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Tolerance to etoricoxib in 37 patients with urticaria and angioedema induced by nonsteroidal anti-inflammatory drugs Lionello Muratore, MD*; Mariateresa Ventura, MD†; Gianfranco Calogiuri, MD‡; Fabio Calcagnile, MD§; Eugenio Quarta, MD§; Maurizio Muratore, MD§; and Antonio Ferrannini, MD† Background: The use of cyclooxygenase-2 inhibitors, a new class of analgesic drugs, is suggested in patients with hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs). Objective: To evaluate tolerance to etoricoxib, a new cyclooxygenase-2 inhibitor, in NSAID-sensitive patients with urticaria- type adverse reactions. Patients: Thirty-seven patients with adverse reactions to NSAIDs. Methods: Single-blind, placebo-controlled oral challenge with increasing doses of etoricoxib. Results: Thirty-four patients tolerated etoricoxib treatment without adverse reactions, but a generalized urticarial rash developed in 3 patients (8%). Conclusions: Etoricoxib, like other cyclooxygenase-2 inhibitors, is a well-tolerated drug in most NSAID-sensitive patients. However, according to our experience, a previous challenge test in a safe environment may be necessary before prescribing the drug to such patients. Ann Allergy Asthma Immunol. 2007;98:168–171. INTRODUCTION The urticaria-angioedema syndrome is an adverse cutaneous reaction that is recognized by 3 pathogenetic mechanisms. The IgE-mediated mechanism has been suspected, 1 and it has been confirmed, in some cases, by means of allergologic tests and identification of specific IgE in patients’ serum. 2,3 The second mechanism could be the initial symptom of an auto- immune phenomenon. In fact, it has been shown that idio- pathic chronic urticaria 4 is due to the presence of histamine- releasing factors derived from basophils and mast cells, 5 which are often autoantibodies of the IgG class with antigen- dependent binding for the high-affinity receptors for IgE (FcRI) or anti-IgE, IgG antibodies. 6 The third mechanism, in susceptible individuals, seems to be correlated to an altered metabolism of archidonic acid products. In particular, the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is to induce an imbalance of lipoxygenase/ cyclooxygenase enzymatic pathways with a reduction of pros- taglandin E synthesis owing to the inhibition of cyclooxygenase and the overproduction of cysteinyl leukotrienes (Cys-LTs). 7 The Cys-LTs C4, D4, and E4, released by mast cells, eosinophils, basophils, and macrophages, cause increased vascular permeability. After in vitro NSAID incubation, in- creased Cys-LT secretion was demonstrated using the cell antigenic stimulation test on the leukocytes, basophils, and eosinophils of patients with NSAID-correlated urticaria. 8 A study 9 of 74 patients with chronic idiopathic urticaria and hypersensitivity to aspirin or NSAIDs showed increased urinary LTE4 excretion after a placebo-controlled oral chal- lenge test (OCT) with aspirin. All the urinary LTE4 concen- trations were measured using enzyme-linked immunosorbent assay at baseline and after the OCT. Furthermore, patients underwent genotyping for the LTC4 synthetase promoter to investigate their polymorphism. 9 Cyclooxygenase-2 inhibitors belong to a new class of analgesic and anti-inflammatory drugs that exert their phar- macologic action by selectively inhibiting a cyclooxygenase isoform, allowing a notable reduction in NSAID-induced gastric injury 10 ; nevertheless, their use has also been sug- gested in patients who show urticarial or asthmatic reactions after NSAID ingestion. 7 The aim of this work is to evaluate tolerance to etoricoxib, a second-generation cyclooxygen- ase-2 inhibitor, in a group of patients with a clinical history of aspirin- or NSAID-induced urticarial rashes. METHODS Patients We recruited 37 patients who had never taken etoricoxib in the past from the patients observed in the first 6 months of 2004 (January 1 to June 30, 2004) at the Allergy and Clinical * Allergology and Clinical Immunology Service, Vito Fazzi Hospital, Lecce, Italy. † Department of Internal Medicine, Immunology, and Infectious Diseases, University of Bari Medical School, Policlinico, Bari, Italy. ‡ IV Division of Pneumology, Galateo Hospital–San Cesario di Lecce, Lecce, Italy. § Unit of Rheumatology, Galateo Hospital–San Cesario di Lecce, Lecce, Italy. Received for publication October 1, 2006. Accepted for publication in revised form October 24, 2006. 168 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

Tolerance to etoricoxib in 37 patients with urticaria and angioedema induced by nonsteroidal anti-inflammatory drugs

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Tolerance to etoricoxib in 37 patients withurticaria and angioedema induced bynonsteroidal anti-inflammatory drugsLionello Muratore, MD*; Mariateresa Ventura, MD†; Gianfranco Calogiuri, MD‡;Fabio Calcagnile, MD§; Eugenio Quarta, MD§; Maurizio Muratore, MD§; andAntonio Ferrannini, MD†

Background: The use of cyclooxygenase-2 inhibitors, a new class of analgesic drugs, is suggested in patients withhypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs).

