Differences in effects of omalizumab on late-phase responses to allergen challenge in the skin and nose at the time of basophil hyporesponsiveness.
TO THE EDITOR Omalizumab is a mAb therapeutic directed against IgE. It is FDA (Food and Drug Administration) approved for use in allergic asthma (Presta et al., 1993; Strunk and Bloomberg, 2006). It binds IgE at the same site on its Fc domain as the a-chain of the high– affinity IgE receptor (FceRI) and blocks the interaction between IgE and FceRI on mast cells, basophils, and dendritic cells (Presta et al., 1993; Schulman, 2001; Prussin et al., 2003). As the IgE level decreases with omalizumab, FceRI expression on basophils and mast cells are reduced within 7 days for basophils (MacGlashan et al., 1997) and within 56–70 days for skin mast cells (Beck et al., 2004; Ong et al., 2005). In a recent study, we found that in cat–allergic subjects receiving omalizumab, the acute–phase clinical responses to nasal allergen challenge (NAC) were decreased at a time when blood basophils (6–8 weeks), but not nasal mast cell–mediator responses, were depressed (Eckman et al., 2010). This suggests that some process, other than mast cell secretion, has a part in defining the acute–phase clinical responses of an NAC response. Acute–phase skin test suppression occurred at 14 weeks. In this different study, we examined the effects of omalizumab on the nose and skin late–phase reactions at the time of basophil, but not mast cell, hyporesponsiveness. The study was a 16-week, double–blind, placebo–controlled trial of 19 cat–allergic adult subjects, who were randomly assigned to receive either omalizumab or matched placebo in a 1:1 ratio on the basis of the FDA– approved dosing schedule for allergic asthma. Subjects underwent basophil histamine response (BHR) and prostaglandin D2 testing, as well as NAC as previously described (Eckman et al., 2010) with three separate challenges of cat allergen (100, 300, and 1,000 BAU ml ). Late– phase sneeze counts were measured 4, 8, and 24 hours after NAC. Cat allergen– titrated intradermal skin testing (IDST) was performed at two half–log concentrations of allergen solution beginning with either 0.1 or 0.3 BAU ml 1 depending on the cat puncture skin test result. Concentrations were then increased until the average wheal of a single injection was X15 mm. Late– phase–induced skin induration was measured at 8 and 24 hours. When a subject’s cat allergen–induced BHR area under the curve (AUC) decreased to o20% of the baseline value or on study day 56 (week 8), whichever occurred first, a second NAC (NAC-2), IDST, and BHR were performed. No significant differences were present between baseline characteristics (age, gender, cat puncture test size, total IgE, cat–specific IgE, and percentage of subjects reporting mild asthma (FEV1X80%)) in the 10 active and 9 placebo subjects who completed the study. The IgE ranges were 53– 298 kU l 1 for total IgE, and 1.0–41.5 for cat–specific IgE, for all subjects. Specific to total IgE ratio levels fell into the previously reported atopic population range of 0.002–35.8% for cat–sensitized individuals and were maintained during omalizumab treatment, as seen previously (Hamilton et al., 2010). The average day of NAC-2 was day 48 for treatment group and day 65 for placebo. Consistent with our previous study, at NAC-2, the median cat BHR AUC showed a 57% decrease on omalizumab treatment compared with a 21% increase on placebo administration (P1⁄4 0.008, data not shown). As was seen in our previous study (Eckman et al., 2010), the acute–phase sneezes trended toward a greater decrease from NAC-1 in the treated group compared with placebo. The change from baseline for the treatment group was a median of 12 sneezes (interquartile range (IQR): 1.5–18.5), or 36%, compared with 4 sneezes (IQR: 8.5–11.5), or 4%, for the placebo group. Within the treatment group, the sneezes at NAC-1 were statistically different compared with NAC-2 (P1⁄40.01, two tailed). There were no differences between or within groups at 8 or at 24 hours (Figure 1). Measures of nasal mast cell allergen responses (nasal lavage PGD2) did not change at the time of NAC-2 (data not shown). For the late–phase nasal reaction, of the 74% of subjects who had late–phase sneezes recorded, no significant change from baseline was seen in the omalizumab treatment group compared with placebo. IDST flares were similar between groups at baseline at all time points during the baseline NAC-1. The acute skin flare size at NAC-1 was 134.0 mm (IQR: 119.8–146.5) for treatment group and 112.0 mm (IQR: 103.0–136.0) for placebo. There was no difference in acute skin flare changes at NAC-2 LETTERS TO THE EDITOR