The cutoff time of 8 days between fast and slow responders was chosen because it corresponds with the peak plasma level of omalizumab after its initial injection.3 We hypothesized that a slow ...response to omalizumab occurs in patients with CSU in whom IgG antibodies to unoccupied IgE receptors (FcepsilonRI) activate mast cell mediator release to cause wheal and angioedema formation.4 This hypothesis is based on the knowledge that omalizumab first complexes soluble IgE then sequesters IgE released from mast cells, thus uncovering membrane FcepsilonRI, which subsequently decays slowly over several weeks.5 To test this, the basophil histamine release assay (BHRA) was used. Quantification of free serum IgE, IgE neutralization, and omalizumab concentrations A commercially available recoveryELISA kit was used for the quantification of free IgE, IgE neutralization rates, and omalizumab levels in patient serum (BioTeZ Berlin Buch GmbH, Berlin, Germany) as described previously.E4 Characteristic All complete responders (n = 56) Complete response within 8 d Complete response after 8 d P value Age (y) 48 (33-60) 49 (37-58) 42 (31-63) .544 Sex Female 40 (71.4%) 28 (71.8%) 12 (70.6%) .583 Male 16 (28.6%) 11 (28.2%) 5 (29.4%) BMI 27.3 ± 4.8 27.9 ± 4.9 26.1 ± 4.6 .192 UAS7low * 24.0 ± 9.7 23.0 ± 9.3 26.5 ± 4.6 .215 Disease durationlow * 36 (16-102) 40 (18-103) 24 (14-85) .240 ASST+low * 23 of 46 (50.0%) 12 of 33 (36.4%) 11 of 13 (84.6%) <.01 BHRA+low * 9 of 55 (16.4%) 1 of 38 (2.6%) 8 of 17 (47.1%) <.001 Anti-FcepsilonRI+low * 5 of 44 (11.4%) 4 of 30 (13.3%) 1 of 14 (7.1%) .485 Anti-IgE+low * 1 of 44 (2.3%) 1 of 30 (3.3%) 0 of 14 (0.0%) .682 Total IgElow * 205.4 ± 229.6 239.2 ± 250.6 130.0 ± 155.0 .104 Free IgE after omalizumabdagger 31.8 ± 47.7 31.2 ± 39.6 33.2 ± 64.7 .893 % IgE neutralizationdagger 94.7 ± 13.4 96.7 ± 2.2 90.0 ± 24.5 .106 Omalizumab (μg/mL)dagger 16.2 ± 7.8 16.6 ± 7.2 15.2 ± 9.2 .557 Table I CSU responders to omalizumab:
Background Chronic urticaria is a frequent and debilitating skin disease. Its symptoms commonly fluctuate considerably from day to day. As of yet, the only reliable tool to assess disease activity is ...the Urticaria Activity Score, which prospectively documents the signs and symptoms of urticaria for several days. Objective We sought to develop and validate a novel patient-reported outcome instrument to retrospectively assess urticaria control, the Urticaria Control Test (UCT). Methods Potential UCT items were developed by using established methods (literature research and expert and patient involvement). Subsequently, item reduction was performed by using a combined approach, applying impact and regression analysis. The resulting UCT instrument was then tested for its validity, reliability, and screening accuracy. Results A 4-item UCT with a recall period of 4 weeks was developed based on 25 potential UCT items tested in 508 patients with chronic urticaria. A subsequent validation study with the 4-item UCT in 120 patients with chronic urticaria demonstrated that this new tool exhibits good convergent and known-groups validity, as well as excellent test-retest reliability. In addition, the screening accuracy to identify patients with urticaria with insufficiently controlled disease was found to be high. Conclusions The UCT is the first valid and reliable tool to assess disease control in patients with chronic urticaria (spontaneous and inducible). Its retrospective approach and simple scoring system make it an ideal instrument for the management of patients with chronic urticaria in clinical practice.
