COX-2–selective inhibitor valdecoxib induces severe allergic skin reactions

Abstract

To the Editor: Since the 1960s, when the nonsteroidal anti-inflammatory drugs (NSAIDs) were launched into the market, several adverse events have been reported,1Dieppe P.A. Ebrahim S. Martin R.M. Juni P. Lessons from the withdrawal of rofecoxib.BMJ. 2004; 329: 867-868Crossref PubMed Scopus (112) Google Scholar including skin eruptions mostly caused by nonimmunological rather than allergic mechanisms.2Szczeklik A. Stevenson D.D. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management.J Allergy Clin Immunol. 2003; 111: 913-921Abstract Full Text PDF PubMed Scopus (405) Google Scholar, 3Kruse R. Ruzicka T. Grewe M. Intolerance reactions due to the selective cyclooxygenase type II inhibitors rofecoxib and celecoxib: results of oral provocation tests in patients with NSAID hypersensitivity.Acta Derm Venereol. 2003; 83: 183-185Crossref PubMed Scopus (11) Google Scholar NSAIDs exert their analgesic, antipyretic, anti-inflammatory, and antithrombotic effects by inhibiting both COX-1 and COX-2 activities.4Sanchez Borges M. Capriles-Hulett A. Caballero-Fonseca F. Perez C.R. Tolerability to new COX-2 inhibitors in NSAID-sensitive patients with cutaneous reactions.Ann Allergy Asthma Immunol. 2001; 87: 201-204Abstract Full Text PDF PubMed Scopus (118) Google Scholar, 5Grob M. Sheidegger P. Wuthrich B. Allergic skin reaction to celecoxib.Dermatology. 2000; 201: 383Crossref PubMed Scopus (37) Google Scholar, 6Munoz-Bellido F.J. Terron M. Leon A. Safety of rofecoxib in nonsteroidal anti-inflammatory drugs intolerance.Allergy. 2003; 58: 1072-1075Crossref PubMed Scopus (8) Google Scholar However, the primary responsibility for the synthesis of prostanoids involved in acute and chronic inflammatory states has been credited to COX-2, whereas the gastrointestinal adverse effects have been attributed to COX-1 activity.1Dieppe P.A. Ebrahim S. Martin R.M. Juni P. Lessons from the withdrawal of rofecoxib.BMJ. 2004; 329: 867-868Crossref PubMed Scopus (112) Google Scholar, 6Munoz-Bellido F.J. Terron M. Leon A. Safety of rofecoxib in nonsteroidal anti-inflammatory drugs intolerance.Allergy. 2003; 58: 1072-1075Crossref PubMed Scopus (8) Google Scholar The consequent hypothesis that specific inhibition of this enzyme could have therapeutic effects similar to those of other NSAIDs but without causing gastrointestinal side effects led to the development of COX-2–selective antagonists. Valdecoxib (Bextra, Pfizer, Buckinghamshire, United Kingdom) is one of these new drugs. In the last few years, it has been increasingly prescribed for the treatment of osteoarthritis, rheumatoid arthritis, primary dysmenorrhea, and moderate to severe postoperative pain.7Chavez M.L. DeKorte C.J. Valdecoxib: a review.Clin Ther. 2003; 25: 817-851Abstract Full Text PDF PubMed Scopus (81) Google Scholar COX-2–specific inhibitors have an alleged safer profile compared with other nonselective NSAIDs.4Sanchez Borges M. Capriles-Hulett A. Caballero-Fonseca F. Perez C.R. Tolerability to new COX-2 inhibitors in NSAID-sensitive patients with cutaneous reactions.Ann Allergy Asthma Immunol. 2001; 87: 201-204Abstract Full Text PDF PubMed Scopus (118) Google Scholar, 5Grob M. Sheidegger P. Wuthrich B. Allergic skin reaction to celecoxib.Dermatology. 2000; 201: 383Crossref PubMed Scopus (37) Google Scholar, 6Munoz-Bellido F.J. Terron M. Leon A. Safety of rofecoxib in nonsteroidal anti-inflammatory drugs intolerance.Allergy. 2003; 58: 1072-1075Crossref PubMed Scopus (8) Google Scholar However, several adverse events caused by selective COX-2 inhibitors have been described.8Alonso J.C. Ortega J.D. Gonzalo M.J. Cutaneous reaction to oral celecoxib with positive patch test.Contact Dermatitis. 2004; 50: 48-49Crossref PubMed Scopus (7) Google Scholar, 9Goeschke B. Braathen L.R. Acute generalized exanthematic pustulosis: a case and an overview of side effects affecting the skin caused by celecoxib and other COX-2 inhibitors reported so far.Dermatology. 2004; 209: 53-56Crossref PubMed Scopus (21) Google Scholar We report here a case of severe hypersensitivity skin reaction caused by valdecoxib. A 58-year-old man presented with a 2-day history of exanthem, malaise, and fever. For the treatment of arthralgy, the patient had been taking a daily dose of 20 mg valdecoxib for 6 days before the onset of skin lesions. No previous history of skin reactions to other NSAIDs or sulfonamides was reported. On admission, physical examination showed a generalized confluent maculopapular exanthem without mucous membrane involvement (Fig 1, A). Routine blood examination revealed leukocytosis and increased values of creatinine, lactate dehydrogenase, total bilirubin, C-reactive protein, and eosinophil