In this report, we examine the safety and efficacy of anti-IgE therapy in EGID patients. We show that omalizumab therapy is associated with significant decreases in peripheral eosinophilia and gastrointestinal symptoms, and a trend towards lower eosinophil number in the gastric antrum and duodenum. Omalizumab was well tolerated. These results demonstrate that IgE mediated processes contribute to the generation of the eosinophilic inflammation in EGID, and suggest that anti-IgE therapy may be effective in these disorders.
In a recent study of children with EE, AEC correlated with tissue eosinophilia and disease activity, supporting its use as a biomarker of EGID disease activity.16
We thus used AEC as the primary endpoint to measure the impact of anti-IgE therapy on EGID disease activity. Almost all study endpoints improved in association with omalizumab therapy, and thus support the need for a multi-center placebo controlled study to definitively study anti-IgE therapy in EGIDs.
The partial AEC response found in most subjects, suggests that there are both IgE dependent and IgE independent inflammatory pathways operating in EGID.1
The magnitude of AEC decline was variable between subjects, suggesting heterogeneity in disease mechanism (). This is most clearly seen in the 2 subjects who had the largest and the most rapid decline in AEC. This finding is not simply due to more effective IgE blocking in these subjects, as the data from and indicate less effective IgE blocking in these subjects. Conversely, subject 4, who had the lowest IgE, had a dramatic increase in tissue eosinophilia. This suggests that EGID patients with IgE predominant disease may preferentially respond to omalizumab.
Omalizumab decreased both stomach and duodenum tissue eosinophilia, although these results did not achieve statistical significance (). We performed a retrospective power analysis that indicated a minimum of 17 subjects was needed to give a 90% likelihood of detecting the magnitude of tissue eosinophil decrease we noted. This suggests that the lack of significance in our study is likely due to the small sample size (type 2 statistical error). In contrast to the decreases noted in the stomach and duodenum, the number of esophageal eosinophils trended upwards. Despite this increase in eosinophil number, there was not a concomitant increase in esophageal symptoms. Although the mechanistic basis for this finding is unclear, it further underscores the dichotomy between the esophagus and stomach/duodenum as distinct inflammatory sites in EGIDs, with differing epidemiology, pathophysiology and therapeutic response.
We used multiple techniques to verify that IgE and immediate hypersensitivity were effectively blocked (–). However, the level of IgE blockade in our study was substantially less than the 99% decrease in obtained in early phase studies17
, suggesting more potent anti-IgE drugs may have greater efficacy in these disorders. We unexpectedly found increased CD63 expression in the baseline samples18
, which suggests that basophils in EGIDs are constitutively active or have been activated in vivo
. This finding is reminiscent of previous reports in subjects with food allergy19, 20
and chronic urticaria.21
Additionally, omalizumab decreased this constitutive basophil activation. Taken together, these results suggest that constitutive CD63 expression is a consequence of in vivo
activation by allergen, and its decrease with omalizumab therapy reflects a reduction in IgE mediated basophil activation in vivo
This study was open label in which subjects' diets and medications were held constant and the only variable introduced was omalizumab. This uncontrolled design is subject to sources of error, including placebo effect, changes in disease activity, and changes in therapy. Additionally, although no correlation between AEC decrease and aeroallergen season was found, it is possible that some subjects improved due to decreases in pollen allergen levels during the study. Thus, it is not possible to attribute the symptom improvement to the study drug alone. To measure EGID disease symptoms we modified the well accepted Crohn's Disease Activity Index. To our knowledge, this represents the first report of a symptom score to measure EGID disease activity. This scoring system is not validated, thus additional efforts are needed to validate this or similar symptom scores.
EGIDs represent a spectrum of diseases with increasing incidence, which lack safe and effective treatments. Progress in understanding EGID pathogenesis is needed to improve therapy. Our results demonstrate that omalizumab is effective in decreasing peripheral blood eosinophilia in EGIDs, and suggest that IgE mediated processes play a major role in the generation of eosinophilic inflammation in EGIDs. These results suggest that anti-IgE therapy, either alone or in combination with other antagonists, may be an effective treatment for EGIDs.