Elevated baseline soluble FcεRI may be linked to early response to omalizumab treatment in chronic spontaneous urticaria.

BACKGROUND: Omalizumab, an anti-IgE monoclonal antibody, is an effective treatment in chronic spontaneous urticaria (CSU). Predictors of fast and good response for omalizumab treatment have not yet been identified and characterized. OBJECTIVE: To evaluate whether soluble FcεRI (sFcεRI), a marker of IgE-mediated mast cell activation, predicts the time of response to omalizumab in CSU. METHODS: Sera of 67 CSU patients were obtained before omalizumab treatment and analysed for sFcεRI levels by ELISA (2 ng/mL was used as cut-off for elevated sFcɛRI). Treatment response during the first 4 weeks was assessed with the urticaria activity score (UAS7), urticaria control test (UCT) and the rolling UAS7 (rUAS7). RESULTS: Elevated pre-treatment sFcɛRI levels were detected in more than 70% of patients with completely controlled disease (UCT = 16) and well-controlled disease (UCT = 12-15) and were significantly associated with disease control (χ2 = 4.94, p < 0.05). More than half of the patients (14/25) with low levels had poor disease control (UCT < 12). Of the patients who achieved complete and marked UAS7 response, respectively, 75% and 63% had elevated baseline sFcɛRI levels. Post-treatment UAS7 scores were lower in patients with elevated sFcɛRI levels reaching statistical significance at Week 3 (p < 0.05). Patients with elevated baseline sFcɛRI levels achieved rUAS7 ≤ 6 and = 0 earlier than those with lower levels (Days 9 vs. 13 and Days 12 vs. 14, respectively). CONCLUSION: Elevated sFcεRI serum levels predict early and good response to treatment with omalizumab, which may help to better design treatment options for CSU patients.

Comparison and interpretability of the available urticaria activity scores.

The urticaria activity score (UAS) is the gold standard for assessing disease activity in patients with chronic spontaneous urticaria (CSU). Two different versions, the UAS7 and UAS7TD , are currently used in clinical trials and routine care. To compare both versions and to obtain data on their interpretability, 130 CSU patients applied both versions and globally rated their disease activity as none, mild, moderate, or severe. UAS7 and UAS7TD values correlated strongly (r = .90, P < .001). Interquartile ranges for UAS7 and UAS7TD values for mild, moderate, and severe CSU were 11-20 and 10-24, 16-30 and 16-32, and 27-37 and 28-40. UAS7 values were slightly, but significantly lower as compared to UAS7TD values (mean difference: 1.6 ± 4.6, P < .001). This difference was driven by lower wheal subscores (2.1 ± 3.5, P < .001) and was most pronounced in patients with severe CSU (2.5 ± 5.6, P < .01). The UAS7/UAS7TD ratio was 0.96 ± 0.21 and did not differ significantly between mild, moderate, and severe CSU. Since the results of both UAS versions are comparable, we recommend the use of the UAS7, which is less burdensome in administration and scoring.

Increased angiogenesis and VEGF expression correlates with disease severity in prurigo patients.

BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) is known as the major skin angiogenesis factor and can be produced by various resident skin cells including keratinocytes. OBJECTIVES: To identify and characterize the role of VEGF-A in the pathogenesis of prurigo. METHODS: Expression of VEGF, VEGFR2, CD-31, and D2-40 was analyzed in the skin of eleven prurigo patients and seven healthy controls by immunohistochemistry. RESULTS: VEGF immunoreactivity (IR) was markedly increased in the epidermis, dermis and subcutis of prurigo patients, whereas expression of the main receptor for VEGF-A in the skin, VEGFR2, was comparable to that of healthy controls. The increased VEGF expression in the skin was associated with a marked increase in the number (12.8 ± 2.1 vs 5.6 ± 0.5, P < 0.05) but not in the size of blood vessels, as assessed by staining of the endothelial cell marker CD31. This increase in small blood vessels correlated closely with increases in the epidermal thickness in prurigo lesions. The number of lymphatic vessels as assessed by D2-40 staining was found to be similar in prurigo patients and healthy controls. CONCLUSIONS: Based on these findings, we speculate that the observed profound vascular remodelling in prurigo might contribute to the pathogenesis of prurigo and the corresponding clinical symptoms and that targeting of VEGF may present a novel therapeutic strategy in the treatment of prurigo patients.

Omalizumab may not inhibit mast cell and basophil activation in vitro.

BACKGROUND: In March 2014, omalizumab, a monoclonal anti-IgE antibody, was approved for the treatment of chronic spontaneous urticaria (CSU). The primary mode of action of omalizumab is considered to be the reduction in free IgE serum levels and the subsequent down-regulation of FcεRI, the high affinity receptor for IgE, on mast cells and basophils. Recently, it has been suggested that most CSU patients have an autoimmune aetiology which may lead to chronic activation of mast cells and basophils. OBJECTIVE: To understand more of the mechanisms by which omalizumab may exert its effects in CSU, its efficacy was tested on human mast cells and basophils. METHODS: Omalizumab, which was or was not preincubated with serum from healthy donors or CSU patients, was coincubated with isolated healthy donor skin mast cells or peripheral blood-derived monocytes containing 1-2% basophils. Degranulation was induced using anti-human IgE, C5a, or substance P and histamine release determined. RESULTS: Anti-human IgE-induced histamine release from mast cells or basophils was not altered in the presence or absence of omalizumab. In contrast, preincubation of mast cells with DARPin Fc fusion protein, a positive control for negative signalling via FcεRI-FcγRIIb cross activation, significantly diminished histamine release. Moreover, omalizumab, that was preincubated with healthy donor serum, CSU patient serum or auto-reactive CSU serum to allow for the formation of potential immune complexes, did not alter induced histamine release in a coincubation setup with mast cells or basophils as compared to the absence of omalizumab. In vivo, blood basophil numbers and basophil histamine content increase under omalizumab therapy. CONCLUSION: Our results suggest that the rapid response to omalizumab therapy is more likely to result from the elimination of an activating signal rather than the generation of a negative, inhibitory signal.