Incidence of Stevens-Johnson syndrome/toxic epidermal necrolysis among new users of different individual drugs in a European population: a case-population study
- 145 Downloads
To estimate the specific incidences of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) among new users of drugs frequently reported to be associated with this serious event.
We performed a case-population approach, which combined data from a registry of SJS/TEN cases from the Madrid region (numerator) during the study period 2005–2015 and a primary healthcare database from the same catchment population. The proportion of new users of drugs estimated in the primary healthcare database was stratified by calendar year, sex and age (5-year bands), and then applied to the same strata of Madrid’s population census to compute the number of new users (denominator). Incidences were re-estimated using only cases in which the concerned drug had a probable or very probable causal relationship.
A total of 44 SJS/TEN cases aged > 14 years were registered during the study period. The highest SJS/TEN incidence was found for phenytoin with 68.9 per 100,000 new users (95% CI 27.7–141.9), followed by dexamethasone (5.48; 1.49–14.03), allopurinol (3.29; 1.07–7.67) and cotrimoxazole (3.19; 0.87–8.16). Considering only probable and very probable cases, the incidences hardly changed, except for dexamethasone, which was left without cases. Pantoprazole, levofloxacin and lorazepam showed incidences between 1 per 100,000 and 1 per 1,000,000 new users. Ibuprofen, amoxicillin-clavulanic acid, metamizole, amoxicillin, paracetamol and omeprazole showed incidences around 1 per one million new users.
Phenytoin was the drug with the highest incidence of SJS/TEN, followed by allopurinol and cotrimoxazole. For the rest of the drugs, the estimated incidences were below 1 in 100,000 new users.
KeywordsToxic epidermal necrolysis Stevens-Johnson syndrome SCAR Hypersensitivity Case-population study
We are grateful to all members of the PIELenRed Consortium and patients who take part in this study. The authors would like to acknowledge the excellent collaboration of primary care practitioners taking part in BIFAP and the BIFAP staff for their collaboration and provision of resources to access the database. All views expressed in this article are those of the authors and do not necessarily represent the views of their institutions.
The present study was supported by a research grant from the Instituto de Salud Carlos III - Ministerio de Economía y Competitividad (no. PI12/02267), co-founded by FEDER. The Spanish Agency of Medicinal Products and Medical Devices supports the management of the PIELenRed registry and is the owner of the database BIFAP.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Informed consent was obtained from all prospective individual participants or legal representatives. For retrospective cases, the Ethics Research Committee granted us an exemption. BIFAP is a fully anonymised database, and according to the Spanish law, an informed consent is not required when no personal data is collected.
- 2.Diphoorn J, Cazzaniga S, Gamba C, Schroeder J, Citterio A, Rivolta AL, Vighi GD, Naldi L, REACT-Lombardia study group (2016) Incidence, causative factors and mortality rates of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in northern Italy: data from the REACT registry. Pharmacoepidemiol Drug Saf 25:196–203CrossRefGoogle Scholar
- 3.Sekula P, Dunant A, Mockenhaupt M, Naldi L, Bouwes Bavinck JN, Halevy S, Kardaun S, Sidorodd A, Liss Y, Schumacher M, Roujeau JC, RegiSCAR syudy group (2013) Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Investig Dermatol 133:1197–1204CrossRefGoogle Scholar
- 4.Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schröder W, Roujeau JC, SCAR Study Group. Severe Cutaneous Adverse Reactions (2002) Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol 138:1019–1024CrossRefGoogle Scholar
- 5.Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, Auquier A, Bastuji-Garin S, Correia O, Locati F, Mockenhaupt M, Paoletti C, Shapiro S, Shear N, Schöpf E, Kaufman DW (1995) Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 333:1600–1607CrossRefGoogle Scholar
- 6.Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, Sidorodd A, Schneck J, Roujeau JC, Flahault A (2008) Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Investig Dermatol 128:35–44CrossRefGoogle Scholar
