QOTW – “Is there any benefit from Xolair use in HAE?”

Oct 12, 2015

Dr. C:We would like to thank Sally Urbaniak from the HAEA patient services team for forwarding this question. There have evidently been online discussions regarding the use of Xolair for treatment of HAE. I am not aware of any study that would indicate that Xolair is of therapeutic benefit for HAE Type I, II or HAE with normal C1 inhibitor. Xolair (omalizumab) is an anti IgE monoclonal antibody which lowers the level of IgE (the ‘allergic antibody’) and indirectly the receptor or ‘docking site’ for IgE on mast cells. It has been successful in treating chronic urticaria which is mast cell mediated. We know that bradykinin is the mediator of swelling in type I & II HAE. Bruce, any thoughts about the relationship between bradykinin-mediated angioedema and response to Xolair?

Dr. Z:While there is evidence that mast cell release (that is, allergic reactions) may activate the kallikrein-kininsystem and generate bradykinin, there is no evidence that HAE secondarily activates mast cells or involves IgE. More than 30 years ago, some studies suggested that high levels of bradykinin could activate mast cells, however these studies have not been confirmed and there is a lot of clinical evidence that HAE due to C1 inhibitor deficiency does not involve mast cells.

Dr. C:As usual, the picture is less clear when we deal with HAE with normal C1INH. There is mounting evidence that HAE with normal C1 inhibitor is also mediated by bradykinin. We could postulate that a beneficial response to Xolair in some patients may actually indicate a ‘misdiagnosis’ of HAE with normal C1 inhibitor in individuals where the mast cell is still the culprit. In these circumstances “idiopathic angioedema” would be the more appropriate category. It is also possible that some patients with recurrent swelling given a diagnosis of HAE with normal C1 inhibitor could have a blended response to both bradykinin and mast cell mediators. There are some very confusing patients with partial responses to drugs that affect both pathways. This being said I do not think that given the state of our knowledge at the present time that it would be appropriate to categorize these patients as having HAE. Bruce—I know that this sounds confusing, any thoughts here?

Dr. Z:This is an area where the lack of a diagnostic test to establish a definite diagnosis of HAE-nl-C1 inhibitor clearly muddies the water.

Dr. C:There was one report entitled “Positive response to omalizumab in patients with acquire did iopathic non histaminergic angioedema” published in the Annals of Allergy Asthma and Immunology this year where patients did favorably respond to Xolair (omalizumab). The patients did not respond to high dose antihistamines however promptly improved with corticosteroids. This would indicate that the swelling was still involving the mast cell and not the kinin generating pathways important in HAE. In other words–again more likely idiopathic angioedema.

Dr. Z:I think that it’s important to recognize that mast cells release many mediators in addition to histamine, so the failure of antihistamines to control the swelling does not definitively exclude a mast cell basis for the swelling. The fact that the patient responded to corticosteroids is clearly different than what we see in any form of HAE and points to a possible mast cell basis for the swelling.

Dr. C:Thank you, Bruce. We hope that continued careful gathering of information and analysis will lead to more refined answers in the future. We look forward to our next ‘Question of the Week’.

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