Lucia Anna Giliberti

Desensitization for immediate hypersensitivity to oral dimethyl fumarate (Tecfidera)

Dimethyl fumarate (DMF) is one of the new oral drugs available for the treatment of multiple sclerosis (MS). The exact mechanism of action of DMF is still under investigation and seems to involve the modulation of the immune response, the interference with the intracellular redox balance, and, possibly, also an important effect on mitochondria. Recent studies showed a significant clinical impact of DMF on disability progression in patients affected by relapsing-remitting MS, with an overall favorable safety profile. These encouraging results warranted its rapid regulatory approval, first by the US Food and Drug Administration, in 2013, and successively by the European Medicines Agency, in 2014. However, DMF was associated with the appearance of adverse events, particularly gastrointestinal symptoms (nausea, vomiting, abdominal pain) and flushing, which occurred in 30% and 40% of patients, respectively. In the vastmajority of cases, these symptoms subsided within the first 2 to 3 months. Thereafter, less than 5% of the patients treated with DMF still reported such complaints. Also, DMF has been known as a skin irritant and delayed-type contact dermatitis sensitizer (used as a mold growth inhibitor in footwear, clothing, and furniture manufacturing). Moreover, a case of immediate-type contact urticaria was described in a woman wearing DMF-treated trousers. Although DMF has been used as an oral drug since 2013, to our knowledge, no immediate hypersensitivity reactions associated with its administration have been reported, so far. Here, we describe a case of a woman with MS, treated with oral DMF, who complained about immediate hypersensitivity symptoms and was successfully desensitized. A 57-year-old woman, affected by relapsing-remitting MS, had been treated since 2010 with IFN-b-1a, which was discontinued because of unsustainable side effects. In May 2016, the patient commenced an oral treatment course with DMF (240 mg daily). One month after the beginning of treatment, the DMF dose was increased to 240 mg twice a day, as recommended. Two days later, the patient experienced an immediate drug-related hypersensitivity skin reaction, characterized by rapid onset of urticaria with confluent wheels and itching within minutes from drug intake. The lesions were widespread, with prevalence on the lower limbs and the trunk, and disappeared within a few hours, after low-dose antihistamines. After a 7-day washout, the patient resumed taking DMF (240 mg daily). Also, in this case, an immediate generalized urticarial reaction occurred within a few minutes, suggesting a causative role for DMF. The immediate nature of the reaction was confirmed by a lymphocyte proliferation test (LPT), which proved negative. The LPT was carried out by exposing the patient’s lymphocytes to 3 different DMF concentrations: 7 mg/mL, the “therapeutic concentration,” calculated on a distribution volume of 70 L (published distribution volume 1⁄4 53-73 L), 0.70 mg/mL, and 70 mg/mL. Lymphocyte proliferation was assessed by bromodeoxyuridine incorporation. Moreover, skin prick tests were performed with a concentration of 7 mg/mL DMF; the intradermal tests were also performed with 0.7 mg/mL and 0.07 mg/mL DMF. The results of both tests proved negative. Thus, the mechanisms underlying the pathogenesis of these immediate hypersensitivity reactions (ie, IgE-mediated/noneIgE-mediated) remain uncertain. Therefore, the diagnosis was based essentially on the clinical features of the case (time of onset, morphology of the lesions, rapid response to antihistamines). Considering the good clinical response to DMF, we decided to desensitize the patient. To this purpose, we used and adapted a desensitization protocol published by Castells el al. The doseescalating scheme is reported in Table I. On the first day, gradually increasing doses of DMF, given at 30-minute intervals, were tolerated up to dose 7, when the patient experienced a transient local urticarial reaction at the lower right limb. Therefore, we decided to continue the desensitization under prophylactic administration of antihistamines (ebastine, 10 mg twice a day). On the second day, the patient was able to receive all the escalating doses of DMF, with only dose 9 followed by local transient reaction after 30 minutes. The patient developed similar local urticarial reactions for the following 4 days, after dose 9. Afterward, no more reactions were observed. Therefore, the antihistamine prophylaxis was discontinued from day 7. At day 31, the dose of DMF was increased to 240 mg twice a day. Thus, the desensitization scheme was maintained doubling each individual dose (Table I). Also, in this case the drug was well tolerated, without need for antihistamines. From day 40 on, the schedule was further simplified (Table I). Oral DMF was introduced in the clinical practice for the treatment of MS only recently. In spite of the abundant literature on delayed hypersensitivity to DMF, to our knowledge, this is the first hypersensitivity reaction case described for oral DMF, given therapeutically. In addition, a desensitization protocol has never been reported, so far. The number of reactions during the desensitization procedures that we propose was fairly low and their severity mild, comparable to what has previously been reported for other drug desensitization protocols. Notably, in our case, the mild reactions observed subsided with low-dose antihistamines. Neither oral steroids nor adrenalin was needed. In conclusion, this case shows (1) that DMF can be responsible for immediate hypersensitivity drug reactions, even if taken orally. Given the increase in the use of this drug for MS,