Objective: To evaluate tolerance to etoricoxib, a new cyclooxygenase-2 inhibitor, in NSAID-sensitive patients with urticaria-type adverse reactions.

Patients: Thirty-seven patients with adverse reactions to NSAIDs.Methods: Single-blind, placebo-controlled oral challenge with increasing doses of etoricoxib.Results: Thirty-four patients tolerated etoricoxib treatment without adverse reactions, but a generalized urticarial rash

developed in 3 patients (8%).Conclusions: Etoricoxib, like other cyclooxygenase-2 inhibitors, is a well-tolerated drug in most NSAID-sensitive patients.

However, according to our experience, a previous challenge test in a safe environment may be necessary before prescribing thedrug to such patients.

Ann Allergy Asthma Immunol. 2007;98:168–171.

INTRODUCTIONThe urticaria-angioedema syndrome is an adverse cutaneousreaction that is recognized by 3 pathogenetic mechanisms.The IgE-mediated mechanism has been suspected,1 and it hasbeen confirmed, in some cases, by means of allergologic testsand identification of specific IgE in patients’ serum.2,3 Thesecond mechanism could be the initial symptom of an auto-immune phenomenon. In fact, it has been shown that idio-pathic chronic urticaria4 is due to the presence of histamine-releasing factors derived from basophils and mast cells,5

which are often autoantibodies of the IgG class with antigen-dependent binding for the high-affinity receptors for IgE(Fc�RI) or anti-IgE, IgG antibodies.6 The third mechanism, insusceptible individuals, seems to be correlated to an alteredmetabolism of archidonic acid products.

In particular, the effect of nonsteroidal anti-inflammatorydrugs (NSAIDs) is to induce an imbalance of lipoxygenase/cyclooxygenase enzymatic pathways with a reduction of pros-taglandin E synthesis owing to the inhibition of cyclooxygenaseand the overproduction of cysteinyl leukotrienes (Cys-LTs).7

The Cys-LTs C4, D4, and E4, released by mast cells,eosinophils, basophils, and macrophages, cause increasedvascular permeability. After in vitro NSAID incubation, in-creased Cys-LT secretion was demonstrated using the cellantigenic stimulation test on the leukocytes, basophils, andeosinophils of patients with NSAID-correlated urticaria.8

A study9 of 74 patients with chronic idiopathic urticariaand hypersensitivity to aspirin or NSAIDs showed increasedurinary LTE4 excretion after a placebo-controlled oral chal-lenge test (OCT) with aspirin. All the urinary LTE4 concen-trations were measured using enzyme-linked immunosorbentassay at baseline and after the OCT. Furthermore, patientsunderwent genotyping for the LTC4 synthetase promoter toinvestigate their polymorphism.9

Cyclooxygenase-2 inhibitors belong to a new class ofanalgesic and anti-inflammatory drugs that exert their phar-macologic action by selectively inhibiting a cyclooxygenaseisoform, allowing a notable reduction in NSAID-inducedgastric injury10; nevertheless, their use has also been sug-gested in patients who show urticarial or asthmatic reactionsafter NSAID ingestion.7 The aim of this work is to evaluatetolerance to etoricoxib, a second-generation cyclooxygen-ase-2 inhibitor, in a group of patients with a clinical history ofaspirin- or NSAID-induced urticarial rashes.

METHODS

PatientsWe recruited 37 patients who had never taken etoricoxib inthe past from the patients observed in the first 6 months of2004 (January 1 to June 30, 2004) at the Allergy and Clinical

* Allergology and Clinical Immunology Service, Vito Fazzi Hospital, Lecce,Italy.† Department of Internal Medicine, Immunology, and Infectious Diseases,University of Bari Medical School, Policlinico, Bari, Italy.‡ IV Division of Pneumology, Galateo Hospital–San Cesario di Lecce,Lecce, Italy.§ Unit of Rheumatology, Galateo Hospital–San Cesario di Lecce, Lecce,Italy.Received for publication October 1, 2006.Accepted for publication in revised form October 24, 2006.

168 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

Immunology Service of Lecce Civil Hospital “Vito Fazzi”and at the Local Health Service (ASL) Lecce/01 Rheumatol-ogy Department; the study was performed under the super-vision of the Allergy and Clinical Immunology Departmentof Bari University Hospital. All the participants providedwritten informed consent. The study protocol was approvedby the Ethical Committee of the ASL Lecce/01, southernItaly. All the patients (20 women and 17 men; mean age, 34.3years) had shown clinical symptoms characterized by urti-caria–Quincke edema induced by aspirin and NSAID treat-ment in the past 2 years.

