Q:

12/7/2011 
40 year old wife of a physician. A month ago, she started having urticaria, then subsequently angioedema. Urticaria is resolved or controlled. She was on Allegra in the morning and Benadryl 50 mg at night. Pepcid was started but stopped immediately after ent told her to stop antihistamines and ended up in the ER where she was given a medrol dose pack, allegra, benadryl. I first saw her last week.

 

Tried her on zyrtec 6 times a day, hydrozyzine 75 mg at night on top of the medrol dose pack, but still had episodes of angioedema of her tongue, throat and lips. I switched her to doxepin 50 mg at night and continued zyrtec. The zyrtec seems to help some and keeps it at bay sometimes for 5 hours, sometime only 3 hours. Continues to happen at night and more mildly during the day since being on medication. She has 2 children to take care of.

 

I was going to have her start doxepin in the morning too and go to 75 mg at night, but given everything, I am not sure it will control this. Also considering a higher dose of steroids and adding on zantac, though I don't think it will work. C3 and C4 were normal, though C1 esterase and C1q are pending (I know in the very beginning she had hives which would be unusual). The last thing is she gets a very salty taste in her mouth approximately 3 hours after using the zyrtec, I don't know why.

 

Can you give me any advice as to what you would do? She has seen an oncologist and a laryngologist (to visualize her throat). Would you consider xolair (I had patients who had primarily urticaria but some angioedema respond to this) I didn't use it yet, because I was concerned it would make things worse. Singulair? Was concerned if another drug would make things worse. Also what do you think about using Zytrec 20 mg?

A:

Thank you for your inquiry.

We have had a reasonably large number of questions through the years about patients with recalcitrant, difficult to treat angioedema. It is a problem that all allergists see, usually on multiple occasions, in their career. Unfortunately, it is a problem without an "easy answer."

In the majority of cases of angioedema, as you know, antihistamine therapy is usually ineffective. Angioedema, unlike urticaria, appears to have mediators, other than histamine, responsible for its pathogenesis. So it is not unusual that patients fail antihistamine therapy.

When antihistamine therapy fails, a number of alternative treatments have been suggested. There was a recent inquiry to our site regarding such therapies that was submitted and answered. It was posted on 11/7/2011. For your convenience, I have copied the inquiry as well as our response below.

This response would also apply to your patient.

The two Morgan and Kahn references deal with urticaria, but each alternative therapy can be employed for angioedema as well. And more recently, the use of agents specifically designed for C1 inhibitor deficiency syndromes has come into play. Clearly the contact system with generation of bradykinin has been responsible for other causes of angioedema (in addition to C1 inhibitor deficiency syndromes). Therefore there is reason to believe that these drugs might help in idiopathic angioedema as well.

Thus there are a number of alternative therapies that have been reported effective outlined in the Morgan and Kahn articles, and you also have the drugs more recently employed to treat C1 inhibitor deficiency syndromes.

The question becomes as to when to employ them. Although, unlike urticaria, there has been no "official"distinction between chronic and acute angioedema, I would normally reserve alternative therapies for patients who have experienced recalcitrant angioedema for at least six to eight weeks. During that time, I would make attempts to control the condition with as low a dose of corticosteroids as possible. If they have failed at the end of six to eight weeks, then I would consider the alternative therapies. Unfortunately since there has been no controlled trials comparing their efficacy, one simply makes a choice based upon an assessment of side effects, patient preference, et cetera.

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

Recalcitrant, recurrent angioedema
Question:
11/7/2011
I have a 28 year old man who has idiopathic angioedema and despite regular medication use has been experiencing episodes of angioedema weekly requiring oral steroids and I am wondering what other treatments may be used. He started having episodes of angioedema in 10/2010. His symptoms initially started with lip swelling and since then has had tongue, hand, feet, cheek and other skin swelling. He has never had difficulty breathing, abdominal pain, or other severe symptoms. He has no prior episodes of angioedema and no family members with angioedema. He has no hives. When his symptoms started, he was on no medications and there was no association with NSAID use and no problem with trauma, pressure, vibration. He was started on zyrtec initially and medications have been titrated over the past few months. Currently he is on zyrtec 10 mg bid, ranitidine 150 mg bid, and singulair 10 mg daily. I just started him on atarax 25 mg at night, but am wondering what else to do to try to decrease or prevent steroid use. He will use prednisone 40 mg once at onset of swelling which typically resolves his symptoms, but at times may need to do a taper to prevent recurrent swelling.

