Antihistamine-refractory Chronic Spontaneous Urticaria Research Articles

Update on the Treatment of Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is a mast cell-mediated skin disease that presents with wheals, angioedema, or both for more than 6 weeks. Less than 10% of patients have complete control of their CSU (the main goal of CSU treatment) with second generation H1-antihistamines, the first-line treatment. About 70% of patients with antihistamine-refractory CSU do not reach complete control with omalizumab, the second-line treatment. Novel therapies are especially needed for patients with mast cell-activating immunoglobulin (Ig)G autoantibodies (autoimmune CSU) associated with nonresponse or late response to omalizumab. Furthermore, there is a lack of disease-modifying treatments that induce long-term CSU remission after drug withdrawal. Several emerging treatments can address these unmet needs including Bruton tyrosine kinase inhibitors, e.g., remibrutinib and rilzabrutinib; anti-KIT monoclonal antibodies, e.g., barzolvolimab; and anti-cytokine therapies, e.g., dupilumab. In clinical trials, 30-31%, 28-32%, and 38-51% of patients with CSU showed complete response to treatment with dupilumab (phase 3, week 24), remibrutinib (phase 3, week 24), and barzolvolimab (phase 2, week 12), respectively. The most common adverse events were injection site reactions for dupilumab (12%), respiratory tract infections (11%), headache (6%), and petechiae (4%) for remibrutinib and changes in hair color (14%), neutropenia / decreased neutrophil count (9%) and skin hypopigmentation (1%) for barzolvolimab. This review provides an update on the current state of development of treatments for CSU.

Factors associated with the efficacy of omalizumab treatment in chronic spontaneous urticaria.

Factors associated with the efficacy of omalizumab treatment in chronic spontaneous urticaria.

Factors associated with the efficacy of omalizumab treatment in chronic spontaneous urticaria

Factors associated with the efficacy of omalizumab treatment in chronic spontaneous urticaria

A retrospective analysis of factors influencing response to omalizumab treatment in Indian patients with antihistamine refractory chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) presents as a persistent and distressing condition, with varying treatment responses. Omalizumab, a monoclonal anti-IgE antibody, has shown efficacy in managing antihistamine (AH1)-refractory CSU, but its varied response patterns and associated factors remain understudied, particularly in India. We conducted a retrospective study involving 81 antihistamine-resistant CSU patients treated with omalizumab at a tertiary care center in Northern India between 2018 and 2023. Baseline characteristics, treatment response, and adverse effects were analyzed. Patients were categorized into various response groups based on treatment timelines and biomarker correlations. We observed 65% achieved symptom cessation (group 1) following a single omalizumab dose, while 21% responded between second and third doses (group 2). A subset (7.4%) necessitated increased dosing frequency (group 3) for symptom control. Additionally, 6.2% showed persistent symptoms despite increased dosing frequency (group 4), exhibiting distinctive biomarker profiles indicative of an autoimmune endotype. Notably, 27.1% experienced exacerbations during treatment, emphasizing the need for tailored management approaches and response expectations. Omalizumab demonstrated remarkable efficacy in the treatment of AH1-refractory CSU, with a good safety profile. This study highlights the complexity of treatment response to omalizumab and the potential utility of biomarkers in guiding personalized therapeutic strategies. Further research into biomarker-based endotypes is warranted to optimize CSU management.

Omalizumab in Chronic Spontaneous Urticaria: A Real-World Study on Effectiveness, Safety and Predictors of Treatment Outcome.

