A study on the epidemiology of Stevens-Johnson syndrome and toxic epidermal necrolysis

Frey, Noel. A study on the epidemiology of Stevens-Johnson syndrome and toxic epidermal necrolysis. 2018, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_12726

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Pharmacoepidemiology is the science of the use and the effects of drugs in large human populations. Although originally confined to post-marketing drug surveillance of rare or long-latency adverse drug events, the science is gaining increased importance and is regularly applied to assess drug utilization patterns and cost-effectiveness, to characterize target populations of drugs in development, to evaluate undiscovered beneficial or detrimental drug effects, or to provide evidence of effectiveness when randomized controlled trials face ethical or practical barriers.
Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare but life-threatening mucocutaneous diseases that predominantly occur as adverse reactions to newly administered drugs. The current knowledge of SJS/TEN is sparse, mainly due to the rare nature of SJS/TEN and the long-time unclear classification of the disease. As a consequence many aspects of SJS/TEN remain unclear despite the severe impact of SJS/TEN on affected patients.
The aim of this comprehensive SJS/TEN project presented within this thesis was to contribute to the general understanding of SJS/TEN, thereby focusing on the epidemiology and potential culprit drugs. The project comprises five individual observational studies using data from the Clinical Practice Research Datalink (CPRD). This United Kingdom (UK)-based database contains longitudinal primary-care records of millions of patients, representative of the UK population. Information is recorded by general practitioners and includes demographics, lifestyle factors, medical diagnoses, referrals to secondary care, laboratory and diagnostic results, and a complete history of drug prescriptions.
In Study 3.1 we comprehensively validated incident SJS/TEN diagnoses recorded in the CPRD between 1995 and 2013. The aim of this study was to assess whether SJS/TEN can be studied using CPRD data, and to establish a large and valid SJS/TEN case population. Using diagnoses from secondary care as a gold standard, we managed to compose a case population consisting of 551 SJS/TEN patients with a positive predictive value of 90% in cooperation with two specialised clinicians.
In Study 3.2 we calculated an overall incidence rate in the UK of 5.76 SJS/TEN cases/1’000’000 person-years, whereby incidence rates were highest in patients aged <10 or ≥80 years. In a case-control analysis, we further found that patients of black, Asian, or mixed ethnicity were at increased risk of SJS/TEN when compared to Caucasians, and observed associations between SJS/TEN and pre-existing depression, lupus erythematosus, chronic kidney disease, recent pneumonia, and active cancer.
In the Studies 3.3, 3.4, and 3.5, we conducted case-control analyses to assess associations between SJS/TEN and drugs which have previously been associated with SJS/TEN. We furthermore calculated cumulative incidences of SJS/TEN for each of these drugs to assess the absolute risk of SJS/TEN among drug users.
Study 3.3 confirms associations between SJS/TEN and the aromatic antiepileptics carbamazepine, phenytoin, and lamotrigine, with absolute risks of 20-46 SJS/TEN cases/100’000 new users. Conversely to previous reports we did not find any exposed cases for valproate, gabapentin and pregabalin despite high number of new users (>40’000).
While previous case-control studies reported a strong association between SJS/TEN and cotrimoxazole (sulfamethoxazole+trimethoprim), Study 3.4 was the first to show an association between SJS/TEN and trimethoprim as a single agent with an absolute risk of 1 SJS/TEN case/100’000 users. Only few patients were exposed to sulfonamide antibiotics in the CPRD which is why we were not able to study associations for sulfamethoxazole and other anti-infective sulfonamides. This study further corroborates previously reported associations between SJS/TEN and use of penicillins, quinolones, cephalosporins, and macrolides (0.3-1.0 SJS/TEN cases/100’000 users).
Study 3.5 confirms the previously reported association between SJS/TEN and allopurinol with an absolute risk of 6 SJS/TEN cases/100’000 new users. Further drugs identified as possible triggers of SJS/TEN were coxibs (1.9 cases/100’000 new users), sulfasalazine (4.3 cases/100’000 new users), mesalamine (3.8 cases/100’000 new users), mirtazapine (1.6 cases/100’000 new users), and fluoxetine (0.2 cases/100’000 new users). We further observed an association between SJS/TEN and proton pump inhibitors (0.5-1.3 cases/100’000 new users). However, proton pumps are often used in combination with other drugs (e.g nonsteroidal anti-inflammatory drugs) which could potentially confound such an association. Only little evidence previously suggested associations between SJS/TEN and these drugs. For various other drugs which have been suggested as culprit drugs of SJS/TEN in case reports (oxicam analgesics, benzodiazepines, citalopram, sertraline, paroxetine, venlafaxine, and phosphodiesterase-5 inhibitors), we did not find any exposed SJS/TEN cases despite a high number of new users (>100’000) in the CPRD. Our results suggest that these drugs appear to be at least relatively safe in terms of SJS/TEN.
In summary, the population-based observational studies presented in this thesis contribute to the understanding of the epidemiology of SJS/TEN yielding the first calculated incidence rates of SJS/TEN in the UK and information on patients at higher risk of SJS/TEN. They further include comprehensive analyses of culprit drugs of SJS/TEN, which provide important evidence for the successful treatment of SJS/TEN patients, as early discontinuation of the culprit drug is crucial and often decisive for the outcome of SJS/TEN.
Advisors:Meier, Christoph and Krähenbühl, Stephan
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Clinical Pharmacy (Meier)
UniBasel Contributors:Frey, Noel and Krähenbühl, Stephan
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12726
Thesis status:Complete
Number of Pages:1 Online-Ressource (174 Seiten)
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edoc DOI:
Last Modified:08 Feb 2020 14:59
Deposited On:06 Sep 2018 09:26

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