I have a patient who had single episode of severe angioedema with laryngeal swelling requiring intubation. His c1 inhibitor level is 7. During the attack C4 was 0 and C1q was 3. His previous attack was about 4 months before that one and was mild and resolved on its own. He had steroid injection for radiculopathy 16 hours before the attack. He also has history of prostate cancer treated with brachytherapy, hemolytic anemia, MGUS and antiphospholipid syndrome with possible TIA and is on coumadin. I provided him with Icatibant for treatment of acute attacks. Would you also institute prophylaxis or on demand treatment would be sufficient in this case? And what would be the best choice given his comorbidities and relative contraindications for androgens and anti-fibrinolytics? He rejects an idea of self infusing himself with C1 inhibitor concentrate every 4-5 days.


Thank you for your inquiry.

I will try and answer your specific questions regarding therapy, but first I would call to your attention the probability that your patient has acquired angioedema type 2, and that will clearly affect your options for treatment. The reason for this, as you probably are aware, is his low C1q, the presence of MGUS, and the presence of an antiphospholipid antibody. It is highly probable therefore that your patient has a monoclonal antibody directed against C1 causing consumption that is responsible for his episodes. The findings are suggestive of a lymphoreticular malignancy, perhaps a B cell lymphoma.

The importance of establishing the diagnosis is related to the fact that controlling the underlying process may also control his episodes of angioedema. This is particularly true for lymphoreticular malignancies which are treated with rituximab.

Having said that, I will try and answer the direct questions that you posed.

Whether or not to institute prophylactic therapy in this patient is a matter of clinical judgment. It would be certainly permissible to see if he had an adequate response to icatibant before initiating prophylactic therapy. However, the fact that your patient had such a severe episode makes me favor the initiation of prophylactic therapy.

As you mentioned, there are strong relative contraindications to the administration of androgens, not only because of his prostate carcinoma, but because of his hypercoagulable state. And the hypercoagulable state is also a strong contraindication against the use of epsilon-aminocaproic acid.

This leaves you with C1 inhibitor replacement. I can understand why he would be reluctant to administer this to himself every five days, but I wonder if he might be more accepting if you arranged for a home health service to administer the drug, at least initially. In my opinion, that would be the best choice. Occasionally C1 inhibitor replacement is not effective in patients with acquired angioedema type 2 because of the antibodies against the inhibitor, but in many instances this type of treatment is effective, probably because the epitope to which the autoantibody to the inhibitor is directed is not present on the replacement therapy. Regardless, in my opinion, because of his severe episode, I would make every effort to convince the patient to undergo replacement therapy with C1 inhibitor, and would offer a home health service to administer it. I would be very reluctant to start, because of the contraindications mentioned above, either androgens or epsilon-aminocaproic acid.

You could also look into more sophisticated studies of complement which would allow you to further establish the diagnosis of the acquired form of C1 inhibitor deficiency (although I believe that this diagnosis is correct without further studies) by obtaining an autoantibody to the C1 inhibitor. This test is available at the laboratories of National Jewish Health.

In summary, I think the following is indicated:
1. A further search for lymphoreticular neoplasm. Although clearly acquired angioedema can exist with MGUS alone, it is more commonly associated with an MGUS which has progressed to a lymphoreticular neoplasm.

2. If one does find a treatable lymphoreticular neoplasm, the treatment of this condition can cause remission in the angioedema, thus alleviating you from having to make the difficult clinical choices discussed above.

3. You should consider obtaining a C1 inhibitor autoantibody as mentioned above.

4. Although the use of prophylactic therapy is one based on clinical judgment and can be debated, in my opinion, because of the severity of his episode, I would begin prophylactic therapy, and the method of choice in this case, in my opinion, would be C1 inhibitor replacement treatment. This is clearly because of the contraindications mentioned above to the use of androgens or epsilon-aminocaproic acid.

5. The choice of icatibant is of course excellent and should be effective in dealing with acute attacks. However, because of his attack that required intubation, as mentioned, I would add prophylactic therapy to the regimen.

Finally, one of the references copied below (A Focused Parameter Update) contains a succinct review of acquired C1 inhibitor deficiency and the therapeutic options.

Thank you again for your inquiry and we hope this response is helpful to you.

Long-term prophylaxis with C1-inhibitor (C1 INH) concentrate in patients with recurrent angioedema caused by hereditary and acquired C1-inhibitor deficiency Konrad Bork, MD, Witzke PhD Journal of Allergy and Clinical Immunol, 1989, Pages 677¨C682.

Journal of Allergy and Clinical Immunolarch 1989, Pages 677¨C682.
Prevalence of monoclonal gammopathy in patients presenting with acquired angioedema type 2

The American Journal of Medicine
Volume 113, Issue 3, 15 August 2002, Pages 194¨C199.

J Clin Invest. 1989 June; 83(6): 1794¨C1799.
doi: 10.1172/JCI114084

PMCID: PMC303898 Acquired C1 inhibitor (C1-INH) deficiency type II. Replacement therapy with C1-INH and analysis of patients' C1-INH and anti-C1-INH autoantibodies.
Acquired angioedema: a new target for rituximab?

Haematologica 2004; 89:(8)e104-e105
doi: 10.3324/haematol.10769 haematol May 1, 2007 vol. 92 no. 5 716-718.

The Journal of Allergy and Clinical Immunology
Volume 131, Issue 6, Pages 1491-1493.e25, June 2013
A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor¨Cassociated angioedema.

Phil Lieberman, M.D.

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