Discussion
allergic, increases peanut-allergic, first-ever, ’, IgE-mediated anaphylaxis, systemic allergic reactions
FOOD-INDUCED ANAPHYLAXIS
This trial has demonstrated the first-ever treatment to achieve rapid-onset prevention of IgE-induced food reactivity. Results showed that a short course of premedication with standard dosing of the BTK inhibitor acalabrutinib can achieve marked reduction or even complete elimination of clinical reactivity to ingestion of food allergens in allergic patients. Because tolerance to at least 300 mg of peanut protein is considered to be protective against reaction from an accidental exposure (In parallel with their clinical tolerance, patients’ highest negative skin test dilution of peanut also increased several logs. However, acalabrutinib treatment did not completely suppress skin tests as was observed for basophil activation, which was abolished by acalabrutinib treatment. This is in line with prior studies showing that BTK inhibitor doses that can suppress ex vivo basophil activation responses do not completely inhibit skin tests (It is unknown why some patients did not achieve the same magnitude of clinical protection from food-induced anaphylaxis with acalabrutinib treatment as others. Interestingly, these results illustrate the role of mast cells in food-induced anaphylaxis, given that some patients still reacted to peanut ingestion despite complete inhibition of their basophils by acalabrutinib. No correlation was observed between patients’ clinical response and their baseline skin test size or percentage reduction; baseline basophil activation; specific IgE to peanut or components; total IgE or specific-to-total IgE ratios; baseline tryptase level (data not shown); body weight or body mass index, though our study was not powered to detect such correlations. Further trials are necessary to determine the minimum dose of BTK inhibitors required to attain reliable protection against systemic allergic reactions for all patients.Given their remarkably rapid onset of action (within 2 days), BTK inhibitors may be a superior choice as adjunct prophylactic therapy for procedures such as high-risk immunotherapy or desensitizations compared with the anti-IgE monoclonal antibody omalizumab, which requires at least 4–8 weeks to achieve an effect and which does not reliably increase tolerance in every patient (Our results, in addition to prior trials utilizing the first-in-class BTK inhibitor ibrutinib to suppress allergen skin tests (Limitations of our study include a small patient population, the lack of fully blinded OFCs, and the lack of a placebo treatment arm. We attempted to mitigate any potential placebo effects or bias by using a modified PRACTALL scale (In conclusion, we have shown that pretreatment with the oral BTK inhibitor acalabrutinib for just 2 days significantly increases peanut-allergic patients’ tolerance to peanut during oral exposure. These results support the need for larger, placebo-controlled trials to further evaluate the safety and efficacy of these drugs in preventing IgE-mediated anaphylaxis. In particular, dose-finding trials will be necessary to determine the minimal effective dose of BTK inhibitors needed to prevent morbidity and/or mortality from either therapeutic or accidental allergen exposures before these medications can be used in clinical practice.