Although omalizumab has shown success in treating chronic spontaneous urticaria (CSU) patients unresponsive to antihistamines, the exact mechanism of action and predictive markers of response remain unclear. The aim of this study was to examine the correlation between baseline levels of biomarkers and clinical parameters with omalizumab response and response rate in patients with CSU. This retrospective study included 82 adult CSU patients who received omalizumab 300mg every 4 weeks for 16 weeks between January 2022 and December 2023. Treatment response was assessed using UAS7 and DLQI scores at baseline and weeks 4, 8, 12, and 16. Responders were defined as patients achieving UAS7 < 7, with early and late responders categorized based on response within or after 4 weeks, respectively. Baseline clinical features and laboratory biomarkers were compared between responders and non-responders. The overall response rate was 71.95% (59/82), with 23 early responders and 36 late responders. Responders had significantly lower baseline UAS7 (median: 28 vs 35, P < 0.01), DLQI (median: 8 vs 15, P < 0.001), and IL-17 levels (median: 0.53 vs 1.26 pg/mL, P < 0.001) compared to non-responders. Baseline UAS7 > 31, DLQI > 9.5, and IL-17 > 0.775 pg/mL predicted non-response with sensitivities of 78.26%, 100%, and 78.26%, and specificities of 67.8%, 59.32%, and 72.88%, respectively. ASST positivity and comorbid allergic diseases were associated with early response (P < 0.05). Adverse events were reported in 6.09% of patients, including mild injection site reactions and transient urticaria exacerbation, not requiring treatment discontinuation. This study suggests that omalizumab is an effective and safe treatment option for antihistamine-refractory CSU. Baseline UAS7, DLQI, ASST status, serum total IgE levels, and IL-17 may serve as potential predictors of omalizumab response. Notably, ASST positivity and comorbid allergic diseases were associated with an early response to treatment. These findings highlight the importance of considering individual patient characteristics when predicting the likelihood and timing of response to omalizumab in CSU.

CD14 Efficacy of narrowband ultraviolet B phototherapy vs. low-dose oral ciclosporin as second-line management in antihistamine-refractory chronic spontaneous urticaria: a noninferiority, randomized study

CD14 Efficacy of narrowband ultraviolet B phototherapy vs. low-dose oral ciclosporin as second-line management in antihistamine-refractory chronic spontaneous urticaria: a noninferiority, randomized study

Treatment options in refractory chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) patients sometimes do not respond to second-generation antihistamine, and 10-50% patients do not even respond to four-fold the usual dose of nonsedating H1 antihistamine, which further leads to repeated courses of oral corticosteroids to abate the symptoms. There are third-line agents approved by EAACI guidelines, which include omalizumab and cyclosporine. Certain patients are even resistant to the third-line agents. In this review, various other treatment options will be discussed in patients of refractory CSU. Recently, we demonstrated azathioprine as a possible third-line option, which was found noninferior to cyclosporine in antihistamine refractory CSU. There have been trials, studies, case series and reports, which suggest other putative options for refractory CSU management. Studies on the management of refractory CSU are accumulating thereby expanding the armamentarium of dermatologists and allergologist against difficult-to-treat urticaria patients.

The effectiveness of omalizumab therapy in patients with chronic spontaneous urticaria: the experience of a single-centre study in Poland.

Omalizumab, which is a recombinant, humanised anti-immunoglobulin-E antibody, is the only approved drug for antihistamine refractory chronic spontaneous urticaria (CSU). It has been reported that it is an effective and safe drug, but the data about long-term effectiveness are still lacking. To perform a retrospective analysis of the patients with CSU treated with omalizumab at the dermatology department to assess effectiveness of omalizumab therapy in the single centre in Poland. A two-and-a-half-year retrospective analysis of patients with CSU undergoing the therapy with omalizumab was conducted. Patients' data were analysed for many factors such as age, gender, severity indexes (UAS7, DLQI), duration and effects of the treatment used. Sixty-one patients with CSU have been treated with omalizumab in the drug program. The number of female patients - 42 (68.9%) significantly dominated over the number of male patients - 19 (31.1%). The mean UAS7 during the first course of treatment declined from 33.2 to 2.8, during the second from 30.9 to 1.7 and during the third 32.7 to 2.5. In case of DLQI the mean scores decrease from 18 to 2.1 in the first cycle, from 16.9 to 1.9 in the second and from 18.6 to 1.1 in the third. Our study confirmed that omalizumab is an effective medicine in a long-term treatment which improves a physical as well as psychological condition of the patients with antihistamine-resistant CSU. To our knowledge, it is the first study in Poland that presents omalizumab effectiveness during three courses of treatment.

