Mechanisms of action that contribute to efficacy of omalizumab in chronic spontaneous urticaria

The monoclonal anti‐immunoglobulin E (IgE) antibody, omalizumab, was the first drug approved for use in patients with chronic idiopathic/spontaneous urticaria (CIU/CSU) who remain symptomatic despite H₁‐antihistamine treatment. Omalizumab binds to free IgE, which lowers free IgE levels and causes FcεRI receptors on basophils and mast cells to be downregulated. It has been shown to improve symptoms of CIU/CSU, but its mechanism of action is not currently understood. Potential mechanisms in CIU/CSU include reducing mast cell releasability, reversing basopenia and improving basophil IgE receptor function, reducing activity of IgG autoantibodies against FcεRI and IgE, reducing activity of IgE autoantibodies against an antigen or autoantigen that has yet to be definitively identified, reducing the activity of intrinsically ‘abnormal’ IgE, and decreasing in vitro coagulation abnormalities associated with disease activity. However, none of these theories alone or in combination fully account for the pattern of symptom improvement seen with omalizumab therapy, and therefore, no one mechanism is likely to be the definitive mechanism of action. Additional research is needed to further clarify the involvement of omalizumab in relieving symptoms associated with the complex, multifactorial pathogenesis of CIU/CSU.     

Long-term efficacy of fixed-dose omalizumab for patients with severe chronic spontaneous urticaria

BackgroundTreatment of chronic urticaria is challenging because many patients are refractory to or experience adverse effects with conventional therapy. Recently, short-term efficacy of omalizumab has been demonstrated.ObjectiveTo determine both the short- and long-term efficacy of omalizumab in the treatment of chronic urticaria.MethodsSixteen patients with severe chronic spontaneous urticaria at our center received omalizumab, 150 mg every 2 to 4 weeks, between 2010 and 2011. Disease severity was measured by urticaria activity scores before the first injection, during treatment, and at most recent follow-up, ranging from 9 to 24 months. Duration of therapy was determined individually for each patient. In this retrospective analysis, outcome measures include number of treatments required to induce remission and long-term remission sustainability.ResultsTen patients had remission of urticaria after their first injection (62%). Four patients required 2 to 6 treatments to achieve remission. Two patients discontinued treatment after 2 injections. Of the 14 patients who initially benefited (88%), 4 remain in remission more than 9 months after their last treatments. Seven patients continue to achieve remission with maintenance omalizumab, dosed at intervals appropriate for individual remission duration. Three patients became refractory and discontinued treatment (19%).ConclusionOmalizumab is an effective treatment for inducing and maintaining long-term remission for patients with severe chronic urticaria. Onset of remission is rapid, although duration is variable, with some patients requiring maintenance treatment. Large-scale randomized trials are necessary to confirm our findings that support the long-term efficacy of anti-IgE therapy for the treatment of this disease.     

Predictors of treatment response in chronic spontaneous urticaria

The current therapeutic algorithm for chronic spontaneous urticaria (CSU), endorsed by the international guideline, entails treatment escalation from second-generation H₁-antihistamines (sgAHs) to omalizumab and cyclosporine until complete response is achieved. Recently, several predictors of response to these treatment options have been described. Here, we discuss the most promising predictors of response and nonresponse to these treatments in CSU. A systematic search was performed by two independent researchers using the MEDLINE/PubMed database with specific keywords and 73 studies included in the review. Levels of evidence were categorized as strong (robust predictors), weak (emerging predictors) or no association, based on the outcome and number of studies available. High disease activity, high levels of C-reactive protein and D-dimer are robust predictors for a poor or no response to sgAHs. Poor or no response to omalizumab is robustly predicted by low serum levels of total IgE. A good response to cyclosporine is robustly predicted by a positive basophil histamine release assay, whereas low total IgE is an emerging predictor. The response to treatment with sgAHs, omalizumab and cyclosporine can be predicted by the use of markers that are readily available in routine clinical practice. Further studies are needed to confirm these predictors.     

Effect of omalizumab on patients with chronic urticaria.

BACKGROUND: Chronic urticaria (CU) is often difficult to treat. Approximately 40% to 50% of patients with no apparent cause are believed to have an associated autoimmune profile that may play a pathogenetic role. OBJECTIVES: To describe 3 patients with CU refractory to conventional treatment who responded to omalizumab therapy. METHODS: Treatment was maximized with antihistamines, antileukotrienes, and histamine2 blockers with no improvement. Systemic steroids provided only temporary relief. Laboratory workup revealed 1 patient with a low IgE level and elevated anti-IgE receptor antibody level, 1 patient with an elevated IgE level but a normal anti-IgE receptor antibody level, and 1 patient with a very elevated IgE level and an elevated anti-IgE receptor antibody level. All 3 patients were prescribed omalizumab therapy every 2 weeks. RESULTS: Two patients had total clearing of urticaria within 1 week and 1 patient within 6 weeks of starting omalizumab therapy. The patient with the elevated anti-IgE receptor antibody level had normalization of the level after starting treatment. CONCLUSIONS: Omalizumab may have a beneficial effect in the treatment of CU. Further studies are needed to confirm this effect and better elucidate the mechanism for the observed improvement.     

Real-life experiences with omalizumab for the treatment of chronic urticaria

BackgroundEvidence has shown that omalizumab, a subcutaneous anti-IgE monoclonal antibody, is highly effective for the treatment of chronic urticaria.ObjectiveTo evaluate omalizumab 150 mg/month in severe, difficult-to-treat, chronic urticaria in a real-life setting.MethodsThis prospective open-label study evaluated of 150 mg of omalizumab in severe urticaria defined by a 7-day urticaria activity score (UAS-7) higher than 30, a history of oral glucocorticoid use, and by suboptimal response to previous treatments. Two subgroups of patients at different centers (Toronto and Quebec City, Canada) were included. The primary efficacy evaluation was a change in UAS-7 from baseline. A quantitative medication score assessed the use of other anti-urticarial medications.ResultsSixty-eight patients were included: 61 with chronic spontaneous urticaria, 6 with cold urticaria, and 1 with urticarial vasculitis. Patients were followed for up to 25 months. In Toronto, mean UAS-7 decreased from 32.2 at baseline to 5.7 after the last omalizumab treatment. Seventy-nine percent achieved complete remission during omalizumab therapy (UAS-7 0) and 6 (18%) showed improvement but never achieved complete remission. The most common maintenance dosing intervals were 1 to 3 months. In Quebec City, from baseline to 18 months, mean UAS-7 decreased from 24.4 to 2.2 and the quantitative medication score decreased from 13.3 to 3.0. All 6 patients with cold urticaria became symptom free, with a significant decrease of their cold stimulation tolerance test.ConclusionOmalizumab 150 mg was effective in difficult to treat patients with severe, chronic urticaria refractory to recommended treatments who usually required prednisone. Omalizumab induced a long-lasting positive response and was well tolerated without side effects.     

Therapy of antihistamine-resistant chronic spontaneous urticaria

Introduction: Chronic urticaria affects up to 1–3% of the general population and contributes to significant direct and indirect medical costs as well as decreased quality of life, which has a significant economic impact on our health care system.

Areas covered: Given the prevalence of this condition on a large sector of the population, finding lasting relief for refractory cases is essential and is the focus of this review.

Expert commentary: The choice of appropriate therapy in chronic refractory urticaria is not a ‘one-size fits all’ approach. Treatment should take multiple factors into consideration including the chronicity of hives, presence of physical urticaria, type of cellular infiltrate on skin histopathology, patient age, concomitant comorbid conditions, as well as patient preference and cost.     

Potential blood biomarkers in chronic spontaneous urticaria

Chronic spontaneous urticaria (CSU) is a mast cell‐driven disease that is defined as the recurrence of weals, angioedema or both for > 6 weeks due to known or unknown causes. As of yet, disease diagnosis is purely clinical. Objective tools are needed to monitor the activity of CSU and the efficacy of treatment. Recently, several reports have suggested that blood parameters may be considered as potential disease‐related biomarkers. Here, we reviewed available literature on blood biomarkers for CSU diagnosis, activity monitoring, duration, patient subgroup allocation or response to treatment. We performed a PubMed, Google Scholar and Web of Science search and identified and analysed 151 reports published prior to January 2016. We found strong evidence for significant differences between patients with CSU and healthy controls in blood levels or values of D‐dimer, C‐reactive protein (CRP), matrix metalloproteinase‐9 (MMP‐9), mean platelet volume (MPV), factor VIIa, prothrombin fragment 1 + 2 (F1 + 2), tumour necrosis factor, dehydroepiandrosterone sulphate and vitamin D. Also, there is strong evidence for a significant association between CSU activity and blood levels or values of D‐dimer, F1 + 2, CRP, IL‐6 and MPV. Strong evidence for reduced basophil count and high levels of IgG anti‐FcεRI in the subgroup of CSU patients with positive autologous serum skin test was shown. In contrast, the evidence for all reported blood biomarkers for differentiating CSU from other diseases, or a role in prognosis, is weak, inconsistent or non‐existent. Taken together, we identified 10 biomarkers that are supported by strong evidence for distinguishing patients with CSU from healthy controls, or for measuring CSU activity. There is a need for further research to identify biomarkers that predict outcome or treatment response in CSU.