Concerning the dosage of etoricoxib, note that this drugcould be taken in different dosages according to the propertreatment of different pathologic abnormalities. In particular,60 to 90 mg/d is given for rheumatic chronic diseases,whereas 120 mg/d is used in cases of acute gouty arthritis.

To be included in the study, patients had to have experi-enced at least 3 episodes of urticaria-angioedema syndromeafter the ingestion of 2 or more different NSAIDs, taken as asingle therapeutic agent, not associated with other drugs (eg,antibiotics). In the clinical history we report only the NSAIDsresponsible for the last episode because, especially in olderpatients, some of the NSAIDs responsible for urticaria are nolonger available in Italy (eg, glafenin or some pyrazolones).Furthermore, many patients had a list of NSAIDs that causedurticaroid reactions, prepared by their general practitioner,reporting the name of the drug but not the dosage eliciting theadverse reaction; because they had long avoided the drug,patients could not recall the dosage.

Other inclusion criteria were (1) older than 18 years; (2) noclinical history of other different or serious cutaneous adversereactions, such as fixed drug eruption, erythema multiforme,and Steven-Johnson syndrome; (3) no clinical history ofgeneralized urticaria, edema of the glottis, or anaphylacticshock; (4) an interval of at least 60 days since the last episodeof urticaria-angioedema syndrome due to aspirin or NSAIDs;(5) suspension of treatment with other drugs, such as corti-costeroids, antihistamines, and immunosuppressive agents forat least 7 days; (6) the absence of pregancy or nursing; and (7)the absence of bronchial asthma, rhinosinusitis, nasal polyp-osis, chronic urticaria, and renal, cardiac, and liver diseases.

All the patients gave written consent to take part in thestudy after having been fully informed of the formalities andmode of conduction, the aims of the study, and the precau-tions adopted by physicians to reduce the possible risks ofadverse drug reactions during the OCT with etoricoxib.

OCT Execution ProtocolOn the first day at time 0, 25 mg of etoricoxib was admin-istered in tablet form on an empty stomach. The same dosewas repeated every 120 minutes until the sixth hour, reachinga final dose of 100 mg. The patient was controlled in thehospital for 24 hours, and the result of the test was evaluatedon the basis of the appearance of clinical symptoms. Ten daysafter the first OCT, another OCT was performed consisting ofthe administration of 100 mg of etoricoxib twice a day for 2consecutive days.

Peak expiratory flow rate, blood pressure, and cardiacfrequency were measured during the tests. In particular, dur-ing the first OCT vital signs were checked every 30 minutesuntil hour 8 and subsequently every 60 minutes until hour 13,whereas in the second OCT vital signs were monitored everyhour for 12 hours.

Subsequently, with the same formalities and in single-blindmode, a placebo, consisting of lactose powder in water, wasadministered to all the participants after 30 to 45 days. TheOCT was suspended if cutaneous or respiratory phenomenadeveloped, whereas if the patient reported subjective symp-toms or alterations in vital signs (decrease in peak expiratoryflow rate, hypotension, or rhythm alterations), these wererecorded.

RESULTSOf the 37 patients, 3 (8%) showed diffuse urticaria. In thesepatients the OCT was immediately interrupted and antihista-mine therapy was administered (Table 1). The 3 patients werenot previously exposed to etoricoxib. They did not havechronic idiopathic urticaria and had suspended antihistamineuse a fortnight before. After having confirmed the benefits ofthis procedure, the challenges were repeated to show that thefirst hive episode was indeed related to etoricoxib. The cu-mulative dose responsible for symptoms was variable. In 2patients the reaction appeared during the first OCT aftercumulative doses of 75 and 100 mg. In 1 patient the reactionappeared during the second OCT after the second adminis-tration of a cumulative dose of 200 mg. The other 34 patients(92%) underwent OCT without developing any subjectivesymptoms or disturbances.

DISCUSSIONEtoricoxib is a new cyclooxygenase-2 inhibitor recentlyavailable on the Italian pharmaceutical market for the treat-ment of acute and chronic pain, rheumatoid arthritis, gout,and primary dysmenorrhea. It belongs to the second genera-

Table 1. Characteristics of the 3 Patients With Adverse Drug Reactions (ADRs) to Etoricoxib During Oral Challenge Testing

Patient No./sex/age, y Preceding ADR Dose, mg Latency, min Symptoms

1/F/33 Aspirin 75 30 Diffuse urticaria2/M/55 Naproxen sodium 100 30 Diffuse urticaria3/F/36 Nimesulide 200 45 Diffuse urticaria

