Aims: Epidermal necrolysis (EN) is a rare and severe condition characterized by a diffuse skin and mucosal detachment, mainly induced by drugs. Literature is scarce regarding the rate of recurrences and drug re-exposure. The aim was to assess the rate of subsequent EN recurrences such as re-exposure of high notoriety drugs in patients with EN. Methods: We used the French Health system database and included all EN patients. The primary outcome was the rate of EN recurrence. Secondary outcomes were high notoriety drugs re-exposure or cross exposure, i.e., exposure to a drug of the same family, after the acute phase of EN, when initially suspected. Results: A total of 1,203/1,440 patients (83.5%) survived the acute phase, with 27 patients (2.2% (CI95%: 1.5-3.2)) meeting the recurrence criteria. In patients with allopurinol as suspected drug, 10/77 (13.0%) were cross exposed to febuxostat, without recurrence. Similarly, in patients with carbamazepine/oxcarbazepine as suspected drug, 2/26 (7.6%) were cross exposed to lamotrigine, without recurrence. Conversely, 12/38 (31.5%) and 16/37 (43.2%) patients were respectively re-exposed to pantoprazole and esomeprazole when suspected, and 12/42 (28.6%) were re-exposed to amoxicillin. Only one recurrence was noted in a pantoprazole re-exposed patient. Conclusions: Among EN patients, the rate of recurrence seems low, contrasting with several re-exposures among beta lactam antibiotics and proton pump inhibitors, when suspected. Although we cannot exclude that the suspected drugs were not the responsible ones for several patients, future studies should assess the possible existence of transient risk factors inducing EN.

Background: Since the 2002 SCAR study, erythema multiforme(EM), a post-infectious disease, has been distinguished from Stevens-Johnson syndrome (SJS), drug-induced. Nevertheless, EM cases are still reported in the French pharmacovigilance database (FPDB). Objectives: To describe EM reported in the FPDB and to compare the characteristics of the reports. Methods: This retrospective observational study selected all EM cases reported in the FPDB over two periods: period 1 (P1, 2008-2009) and period 2 (P2, 2018-2019). Inclusion criteria were 1) a diagnosis of clinically typical EM and/or one validated by a dermatologist; 2) a reported date of onset of the reaction; and 3) a precise chronology of drug exposure. Cases were classified confirmed EM (typical acral target lesions and/or validation by a dermatologist) and possible EM (not-otherwise-specified target lesions, isolated mucosal involvement, doubtful with SJS). We concluded possible drug-induced EM when EM was confirmed, with onset ranging from 5 to 28 days without an alternative cause. Results: Among 182 selected reports, 140(77%) were analyzed. Of these, 67(48%) presented a more likely alternative diagnosis than EM. Of the 73 reports of EM cases finally included (P1, n=41; P2, n=32), 36(49%) had a probable non-drug cause and 28(38%) were associated with only drugs with an onset time ≤4 days and/or ≥ 29 days. Possible drug-induced EM was retained in 9 cases (6% of evaluable reports). Conclusions: This study suggests that possible drug-induced EM is rare. Many reports describe “polymorphic” rashes inappropriately concluded as EM or post-infectious EM with unsuitable drug accountability subject to protopathic bias.

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as Drug-induced hypersensitivity syndrome (DIHS), is a rare but severe delayed-type drug hypersensitivity reaction [[](#ref-0001)1]. Its reported incidence ranges between 2 and 5 cases per million per year and the mortality between 5 and 10% [[](#ref-0002)2]. DRESS is characterized by the occurrence of an extensive rash with face edema, lymphadenopathy and fever and organ damage, all of which seems to result from massive drug-directed T cell response and associated eosinophilia. DRESS is a complex condition, its clinical presentation varies depending on the cutaneous manifestation(s), affected target organ(s) and reaction severity. The diagnosis of DRESS is further challenged by the clinical overlay with autoimmune, infectious and lymphoproliferative conditions, which have to be considered in the differential diagnosis (Table 1). Eosinophilia is detected in only 80 % of DRESS patients and can be masked by e.g. the administration of systemic glucocorticoids (GCS). Furthermore, there are various differences in the DRESS diagnostic criteria (Table 1) developed by the Japanese SCAR (JSPS) [[](#ref-0003)3] and RegiSCAR [[](#ref-0004)4] groups, the most notable being the inclusion of herpes viremia in the criteria developed by the JSPS. All these clinical challenges underline the importance of a systematic and comprehensive approach when encountering a patient with suspected DRESS. Based on the most recent literature and our clinical expertise, we therefore suggest the medical algorithm depicted in Figure 1. DRESS should be evoked as a differential diagnosis in patients with a rash suspected to be drug-related and associated with head-and-neck edema [[](#ref-0005)5]. Clinical history-taking is a critical element to consolidate or discard a drug-related etiology: most importantly, this should explore the dynamics of both possible DRESS clinical symptoms and drug exposure(s) (date of onset, way and length of administration, previous exposures / reactions). A long drug exposure prior to disease onset, i.e. 2-8 weeks, is indicative for DRESS rather than other drug hypersensitivities – but the duration may vary depending on the causative drug. A thorough clinical examination, basic laboratory work-up, electrocardiogram, and - if a rash is present - a skin biopsy should also be performed. If the clinical presentation and drug exposure history substantiate the DRESS diagnosis, additional investigations should be performed depending on the suspected target organ damage (cf. case “complementary, patient-specific work-up”). Once the diagnosis is established, a severity assessment is warranted, since DRESS can range from mild forms with very limited organ damage to fulminant ones, e.g. characterized by (multi-)organ failure. There are no consensual severity scoring. In this algorithm, we suggest the scoring system used in France (RCT DRESSCODE, https://clinicaltrial.gov NCT01987076).

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