Association between Stevens-Johnson syndrome and toxic epidermal necrolysis with ibuprofen: A pharmacovigilance study in the UK Yellow Card scheme and systematic review of case reports

Introduction Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a group of severe acute muco-cutaneous blistering disorders with a significant burden of morbidity and mortality. Drugs are commonly identified as potential precipitants of SJS/TEN, although it can be difficult to firmly identify causative agents. Ibuprofen has been proposed as a rare trigger for SJS/TEN and given the widespread use of this non-steroidal anti-inflammatory and significance of reaction, further pharmacovigilance analysis is warranted. Methods Serious or fatal adverse drug reaction (ADR) data from 1998 – October 2023 were downloaded from the UK MHRA Yellow Card Scheme website. Proportional reporting ratios (PRR) and 95% confidence intervals were calculated for SJS and TEN associated with ibuprofen using standard pharmacovigilance methods. Secondly, a systematic review of literature was conducted to explore reported cases where ibuprofen was the suspected trigger for a case of SJS/TEN. Eligible cases were assessed for the likelihood of ibuprofen being the causative agent by two reviewers using the Naranjo adverse drug reaction probability scale and the ALDEN algorithm for the assessment of drug causality in SJS/TEN. Results In total, 1, 994, 967 ARDs, relating to 1,811 SJS reports and 1,299 TEN reports. There was an increased signal for reports of SJS-TEN associated with ibuprofen use. The PRR for SJS with ibuprofen was 3.73 (95% confidence interval 2.68 – 5.18) and 4.49 (95% confidence interval 3.15 – 6.41). In our literature review, 23 individual case reports were deemed eligible for inclusion and the majority of these cases were determined as being doubtful in causality assessment. Difficulty in attributing causality was related to poorly defined temporal relationships between ibuprofen and SJS-TEN or poor reporting standards of case reports. Conclusions There are pharmacovigilance signals suggesting increased reporting of SJS/TEN in patients exposed to ibuprofen within UK data. However, more detailed case reports describing this association in literature have low likelihood of supporting causality. It is possible that reverse causality or co-causality is mediating this association. Further studies and pharmacovigilance is required to clarify the association between SJS/TEN and ibuprofen.