Cookie Notice

This site uses cookies. By continuing to browse this site, you are agreeing to our use of cookies. Review our cookies information for more details.

skip to main content

Persistent cholinergic urticaria


I have a 15 yo male with the working diagnosis of cholingeric urticaria with uncontrolled symptoms that I would greatly appreciate your help with.

Pt symptoms began a 1.5 years ago. Pt develops lesions on his skin anytime the skin becomes warm after being cool. Lesions are described as smooth, red, and raised bumps of similar size. Pt showed me pictures of 100s of raised red 1-3mm papules on his forearm. They can occur on any part of the body. They are pruritic and painful at times as well. They have not remained in the same location for more than 24 hours. There is not residual bruising at the site of lesions once they resolve. Pt will develop the lesions after walking into a warm room from a cold environment or sitting in a warm room for long periods of time. Pt also develops the lesions after becoming embarrassed/scared or during exercise. or after getting out of cold water to warmer air.

He is currently abstaining from PE at school due to these symptoms. They are significantly interfering with daily activity and have also interfered with sleep. He is no longer playing sports given these lesions. Rarely takes ibuprofen or acetaminophen. He does not develop these symptoms without a notable trigger of heat. Patient has been in good health otherwise with no fevers, chills, night sweats, easy bruising, new fatigue.  No associated respiratory or gastrointestinal symptoms. During an episode, cooling his skin will offer improvement. His identical twin brother experiences similar symptoms which were controlled with omalizumab (Xolair). After symptoms started for this patient attempted treatment cetirizine (Zyrtec) and ranitidine (Zantac) twice daily with mild to no improvement. Then started on omalizumab (Xolair) with good initial response.

Then around 3 months ago started having frequent symptoms again. Was taking cetirizine 10mg twice to three times a day and famotidine 20 mg twice a day and Xolair 300mg monthly. Montelukast 10mg daily was added without any effect. he no longer wants to go outside as the cool air with activity causes the rash. He is not playing any sports anymore. He is rarely seeing his friends as they usually would end up playing sports together.

Derm had placed patient on propranolol for this as well without improvement.
Testing: CRP, ESR, CBC w diff, complete metabolic panel normal.

1. Any doubt this is cholingeric urtcaria? Twin brother was seen by dermatology who agreed with the diagnosis. Twin BTW was diagnosed around age 9 and is still doing well on Xolair.

2. This is having a major QOL impact for the patient. Any suggestions for next line of tx? There's a paper on using Danazol but I'd like to stay away from this if possible.


The description is convincing for cholinergic urticaria, although findings on the arms and symptoms of pain are quite unusual in my experience. However, I would still favor the diagnosis of cholinergic urticaria. The association with an identical twin is very interesting. There are descriptions of autoimmune responses in cholinergic urticaria, both to autologous sweat and possibly to the high affinity IgE receptor (1). Autoimmunity is genetic but I could only find case report of acquagenic urticaria in twins, not cholinergic (2,3).

Treatment of cholinergic urticaria generally focuses on symptom control and avoidance of conditions that stimulate the hives, i.e. heat or core body temperature change. Danazol has been reported to be beneficial and associated with an increase in protease inhibitors that may be decreased in cholinergic urticaria (4). There are insufficient data to advise use of immunomodulators or even dapsone other than cautious therapeutic trial. Omalizumab is approved for physician urticaria, including cholinergic urticaria, in Europe, which is consistent with the clinical response. There are also reports of the standard dose, 150-300 mg/month, being inadequate and higher doses have been utilized with success (5,6). However, among the physical urticarias, omalizumab may be more effective for dermatographia, solar urticaria and cold urticaria compared to cholinergic, vibratory, contact or aquagenic urticaria (7,8). The possibility of a dose response with omalizumab in urticaria, although not physical urticaria per se, is provided by the slightly greater response of 300 mg vs 150 mg in the clinical trials and the potentially greater efficacy of ligelizumab, a monoclonal with a higher affinity for the IgE receptor (9). Making any conclusion about dosing based upon this limited information and comparison across studies is suspect.

I would continue to utilize high dose, second or third generation antihistamine therapy, a dose of 4 times the FDA label. I would try changing antihistamine as occasionally there may be some benefit. I would try to increase the dose of omalizumab to 300 mg every 2-3 weeks SQ, recognizing this is off label but I think is reasonably safe, with published literature showing a greater effect in select physical urticaria subjects with a higher dose. Ligelizumab would be an attractive consideration but is currently in therapeutic trial and not available for compassionate use. To my knowledge, there are not current trial for physical urticaria with ligelizumab. If all of the above is ineffective, I would consider a trial of dapsone (4).

I hope this information is of help to you and your practice.
All my best.
Dennis K. Ledford, MD, FAAAAI, FACAAI

1. Horikawa, Tastuya, Atsushi Fukunaga, and Chikako Nishigori. "New concepts of hive formation in cholinergic urticaria." Current allergy and asthma reports 9.4 (2009): 273-279.

2. Kai, Anneke C., and Carsten Flohr. "Aquagenic urticaria in twins." World Allergy Organization Journal 6 (2013): 2.

3. Seize, M. B., et al. "Familial aquagenic urticaria: report of two cases and literature review." Anais brasileiros de dermatologia 84.5 (2009): 530.

4. WONG, ELIZABETH, et al. "Beneficial effects of danazol on symptoms and laboratory changes in cholinergic urticaria." British Journal of Dermatology 116.4 (1987): 553-556.

5. Metz, Martin, et al. "Anti-immunoglobulin E treatment of patients with recalcitrant physical urticaria." International archives of allergy and immunology 154.2 (2011): 177-180.

6. Metz, Martin, et al. "Omalizumab is effective in cold urticaria—results of a randomized placebo-controlled trial." Journal of Allergy and Clinical Immunology 140.3 (2017): 864-867.

7. Sabroe, R. A. "Failure of omalizumab in cholinergic urticaria." Clinical and Experimental Dermatology: Experimental dermatology 35.4 (2010): e127-e129.

8. Maurer, Marcus, et al. "Omalizumab treatment in patients with chronic inducible urticaria: a systematic review of published evidence." Journal of Allergy and Clinical Immunology 141.2 (2018): 638-649.

9. Maurer, Marcus, et al. "Ligelizumab for chronic spontaneous urticaria." New England Journal of Medicine 381.14 (2019): 1321-1332.