The patient was a 27-year-old man with a history of recurrent episodes of angioedema. The episodes begun when he was 19 years old, and their frequency and severity had been rising over the previous six months. There was a history of urticaria following penicillin administration in early childhood, but there were no other known allergies.\nInitially, the episodes were manifested by mild urticaria which resolved spontaneously. But the severity and frequency of attacks increased over the years. In the last few months, the attacks became more frequent, at least twice a month, and included autonomic dysfunction: one episode of syncope and a few presyncopal episodes associated with scrotal and neck swelling and abdominal pain. Two of the episodes were considered “life threatening” due to imminent airway obstruction and were treated with subcutaneous epinephrine and intravenous steroids, which were tapered down gradually after each episode. Due to the severity of the episodes, the patient was instructed to carry epinephrine 0.3 mg autoinjector (EpiPen) at all times.\nExtensive search for possible etiology was carried out. Ancillary studies were nonproductive. Blood tests included a complete blood count, full chemistry panel, serum levels of thyroid stimulating hormone, antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies, C-1 inhibitor activity, tryptase, and chromogranin. Urinary vanillylmandelic acid and 5-hydroxyindoleacetic acid were also negative, as were urine and stool tests for OVA and parasites. Imaging studies (chest roentgenograms, abdominal ultrasound) did not show evidence of echinococcal infection, and endoscopically obtained biopsies from the GI tract did not show eosinophils or mast cells. Skin biopsy was negative for C-KIT, and bone marrow aspiration showed no evidence of increased mast cell count and was negative for tryptase and C-KIT. While the workup was in progress, the patient was placed on prophylactic antihistamines, using several preparations, but the attacks persisted, and periodically supplemental steroids were necessary.\nThe patient disclosed that from time to time he was using marijuana socially and that it seemed to him that the attacks were less frequent when he did. The patient declared that he did not prepare the cigarette himself, so we presumed he did not have a significant skin contact with cannabis. The history was consistent with the known effect of cannabis on the immune system as described in the introduction, so we conjectured that marijuana may have had a modulatory effect facing failure of other treatment modalities. We suggested that the patient should try medical grade marijuana inhalations (cannabis products for medical indications may be legally used in Israel, but authorization by the Ministry of Health is required for each individual patient and prescription must be renewed monthly). The patient was informed that there was no supporting evidence in the medical literature for this treatment in his condition but that the potential risk for side effects was minimal and he consented to try. He was instructed not to drive or engage in other potentially risky activities during treatment.\nWe prescribe a total of 20 grams of medical grade marijuana per month, inhaled two to three times a week, which in Israel is the minimal accepted dosage for medical indications. The patient stayed on this dose for two years during which the patient did not have a single attack and no adverse effects were observed. After two years, the patient tried to stop treatment, on his own initiative, but developed a recurrent severe attack a week later. After resuming the treatment no further attacks were observed over the next 4 months of close followup (the regulations for legal use of medical marijuana stipulate that the prescription must be renewed monthly). The timeline of the course of the disease is depicted in .
A 47-year-old man had symptoms of weekly recurrent angioedema attacks in lips, tongue, larynx, and scrotum for seven years and experienced swelling of larynx twice weekly in the last 3 months. He had been receiving antihistamines and the symptoms were relapsing during the antihistamine treatment. His signs and symptoms did not improve during administration of different nonsedating H1-antihistamines or increasing of the standard dosage up to fourfold of the daily. Emergency treatment with prednisolone and short acting antihistamines led him to a remission in emergency department visits. Urticaria was absent. Physical examination was unremarkable. He had no other disease and did not receiving drugs such as angiotensin-converting-enzyme inhibitors. Any of the relatives had no angioedema. Laboratory findings included normal values for complete blood count with differential, comprehensive metabolic panel including antinuclear antibody, thyroid stimulating hormone level, C4 level, C1 inhibitor function and level and total immunoglobulin (Ig) E level of 183 kU/L. Also C4 levels were all in normal range during the angioedema attacks. The patient did not attribute his angioedema to certain foods. But the stress is a trigger for him. Fluoksetine and 0.5 mg/kg prednisolon therapy was initiated and clemastine was recommended for the emergency new attacks during corticosteroid therapy. Soon after corticosteroid therapy patient's angioedema regressed. However he felt more depressed after the therapy and the treatment started to be tapered for this side effect. After reducing the corticosteroid dose angioedema attacks again progressed. Because of the patient's angioedema, 300 mg of omalizumab every 4 weeks administered subcutaneously after obtaining written informed consent. His last episode of angioedema was seen 3 days before initiation of therapy. He has tolerated tapering and cessation of his oral steroids and he has remained free of angioedema during 4 months of omalizumab therapy. After 3 months of stopping omalizumab therapy, during the 4-week period he had two mild lip swelling in his lips that resolved with antihistamines.