A desensitization protocol for delayed allergy to cytarabine: analysis of two cases

The chemotherapeutic agent cytarabine represents an effective treatment for acute myeloid leukemia and lymphomas. Cytarabine is a pyrimidine nucleoside that induces DNA damage in the S phase of the cell cycle. Moreover, cytarabine inhibits DNA and RNA polymerases as well as nucleotide reductase. Thereby, rapidly cycling cells are the most affected. Due to its strong biological effects on a variety of cells and tissues, important adverse reactions might occur during treatment with cytarabine, such as myelosuppression, gastrointestinal disorders, neurotoxicity, hepatitis and an immediate infusion reaction, known as “cytarabine syndrome”. This latter clinical entity is dose-dependent and includes fever, diaphoresis, myalgia and skin eruptions [1]. Although cases of hypersensitivity reactions to chemotherapeutic agents have been observed, allergy to cytarabine is uncommon and only sporadic reports exist [2]. Particularly, no delayed hypersensitivity reactions have been described in adults, so far. Here, we report 2 cases of adult patients with delayed hypersensitivity to cytarabine that resolved successfully after desensitization. Case 1: A 66-year-old woman was diagnosed with acute myeloid leukemia in March 2012 and started a cytarabine treatment (160 mg/day, for 3 days), with no adverse effects. Likewise, in April and May 2012, two further cytarabine courses were well tolerated. However, in June 2012, she developed a severe cutaneous rash with intensively itchy and partially eroded erythematous maculae, widespread to the trunk and the extremities, 3 days after the treatment (Figure 1 A). Of note, the patient presented a marked eosinophilia (4730 cells/μl) and developed a sterile dental abscess after the cytarabine administration course, in the absence of any dental diseases prior to the therapy. In order to exclude a possible cytarabine syndrome, a second cycle of treatment with reduced dosage was performed (80 mg/day, for 3 days). However, the patient developed the same symptoms, with similar time of onset as above (including the same sterile dental abscess), suggesting that the adverse reaction was immunologic in nature and delayed in presentation. After 15 days, we performed skin tests, with two distinct techniques: skin prick testing and intradermal testing. The patient was first subjected to skin prick testing, using a 20 mg/ml cytarabine solution and, successively, to intradermal tests with 4 different 10-fold concentrations (0.02, 0.2, 2 and 20 mg/ml). Both skin testing procedures proved negative. Neither patch tests (the patient declined) nor any in vitro tests were performed. Lymphocyte proliferation test (LPT) was not yet established. Thus, based on the clinical symptoms, the time of onset of the adverse reaction, the lack of dependency on the dose administered and the negative results of the skin tests, the patient was diagnosed with delayed hypersensitivity to cytarabine (clinically). Importantly, the eosinophilia at the time of diagnosis and the finding of the recurrent sterile dental abscess concomitant with cytarabine treatment rendered the adverse reaction compatible with a possible drug reaction with eosinophilia and systemic symptom (DRESS), according to RegiSCAR scoring system [3]. Case 2: A 69-year-old man, also diagnosed with acute myeloid leukemia, started a cytarabine treatment course in December 2015 with no adverse effects. Likewise, in January 2016, a second cytarabine course was well tol-