cationic protein. Serological tests for adenovirus, echovirus, coxsackie, measles, and hepatitis virus were negative, and antibodies to rubella and Epstein-Barr virus showed signs of previous infection. Ultrasonography revealed enlargement of lymph nodes caused by local inflammation. After discontinuation of valdecoxib and treatment with systemic glucocorticosteroids, antihistamines, and local glucocorticosteroids, the exanthem disappeared. Histopathological examination of a skin biopsy revealed slight spongiosis of the epidermis and a perivascular inflammatory infiltrate consisting mostly of lymphocytes, neutrophils, and few eosinophils. Skin prick tests with seasonal and perennial airborne allergens as well as standard food allergens were uniformly negative. Scratch tests performed with nonspecific NSAIDs (acetylsalicylic acid, metamizol, paracetamol, diclofenac, indometacin, ibuprofen) as well as the COX-2–selective inhibitors celecoxib and valdecoxib showed no skin reactions after 20 minutes. However, 24 hours later, a severe erythematous and edematous skin lesion occurred, spreading over the forearm where scratch tests had been performed (Fig 1, B). Notably, subsequent scratch tests with acetylsalicylic acid, metamizol, paracetamol, diclofenac, indometacin, ibuprofen, and celecoxib, but without valdecoxib, were uniformly negative at 20 minutes as well as 24 hours after exposure. In epicutaneous patch testing with standard allergens and Bextra, the tests with benzalkonium chloride and cetalkonium chloride were + (according to the International Contact Dermatitis Research Group criteria),10Wilkinson D.S. Fregert S. Magnusson H. Bandmann H.J. Calnan C.D. Cronin E. et al.Terminology of contact dermatitis.Acta Derm Venereol. 1970; 50: 287-292PubMed Google Scholar and in the test with Bextra, a +++ delayed-type skin reaction with a peak response on day 3 developed. In addition, patch testing with single components of Bextra revealed +++ skin reactions to the pure active substance valdecoxib (1% and 10% in acqua) with peak responses on days 2 and 3 (Fig 1, C). To exclude valdecoxib-induced irritant responses, healthy individuals (n = 4) were patch-tested with valdecoxib (1%, 10%) and demonstrated no skin reactions. Nonimmunological hypersensitivity reaction to nonspecific NSAIDs is a well-known and frequent cause of skin reactions. An increasing number of studies suggest that the COX-2–selective antagonists can be safely taken by patients who develop cutaneous reactions caused by nonselective NSAIDs.3Kruse R. Ruzicka T. Grewe M. Intolerance reactions due to the selective cyclooxygenase type II inhibitors rofecoxib and celecoxib: results of oral provocation tests in patients with NSAID hypersensitivity.Acta Derm Venereol. 2003; 83: 183-185Crossref PubMed Scopus (11) Google Scholar, 4Sanchez Borges M. Capriles-Hulett A. Caballero-Fonseca F. Perez C.R. Tolerability to new COX-2 inhibitors in NSAID-sensitive patients with cutaneous reactions.Ann Allergy Asthma Immunol. 2001; 87: 201-204Abstract Full Text PDF PubMed Scopus (118) Google Scholar, 6Munoz-Bellido F.J. Terron M. Leon A. Safety of rofecoxib in nonsteroidal anti-inflammatory drugs intolerance.Allergy. 2003; 58: 1072-1075Crossref PubMed Scopus (8) Google Scholar However, here we report that the COX-2–selective inhibitor valdecoxib may induce severe allergic skin reactions. Because valdecoxib and celecoxib have an analogous chemical structure,7Chavez M.L. DeKorte C.J. Valdecoxib: a review.Clin Ther. 2003; 25: 817-851Abstract Full Text PDF PubMed Scopus (81) Google Scholar, 8Alonso J.C. Ortega J.D. Gonzalo M.J. Cutaneous reaction to oral celecoxib with positive patch test.Contact Dermatitis. 2004; 50: 48-49Crossref PubMed Scopus (7) Google Scholar one could expect a cross-reaction between these 2 drugs. However, in previous reports showing allergic skin reactions to celecoxib, tests with other specific COX-2 inhibitors were either negative8Alonso J.C. Ortega J.D. Gonzalo M.J. Cutaneous reaction to oral celecoxib with positive patch test.Contact Dermatitis. 2004; 50: 48-49Crossref PubMed Scopus (7) Google Scholar or not mentioned.5Grob M. Sheidegger P. Wuthrich B. Allergic skin reaction to celecoxib.Dermatology. 2000; 201: 383Crossref PubMed Scopus (37) Google Scholar A scratch test with celecoxib demonstrated no reaction in our patient. Although these findings suggest that a cross-reaction is unlikely, further studies are necessary to confirm this. To the best of our knowledge, this is the first report of valdecoxib-induced skin allergy confirmed by a positive patch test. The presented case shows that the COX-2–selective inhibitors valdecoxib may cause severe allergic cutaneous reactions, adding a new aspect to the side effect profile of this drug.