Urticaria and cyclosporine

NONALLERGIC URTICARIA (NAU), previously called chronic urticaria (1), is considered idiopathic in most cases. An autoimmune basis has been confirmed by several authors as a result of anti-FceRIa or anti-IgE autoantibodies in 25–45% of NAU cases (2). Routine management of NAU includes antihistamines, doxepin and systemic corticosteroids. Leukotriene antagonists, plasmapheresis, intravenous immunoglobulin and cyclosporin have been used in severe cases that are recalcitrant to the above measures, with variable results (2). We studied a 62-year-old woman who had seven or eight recurrent episodes of generalized hives and angioedema on her face and hands during the previous two months. These episodes were controlled by systemic corticosteroids in 24–48 h. The first episode occurred after taking Aspirin 500 mg. She tolerated acetaminophen 650 mg. Physical examination showedurticarial lesionsonly on her legs. Laboratory investigations were normal, except for cholesterol 287 mg/dl (normal 140–240 mg/dl), TSH 8.83 mU/ ml (0.27–4.2), and antiperoxidase antibodies 336 U/ml (,35). Free T4 and antithyroglobulin antibodies were normal. Total IgE was ,2 kU/l. Specific IgE to Echinococcus granulosus, Anisakis simplex and latex was negative. Prick tests with common commercial foods, Anisakis and latex extracts were negative. Placebocontrolled oral challenge tests with nonsteroidal anti-inflammatory drugs (NSAIDs) were carried out in a singleblind fashion (after withdrawal of antihistamines and corticosteroids). The patient tolerated clonixin (Dolalgial), but 18 h after taking acetaminophen 1 g developed a generalized urticaria and facial angioedema. The patient was diagnosed from NAU with nonallergic NSAID hypersensitivity and subclinical hypothyroidism. Despite treatment with cetirizine 40 mg/ day and deflazacort 7.5–45 mg/day during the following 8 months, the patient was symptomatic almost daily. Skin biopsy showed edematous dermis with mild perivascular mononuclear cell infiltration, compatible with chronic urticaria. An intradermal test with autologous serum (3) showed a positive immediate reaction (histamine 534 mmofwheal after 30 min, saline solution 0 mm and autologous serum332 mm)without late response.We started a second treatment which included avoidance of additives and salicylates, doxepin 25 mg/8 h, zafirlukast 20 mg/ 12 h, deflazacort 45 mg/24 hand cetirizine 10 mg/6 h. After 1 month with no response to treatment, cyclosporin (Sandimmun Neoral) 3.2 mg/kg/day was given (in two equal doses); doxepin and zafirlukast were withdrawn. After 10 days of treatment the patient became asymptomatic, deflazacort was decreased to 7.5 mg/day and cetirizine was withdrawn.After 1 month deflazacortwas withdrawn and the cyclosporin dose was decreased 0.8 mg/kg/day every 15 days. Cyclosporin was withdrawn 3 after months. We detected only a mild increase in alkaline phosphatase (312 UI/l; normal 90–280 UI/l). Blood pressure was increased (180/105 mmHg) during cyclosporin treatment, but was controlled with nifedipine 2.5 mg/12 h. Alkaline phosphatase and blood pressure normalized after cyclosporin withdrawal and nifedipine was stopped. After 15 days without cyclosporin, acetaminophen 1300 mg/day was tolerated. A new intradermal test with autologous serum (venous blood was taken that day from an asymptomatic patient) was unequivocally negative. After 4 months without treatment the patient continued to be asymptomatic and tolerated single blind oral challenge with mefenamic acid 500 mg, nimesulide 200 mg and Aspirin 875 mg. Low-dose cyclosporin (2–6 mg/kg/day) has been found to be effective in treatment of NAU with full remission or important improvement in about 75% of patients (4–7). Positive or negative autologous serum skin tests correlated neither with disease activity nor predicted response to cyclosporin treatment (6). The most effective dose is 3 mg/kg/day (given as two doses) for 6 weeks, followed by 3 weeks at 2 mg/kg/day, then 3 weeks at 1 mg/kg/ day; then it is discontinued (6). Side effects at thatdoseof cyclosporinare commonbut not severe enough for withdrawal; they include tremor, agitation, sleeplessness, nausea, paraesthesia, gastrointestinal upset, headache, and hypertrichosis. Side effects resolve after treatment cessation or reduction (6,7). Frequent side effects are seen with cyclosporin doses higher than 5 mg/kg/day; most important are nephrotoxicity, hypertension, increased risk of malignancy, and rise in serum bilirubin and liver enzyme levels. Therefore serum creatinine and urea, liver function and blood pressure must be monitored. The exact mode of action of cyclosporin on urticaria is still unknown, although it could involve direct inhibition of mast-cell degranulation, and inhibition of immunoglobulin production in activated B cells. Accordingly, cyclosporin can lower levels of both IgG anti-IgE or anti-FceRIa autoantibodies (5–7). We conclude that low-dose cyclosporin (approximately 3 mg/kg/day) is effective and safe in patients with autoimmune or NAU whose response to conventional treatment is unsatisfactory, even with associated nonallergic NSAID hypersensitivity. Blood pressure and renal and liver functions must be monitored.