No relationship between non-IgE-mediated mechanisms (complement activation or direct activation of mast cells and basophils) during diclofenac etalhyaluronate (SI-613/ONO-5704)-induced anaphylaxis.

Abstract

It was previously reported that half of the anaphylaxis cases occurring after intra-articular administration of diclofenac etalhyaluronate (DEH) - developed as SI-613/ONO-5704 and marketed as JOYCLU^® - were induced by IgE-mediated mechanisms; mechanisms for the remaining cases remain unclear. In this study, we investigated the relationship of DEH-induced anaphylaxis to non-IgE-mediated mechanisms in vitro. Assays were carried out based on the production of downstream products of the complement cascade, calcium influx due to Mas-related G protein-coupled receptor-X2 (MRGPRX2) activation, mast cell degranulation, and expression of basophil activation markers. Human plasma, CHO-K1 cells stably expressing MRGPRX2, the human mast cell line LAD2, and the human basophil leukemia cell line KU812 were used for these evaluations. No effect of DEH treatment was found on complement activation, MRGPRX2 agonist activity, direct mast cell activation, or direct basophil activation. From this it could be concluded that DEH-induced anaphylaxis is unlikely to involve complement activation or direct activation of mast cells and basophils. However, the possibility remains that the anaphylaxis might be a non-immunological hypersensitivity reaction due to inhibition of cyclooxygenase-1 by non-steroidal anti-inflammatory drugs (NSAID). Further investigation into the relationship between the non-immunological hypersensitivity and anaphylaxis following DEH administration is warranted.