Fixed Drug Eruption After Ingestion of Naproxen in a Patient Who

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13. Bousquet J, Heinzerling L, Bachert C, Papadopoulos NG, Bousquet PJ, Burney PG, et al. Practical guide to skin prick Fixed Drug Eruption After Ingestion of Naproxen tests in allergy to aeroallergens. Allergy. 2012;67:18-24 in a Patient Who Tolerated Ibuprofen and 14. Sørensen M, Klingenberg ,Wickman M, Sollid JUE, Fusberg Dexketoprofen AS, Bachert C, et al. Staphylococcus aureus enterotoxin sensitization is associated with allergic poly-sensitization and Reguero Capilla M, De Aramburu Mera T, Ochando Díez-Canseco allergic multimorbidity in adolescents. Allergy. 2017;72:1548- M, Prados Castaño M 55. Department of Allergology, University Hospital Virgen del Rocío, 15. Abdurrahman G, Schemiedeke F, Bachert C, Bröker BM, Seville, Spain Holtfreter S. Allergy-A new role for T cell superantigens of Staphylococcus aureus? Toxins. 2020;12:176. J Investig Allergol Clin Immunol 2021; Vol. 31(2): 173-175 doi: 10.18176/jiaci.0518

Key words: Fixed drug exanthema. Naproxen. Arylpropionic acid derivatives. NSAIDs. Manuscript received April 28, 2020; accepted for publication June 29, 2020. Palabras clave: Exantema fijo medicamentoso. Naproxeno. Arilpropiónicos. AINE. Pilar Barranco Department of Allergy La Paz University Hospital Madrid, Spain E-mail: [email protected] Nonsteroidal anti-inflammatory drugs (NSAIDs) are used worldwide because of their analgesic, anti- inflammatory, and antipyretic effects. NSAIDs are one of the most frequent causes of drug-induced hypersensitivity reactions, with urticaria and angioedema as the most common manifestations [1]. Patients who present symptoms after the intake of an NSAID do not usually tolerate others from the same chemical group owing to marked cross-reactivity between NSAIDs that are structurally similar [2,3]. Controlled oral challenge test with the culprit NSAID is currently the diagnostic gold standard for confirming a case of hypersensitivity to NSAIDs [1-3]. Naproxen is a nonsteroidal anti-inflammatory drug belonging to the arylpropionic acid family and a nonselective COX inhibitor that is used to treat menstrual cramps, inflammatory diseases such as rheumatoid arthritis, and fever. Fixed drug eruption involves the appearance of a well-circumscribed erythematous patch as a consequence of systemic exposure to a drug. It is an allergic reaction to a medicine that characteristically recurs at the same site or sites each time a particular drug is taken. While many drugs cause fixed drug eruption, the condition is frequently associated with antibiotics and NSAIDs such as ibuprofen [1,2,4]. In this paper, we report a case of fixed drug eruption that developed several hours after taking naproxen. The patient tolerated other arylpropionic acid derivatives (ibuprofen and dexketoprofen), as confirmed with a controlled oral challenge for each drug. The patient was a 25-year-old woman with no history of interest other than polycystic ovary syndrome. She was referred to our allergy unit because 10 years previously, she developed an itchy erythematous-violaceous patch on the right side of her neck approximately 4 hours after taking naproxen. No urticaria/angioedema or systemic symptoms were recorded. The eruption resolved in 48 hours without treatment. She has not taken naproxen since then but has subsequently tolerated ibuprofen and dexketoprofen. She also occasionally consumes paracetamol and metamizole without problems. We performed a series of diagnostic tests, with an interval of at least 1 week between doses, as follows:

– Patch test with naproxen, ibuprofen, and dexketoprofen, between 30 minutes and 8 hours after intake, although this with readings at 48 and 96 hours (preparations were interval may be shorter in the case of recurrent contact with made using petrolatum as a vehicle and at concentrations the drug [4]. similar to those suggested in other studies [6]; naproxen The final diagnosis was fixed drug eruption induced by 30%, ibuprofen 5%-10%, and ketoprofen 1%-10%). The naproxen. result was negative. Recent data show that NSAIDs are the most frequent cause – Patch-test with naproxen applied to the patient’s neck. of drug hypersensitivity reactions [5]. The second most frequent The control was a petrolatum patch, with readings at 48 cause of these reactions, after pyrazolones [1], is arylpropionic and 96 hours. The result was negative. acid derivatives, specifically ibuprofen. The NSAID most – Day 1: A single-blind placebo-controlled oral challenge commonly associated with fixed drug eruption is ibuprofen. (SBPCOC) with ibuprofen at doses of 50, 100, and The patient can be considered to have experienced a single 250 mg at intervals of 30, 60, and 120 minutes, and an NSAID–induced hypersensitivity reaction because she tolerates observational period of 4.5 hours. The result was negative. NSAIDs from other chemical groups. Patients with immediate – Day 2: SBPCOC with the intake of a single dose of 600 reactions to 2 or more NSAIDs that are not structurally related mg of ibuprofen (higher dose than the day before because and who tolerate aspirin have been reported, with the result that the patient reported taking 600 mg at home) and an this phenotype must be taken into account [7]. In the present observational period of 4.5 hours. The result was negative. case, the patient also tolerated another NSAID that is structurally – SBPCOC with dexketoprofen 6, 6, and 12 mg at similar to naproxen, the culprit drug. Cases of urticaria and/or intervals of 30, 30, and 120 minutes, respectively, angioedema associated with one drug have been described in until the therapeutic dose was reached, followed by an patients who tolerate others from the same family [2]. However, observational period of 4 hours. The result was negative. in this paper, we report a case of fixed drug eruption after – SBPCOC with naproxen 50, 150, and 300 mg every administration of an arylpropionic acid derivative (naproxen) in 30 minutes, with 240 minutes of observation. The result a patient who tolerated other drugs from this family (ibuprofen was positive (itchy erythematous eruption on the side and dexketoprofen). The time interval between the intake of of the neck, with no associated urticaria, angioedema, the NSAID and the appearance of erythema in the present case was about 4 hours. or systemic symptoms) (Figure). The usefulness of skin testing has been documented We established time intervals of 30 to 60 minutes between for pyrazolones [8], although few data are available on its each DPT because, once sensitized, the reaction appeared utility with arylpropionic acid derivatives because of its poor reliability. Oral challenge remains the gold standard for diagnosing allergy to NSAIDs; it is not indicated in patients with a history of generalized exanthema or when the exanthema involves mucous tissues. In patients without generalized reactions or extended mucous involvement, oral challenge is considered relatively safe and remains the gold standard, thus confirming the affected area and the culprit agent [4]. Fixed drug eruption characteristically reappears at the same location and with a similar extension [9]. In this case, with a small skin area affected, and given the negative result in the patch test and tolerance to ibuprofen and dexketoprofen in the oral challenge, as well as the remarkable cross-reactivity between members of the arylpropionic family, we decided to perform a diagnostic test with naproxen in order to prove the reproducibility of the symptoms. The result was positive (erythematous-violaceous oval lesion on the side of the patient’s neck). We report a case of fixed drug eruption induced by naproxen, with no associated urticaria/angioedema and no cross-reactivity between the same structural groups. Diagnosis was by single-blind placebo-controlled oral challenge. We conclude that arylpropionic acid derivatives may induce fixed drug eruption as a hypersensitivity reaction in patients with good tolerance to other drugs from the same chemical group. While more studies are needed, we would like to emphasize the importance of carrying out tolerance tests with another NSAID within the same group because of the probability of tolerance. Cases should be managed on an individual basis.

Funding Figure. Fixed drug eruption on the patient’s neck after oral challenge The authors declare that no funding was received for the testing with naproxen. present study.

Conflicts of Interest Phospholipase A2 Triggers Anaphylaxis to Snake The authors declare that they have no conflicts of Venom by Repeated Skin Sensitization: A Case interest. Report

1 2 1,3 4 5 References Swiontek K , Planchon S , Ollert M , Eyer F , Fischer J , Hilger C1 1Department of Infection and Immunity, Luxembourg Institute of 1. Blanca-Lopez N, Perez-Alzate D, Andreu I, Doña I, Agundez JA, Health (LIH), Esch-sur-Alzette, Luxembourg Garcıa-Martın E, et al. Immediate hypersensitivity reactions 2Green Tech Platform, Luxembourg Institute of Science and to ibuprofen and other arylpropionic acid derivatives. Allergy. Technology (LIST), Esch-sur-Alzette, Luxembourg 2016;71:1048-56. 3Department of Dermatology and Allergy Center, Odense 2. Ortega N, Doña I, Moreno E, Audicana MT, Barasona MJ, Research Center for Anaphylaxis, University of Southern Berges- Gimeno MP, et al. Practical guidelines for diagnosing Denmark, Odense, Denmark hypersensitivity reactions to nonsteroidal anti-inflammatory 4Department of Clinical Toxicology and Poison Control Center drugs. J Investig Allergol Clin Immunol. 2014;24:308-23. Munich, Technical University of Munich, Munich, Germany 3. Doña I, Barrionuevo E, Blanca-López N, Torres MJ, Fernández 5 TD, Canto G, et al. Trends in hypersensitivity drugs reactions: Department of Dermatology, Eberhard Karls University, more drugs, more response patterns, more heterogeneity. J Tuebingen, Germany Investig Allergol Clin Immunol. 2014;24:143-53. 4. Fernández Sánchez FJ, Blanca Gómez M, Jerez Domínguez J, J Investig Allergol Clin Immunol 2021; Vol. 31(2): 175-177 doi: 10.18176/jiaci.0545 Rodríguez Fernández F, Martín Casañez E. Reacciones cutáneas graves producidas por fármacos: eritema exudativo multiforme, síndrome de Lyell, síndrome de hipersensibilidad a fármacos. Key words: Snake venom. Allergen. Anaphylaxis. Phospholipase A2. Skin In: Peláez Hernández A, Dávila González IJ, Editors. Tratado de sensitization. Alergología II. Majadahonda (Madrid). Ergon, 2007; 1515-24. Palabras clave: Veneno de serpiente. Alérgeno. Anafilaxia. Fosfolipasa 5. 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Ergon, 2016; 1679-86. through inhalation [3,4]. Snake handlers are at particular 7. Pérez-Alzate D, Cornejo-García JA, Pérez-Sánchez N, Andreu risk of developing IgE-mediated symptoms to snake venom. I, García-Moral A, Agúndez JA, et al. Immediate Reactions Medeiros et al [5] reported the prevalence of specific IgE to to More Than 1 NSAID Must Not Be Considered Cross- snake venom to be 10.4% in professional snake handlers and Hypersensitivity Unless Tolerance to ASA Is Verified. J Invest identified contact with dried venom as a major risk factor in Allergol Clin Immunol. 2017;27(1):32-9. their cohort. 8. Himly M, Jahn-Schmid B, Pittertschatscher K, Bohle B, We describe a case of anaphylaxis to snake venom Grubmayr K, Ferreira F, et al. IgE-mediated immediate-type following skin sensitization without a bite. An 18-year-old man hypersensitivity to the pyrazolone drug propyphenazone. J with no known atopic dermatitis or allergy to insects, no history Allergy Clin Immunol. 2003;111:882-8. of anaphylaxis, and no clinical evidence of mastocytosis was 9. Mahboob A, Haroon TS. Drugs causing fixed eruptions: a admitted to our Toxicology Department with anaphylactic study of 450 cases. Int J Dermatol. 1998;37:833-8. shock following skin contact with snake venom. The patient kept venomous snakes in his apartment and had been milking their venom on a regular basis without wearing protective gloves. During the cleaning of objects used for milking the Manuscript received March 25, 2020; accepted for snakes, the back of the left hand, which had small superficial publication June 30, 2020. skin lesions caused by outdoor activities, came into contact with draining tap water. Immediately afterwards, the patient Marta Reguero Capilla felt a burning sensation on the back of the left hand, followed Department of Allergology by shortness of breath and sweating. Upon arrival of the University Hospital “Virgen del Rocío” emergency physician, the patient had a Glasgow Coma Scale C/ Manuel Siurot 41013 Sevilla, Spain (GCS) score of 13, systolic blood pressure of 60 mmHg, E-mail: [email protected] heart rate of 170 bpm (sinus rhythm), and oxygen saturation