Nonsteroidal anti-inflammatory drug hypersensitivity syndrome. A multicenter study. I. Clinical findings and in vitro diagnosis.

BACKGROUND: We present the results obtained from the largest series of in vitro diagnostic tests ever reported in patients with clinically validated hypersensitivity to acetylsalicylic acid (ASA)/nonsteroidal anti-inflammatory drugs (NSAID) compared with various categories of controls tolerating ASA/NSAIDs. This multicenter study, which was performed within the framework of the European Network for Drug Allergy (ENDA) group, showed that the basophil activation test (BAT), particularly when used with the 3 NSAIDs aspirin (ASA), diclofenac (DIC), and naproxen (NAP), allows us to confirm the diagnosis of NSAID hypersensitivity syndrome. The results of the cellular allergen stimulation test (CAST) frequently correlate with those of the BAT, although not always. An unexpected finding was that basophil activation by NSAIDs is not an all-or-nothing phenomenon restricted to clinically hypersensitive patients, but that it also occurs in a dose-related manner in some NSAID-tolerant control individuals.Therefore, NSAID hypersensitivity appears as a shift in the normal pharmacological response to NSAIDs. These findings allow us to formulate a new rational hypothesis about the mechanism of NSAID hypersensitivity syndrome, a mechanism that most authors continue to describe as "unknown." METHODS: We enrolled 152 patients with a history of hypersensitivity to NSAIDs and 136 control participants in 11 different centers between spring 2003 and spring 2006. Flowcytometric BAT was performed. RESULTS: The most noteworthy results of our study were that 57% of 140 patients presented very clear-cut positive BAT results to multiple NSAIDs, and 16% were entirely negative. In about 27% of cases, positive results were obtained with 1 or 2 concentrations of a single NSAID. There is clearly a correlation between the results of BAT and CAST. CONCLUSIONS: BAT seems particularly indicated in patients with a clinical history of NSAID intolerance, and in whom a provocation test is not advisable for ethical, clinical, or other reasons. Clear-cut positive results can be considered as confirming a history of NSAID hypersensitivity, although negative results may not exclude it.

The flow-cytometric determination of basophil activation induced by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is useful for in vitro diagnosis of the NSAID hypersensitivity syndrome.

BACKGROUND: Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs), manifested by cutaneous symptoms and/or airway manifestations represent 20-25% of all hypersensitivity reactions to drugs. Today, it is still claimed that no in vitro diagnostic tests exist for that condition and that the only way to confirm the diagnosis is a provocation challenge. OBJECTIVE: The objective of this study was to assess whether NSAIDs may provoke blood basophil activation in vitro in such patients, as detected by a flowcytometric technique. METHODS: Sixty NSAID hypersensitive patients (38 with cutaneous, 20 with airway and two with cutaneous and airway symptoms) and 30 control patients (15 asthmatics) were selected. Their hypersensitivity was confirmed by documented history indicating at least two clinical episodes to two or more different NSAIDs or by positive oral provocation challenge. Isolated buffy coat leukocytes were stimulated in vitro with aspirin, paracetamol, metamizol, diclofenac, and naproxen. The percentage of activated basophils was evaluated by an anti-CD63. RESULTS: Aspirin showed a sensitivity of 43.3%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 99.4%. For the other NSAIDs, the sensitivity and specificity values were: for paracetamol 11.7% and 100%, for metamizol 15% and 100%, for diclofenac 43.3% and 93.3% and for naproxen 54.8% and 74.1%. When considering the first four NSAIDs, the global sensitivity raised to 63.3% and specificity to 93.3%. If the number of tests is to be limited for practical reasons, the combination of acetylsalicylic acid and diclofenac at two concentrations yields a sensitivity of 58.3% and a specificity of 93.3%. CONCLUSIONS: Flowcytometric determinations of basophil activation following stimulation with NSAIDs show a high sensitivity (60-70%) with specificity above 90%. So this test may help avoiding some cumbersome and dangerous provocation challenges.

Immune thrombocytopenia resulting from sensitivity to metabolites of naproxen and acetaminophen.

