Antiinflammatory Actions of Omalizumab

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Clinical studies have provided some indirect evidence of the antiinflammatory actions of omalizumab, as patients have been able to reduce their dose of inhaled corticosteroids or withdraw completely from inhaled corticosteroid treatment. To further explore the mechanisms involved, a number of studies have been conducted with the aim of defining the markers, factors, and mediators affected by omalizumab in the immunological and cellular reactions of the inflammatory cascade. Together the data suggest that omalizumab may act on multiple components of the inflammatory cascade.

As previously discussed, a study in allergic individuals showed that omalizumab down-regulates FceRI expression on basophils by reducing serum levels of free IgE (55), and this process attenuates the EAR. This was again demonstrated in a study of 24 subjects with ragweed-induced allergic rhinitis (56). Alongside a decline in IgE levels (>95%), there was a reduction in FceRI expression on basophils at 7, 14, 28, and 42 days after starting 72-hour omalizumab treatment as compared with baseline (p < 0.0001) and placebo (p < 0.01), and the maximum reduction occurred within 14 days (median change -73%).

Similarly to its effect on FceRI expression on basophils, omalizumab was found to reduce dendritic cell FceRI expression in patients with allergic rhinitis within 14 days (median change -78%, p = 0.004) (95). Dendritic cells are central to allergen presentation and the induction of Th2 responses in the LAR. The demonstration that an anti-IgE antibody inhibits proliferation of allergen-specific T cells, even at low allergen concentrations (96), reaffirmed this. In addition to the interaction of allergen-bound IgE with FceRI on dendritic cells, the interaction of allergen-bound IgE with FceRII RII on B cells is important in T-cell activation, and the effects of omalizu-mab may have been due, in part, to this. Further studies are needed to assess the role of omalizumab in reducing dendritic-cell-mediated antigen presentation.

Other inflammatory mediators are also reduced in patients with asthma receiving omalizumab treatment. In a multicenter, randomized, placebo-controlled study of 35 patients with moderate to severe asthma, circulating levels of IL-13 decreased after 16 weeks of omalizumab treatment compared to the placebo group (-2.4pg/mL; p < 0.01), and non significant reductions were seen in IL-5 (-2.65pg/mL) and IL-8 (-1.64pg/mL) (97). No differences were detected for IL-6, IL-10, or s-ICAM throughout the study. As IL-13 and IL-5 are produced by Th2 cells, eosinophils, mast cells, and basophils, while IL-6 and IL-10 are produced by Th1/Th2 cells, macrophages and endothelial cells, these results reflect the proposed mechanisms of action of omalizumab. The authors also found that, after 16 and 52 weeks of omalizumab treatment, blood eosinophils were decreased compared with placebo (-25% and -50%, respectively, both p < 0.01).

Eosinophilia is one established feature of inflammation (29,30), and interaction between IgE and FceRII expressed on the surface of eosinophils may play an important role (34-36). A study in 74 asthma patients with disease severity ranging from intermittent to mild-to-moderate and severe persistent asthma, and 22 healthy non-atopic control subjects, was conducted to investigate the association between airways inflammation and disease severity (29). Using the method of induced sputum, asthma severity was monitored alongside sputum eosinophilia and eosinophil cationic protein (ECP). Sputum eosinophil counts were higher in patients from across the spectrum of asthma severity than in control subjects, and increased with asthma severity (p < 0.05). ECP concentration also increased with asthma severity (p < 0.05). Lung function parameters, symptom scores, and the inflammatory index PC20 in asthma patients all correlated with eosinophil count and ECP concentration. These results indicated that eosinophilic inflammation, which occurs during the LAR, can be used as a marker of asthma severity.

Similar results were obtained in a randomized, placebo-controlled trial that compared the efficacy of asthma management by normalization of induced sputum eosinophil count with that by standard British Thoracic Society guidelines (30). In 74 patients with moderate to severe asthma treated with corticosteroids, there were fewer asthma exacerbations (35 vs. 109, p = 0.01) and fewer asthma-related hospitalizations (1 vs. 6, p = 0.047) during the 12-month study period in those in the sputum management group compared with those in the BTS management group. Eosinophilia is therefore a valuable indicator of asthma control.

As eosinophilia correlates with asthma severity, it was hypothesized that reducing IgE in the airway mucosa would reduce airway inflammation. The effect of omalizumab on the eosinophil-mediated part of the inflammatory cascade was tested in a 16-week, five-center, double-blind, and placebo-controlled, parallel-group study by Djukanovic et al. (98). To avoid interference from concomitant ICS, the 45 patients in this study were selected to have mild asthma that did not require ICS. Previous studies on eosinophils had included patients receiving ICS (57,97). The primary outcome measure was the effect of omalizumab on sputum eosinophilia. The mean percentage sputum eosinophil count decreased from 6.6% to 1.7% in 21 omalizumab recipients analyzed (p < 0.001), a reduction greater (p = 0.05) than in the 22 placebo recipients (8.5-7.0%) (Fig. 11A). There was a concomitant reduction in epithelial and submucosal eosinophils, as measured by immunohistochemical analysis of bronchial biopsies, from 8.0 cells/mm2 to 1.5 cells/mm2 (p < 0.001) in the 10 omalizumab recipients analyzed, compared to the nonsignificant change from 6.3 cells/mm2 to 6.4 cells/mm2 (p = 0.03) observed in the placebo group (Fig. 11B). These findings indicate that omalizumab does indeed act on the eosinophil-mediated component of airways inflammation in asthma. This considerably

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