Background Patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) often continue to experience symptoms despite receiving standard-of-care therapy with H1 -antihistamines ...along with 1 or more add-on therapies. Objectives We sought to evaluate the safety and efficacy of 24 weeks of treatment with omalizumab in patients with persistent CIU/CSU despite treatment with H1 -antihistamines at up to 4 times the approved dose plus H2 -antihistamines, leukotriene receptor antagonists, or both. Methods In this phase III study patients were randomized to receive 6 subcutaneous injections at 4-week intervals of either 300 mg of omalizumab or placebo, followed by a 16-week observation period. The primary objective of the study was to evaluate the overall safety of omalizumab compared with placebo. Efficacy (itch severity, hive, and urticaria activity scores) was evaluated at weeks 12 and 24. Results The overall incidence and severity of adverse events and serious adverse events were similar between omalizumab and placebo recipients; the safety profile was consistent with omalizumab in patients with allergic asthma. At week 12, the mean change from baseline in weekly itch severity score was −8.6 (95% CI, −9.3 to −7.8) in the omalizumab group compared with −4.0 (95% CI, −5.3 to −2.7) in the placebo group ( P < .001). Significant improvements were seen for additional efficacy end points at week 12; these benefits were sustained to week 24. Conclusion Omalizumab was well tolerated and reduced the signs and symptoms of CIU/CSU in patients who remained symptomatic despite the use of H1 -antihistamines (up to 4 times the approved dose) plus H2 -antihistamines, leukotriene receptor antagonists, or both.
Chronic spontaneous urticaria (CSU) is a mast cell–driven skin disease characterized by the recurrence of transient wheals, angioedema, or both for more than 6 weeks. Autoimmunity is thought to be ...one of the most frequent causes of CSU. Type I and II autoimmunity (ie, IgE to autoallergens and IgG autoantibodies to IgE or its receptor, respectively) have been implicated in the etiology and pathogenesis of CSU. We analyzed the relevant literature and assessed the existing evidence in support of a role for type I and II autoimmunity in CSU with the help of Hill's criteria of causality. For each of these criteria (ie, strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy), we categorized the strength of evidence as “insufficient,” “low,” “moderate,” or “high” and then assigned levels of causality for type I and II autoimmunity in patients with CSU from level 1 (causal relationship) to level 5 (causality not likely). Based on the evidence in support of Hill's criteria, type I autoimmunity in patients with CSU has level 3 causality (causal relationship suggested), and type II autoimmunity has level 2 causality (causal relationship likely). There are still many aspects of the pathologic mechanisms of CSU that need to be resolved, but it is becoming clear that there are at least 2 distinct pathways, type I and type II autoimmunity, that contribute to the pathogenesis of this complex disease.
Cold urticaria is a potentially life-threatening disease and placebo treatment of patients does not provide protection from cold-induced systemic reactions including anaphylactic shock. Because the ...interim analysis showed marked clinical and statistical superiority of omalizumab compared with placebo, the study was terminated. ...omalizumab in doses of 150 mg and 300 mg resulted in a high rate of complete and partial responders in patients with cold urticaria and a pronounced overall reduction in disease activity. There were no visible differences between omalizumab and placebo; however, the viscosity of the 2 differed. ...a separate and independent unblinded study team, which did not engage in study-specific communication with the blinded study team, was responsible for the preparation and injection of the study drug. ...a sample size calculation based on previous data was not possible.
Background Chronic spontaneous urticaria (CSU) is defined by itchy hives, angioedema, or both for at least 6 weeks. Omalizumab, an anti-IgE antibody that affects mast cell and basophil function, is a ...promising new treatment option. As of now, however, the efficacy and safety of different doses of omalizumab used in clinical trials for CSU have not been systematically analyzed and summarized. Objective We sought to assess the efficacy and safety of different doses of omalizumab for the treatment of CSU in a meta-analysis of clinical trial results. Methods Suitable trials were identified by searching PubMed, Medline, Embase, and Web of Science databases and with the help of omalizumab's manufacturers. Only double-blind, randomized, placebo-controlled studies with omalizumab-treated versus placebo-treated patients with CSU were included in this analysis. Results We identified 7 randomized, placebo-controlled studies with 1312 patients with CSU. Patients treated with omalizumab (75-600 mg every 4 weeks) had significantly reduced weekly itch and weekly wheal scores compared with the placebo group. Omalizumab's effects were dose dependent, with the strongest reduction in weekly itch and weekly wheal scores observed with 300 mg. Rates of complete response were significantly higher in the omalizumab group (relative risk, 4.55; P < .00001) and dose dependent, with the highest rates in the 300-mg group. Rates of patients with adverse events were similar in the omalizumab and placebo groups. Conclusion This meta-analysis provides high-quality evidence for the efficacy and safety of omalizumab in patients with CSU and for treating these patients with 300 mg of omalizumab every 4 weeks.