In patients suspected of having drug-induced immune thrombocytopenia, antibodies reactive with normal platelets in the presence of the suspect drug can sometimes be identified, but negative results are often obtained. One reason for this is that drug metabolites, formed in vivo, can be the sensitizing agents, but very little is known about the specific metabolites that can cause this complication. Five patients were studied who developed thrombocytopenia after taking the nonsteroidal anti-inflammatory drug naproxen (3 cases) or acetaminophen (2 cases) but in whom drug-dependent antibodies could not be detected by means of the unmodified drugs. In each case, antibodies that reacted with normal target platelets in the presence of a known drug metabolite (naproxen glucuronide or acetaminophen sulfate) were identified. Four of the antibodies were specific for the glycoprotein (GP) IIb/IIIa complex, but one acetaminophen sulfate-dependent antibody reacted preferentially with GPIb/IX/V. In patients with a clinical picture suggestive of drug-induced immune thrombocytopenia, tests for metabolite-dependent antibodies can be helpful in identifying the responsible agent. (Blood. 2001;97:3846-3850)

Efecto del naproxeno sódico en las concentraciones séricas de IL-1, IL-6 y TFN en pacientes con faringoamigdalitis aguda purulenta / The effect of sodium naproxeno in the scrum concentration of IL-1, IL-6 and TNF in acute infectious process

Antecedentes. En el proceso infeccioso las citocinas producidas por los macrófagos y neutrófilos participan en los mecanismos de defensa del huésped. En estos mecanismos de fase aguda intervienen interleucinas como IL-1, IL-6 y el factor de necrosis tumoral (INF). Objetivo. Conocer el efecto del naproxeno sódico en las concentraciones séricas de IL-1, IL-6 y TNF, en un receso infeccioso agudo. Material y método. Se estudiaron al azar 18 pacientes, que se dividieron en dos grupos iguales, con diagnóstico clínico de faringoamigdalitis aguda purulenta. A un grupo se le dio naproxeno sódico y al otro placebo, ambos recibieron tratamiento antibacteriano con penicilina G procaínica. Resultados. El grupo que recibió naproxeno sódico tuvo disminución del síndrome febril e infeccioso a partir de las 72 horas. En los que recibieron placebo los síntomas y signos de los síndromes febril e infeccioso persistieron por más de tres días. Discusión. Los pacientes que recibieron tratamiento con naproxeno sódico tuvieron una disminución en la concentración sérica de IL-1B con diferencias estadísticamente significativas con respecto a las mediciones basal y a las 72 horas; también se observaron diferencias estadísticamente signficativas con los pacientes que recibieron placebo. Los resultados muestran que las concentraciones séricas de IL-1b disminuyeron en ambos grupos pero fue más acentuada la disminución en el grupo que recibió naproxeno sódico con disminución de los síntomas en forma más rápida

Rat serum albumin modified by diflunisal acyl glucuronide is immunogenic in rats.

Acyl glucuronide metabolites of carboxylic acid drugs such as the salicylate derivative diflunisal (DF) have been shown to react with proteins in vitro and in vivo to produce covalent adducts. Such attachment of foreign compounds to endogenous molecules could be associated with toxic and/or immune consequences. In this study we have injected rats with rat serum albumin (RSA) modified (a) by DF using a carbodiimide reagent (-->DF-RSA-I, 4.9 micrograms DF/mg RSA) and (b) by incubation with DF acyl glucuronide (DAG) and its rearrangement isomers (iso-DAG) (-->DF-RSA-II, 0.34 micrograms DF/mg RSA). All of the six rats injected with DF-RSA-I produced antibodies reactive with DF-modified keyhole limpet hemocyanin (KLH), the coating protein used in the ELISA. Three out of six animals injected with DF-RSA-II generated similar antibodies. Cross-reactivity with other non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen and ketoprofen (as the free drugs) was not observed. This study shows that a self protein covalently modified by incubation with DAG and iso-DAG is immunogenic in rats. The data thus support the hypothesis that covalent modification of macromolecules by acyl glucuronide metabolites of acidic drugs in vivo can lead to the production of circulating antibodies which may be involved in aberrant immune responses such as drug hypersensitivity.

Immunomodulatory effects of treatment with naproxen in patients with rheumatic disease.

We evaluated the effects of a nonsteroidal antiinflammatory drug, naproxen, on phytohemagglutinin (PHA)-induced lymphocyte proliferation. When added in vitro to cultures of peripheral blood mononuclear cells, naproxen enhanced the proliferative response toward PHA of lymphocytes from rheumatoid arthritis (RA) patients but not from healthy volunteers, and it reduced prostaglandin E2 (PGE2) synthesis in the cultures. Oral treatment for 7 days with naproxen also resulted in a significant enhancement of the in vitro PHA-induced proliferation of lymphocytes from RA patients and from age-matched control patients with noninflammatory rheumatic diseases, but not from young healthy controls. This enhancement of PHA-induced lymphocyte proliferation after oral intake of naproxen was not accompanied by diminished in vitro PGE2 production in the cultures. It did occur when PGE2-producing monocytes were removed and when in vitro PGE2 synthesis was blocked with indomethacin. We conclude that oral treatment with naproxen has an immunomodulatory effect and improves in vitro PHA-induced proliferation of lymphocytes from rheumatic disease patients. This effect is not due to reduced PGE2 synthesis in the in vitro cultures, but reflects a more fundamental in vivo change in immunoregulation.