IgE‐mediated hypersensitivity reaction and desensitization to glatiramer acetate in a pediatric patient

To the Editor: Glatiramer acetate (Copaxone) is a polymer of four amino acids, and it closely resembles myelin basic protein. It is widely used as a disease-modifying agent with established efficacy in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS) (1). Glatiramer acetate is usually dosed as a 1 ml subcutaneous daily injection. Immediate cutaneous reactions at the site of injection are very common, occurring in up to 60% of patients, often presenting as erythema, edema, and pruritus (2). These reactions are thought to be due to direct mast cell activation at the site of injection causing the release of histamine and other mediators. Other reactions localized to the skin have also been described and thought to be caused by either direct drug toxicity (skin necrosis, lobular panniculitis) or immunomodulation (erythema nodosum, urticarial vasculitis) (3). About 10% of patients are reported to experience an immediate postinjection systemic reaction (IPISR) characterized by flushing, chest pain, anxiety, subjective sensation of dyspnea, and throat constriction. Most of these reactions resolve spontaneously within several minutes (2); however, few of them require immediate medical treatment. Systemic reactions to glatiramer acetate usually result in discontinuation of this effective treatment option with an otherwise relatively benign side effect profile. This can be detrimental, especially for those patients who may not be candidates for other treatments. Some of these reactions may represent IgE-mediated anaphylaxis (4), while others may be due to alternative immunologic mechanisms (2, 5, 6). Reliable testing for evaluation of IgE-mediated reaction has not been established. Furthermore, there are no reports of glatiramer acetate allergy or desensitization in the pediatric population. We report the first case of severe, IgE-mediated reaction followed by successful desensitization to glatiramer acetate in a pediatric patient using novel skin test and desensitization protocols. A 14-year-old adolescent female was referred to our allergy clinic for evaluation of hypersensitivity to glatiramer acetate. The patient had been diagnosed with MS at 11 yr of age, following an episode of severe bilateral optic neuritis, leftsided weakness and ataxia. She was initially treated with intravenous and oral corticosteroids, intravenous immunoglobulin infusions, and plasma exchange. The patient was then transitioned to subcutaneous glatiramer acetate (20 mg daily) for long-term disease control. She experienced pain, itching, mild swelling, and erythema at the injection sites after each dose. She also developed dizziness, shortness of breath, and a sensation of her heart racing for up to 60 min following glatiramer acetate administration. However, symptoms seemed to decrease with continued use and were felt to be consistent with non-specific, immediate reactions reported to occur in association with glatiramer acetate administration (2). Approximately 18 months into her treatment course of daily injections, the patient suddenly developed severe shortness of breath, dizziness with shivering, and tachycardia immediately after the injection of glatiramer acetate. She appeared flushed, diaphoretic with perioral cyanosis and experienced brief loss of consciousness. Emergency personnel were alerted, but by the time of their arrival the symptoms subsided and no treatment was needed. Tryptase level was not measured at the time of the reaction. The severity of this reaction prompted the discontinuation of glatiramer acetate injections and the patient was then started on an alternative disease-modifying agent, namely Interferon beta. However, she soon developed significant liver toxicity from this latter treatment leading to its discontinuation. The patient was then referred to our clinic for further evaluation and possible reintroduction of glatiramer acetate. Apart from MS, the patient had well-controlled mild intermittent asthma and allergic rhinitis with positive skin prick test reactions to dust mite, cat, ash tree, and ragweed. She had no known allergies to other medications or to foods. As glatiramer acetate solution contains 20 mg/ml of active ingredient and 40 mg/ml of mannitol, the patient underwent skin testing to both ingredients (Table 1). Skin prick testing was negative to both glatiramer acetate and mannitol. Intradermal testing to glatiramer acetate resulted in a 7 mm wheal and 20 mm flare at the concentration of 0.0002 mg/ml which was the maximum non-irritating concentration in a control subject. The patient had a negative intradermal reaction to mannitol at the concentration of 0.0004 mg/ml which also was the maximum non-irritating concentration in a control subject. Based on these results and the patient’s history, the presence of an IgE-mediated allergy to glatiramer acetate was deemed likely. As there were no alternative MS treatments available that were felt to provide a favorable risk-benefit profile for her, she was admitted to the step-down ICU unit in order to undergo desensitization to glatiramer acetate. A subcutaneous