Background Schnitzler syndrome is an adult-onset autoinflammatory disease characterized by urticarial exanthema and monoclonal gammopathy accompanied by systemic symptoms such as fever, bone, and ...muscle pain. Up to now, approved treatment options are not available. Objective We assessed effects of the anti–IL-1β mAb canakinumab on the clinical signs and symptoms of Schnitzler syndrome. Methods In this phase II, randomized placebo-controlled multicenter study, 20 patients with active disease enrolled in 4 German study centers. Patients were randomly assigned to receive single subcutaneous canakinumab 150 mg or placebo injections for 7 days, followed by a 16-week open-label phase with canakinumab injections on confirmed relapse of symptoms. The primary end point was the proportion of patients with complete clinical response evaluated by physician global assessment at day 7. Key secondary end points included changes in patient-reported disease activity (Schnitzler activity score), inflammation markers (C-reactive protein and serum amyloid A), and quality-of-life assessments (Dermatology Life Quality Index and 36-item short form health survey). Results The proportion of patients with complete clinical response at day 7 was significantly higher ( P = .001) in the canakinumab-treated group (n = 5 of 7) than in the placebo group (n = 0 of 13). Levels of inflammation markers C-reactive protein and serum amyloid A and quality-of-life scores were significantly reduced in canakinumab-treated but not in placebo-treated individuals. Positive effects continued up to 16 weeks. Adverse events were manageable and included respiratory tract infections, gastrointestinal symptoms, and hypertension. Conclusions In this first placebo-controlled study, canakinumab was effective in patients with Schnitzler syndrome, and thus canakinumab may be further evaluated as a therapeutic option for this rare disease.
Background A subgroup of patients with chronic spontaneous urticaria (CU) exhibits IgE antibodies directed against autoantigens, such as thyroperoxidase (TPO). We conducted this study to investigate ...whether such patients with CU with IgE against TPO benefit from treatment with omalizumab, a humanized anti-IgE mAb licensed for the treatment of severe persistent allergic (IgE-mediated) asthma. Objectives We sought to assess the efficacy of omalizumab treatment in patients with CU with IgE autoantibodies against TPO. Methods In this multicenter, randomized, double-blind, placebo-controlled study patients with CU (male/female, 18-70 years of age) with IgE autoantibodies against TPO who had persistent symptoms (wheals and pruritus) despite standard antihistamine therapy were randomized to receive either omalizumab (75-375 mg, dose determined by using the approved asthma dosing table) or placebo subcutaneously once every 2 or 4 weeks for 24 weeks. The primary end point was the change from baseline in mean weekly urticaria activity score after 24 weeks of treatment, as calculated from patients’ diaries. The safety and tolerability of omalizumab were also assessed. Results Of the 49 randomized patients (omalizumab, n = 27; placebo, n = 22), 42 completed the study. At week 24, patients demonstrated a mean reduction in the weekly urticaria activity score from baseline of 17.8 with omalizumab and 7.9 with placebo ( P = .0089). Complete protection from wheal development was observed in 19 (70.4%) patients in the omalizumab group compared with only 1 (4.5%) patient in the placebo group. The rate of adverse events was similar in both groups. Conclusions The results of this study indicate that omalizumab is an effective treatment option for patients with CU with IgE autoantibodies against TPO who are refractory to conventional treatment.
Short Summary This study demonstrates the responsiveness of the Urticaria Control Test (UCT). Changes of its score by 3 points or more reflect a clinically relevant change of disease control (minimal ...important difference).
Background Proof-of-concept studies with omalizumab in patients with chronic idiopathic urticaria (CIU) have shown significant decreases in mean urticaria activity scores (UASs). Objective We sought ...to evaluate the efficacy and safety of omalizumab in patients with CIU who remain symptomatic despite concomitant H1 -antihistamine therapy. Methods This phase II, prospective, double-blind, placebo-controlled, dose-ranging study investigated omalizumab in patients aged 12 to 75 years in the United States and 18 to 75 years in Germany with a UAS over 7 days (UAS7) of 12 or greater despite antihistamine therapy. Patients were randomized 1:1:1:1 to receive a single subcutaneous dose of 75, 300, or 600 mg of omalizumab or placebo added to a stable dose of H1 -antihistamine. The primary efficacy outcome was change from baseline to week 4 in UAS7. Patients were followed for an additional 12 weeks to monitor safety. Results Ninety patients from the United States or Germany were enrolled. Both the 300-mg omalizumab group (−19.9 vs −6.9, P < .001) and the 600-mg omalizumab group (−14.6 vs −6.9, P = .047) showed greater improvement versus the placebo group in UAS7. No meaningful difference was observed for the 75-mg omalizumab group. Similar results were seen for key secondary end points of weekly hive and itch scores. Onset of effect occurred after 1 to 2 weeks. Omalizumab was well tolerated, and the incidence of adverse events was similar across treatment groups. Conclusion This study demonstrated that a fixed dose of 300 or 600 mg of omalizumab provides rapid and effective treatment of CIU in patients who are symptomatic despite treatment with H1 -antihistamines.
PDF