VOLUME 98, FEBRUARY, 2007 169

tion of cyclooxygenase inhibitors.11 It contains a (4-methyl-sulfonyl)phenyl group on the central ring, reported to beessential for cyclooxygenase-2 inhibition. It is quickly ab-sorbed via the oral route, and most of the drug (92%) staysfast bound to plasma proteins. It is metabolized by the liverbefore being eliminated, 60% in the urine and 40% throughthe biliary pathway.12

In view of their pharmaceutical mechanism of action, cy-clooxygenase inhibitors could theoretically represent alterna-tive molecules in all individuals with hypersensitivity reac-tions correlated to NSAIDs. In many studies rofecoxib, nowoff the market, had been used to challenge patients with ahistory of urticaria/angioedema reactions to NSAIDs. Tosummarize, rofecoxib-induced urticaria/angioedema reac-tions range from 2% to 20% according to different stud-ies.13–15

Although most studies attribute good tolerance to cyclo-oxygenase inhibitors in patients affected by NSAID-hyper-sensitive diseases, in our opinion, before prescribing them itis advisable to perform an OCT in a safe environment, assuggested by some researchers.14 The present study reflectsthis attitude, and our admission criteria were highly restric-tive as we recruited only patients in apparent good health,except for some osteoarticular diseases, and affected by cu-taneous aspirin or NSAID hypersensitivity.

We preferred a single-blinded OCT with a placebo becausethe OCT plays a key role in the management of patients witha suspected drug allergy, and the challenge with inactiveplacebo allows us to avoid or to reveal a possible “noceboeffect,” potentially present during execution of the test.16 TheOCT permitted us to identify 3 patients (8%) in whom urti-caria appeared after etoricoxib administration, as in the studyby Sanchez-Borges et al.17 These symptoms were related tothe drug and were not imputable to stress conditions (hospi-talization, frequent medical examinations, etc), which arefrequent during OCT execution.

In a further study17 investigating tolerance to etoricoxiband celecoxib in 58 NSAID-sensitive patients, the OCT wasperformed in a double-blind, placebo-controlled design pro-tocol in which 24 patients experienced cutaneous and respi-ratory symptoms and the other 54 showed cutaneous clinicalmanifestations. Among the 56 patients challenged with etori-coxib, urticaria developed in 3 and angioedema of the tongue,eyelid, and lip in 1. When they opened the code, the research-ers17 observed that 4 patients sensitized to celecoxib welltolerated etoricoxib, whereas only 1 patient showed an ad-verse reaction.

Currently, etoricoxib is sold in 3 different doses, 60, 90,and 120 mg, according to whether the analgesic effect isrequired for dysmenorrhea, the painful phase of rheumatoidarthritis, or acute gouty arthritis. Because the clinical phar-macologists who synthesized the drug have allowed its com-mercialization up to doses of 120 mg, we cannot say whyhigh doses of etoricoxib cause an adverse skin reaction.Nevertheless, a study by Kruse et al18 suggests the existenceof a subgroup of patients with hypersensitivity to NSAIDs,

showing the same clinical manifestations also with cycloox-ygenase-2 inhibitors. After having observed 13 patients withdocumented adverse skin, respiratory, or anaphylactoid reac-tions to nonselective NSAID molecules, such as aspirin,diclofenac, and ibuprofen, the researchers subjected 9 ofthese patients to an OCT with scaled doses of rofecoxib, upto a cumulative dose of 25 mg, and 5 patients to an OCT withscaled doses of celecoxib, up to a cumulative dose of 200 mg.Of the 9 patients, 2 had symptoms such as endoral paresthe-sia, dizziness, and globus sensation shortly after taking rofe-coxib (12 mg); the first patient had previously experienced ananaphylactoid reaction with diclofenac and the second patientelicited facial erythema, globus sensation, restlessness, andnausea after receiving rofecoxib and celecoxib. In light oftheir experience, the authors argued that there may be 2further groups of patients with NSAID intolerance: one withintolerance to all cyclooxygenase inhibitors and a secondwith intolerance to cyclooxygenase-1 inhibitors only, butthey did not formulate any biochemical or pharmaceuticalhypothesis regarding their study.

CONCLUSIONEtoricoxib seems to be a good alternative in patients withurticaria/angioedema caused by NSAIDs. However, becauseetoricoxib may be taken in different dosages according to theproper treatment of different pathologic abnormalities, fur-ther and more extensive investigations are still needed toconfirm its complete tolerability in patients taking aspirin andNSAIDs.

ACKNOWLEDGMENTSWe acknowledge the assistance of M. V. C. Pragnell, BA, inthe preparation of the English translation.

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Requests for reprints should be addressed to:Mariateresa T. Ventura, MDDepartment of Internal Medicine, Immunology and Infectious DiseasesUniversity of Bari Medical SchoolPoliclinicoPiazza G. Cesare n° 1170124 Bari, ItalyE-mail: [email protected]

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