Severe refractory cholinergic urticaria treated with danazol

Journal of Drugs in Dermatology, July-August, 2006 by Mark S. La Shell, Ronald W. England

Abstract

Background: Cholinergic urticaria is a form of physical urticaria triggered by a rise in core body temperature. Antihistamines are the mainstay of treatment; however, adequate symptom control can sometimes be difficult to maintain. Limited data suggest danazol may be an effective alternative in severe, refractory cases.

Methods and Results: We present a case of a 22-year-old male with severe, refractory cholinergic urticaria. Despite treatment with high doses of antihistamines, he continued to have symptoms that impaired his ability to function. Treatment with danazol resulted in a significant improvement in the control of his urticaria.

Discussion: Cholinergic urticaria can sometimes be severe. In cases that fail to respond to traditional forms of treatment, danazol is a viable alternative for the treatment of cholinergic urticaria. Given the potential adverse effects associated with its use, danazol should be reserved for more severe and refractory cases.

Introduction

Cholinergic urticaria is a distinct form of urticaria first described in 1924. (1) It accounts for approximately 30% of all cases of physical urticaria. (2) Otherwise known as generalized heat urticaria, symptoms are precipitated by a rise in core body temperature. While generally not considered life threatening, treatment of cholinergic urticaria may be problematic and patients can experience significant impairment in quality of life. (3) The attenuated androgen danazol has been reported to be an effective means of treatment. (4,5) We present the case of a patient with severe, refractory cholinergic urticaria successfully treated with danazol.

Case Report

A 22-year-old Caucasian male presented with a history of refractory cholinergic urticaria. His symptoms started at 12 years of age when he experienced pruritus and erythema with increased body temperature. He identified exercise, sunlight, hot showers, walking, and anxiety as triggers. His symptoms had been tolerable; however, over the 2 years prior to presentation, his symptoms worsened and he noted the emergence of cholinergic urticaria (Figure 1). Eighteen months prior to presentation, he developed urticaria while working in a warm warehouse; he continued working despite his symptoms and subsequently experienced shortness of breath. His symptoms were relieved after going outside to cool down.

At this point, he sought medical care and was treated with numerous medications over the ensuing months with limited success. At one point, he was taking doxepin 50 mg at bedtime, cyproheptadine 8 mg 3 times a day, cetirizine 10 mg twice a day, montelukast 10 mg once a day, and hydroxyzine 25 to 50 mg every 6 hours as needed. This treatment regimen made his symptoms more tolerable although they did not completely suppress his outbreaks. He was still unable to exercise or exert himself without developing urticaria. He was also experiencing significant sedation, and his symptoms were adversely impacting his job performance. Prior treatment had included 3 10-day bursts of oral corticosteroids, which suppressed his symptoms; however, symptoms returned shortly after completing each burst. His usual means of obtaining additional relief consisted of going outside on a cold day or immersion in cold water, providing symptom resolution within 5 minutes.

His review of systems provided no evidence of etiology. Concurrent with his allergy evaluation, he was evaluated by hematology-oncology and gastroenterology for iron deficiency anemia. This evaluation included 2 normal upper gastrointestinal series with small bowel follow through, normal esophagogastroduodenoscopy, normal colonoscopy as well as normal computed tomography of the chest, abdomen, and pelvis. Bone marrow evaluation demonstrated reduced iron stores and was otherwise negative. His initial complete blood count was significant for a hemoglobin of 11.0 (13.3-17.7 gm/dl), hematocrit 35.2 (39.7-52.1%), and a mean corpuscular volume of 64 (75-100 fL). His iron level was low at 32 (45-182 [micro]g/dl) as was his ferritin level at 6.33 (17-464 ng/ml). His iron binding capacity was elevated at 456 (255-450 [micro]g/dl). Liver panel, electrolyte panel, thyroid stimulating hormone, free T4, thyroglobulin antibody titer, antimicrosomal antibody titer, erythrocyte sedimentation rate, antinuclear antibodies titer, hemoglobin electrophoresis, vitamin [B.sub.12] level, and folate level were all normal. It was concluded that his anemia was due to poor iron absorption and utilization, most likely secondary to an inflammatory state associated with his chronic cholinergic urticaria. His past medical history was otherwise noncontributory.

On allergy examination, the patient was appeared well with no abnormal findings. As the patient continued to have outbreaks despite high-dose antihistamines, an exercise challenge was performed while continuing antihistamine therapy. Small pinpoint erythematous macules and pruritus developed after 3 minutes of exercise. These findings resolved after several minutes and no systemic symptoms were noted. Given the refractory nature of his urticaria, impaired quality of life, and adverse impact on job performance, the option of danazol was considered. By this time his anemia had resolved after treatment with 325 mg of iron twice daily. Following a detailed review of the potential adverse effects associated with danazol, he was started on 200 mg 3 times a day. At follow-up 4 weeks later, he noted significant improvement. He had stopped all of his antihistamines 2 to 3 weeks prior. He was able to run 1.5 miles, do aerobics, and run for 40 minutes on an elliptical treadmill without developing any urticaria, erythema, or pruritus. Noted adverse effects were nausea and vomiting if he took danazol without food, slight loss of appetite, and mild acne. He also noted an increased frequency in his migraine headaches from once a month to twice a week, and these responded well to over-the-counter headache remedies. For him, the benefit of continued treatment out-weighed these adverse effects.