Delayed allergy to acyclovir revealed by the lymphocyte proliferation test

Address for correspondence: Dr. Marcello Albanesi, Department of Emergency and Organ Transplantation, Section of Allergology and Clinical Immunology, University of Bari-Aldo Moro, Piazza Giulio Cesare, Policlinico, 70124 Bari, Italy, phone: +39 080 5478817, fax: +39 080 5593576, e-mail: marcello.albanesi@uniba.it Received: 9.05.2017, accepted: 23.08.2017. Delayed allergy to acyclovir revealed by lymphocyte proliferation test

Fennel (Foeniculum vulgare) allergy.

Background: The association between the development of childhood allergic diseases and consumption of certain foods had been reported. However, the relationship between adult-onset asthma and consumption of certain foods had never been assessed. Method: This study was conducted using two nationwide stratified random sampled surveys; the eighth Korea Youth Risk Behavior Web-based Survey (KYRBWS), 2012 and the fifth Korean National Health and Nutrition Survey (KNHANES V), 2011. KYRBWS was a nationwide crosssectional survey of Korean middleand high-school students aged 13–18 years and KNHANES V was a survey of Koreans of all age. For balanced sampling, both of the surveys adopted a complex sample design. Having diagnosed with asthma within past 1 year was regarded as the development of asthma. Consumption of instant foods was defined as taking the food more than five times a week for the adolescents and more than once a week for the adults. Multivariable analyses were performed adjusting for age, gender, region, body mass index, smoking and physical activity. The development of asthma after 30 years old was defined as adult onset asthma. Results: The estimated number of adolescents who had ever diagnosed with asthma was 350 000 (9.3%) and 25% of them diagnosed asthma within past 12 months (recent diagnosis of asthma) according to the KYRBWS data. The prevalence of physician diagnosed asthma was 3.6% in whole Korean population and about 90 000 cases were newly diagnosed within 12 months according to the KHANES V data. Consumption of instant foods was significantly associated with the development of asthma in Korean adolescent (OR 1.7, 95% CI 1.36–2.19) and also in Korean adult (OR 3.7, 95% CI 1.38–9.7) aged 30 years old or more after multivariable analysis. Conclusion: In nationwide surveys from Korea, there was significant association with consumption of instant foods and the development of asthma in Korean adults as well as adolescents.Background: It is suggested that allergic immune activation, combined with a genetic predisposition, may contribute to the expression of aberrant social behaviour relevant to autism. We have previously shown that a food allergic response reduced social behaviour in mice, which was associated with altered dopaminergic activity in brain regions relevant for social and emotional behaviour. Dietary fatty acid composition has been shown to affect both the immune system and neurological processes and may therefore contribute to the prevention of food allergy-induced abnormalities in social behaviour. Method: The aim of this study was to assess whether dietary supplementation with fish oil rich in long chain omega-3 polyunsaturated fatty acids (n-3 LCPUFA) prevents food allergy-induced abnormalities in social behaviour and associated deficits of the dopaminergic system in the prefrontal cortex of whey-sensitised mice. Results: The n-3 LCPUFA-enriched fish oil diet decreased the acute allergic skin response and was able to prevent the disturbance in social behaviour of whey-sensitised mice. N-3 LCPUFA supplementation increased docosahexaenoic acid (DHA) incorporation in the brain and restored levels of dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA) in the prefrontal cortex of allergic mice. Moreover, reduced levels of 5-HIAA, metabolite of serotonin, in intestines of allergic mice was also restored by the n-3 LCPUFA-enriched diet. Conclusion: In addition to its effects on the allergic skin response, n-3 LCPUFA restored allergy-induced deficits in social behaviour and in prefrontal dopamine and metabolite levels. Therefore, n-3 LCPUFA may exert its beneficial effect on behaviour via modulation of the dopaminergic system in the prefrontal cortex and may therefore be an interesting target in the use of dietary interventions for immune-mediated psychiatric disorders such as ASD.