Cholinergic urticaria is typically characterized by intense pruritus and pin-sized wheals surrounded by erythema. Symptoms are provoked by an increase in body core temperature induced by passive warming (e.g. hot bath), physical exercise and/or emotional stress. Although most patients with cholinergic urticaria present only mild to moderate reactions, the symptoms can be severe with massive pruritus and wheal and flare reactions covering the whole body, sometimes with concomitant systemic reactions (1). An additional problem in these severe cases of cholinergic urticaria is that conventional antihistamine treatment is often unsuccessful.
We present the case of a 25-year-old caucasian male with severe cholinergic urticaria who experienced unbearable pruritus and wheals, occasionally associated with dizziness and cardiac palpitations, induced by even mildly elevated outside temperatures, hot beverages, minimal physical exercise (e.g. by carrying grocery bags or walking stairs), and by emotional stress such as driving a car in heavy traffic or giving presentations in front of an audience. The patient was diagnosed with cholinergic urticaria 5 years ago and had been treated since then with various sedating and nonsedating antihistamines, disodium cromoglycate, ketotifen, leukotriene receptor antagonist, corticosteroids (up to 60 mg/day), dapsone, danazol, doxepin, beta-blocker, photochemotherapy (PUVA) as well as various diets, none of which resulted in a significant reduction in symptoms.
At the time the patient presented himself in our department, his medication consisted of a combination of desloratadine (3 × 5 mg), levocetirizine (2 × 5 mg), hydroxyzine (1 × 25 mg), montelukast (1 × 10 mg), ketotifen (2 × 1 mg), and propranolol (2 × 40 mg). Even under this medication, the patient was severely impaired in his every day life and we were able to provoke cholinergic urticaria symptoms (pruritus, wheal, and flare) in the patient by moderate physical exercise at room temperature. The patient also suffers from seasonal allergic rhinoconjunctivitis but is otherwise healthy.
The pathogenesis of cholinergic urticaria is still poorly understood. It is generally assumed that an increase in body temperature in cholinergic urticaria patients results in the upregulation of one or more mast cell secretagogues and thereby mast cell degranulation in the skin, which subsequently induces vasodilation, extravasation, and erythema (2). Passive transfer experiments from human to monkey indicate that a serum factor may exist in some patients with cholinergic urticaria (3). Thus, as of yet, the mast cell activating mechanisms and signals remain largely unclear.
Omalizumab is a recombinant humanized monoclonal antibody against immunoglobulin E (IgE). It acts by binding free IgE at the same site that IgE would bind to its high-affinity receptor (FcɛRI) on mast cells, thereby reducing free IgE in the serum (4). Moreover, as a result of depleting free IgE, omalizumab strongly downregulates the expression of FcɛRI on mast cells (5). Recently, successful treatment of a patient with cold urticaria (6) and three patients with chronic urticaria (7) with omalizumab has been reported. Because of these positive reports, and because none of the previous treatment strategies had resulted in an improvement of cholinergic urticaria in our patient, we began to treat our patient with omalizumab (with 300 mg every 2 weeks). To our surprise, our patient reported back to us after the second injection (i.e., in week 3 after start of treatment), with a significant improvement of his symptoms (Fig. 1). Also, he had reduced his concomitant medication to desloratadine 3 × daily and propranolol once daily. His condition continued to improve and in week 5 after the start of omalizumab our patient reported to not have experienced any symptoms for an entire week [(his) best week during the past 5 years]. We performed physical exercise provocation tests in weeks 10 and 20 of treatment with omalizumab, which were completely negative, even under maximal physical strain. In week 11, the patient stopped all concomitant medication. Today, the patient has been free of any symptoms for 22 weeks and he is able to resume all activities, including hot baths and extensive workouts.
This is, to our knowledge, the first report of a successful treatment of cholinergic urticaria with omalizumab. The observed rapid improvement in the symptoms during anti-IgE therapy supports the hypothesis that cholinergic urticaria might be mediated by IgE and gives rise to the speculation that IgE might constitute the serum factor found by serum transfer studies in some patients with cholinergic urticaria (3). Further clinical trials should investigate whether anti-IgE treatment is in general beneficial for patients with cholinergic urticaria; these future investigations might also help to understand the pathogenetic mechanism of the disease. This case shows that cholinergic urticaria can be rapidly and successfully treated with omalizumab at the recommended dosage without side-effects.
We thank Nikki Rooks for excellent technical assistance and Jodie Urcioli for proofreading the manuscript.