Evaluation of antihistamine-refractory chronic urticaria patients who used biological agent treatment in terms of cardiovascular risk.

The idea that chronic inflammatory processes may play a role in the etiopathogenesis of both treatment - refractory chronic spontaneous urticaria and cardiovascular diseases is an important research topic. Within the scope of this research, we aimed to elucidate a new perspective on the follow-up of chronic urticaria patients by evaluating the 10-year cardiovascular risk and metabolic syndrome in resistant chronic spontaneous urticaria patients who were unresponsive to maximum antihistamine treatment. A total of 170 individuals who applied to our institution's Health Science University, Tepecik Education and Research Hospital, allergy and immunology outpatient clinic have been analysed in this retrospective case-control study. Metabolic syndrome was calculated according to the National Cholesterol Education Program -- Adult Treatment Panel III, and the cardiovascular risk was calculated according to the Framingham Heart Study of the National Heart, Lung and Blood Institute. The study included 85 patients diagnosed with chronic spontaneous urticaria (CSU) alongside 85 control subjects. Comparative analysis between the CSU patient group and the control group revealed substantial differences in terms of gender distribution, smoking habits, metabolic syndrome prevalence, waist circumference measurements, body mass index (BMI), hypertension incidence, and levels of C-reactive protein (CRP) (p < 0.05). However, factors such as patient age, fasting blood glucose, diabetes status, triglyceride (TAG), high density lipoprotein (HDL), low density lipoprotein (LDL), and the percentage risk of cardiovascular events over 10 years were not found to influence CSU (p > 0.05). Regarding the outcomes of this study, the presence of hypertension, obesity, waist circumference and C-reactive protein values associated with metabolic syndrome should be followed for antihistamine-refractory CSU. Early diagnosis and treatment of metabolic syndrome and its components in these patients may play a role in preventing potential complications. No significant increase in the 10-year cardiovascular risk was observed.

Clinical Response to Low-dose Omalizumab Treatment in Chronic Spontaneous Urticaria: A Retrospective Study of 179 Patients.

Omalizumab is effective in chronic spontaneous urticaria unresponsive to antihistamines. Of the licensed dosing schedules, Korean patients prefer a low dose, of 150 mg/month, for financial reasons. However, real-world experiences of low-dose omalizumab consumption have not been reported. The aim of this retrospective study was to assess the treatment outcomes and long-term clinical course of patients with chronic spontaneous urticaria who were treated with low-dose omalizumab. The study included 179 patients aged ≥ 20 years who were treated with omalizumab 150 mg/month for ≥ 12 weeks. Baseline disease activity was mild, moderate, and severe in 54.7%, 35.2%, and 10.1% of patients, respectively. A complete response was observed in 133 patients at 12 weeks, among whom 88 patients showed early responses within 4 weeks. Overall, 158 patients finally achieved a complete response. Multivariate analyses revealed that baseline disease activity is more likely to be mild in patients who experience early and final complete responses. The absence of atopic comorbidities correlated with an early response. Smoking was associated with a final complete response. This study shows that low-dose omalizumab provides favourable treatment outcomes in antihistamine-refractory chronic spontaneous urticaria. Disease severity, atopic comorbidity, and smoking may be predictive factors for studying the response to omalizumab.