- 7.Moore N, Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R, Jové J, Pariente A, Blin P, Bénichou J, Bégaud B (2013) Choice of the denominator in case population studies: event rates for registration for liver transplantation after exposure to NSAIDs in the SALT study in France. Pharmacoepidemiol Drug Saf 22:160–167CrossRefGoogle Scholar
- 15.Yang MS, Lee JY, Kim J, Kim G, Kim BK, Kim JY, Park HW, Cho SH, Min KU, Kang HR (2016) Incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis: a nationwide population-based study using National Health Insurance Database in Korea. PLoS One 11(11):e0165933. https://doi.org/10.1371/journal.pone.0165933 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.The RegiSCAR Project Available at: http://www.regiscar.org. Accessed 30 Jan 2018
- 19.PIELenRed. ConsorcioPIELenRed Available at: http://pielenred.hol.es/PIELenRed/2015. Accessed 24 Mar 2018
- 20.Agencia Española de Medicamentos y Productos Sanitarios BIFAP: Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria Available at: http://bifap.aemps.es/. Accessed 24 Mar 2018
- 21.Rodríguez-Martín S, Martín-Merino E, Lerma V, Rodríguez-Miguel A, González O, González-Herrada C, Ramírez E, Bellón T, de Abajo FJ (2018) Active surveillance of severe cutaneous adverse reactions: a case-population approach using a registry and a healthcare database. Pharmacoepidemiol Drug Saf:1–9. https://doi.org/10.1002/pds.4622 CrossRefGoogle Scholar
- 22.González-Herrada C, Rodríguez-Martín S, Cachafeiro L, Lerma V, González O, Lorente JA, Rodríguez-Miguel A, González-Ramos J, Roustan G, Ramírez E, Bellón T, de Abajo FJ, PIELenRed Therapeutic Management Working Group (2017) Cyclosporine use in epidermal necrolysis is associated with an important mortality reduction: evidence from three different approaches. J Investig Dermatol 137:2092–2100CrossRefGoogle Scholar
- 23.Huerta C, Abbing-Karahagopian V, Requena G, Oliva B, Alvarez Y, Gardarsdottir H (2013) Prevalence of use of benzodiazepines and related drugs in seven European databases: a cross-national descriptive study from the PROTECT-EU project. Pharmacoepidemiol Drug Saf 22:1–512Google Scholar
- 24.De Abajo FJ, Gil MJ, García-Poza P, Bryant V, Oliva B, Timoner J, García-Rodríguez LA (2014) Risk of nonfatal acute myocardial infarction associated with non-steroidal antiinflammatory drugs, non-narcotic analgesics and other drugs used in osteoarthritis: a nested case-control study. Pharmacoepidemiol Drug Saf 23:1128–1138CrossRefGoogle Scholar
- 27.Instituto de Estadística. Comunidad de Madrid. Available at: http://www.madrid.org/iestadis/fijas/otros/estructu_cen.htm. Accessed 10 Jan 2018
- 28.Sassolas B, Haddad C, Mockenhaupt M, Dunant A, Liss Y, Bork K, Haustein UF, Vieluf D, Roujeau JC, Le Louet H (2010) ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson syndrome and toxic epidermal necrolysis: comparison with case-control analysis. Clin Pharmacol Ther 88:60–68CrossRefGoogle Scholar
- 29.Council for International Organisations of Medical Sciences (1995) Guidelines for preparing core clinical safety information on drugs. Geneva: CIOMS. Available at: https://cioms.ch/shop/product/guidelines-preparing-core-clinical-safety-information-drugs-second-edition-report-cioms-working-groups-iii-v/. Accessed 16 June 2018
- 30.Lee HY, Dunant A, Sekula P, Mockenhaupt M, Wolkenstein P, Valeyrie-Allanore L, Naldi L, Halevy S, Roujeau JC (2012) The role of prior corticosteroid use on the clinical course of Stevens-Johnson syndrome and toxic epidermal necrolysis: a case-control analysis of patients selected from the multinational EuroSCAR and RegiSCAR studies. Br J Dermatol 167:555–562CrossRefGoogle Scholar
- 31.Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Bouwes Bavinck JN, Sidoroff A, Naldi L, Dunant A, Viboud C, Roujeau JC, EuroSCAR Study Group (2008) Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol 58:25–32CrossRefGoogle Scholar
- 33.Saksit N, Tassaneeyakul W, Nakkam N, Konyoung P, Khunarkornsiri U, Chumworathayi P, Sukasem C, Suttisai S, Piriyachananusorn N, Tiwong P, Chaiyakunapruk N, Sawanyawisuth K, Rerkpattanapipat T, Tassaneeyakul W (2017) Risk factors of allopurinol-induced severe cutaneous reactions in Thai population. Pharmacogenet Genomics 27:255–263CrossRefGoogle Scholar