effective complementary treatment modality to manage refractory CSU.

Effect of vitamin D supplementation on clinical outcome and biochemical profile in South Indian population with vitamin D-deficient chronic urticarial - A randomized double-blind placebo controlled trial.

BACKGROUND: Chronic urticaria (CU) is a debilitating inflammatory skin disease. Prior studies have shown reduced concentrations of vitamin D in CU and there are limited reports of potential beneficial role for vitamin D supplementation in the treatment of subjects with CU. We assessed the effect of vitamin D supplementation in vitamin D deficient CU patients on the clinical outcome and inflammatory markers in South Indian patients with CU. METHODS: This randomized controlled trial involved 120 vitamin-D deficient CU patients. Urticaria activity score (UAS7) and autologous plasma skin test (APST) status was assessed in all cases. CU patients were supplemented with vitamin D with a dose of 60,000 IU fortnightly for a period of 12 weeks and those in the placebo arm received matched placebo. Five milliliters of blood was drawn from all study subjects at baseline and after 12 weeks for assessing inflammatory markers. RESULTS: We observed a significant reduction in UAS7 scores after 12 weeks in the vitamin D treated group in comparison to that of placebo. We also noted a significant reduction of the inflammatory cytokines in the vitamin D treated group. CONCLUSION: Supplementation with vitamin D among patients with vitamin D deficient CU significantly decreases disease severity which is probably mediated through reduction of systemic inflammation.