Safety and Clinical Activity of Multiple Doses of Barzolvolimab, an anti-KIT Antibody, in Patients with Chronic Spontaneous Urticaria

Safety and Clinical Activity of Multiple Doses of Barzolvolimab, an anti-KIT Antibody, in Patients with Chronic Spontaneous Urticaria

Efficacy and safety of medications for antihistamine-refractory chronic spontaneous urticaria: a systematic review and network meta-analysis

Summary Purpose Most medications for antihistamine-refractory chronic spontaneous urticaria (CSU) have not been compared head-to-head. This systematic review and network meta-analysis evaluates their relative efficacy and safety. Methods Electronic databases were searched until 05 May 2022 for randomized controlled trials investigating systemic medications for antihistamine-refractory CSU. The change in the urticaria activity score over seven days (UAS7) and occurrence of adverse events were compared between treatments using random-effects network meta-analysis models. Results In all, 32 studies with 3641 patients receiving 31 different systemic medical interventions were included. Among currently available drugs, omalizumab 300 mg injected every 4 weeks and cyclosporine 3–5 mg/kg daily per os were most effective in reducing the UAS7 with a reduction of −10.45 (95% confidence interval [CI]: −12.35, −8.55) and of −10.40 (95% CI: −19.4, −1.4) compared to placebo. Similar efficacies were shown by the nonapproved agents ligelizumab 72 mg injected every 4 weeks (−11.67, 95% CI: −16.80, −7.15) and fenebrutinib 400 mg daily per os (−9.50, 95% CI: −17.56, −1.44). The odds ratio for the occurrence of an adverse event with placebo as comparator was 1.09 for omalizumab (95% CI: 0.83, 1.42), 2.16 for cyclosporine (95% CI: 0.77, 6.07: GRADE; moderate certainty), 0.89 for ligelizumab (95% CI: 0.47, 1.69), and 2.14 for fenebrutinib (95% CI: 0.62, 7.38) in the mentioned dosages. Conclusion Omalizumab 300 mg injected every 4 weeks and cyclosporine 3–5 mg/kg daily per os are the most effective currently available drugs for antihistamine-refractory CSU. Cyclosporine shows a relatively less favorable safety profile.

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.

Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial

Bruton’s tyrosine kinase (BTK) is crucial for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU). Fenebrutinib, an orally administered, potent, highly selective, reversible BTK inhibitor, may be effective in CSU. This double-blind, placebo-controlled, phase 2 trial (EudraCT ID 2016-004624-35) randomized 93 adults with antihistamine-refractory CSU to 50 mg daily, 150 mg daily and 200 mg twice daily of fenebrutinib or placebo for 8 weeks. The primary end point was change from baseline in urticaria activity score over 7 d (UAS7) at week 8. Secondary end points were the change from baseline in UAS7 at week 4 and the proportion of patients well-controlled (UAS7 ≤ 6) at week 8. Fenebrutinib efficacy in patients with type IIb autoimmunity and effects on IgG-anti-FcεRI were exploratory end points. Safety was also evaluated. The primary end point was met, with dose-dependent improvements in UAS7 at week 8 occurring at 200 mg twice daily and 150 mg daily, but not at 50 mg daily of fenebrutinib versus placebo. Asymptomatic, reversible grade 2 and 3 liver transaminase elevations occurred in the fenebrutinib 150 mg daily and 200 mg twice daily groups (2 patients each). Fenebrutinib diminished disease activity in patients with antihistamine-refractory CSU, including more patients with refractory type IIb autoimmunity. These results support the potential use of BTK inhibition in antihistamine-refractory CSU.

Evaluation of Pharmacologic Treatments for H1 Antihistamine–Refractory Chronic Spontaneous Urticaria

The comparative benefits and harms of all available treatments for H1 antihistamine-refractory chronic spontaneous urticaria (CSU) have not been established. To evaluate different treatment effects of pharmacologic treatments among patients with H1 antihistamine-refractory CSU. Searches were conducted of MEDLINE, Embase, PubMed, Cochrane Library, Web of Science, Scopus, and CINAHL from inception to April 19, 2021, with no language restrictions. Gray literature from Google Scholar, ongoing trial registers, and preprint reports was added to the searches of electronic databases. Randomized clinical trials using validated measurement tools that investigated the benefits and harms of pharmacologic treatments among adolescent or adult patients with CSU who had an inadequate response to H1 antihistamines were screened for inclusion independently by 2 investigators. Two investigators independently extracted study data according to the predefined list of interests. A random-effects model was used to calculate the network estimates reported as standardized mean differences and odds ratios with corresponding 95% CIs. The primary outcomes that reflect the patient's perspective included changes in urticaria symptoms from baseline and unacceptability of treatment (all-cause dropouts). Twenty-three randomized clinical trials with 2480 participants that compared 18 different interventions or dosages and placebo were included. The standardized mean differences for change in urticaria symptoms were -1.05 (95% CI, -1.37 to -0.73) for ligelizumab, 72 mg; -1.07 (95% CI, -1.39 to -0.75) for ligelizumab, 240 mg; -0.77 (95% CI, -0.91 to -0.63) for omalizumab, 300 mg; and -0.59 (95% CI, -1.10 to -0.08) for omalizumab, 600 mg. No significant differences in treatment unacceptability were observed. With respect to benefits and harms, the network estimates illustrated that the most efficacious treatments were achieved with ligelizumab, 72 or 240 mg (large beneficial effect) and omalizumab, 300 or 600 mg (moderate beneficial effect). The findings in this meta-analysis suggest that the biologic agents ligelizumab, 72 or 240 mg, and omalizumab, 300 or 600 mg, can be recommended as effective treatments for patients with CSU who have had an inadequate response to H1 antihistamines. Head-to-head trials with high methodologic quality and harmonized design and outcome definitions are needed to help inform subsequent international guidelines for the management of CSU.

Efficacy of drug therapies in antihistamine refractory chronic spontaneous urticaria: Real life data.

Omalizumab is a safe and effective treatment for antihistamine-refractory chronic spontaneous urticaria (CSU) but is insufficient in one-third of patients. For serious cases in which omalizumab is ineffective, cyclosporine or methotrexate may be preferred. Most drug trials in CSU have focused on omalizumab or cyclosporine monotherapy. This retrospective study evaluated responses to monotherapy or combined therapy and real-life data on the effectiveness and safety of omalizumab in antihistamine-refractory CSU. A total of 133 patients who received omalizumab due to antihistamine-refractory CSU were evaluated in terms of 7-day urticaria activity score, total IgE, anti-thyroid peroxidase, C-reactive protein, skin prick test with aeroallergens and disease duration. Partial or nonresponders to omalizumab monotherapy were given antihistamine, omalizumab, cyclosporine, and methotrexate as combined or monotherapy. Ninety-eight (73.7%) of the 133 patients were female and the mean age was 40.7 ± 14.4 years; 70.6% of the patients received omalizumab monotherapy and the others received combined or non-omalizumab monotherapy. Omalizumab monotherapy was effective in 66.9% of the patients. Of those with complete response to omalizumab monotherapy, 65.4% had early recurrence after discontinuing treatment. Treatment response was significantly better in patients who had high total IgE (p = 0.001). Patients with longer disease duration had significantly higher likelihood of early recurrence (p = 0.035). Omalizumab monotherapy was as effective in real life as in placebo-controlled trials. Omalizumab was well tolerated by all patients. Treatment responses were comparable in patients treated with combined therapy and those who received monotherapy.

Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria

Background: Approximately 50% of patients with chronic spontaneous urticaria (CSU) experience symptoms that are not fully controlled by antihistamines, indicating an unmet clinical need. Objective: To evaluate the effects of the selective CRTh2 antagonist AZD1981 on symptoms and targeted leukocytes in adults with persistent CSU despite treatment with H₁-antihistamines. Methods: We performed a single-center, randomized, placebo-controlled study involving adult CSU subjects with symptoms despite daily antihistamines. The subjects underwent a 2-week placebo run-in and 4 weeks of double-blinded therapy with either AZD1981 40 mg TID or placebo, followed by a 2-week placebo washout. The primary objective was to assess the effect of AZD1981 on CSU signs and symptoms. Secondary objectives included the effects of AZD1981 on prostaglandin D₂ (PGD₂)-induced eosinophil shape change, circulating leukocyte subsets, CRTh2 expression on blood leukocytes, and total blood leukocyte histamine content. Results: Twenty-eight subjects were randomized to AZD1981 or placebo, with 26 subjects completing the study. The urticaria activity scores declined during the treatment phase in both groups, and they were significantly reduced in the AZD1981 group at the end of washout. AZD1981 treatment increased circulating eosinophils and significantly impaired PGD₂-mediated eosinophil shape change. CRTh2 surface expression rose significantly on blood basophils during active treatment. No serious adverse events were observed. Conclusions: This is the first study to examine the efficacy of a CRTh2 antagonist in antihistamine-refractory CSU. AZD1981 treatment was well tolerated, effectively inhibited PGD₂-mediated eosinophil shape change, shifted numbers of circulating eosinophils, and reduced weekly itch scores more than hives during treatment and into washout. Further studies are needed to determine whether inhibition of the PGD₂/CRTh2 pathway will be an ­effective treatment for CSU.

Treatment of chronic spontaneous urticaria with an inadequate response to H1-antihistamine.

The second-generation H1-antihistamines (sgAH) are the first-line symptomatic treatment of patients with chronic spontaneous urticaria (CSU). Up to 50% of the patients will not respond to licensed doses of sgAH. According to the guidelines, the dose of sgAH may be increased up to 4 times the conventional dose. However, even at higher doses, there is a subgroup of patients refractory to the antihistamine treatment. The purpose of this article was to review the different treatment options of antihistamine-refractory CSU patients. This revision examines the available literature for therapies used in chronic urticaria, including omalizumab, ciclosporin A, oral glucocorticoids, leukotriene receptor antagonists, H2 antihistamines, doxepin, dapsone, hydroxychloroquine, phototherapy, methotrexate, mycophenolate mofetil, azathioprine, autohemotherapy, intravenous immunoglobulins and rituximab, between others. After the exhaustive review of the medical literature only few high-quality studies have been identified, mostly for omalizumab. Omalizumab is an anti-immunoglobulin E monoclonal antibody, approved for the treatment of CSU, that has radically changed the management of the patients without good response to sgAH, allowing to reach complete responses in a high percentage of patients. Although actually the therapeutic management of CSU is more effective and safer than before 2014, there is place even for new and more effective treatments. A good number of partial responders and slow responders to omalizumab and a little percentage still of non-responders to available therapies stimulate the development of new drugs that will also be discussed.

Comparing azathioprine with cyclosporine in the treatment of antihistamine refractory chronic spontaneous urticaria: A randomized prospective active-controlled non-inferiority study

Comparing azathioprine with cyclosporine in the treatment of antihistamine refractory chronic spontaneous urticaria: A randomized prospective active-controlled non-inferiority study

Emerging Therapies in Chronic Spontaneous Urticaria

Chronic spontaneous urticaria (CSU) is characterized by typically short-lived and fleeting wheals, angioedema or both, which occur spontaneously and persist for longer than 6 weeks. This term is applied to the most common subtype of chronic urticaria. The underlying pathophysiology for CSU involves mast cell and basophil degranulation with release of histamine, leukotrienes, prostaglandins and other inflammatory mediators. Although a variety of treatments exist, many patients do not tolerate or benefit from the existing therapies and even require more effective treatments. Omalizumab is currently the only licensed biologic for antihistamine-refractory CSU, and novel drugs are under development. This article reviews its current status regarding pathogenesis and approach to treatment as well as therapeutic agents that are under development for the treatment of CSU.