Autoreactivity is highly prevalent in patients with multiple intolerances to NSAIDs Riccardo Asero MD*; Alberto Tedeschi MD†; and Maurizio Lorini† Background: A subset of drug-allergic patients show a marked propensity to react against several, chemically unrelated nonsteroidal anti-inflammatory drugs (NSAIDs). The pathogenesis of such multiple drug reactions is unclear. Approxi- mately 30% of patients with chronic idiopathic urticaria, a condition frequently characterized by autoreactivity on autologous serum skin test (ASST), experience flares of hives after taking chemically unrelated NSAIDs. Objective: To detect whether a clinically unapparent autoreactivity may repre- sent the nonspecific mechanism facilitating drug-induced histamine release in patients with a history of urticaria/angioedema induced by several, chemically unrelated NSAIDs. Methods: Thirty-six adults with a history of acute NSAID-induced urticaria (22 with multiple NSAID sensitivity [MNS]; 14 with single NSAID sensitivity [SNS]; and 20 atopic controls without a history of drug allergy) underwent ASST. Sera from 14 MNS and 4 SNS subjects (all ASST-positive) underwent histamine release assay with basophils from normal donors. Sera from five MNS patients were tested on autologous basophils as well. Results: Twenty of 22 (91%) MNS subjects versus 5 of 14 (36%) SNS subjects were positive on ASST (P  0.01). No atopic control was ASST-positive. Sera from 4 of 14 (29%) MNS patients versus 0/4 SNS subjects (P = NS) induced significant histamine release from basophils of normal donors. The use of autologous basophils did not significantly change these results. Conclusion: Most patients with multiple NSAID intolerance and approximately one-third of those with single NSAID hypersensitivity are characterized by the presence of circulating histamine-releasing factors. Their nature is still unclear, but the fact that only a minority of sera from ASST+ subjects were able to induce histamine release from normal basophils in vitro suggests that these factors might not differ from those involved in most patients with chronic urticaria. These factors might play a relevant pathogenic role in NSAID-induced urticaria reactions. Ann Allergy Asthma Immunol 2002;88:468– 472. INTRODUCTION The term “pseudoallergic” identifies drug-induced adverse reactions charac- terized by clinical manifestations that are suggestive of or compatible with immunopathologic mechanisms but that are known to lack an immune ba- sis. 1 Such reactions probably represent the majority of drug-induced skin dis- orders seen by allergists. Their patho- genesis is still obscure; a number of studies tried to identify possible im- mune-mediated mechanisms, such as immunoglobulin (Ig)E specific for metabolic breakdown products of the parent offending drugs, or specifically sensitized lymphocytes, with little suc- cess. A subset of patients with a his- tory of nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria and/or angioedema seem to show a marked propensity to react to several, chemi- cally unrelated compounds. 2,3 These patients are otherwise normal subjects without a clinical history of chronic or recurrent urticaria, a condition that is frequently associated with multiple NSAID intolerance, 4 and have been classified as a specific category in re- cently proposed classification system. 5 Mechanisms underlying multiple drug reactivity remain elusive, and the marked differences between offending drugs seem to rule out a possible pathogenesis based upon immunologic recognition of specific chemical struc- tures (ie, cross-reactivity) but rather suggest the existence of nonspecific, patient-related factors leading to direct histamine release from mast cells and/or basophils. Recent studies re- ported good results both on the pri- mary skin disorder and on NSAID re- activity in some patients with chronic urticaria by leukotriene antagonists, 6 –10 suggesting that inhibition of cyclooxy- genase (COX) pathway may play a role in these drug-induced reactions. The recent observation that selective COX-2 inhibitors are well tolerated by a majority of these patients supports this hypothesis. 11,12 However, some patients experience urticaria even after taking weak COX-inhibitors such as acetami- nophen (paracetamol), floctafenine, ro- fecoxib, and/or nimesulide, 3,12 suggest- ing the possible involvement of other pathogenic mechanisms as well. One of these might be a condition characterized by a facilitated histamine release from both mast cells and basophils. Several studies demonstrated that a high proportion (up to 60%) of patients with chronic idiopathic urticaria show a wheal-and-flare reaction upon intra- dermal injection of autologous se- rum. 13–15 In these patients, serum his- tamine-releasing activity has long been ascribed to the presence of circulating IgG autoantibodies specific either for the high-affinity IgE receptor, FcRI, or for IgE; such autoantibodies would be responsible for histamine release from both basophils from normal do- * Allergy Unit, Ospedale Caduti Bollatesi, Bol- late (MI), Italy. † First Division of Internal Medicine, IRCCS Ospedale Maggiore Policlinico, Milano, Italy. Received for publication October 2, 2001. Accepted for publication in revised form De- cember 27, 2001. 468 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY