Couto, M

Duarte, C

Geraldes, L

Inês, L

Malcata, AB

Repositório Institucional dos Hospitais da Universidade de Coimbra

ARTICLE IN PRESSwww.elsevier.es/aiAllergol Immunopathol (Madr). ]]]];](]):]]]–]]]0301-0546/$ - seedoi:10.1016/j.allePlease cite thisAllergol ImmunoRESEARCH LETTERAnaphylaxis to mefenamic acid in a patientwith new onset of systemic lupuserythematosusTo the Editor:Many studies have addressed the frequency of drug allergy(DA) in systemic lupus erythematosus (SLE) patients. Somestudies suggest that there may be an increased risk in thesepatients1–4 while others do not conﬁrm this.5–7 The conﬂictingresults may be due to differences in deﬁnition of drug allergy;in the means of ascertaining allergic manifestations; and in thechoice of controls. SLE patients are more frequently exposedto drugs, which, ‘‘per se’’, represent a risk factor for drugallergy. Prompt recognition of DA, particularly anaphylaxis, iscrucial, as it may be life-threatening and the appropriatetreatment cannot be delayed. In a patient with SLE, thedifferential diagnosis of drug allergy is challenging. Featuressuch as rash, fever and cytopenia may result from drug allergybut may also be part of SLE manifestations. Furthermore,drugs like sulphonamides are well known to exacerbate, oreven induce SLE.8,9The authors report a case of a 32-year-old Caucasianfemale housewife who presented at the emergency roomwith rash, diffuse myalgias, dry mouth, paraesthesia anddizziness. The symptoms started 90 minutes after taking a250 mg tablet of mefenamic acid. She was thought to havean allergic drug reaction and was treated with intramuscularclemastin and IV methylprednisolone 250 mg. She was alert,her blood pressure was 100/57 mmHg, her heart rate was124 per minute and her temperature was normal. Despitereceiving clemastin and methylprednisolone, two hours latershe had a clinical deterioration starting with generalisedpruritus and worsening of generalised exanthema, myalgiasand arthralgias. She rapidly developed angio-oedema andanaphylactic shock. Her temperature was 37.4 1C, her bloodpressure dropped to 73/45 mmHg and her heart rate was120 per min. She was given dopamine, epinephrine and250 mg of IV methylprednisolone and intravenous ﬂuids.Blood cell count revealed a haemoglobin level of 7.9 g/dl[11.5–16.5], a white blood cell count of 5.4 103/mL [4–11],prothrombin time 22 s [13], d-dimers of 7.17 mg/L [0–0.6],ﬁbrinogen of 2.6 g/L [2–5.0], SGPT 219 U/l [555]; SGOT337 U/l [5–34]; SGGT 15 U/l [9–36], total bilirubin 0.8 mg/dlfront matter & 2009 SEICAP. Published by Elsevier Espr.2009.09.011article as: Couto M, et al. Anaphylaxis to mefenamic apathol (Madr). 2010. doi:10.1016/j.aller.2009.09.011[0.2–1.2], LDH 628 U/l [125–243], albumin 2.8 g/dl [3.5–5],CRP 6.31 mg/dl [0–0.8] and ESR 69 mm [0–2 5]. Chest x-rayand ECG were normal. She was diagnosed with DA tomefenamic acid and acute hepatic failure and was admittedinto the Intensive Care Unit.In the Intensive Care Unit, life support care wasmaintained and she started prednisolone 1 mg/Kg/day andtopical silver sulphadiazine for skin lesions. By the third dayshe was haemodynamically stable, her liver function wasalmost normal and the skin lesions were resolving.This patient had a history of new onset of polyarthralgiathree weeks previous to this episode which was treated byher general practitioner with mefenamic acid 250 mgtablets bid. One week later, she had not improved andcyclobenzaprine 10 mg qd was added to her treatment. Shestopped both drugs the following day because of malaise andfacial exanthema that resolved completely. She did not takeany other medications except for chronic treatment withthyroxine for hypotiroidism. Laboratory tests done by hergeneral practitioner 11 days before this episode showed ananti-nuclear antibody (ANA) of 1/2500 [o1/40] withhomogenous pattern, anti-dsDNA of 1/80 [o1/10], Rheu-matoid Factor of 28 IU/ml [o14], negative Waaler-Rosetest, white blood cell count 3.96 103/mL [4–11 103/mL],lymphocytes of 1.0 103/mL [1.5–3.5], CPR 3.94 [o6.0] andESR of 90 mm [o20].Repeat testing at the hospital conﬁrmed ANA positivity,anti-dsDNA of 40.0 IU/ml [o4.2], anti-histone 200 U/ml[o40], positive anti-SSA and anti-SSB, negative anticardio-lipin and anti-beta2GPI antibodies, low complement levelswith C3 0.78 g/L [0.9–1.8] and C4 0.15 g/L [0.1–0.4],haptoglobin 3.14 g/L [0,3–2], positive Coombs test, freeT3 was 71 pg/% [230–530], free T4 1.2 ng/% [0.78–1.94] andTSH 6.5 mU/ml [0.4–4]. As her d-dimer was above normallevel, a peripheral limbs Doppler test was done but itshowed no vascular occlusions.Lymphoblastic proliferation test to mefenamic acid wasnegative. Drug challenge test was not performed as it mightbe hazardous in this patient.SLE was diagnosed on the basis of a positive ANA and anti-dsDNA, Coombs positive haemolytic anaemia, leucopenia,lymphopenia, arthritis and low C3 and C4 levels. Prednisonewas tapered to 20 mg by the time of hospital discharge andadded hydroxychloroquine 200 mg qd. Her clinical andlaboratory (Figure 1) evolution were favourable and shewas discharged on the 21st hospital day in a healthycondition.an˜a, S.L. All rights reserved.cid in a patient with new onset of systemic lupus erythematosus.ARTICLE IN PRESS400350300250200150100500Hospital daySGOTSGPTHgb1 5 10 2014121086420Hgb (g/dl)SGOT and SGPT (U/L)Evolution of Hgb, SGOT and SGPT3Figure 1 Evolution of Hgb, SGOT and SGPT over time. Hgb-haemoglobin, SGOT-Serum glutamic oxaloacetic transaminase,SGPT-Serum glutamic pyruvic transaminase.RESEARCH LETTER2She continues to be followed up as an outpatient for herSLE. One year after this episode, the ANA, anti-dsDNA, anti-SSA, anti-SSB and anti-histone autoantibodies remain posi-tive at nearly identical levels.Although pharmacological inhibition of cyclooxygenasewith overproduction of cysteinyl leukotrienes is one of themost important mechanisms of the adverse mechanism ofNSAIDs, in this patient the occurrence of a rapid onset ofrash, generalised pruritus, angio-oedema and hypotensionsuggest an allergic-type response, presumably by immuno-logical IgE-mediated mechanism.10 Previous contact withthe culprit drug, corresponding to the sensitisation period,supports the diagnosis of DA.11 Skin testing to NSAIDs, prickand intradermal testing, are usually negative and correlatepoorly with the clinical history of hypersensitivity reactions.Moreover, in vitro tests are not useful in establishingdiagnosis.10 Controlled oral challenge test remains the goldstandard but it was not performed because of its high risk ofinducing a life threatening reaction.In this case, a two-step reaction with rash and dizzinessoccurring 90 min after the ingestion of mefenamic acid andthen the worsening of exanthema, pruritus, angio-oedemaand hypotension two hours after the ﬁrst clinical manifesta-tions that were treated with parental steroids and anti-histamines, support mefenamic acid as the most likely causefor anaphylaxis. Anaphylaxis usually begins within 5 to30 min after antigen exposure, but a delay of one hour ormore can occur.11 Anaphylactic shock can be biphasic and,several hours after its initial presentation, a new episodemay begin and it is not unusual for the second episode to bemore severe.11 Causality assessment was done applying theHutchinson et al. algorithm for Adverse Drug Reaction, andcorroborates the association between the drug and DA(score 5=probable).12Concerning laboratory results, the raise in hepaticenzymes, thrombocytopenia, lymphopenia and haemolyticanaemia may be due to drug toxicity or to concomitantcomplement and ﬁbrinolytic cascade activation and immunecomplex activation. Renal and hepatic manifestations mayalso occur as a part of a generalised allergic reaction.11 Also,both anaphylaxis and mefenamic acid can lower C3 and C4levels. The presence of haemolytic anaemia, lymphopenia,low C3 and C4 are features of SLE, but could not bedeﬁnitively attributed in this context.Please cite this article as: Couto M, et al. Anaphylaxis to mefenamicAllergol Immunopathol (Madr). 2010. doi:10.1016/j.aller.2009.09.011Another diagnostic hypothesis is a drug-induced lupus(DIL). This has been reported for more than 80 drugs. Thestrongest evidence of causality is for procainamide, hydra-lazine and isoniazid.8,13 Drugs such as anti-hypertensives,antibiotics and anti-convulsivants are of low risk.8 AmongNSAID only celecoxib14 has been implicated in DIL and thereare no published case reports for mefenamic acid. Thetypical features of systemic DIL are mild SLE manifestationswith positive ANA and anti-histone antibodies temporallyrelated to drug exposure which typically resolves afterdiscontinuation of the offending drug.8,13 Despite thepresence of anti-histones our patient had polyarthritis,anti-dsDNA and hypocomplementemia which play againstthe possibility of DIL. In addition, more than a year after thewithdrawal of mefenamic acid the patient maintained theseclinical and laboratory features.However, drugs such as sulphonamides,9 tetracyclines,15griseofulvin,16 piroxicam,17 ibuprofen18 and oestrogens19have been reported to exacerbate SLE or to trigger newcases. Before this report, mefenamic acid has not beenreported in any of the cases.In this case, the most likely explanation is that anaphy-laxis occurred in a patient with recent SLE. Whethermefenamic acid was implicated in exacerbation of thedisease is difﬁcult to discount or prove.This case illustrates the difﬁculties and the widedifferential diagnosis in an SLE patient who presents witha drug reaction. The attribution of the presenting symptomsto DA, DIL, drug triggering of SLE onset / exacerbation or tothe underlying SLE and/or to the drugs used to treat SLE itscoexisting conditions is a major challenge. We discuss someclues to approach this problem in the clinical setting.AcknowledgmentsWe are extremely grateful to Dr Matthew Liang for his helpin the manuscript preparation.References1. Sequeira JF, Cesic D, Keser G, Bukelica M, Karanagnostis S,Khamashta MA, et al. Allergic disorders in systemic lupuserythematosus. Lupus. 1993;2:187–91.acid in a patient with new onset of systemic lupus erythematosus.ARTICLE IN PRESSRESEARCH LETTER 32. Goldman JA, Klimek GA, Ali R. Allergy in systemic lupuserythematosus. Arthritis Rheum. 1976;19:669–75.3. Petri M, Allbritton J. Antibiotic allergy in systemic lupus erythema-tosus: A case-control study. J Rheumatol. 1992;19:265–9.4. Pope J, Jerome D, Fenlon, Krizova A, Ouimet J. Frequency ofadverse drug reactions in patients with systemic lupuserythematosus. J Rheum. 2003;30:480–4.5. Morton S, Palmer B, Muir K, Powell RJ. IgE and non-IgE mediatedallergic disorders in systemic lupus erythematosus. Ann RheumDis. 1998;57:660–3.6. Becker LC. Allergy in systemic lupus erythematosus. JohnsHopkins Med J. 1973;133:38–44.7. Von Maur K, Turk A, Stevens MB, Adkinson Jr NF, LichtensteinLM. Penicillin hypersensitivity in systemic lupus erythematosus.Int Arch Allergy Appl Immunol. 1975;49:428–33.8. Wallace DJ, Hahn BH. Drugs That May Exacerbate SLE. In Dubois’Lupus Erythematosus. 7th edn. Baltimore. Lippincott Williams &Wilkins, 2007; p. 874–5.9. Honey M. Systemic lupus erythematosus presenting withsulphonamide hypersensitivity reaction. Br Med J.1956;1:1272–5.10. Szczeklik A, Nizankowska-Mogilnicka E, Sanak M. Hypersensi-tivity to Aspirin and other NSAIDs: Mechanisms, ClinicalPresentation and Management. In Drug Hypersensitivity, Karger,Basel, 2007; p. 340–9.11. Adkinson NF Jr, Yunginger JW, Busse WW. Drug Allergy.In Middleton’s Allergy, principles and practice. New York.6th edn, Mosby Co, 2003; p. 1679–94.12. Hutchinson TA, Leventhal JM, Kramer MS, Karch FE, Lipman AG,Feinstein AR. An algorithm for the operational assessment ofadverse drug reactions. II: Demonstration of reproducibility andvalidity. JAMA. 1979;242:633–8.Please cite this article as: Couto M, et al. Anaphylaxis to mefenamic aAllergol Immunopathol (Madr). 2010. doi:10.1016/j.aller.2009.09.01113. Dalle Vedove C, Del Giglio M, Schena D, Girolomoni G. Drug-induced lupus erythematosus. Arch Dermatol Res. 2009;301:99–105.14. Poza Guedes P, Gonza´lez-Pe´rez R, Canto G. Celecoxib-inducedlupus-like syndrome. Rheumatology. 2003;42:916–7.15. Domz CA, McNamara DH, Holzapfel HF. Tetracycline provocationin lupus erythematosus. Ann Intern Med. 1959;50:1217–26.16. Anderson WA, Torre D. Griseofulvin and lupus erythematosus. J MedSoc NJ. 1982;63:161–2.17. Bigby M, Stern R. Cutaneous reactions to nonsteroidal anti-inﬂammatory drugs. A review. J Am Acad Dermatol.1985;12:866–76.18. Sonnenblick M, Abraham AS. Ibuprofen hypersensitivity insystemic lupus erythematosus. Br Med J. 1978;1:619–20.19. Whitelaw DA, Jessop SJ. Major ﬂares in women with SLE oncombined oral contraception. Clin Rheumatol. 2007;26:2163–5.M. Coutoa,b,, C. Duartea, L. Geraldesc, L. Ineˆsa,d,A. Malcataa,baDepartment of Rheumatology, Coimbra University Hospi-tal, Coimbra, PortugalbCoimbra University School of Medicine, Coimbra, PortugalcDepartment of Immunology and Allergy, Coimbra Univer-sity Hospital, Coimbra, PortugaldHealth Sciences School of Medicine, Beira Interior Uni-versity, Covilha˜ PortugalCorresponding author.E-mail address: maura_couto@yahoo.com (M. Couto).cid in a patient with new onset of systemic lupus erythematosus.

Anaphylaxis to mefenamic acid in a patient with new onset of systemic lupus erythematosus

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