In terms of work up: Bloodwork showed normal C4, total IgE elevated at 169, and SPEP with decreased alpha globulin and remaining bloodwork was normal CBC, sed rate, TSH thyroid antibodies, comprehensive panel, immunoglobulins, and ANA negative. Due to recurrent episodes, I repeated C4 level again normal 43 with C1 esterase inhibitor level normal at 32, and functional level normal at 91%.

Is there other work up that should be done? Also is there other medications/treatments that should be used? In reviewing prior questions, it seems there may not be much option in terms of other treatments, but I did see the mention of plaquenil and wonder if others have used this with idiopathic angioedema without urticaria. Thank you!

Answer:
Thank you for your recent inquiry.

I think anyone who has practiced allergy can empathize with your attempts to manage your patient's angioedema. Recalcitrant cases such as this are not uncommon, and represent difficult therapeutic problems which in most instances have no specific answer.

We have a number of different postings on our Academy "Ask the Expert" website that deal with this issue. For your convenience, I have copied below one of the most recent of these. As you can see, it does mention alternative therapies. Unfortunately, there have been no true, placebo-controlled trials of these therapies, and therefore they are used entirely empirically.

There is more abundant literature about alternative therapies for urticaria, and although clearly urticaria (even with angioedema) may have an entirely separate pathogenesis than angioedema alone, the same alternative therapies have been used in individual cases of angioedema with, on some occasions, anecdotal reports of success.

A very comprehensive review of these therapies (in two parts) has been published (1, 2).

I think a review of this would help you choose a potential alternative therapy that you could employ, again on a purely empiric basis should you wish to do so.

Finally, although the use of anti-kinin agents such as ecallantide and icatabant are approved for use only in hereditary angioedema there have also been anecdotal claims of their efficacy in idiopathic angioedema.

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

Question/Answer previous submitted to "Ask the Expert" website:

Question: 44 year-old black female with a 4-year h/o severe facial angioedema (lips, tongue, throat). Episodes occur weekly and last several days. Unresponsive to high doses of sedating and nonsedating antihistamine, asa well as Dapsone. She has been on Enbrel, Plaquenil, and MTX for RA. Previous prolonged usage of oral steroids. These medicines have also not helped the angioedema. C-1 esterase inhibitor total and functional levels nl X 2. No obvious relationship to estrogen. Seen at Mayo Clinic. They recommended atenuated androgens and/or ecallantide. My main question is how to treat her. Are there advantages/disadvantages with Danazol vs. Stanozol. Can ecallantide and or C-1 inhibitor (Cinryze/Berinert) be approved off-label? Other considerations/options?

Answer: Thank you for your recent inquiry.

In answer to your specific questions:
1. Danazol would be the preferred attenuated androgen because it has less tendency to masculinize.
2. There is no way to tell as to whether or not either ecallantide or C1 inhibitor would be approved for off-label use than to set the process in motion for approval.
3. I believe you have, with the previous therapies and the proposed therapies mentioned, exhausted all reasonable therapeutic strategies. However, there are certainly alternative drugs that have been employed in patients with urticaria and angioedema that you could consider. These would be tacrolimus or cyclosporin, and mycophenolate mofetil. Normally they are used for patients with urticaria and angioedema, but in view of the recalcitrant nature of your patient’s angioedema, they could certainly be considered in your case as well.

We have several entries at the Ask the Expert website regarding the use of these two agents in recalcitrant cases of urticaria and angioedema. A recent one regarding the dosage of mycophenolate mofetil, and there are at least two others regarding the use of tacrolimus. You can access them on the Academy’s Ask the Expert website by entering the names of the two drugs (separately) in the search box.
Thank you again for your inquiry and we hope this response is helpful to you.

Sincerely,
Phil Lieberman, M.D.

References:
1. Morgan M, Khan DA. Therapeutic alternatives for chronic urticaria: an evidence- based review, part 1. Ann Allergy Asthma Immunol. 2008;100:403–411.

2. Morgan M, Khan DA. Therapeutic alternatives for chronic urticaria: an evidence- based review, part 2. Ann Allergy Asthma Immunol. 2008;100:517–526

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology