Marcello Albanesi

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,

Importance of Specific IgE/Total IgE Ratio in Disambiguating Amoxicillin Allergy Diagnosis in a Real-Life Setting

Dear Editor, Allergic reaction to β-lactams antibiotics is the most frequent cause of Adverse Drug Reaction (ADR) mediated by immunological mechanisms [1]. In clinical practice, the evaluation of β-lactam-specific IgE levels is instrumental in the establishment of the diagnosis of ADR [2]. Drug-specific IgE titres rise 3–4 weeks upon exposure and decline over time [3]. Assessment of circulating drug-specific IgE is often done using the RAST-CAP system. The specificity of this test was assessed to range between 83.3 and 100%, with a 0.35 kU/L threshold, but the sensitivity was estimated to range only from 12.5 to 25% [4]. However, a 0.1 kU/L threshold is currently considered acceptable, increasing the sensitivity but possibly reducing the specificity [5]. The test-positive predictive value might also be influenced by the total serum IgE. Indeed, 2 different pools of IgE molecules exist: (i) IgE molecules bound on the mast-cell and basophil surface via the interaction with the high affinity receptor FcεRI and (ii) the unbound IgE molecules that circulate freely in plasma [6]. It was recently proposed that the ratio β-lactam-specific IgE/total IgE might be an additional parameter to consider in the ADR diagnostic process [7]. In particular, an elevated drug-specific IgE/total IgE ratio might reflect high levels of drug-specific IgE on mast-cells and basophils, thereby increasing the probability of adverse reaction upon drug administration. Thus, the authors propose the use of a 0.002 threshold for the ratio drug-specific IgE/total IgE. A positive predictive value of 95% is achieved if the ratio is ≥0.002, whereas it diminishes significantly if the ratio is <0.002 [7]. Here we describe 6 cases of suspected ADR to amoxicillin (AMX). We used the 0.002 amoxicilloyl-specific IgE/total IgE ratio to clarify the clinical diagnosis in a real-life setting. The patients (1 men and 5 women; mean of age 38.6 ± 16.3; all from Southern Italy) were referred to our Clinic for a suspected (although ambiguous) immediate ADR to AMX. Five patients had been treated with AMX alone and one with AMXClavulanic Acid (CLV). Five out of 6 had experienced the adverse reaction more than 6 months before the clinical assessment and no other concomitant medications were given (Table 1). In all patients, the amoxicilloyl-specific IgE levels (CAP System) were slightly above the current threshold limit (0.1 kU/L; Fig. 1a). Considering the possible decline of drug-specific IgE [3], these results could have been interpreted as positive. We also evaluated the penicilloyl-G, cefaclor, penicilloyl-V, and ampicillin-specific IgE (Fig. 1b). Notably, in all patients the total IgE levels were above the usually accepted threshold limit of 100 kU/L and in 4 of them were remarkably high (Fig. 1c). As proposed [7], we calculated the amoxicilloyl-specific IgE/total IgE ratio. This ratio was below 0.002 in all the patients (Fig. 1d). Thus, we hypothesized that the amoxicilloyl-specific IgE levels in these patients were not reliable. To further corroborate this finding, we also evaluated the Ambrosia elatior-specific IgE in 2 patients with total IgE >1,000 kU/L and their levels were above the 0.1 kU/L threshold. Clearly false positives, since A. elatior pollen is not detectable in Southern Italy (data not shown; moreover in 5 AMX-tolerant con-

Efficacy and safety of allergen immunotherapy in patients with allergy to molds: A systematic review

Allergen immunotherapy (AIT) with mould extracts has been performed for many years but the final demonstration of its clinical efficacy is still missing, due to the small number of studies and their inconsistent results.

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