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:
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.
In patients given a diagnosis of chronic spontaneous urticaria (CSU), there are no obvious external triggers, and the factors that initiate the clinical symptoms of wheal, flare, and itch arise from ...within the patient. Most patients with CSU have an autoimmune cause: some patients produce IgE autoantibodies against autoantigens, such as thyroperoxidase or double-stranded DNA, whereas other patients make IgG autoantibodies against FcεRI, IgE, or both, which might chronically activate mast cells and basophils. In the remainder of patients with CSU, the nature of the abnormalities has not yet been identified. Accumulating evidence has shown that IgE, by binding to FcεRI on mast cells without FcεRI cross-linking, can promote the proliferation and survival of mast cells and thus maintain and expand the pool of mast cells. IgE and FcεRI engagement can also decrease the release threshold of mast cells and increase their sensitivity to various stimuli through either FcεRI or other receptors for the degranulation process. Furthermore, IgE-FcεRI engagement potentiates the ability of mast cells to store and synthesize de novo inflammatory mediators and cytokines. Administration of omalizumab, by virtue of its ability to deplete IgE, attenuates the multiple effects of IgE to maintain and enhance mast cell activities and hence reduces the ability of mast cells to manifest inflammatory mechanisms in patients with CSU.
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 H1 -antihistamines are first line treatment of chronic urticaria, but many patients do not get satisfactory relief with recommended doses. European guidelines recommend increased ...antihistamine doses of up to 4-fold. Objective To provide supportive evidence for the European guidelines. Methods Eighty tertiary referral patients with chronic urticaria (age range, 19-67 years) were randomized for double-blind treatment with levocetirizine or desloratadine (40/40). Treatment started at the conventional daily dose of 5 mg and then increased weekly to 10 mg, 20 mg, or 20 mg of the opposite drug if relief of symptoms was incomplete. Wheal and pruritus scores, quality of life, patient discomfort, somnolence, and safety were assessed. Results Thirteen patients became symptom-free at 5 mg (9 levocetirizine vs 4 desloratadine), compared with 28 subjects on the higher doses of 10 mg (8/7) and 20 mg (5/1). Of the 28 patients nonresponsive to 20 mg desloratadine, 7 became symptom-free with 20 mg levocetirizine. None of the 18 levocetirizine nonresponders benefited with 20 mg desloratadine. Increasing antihistamine doses improved quality of life but did not increase somnolence. Analysis of the effect of treatment on discomfort caused by urticaria showed great individual heterogeneity of antihistamine responsiveness: ∼15% of patients were good responders, ∼10% were nonresponders, and ∼75% were responders to higher than conventional antihistamine doses. No serious or severe adverse effects warranting discontinuation of treatment occurred with either drug. Conclusion Increasing the dosage of levocetirizine and desloratadine up to 4-fold improves chronic urticaria symptoms without compromising safety in approximately three quarters of patients with difficult-to-treat chronic urticaria.
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