Khalaf Kridin1,2, Marie-Charlotte Brüggen3,4,5,6, Ser-Ling Chua6,7, Anette Bygum6,8, Sarah Walsh6,9, Mirjam C Nägeli3,4, Vesta Kucinskiene6,10,11, Lars French6,12,13, Florence Tétart6,14,15, Biagio Didona6,16, Brigitte Milpied6,14,17, Annamari Ranki6,18,19, Carmen Salavastru6,20,21, Eva Brezinová6,22, Sapna Divani-Patel7, Tine Lorentzen8, Julie Loft Nagel8, Skaidra Valiukeviciene10,11, Viktorija Karpaviciute11, George-Sorin Tiplica6,20,23, Eva Oppel12, Anna Oschmann12, Nicolas de Prost14,24, Artem Vorobyev1,6,25, Saskia Ingen-Housz-Oro6,14,26,27. 1. Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. 2. Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel. 3. Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland. 4. Faculty of Medicine, University of Zurich, Zurich, Switzerland. 5. Medical Campus Davos, Davos, Switzerland. 6. ToxiTEN group, European Reference Network for Rare Skin Diseases, Paris, France. 7. Department of Dermatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom. 8. Department of Dermatology and Allergy Center, Odense University Hospital, Clinical Institute, University of Southern Denmark, Odense, Denmark. 9. Department of Dermatology, King's College Hospital, London, United Kingdom. 10. Department of Skin and Venereal Diseases, Lithuanian University of Health Sciences (LUHS), Hospital of LUHS Kauno Klinikos, European Reference Network for Rare and Complex Diseases of the Skin members, Kaunas, Lithuania. 11. Department of Skin and Venereal Diseases, Lithuanian University of Health Sciences, Kaunas, Lithuania. 12. Department of Dermatology, University Hospital, Munich University of Ludwig Maximilian, Munich, Germany. 13. Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida. 14. Toxic Bullous Dermatoses and Severe Drug Reactions reference center, TOXIBUL FIMARAD network, Assistance Publique-Hôpitaux de Paris, Henri Mondor Hospital, Créteil, France. 15. Department of Dermatology, Inserm U519, Rouen University Hospital, Rouen, France. 16. Rare Disease Unit, I Dermatology Division, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy. 17. Department of Dermatology, Saint André Hospital, Bordeaux, France. 18. Department of Dermatology, Allergology and Venereology, University of Helsinki, Helsinki, Finland. 19. Helsinki University Hospital, Inflammation Center, Helsinki, Finland. 20. Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. 21. Department of Pediatric Dermatology, Colentina Clinical Hospital, Bucharest, Romania. 22. First Department of Dermatovenereology, Masaryk University Faculty of Medicine, St Ann's Faculty Hospital in Brno, Brno, Czech Republic. 23. Department of Dermatology, Colentina Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. 24. Intensive care unit, AP-HP, Henri Mondor Hospital, Créteil, France. 25. Department of Dermatology, University Medical Center Schleswig-Holstein, Lübeck, Germany. 26. Dermatology Department, AP-HP, Henri Mondor Hospital, Créteil, France. 27. University Paris-Est Créteil EpiDermE, Créteil, France.
Abstract
IMPORTANCE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug reactions associated with a high rate of mortality and morbidity. There is no consensus on the treatment strategy. OBJECTIVE: To explore treatment approaches across Europe and outcomes associated with the SJS/TEN disease course, as well as risk factors and culprit drugs. DESIGN, SETTING, AND PARTICIPANTS: A retrospective pan-European multicenter cohort study including 13 referral centers belonging to the ToxiTEN ERN-skin subgroup was conducted. A total of 212 adults with SJS/TEN were included between January 1, 2015, and December 31, 2019, and data were collected from a follow-up period of 6 weeks. MAIN OUTCOMES AND MEASURES: Risk factors for severe acute-phase complications (acute kidney failure, septicemia, and need for mechanical ventilation) and mortality 6 weeks following admission were evaluated using a multivariable-adjusted logistic regression model. One tool used in evaluation of severity was the Score of Toxic Epidermal Necrolysis (SCORTEN), which ranges from 0 to 7, with 7 the highest level of severity. RESULTS: Of 212 patients (134 of 211 [63.7%] women; mean [SD] age, 51.0 [19.3] years), the mean (SD) body surface area detachment was 27% (32.8%). In 176 (83.0%) patients, a culprit drug was identified. Antibiotics (21.2%), followed by anticonvulsants (18.9%), nonsteroidal anti-inflammatory drugs (11.8%), allopurinol (11.3%), and sulfonamides (10.4%), were the most common suspected agents. Treatment approaches ranged from best supportive care only (38.2%) to systemic glucocorticoids (35.4%), intravenous immunoglobulins (23.6%), cyclosporine (10.4%), and antitumor necrosis factor agents (3.3%). Most patients (63.7%) developed severe acute-phase complications. The 6-week mortality rate was 20.8%. Maximal body surface area detachment (≥30%) was found to be independently associated with severe acute-phase complications (fully adjusted odds ratio [OR], 2.49; 95% CI, 1.21-5.12; P = .01) and SCORTEN greater than or equal to 2 was significantly associated with mortality (fully adjusted OR, 10.30; 95% CI, 3.82-27.78; P < .001). Cyclosporine was associated with a higher frequency of greater than or equal to 20% increase in body surface area detachment in the acute phase (adjusted OR, 3.44; 95% CI, 1.12-10.52; P = .03) and an increased risk of infections (adjusted OR, 7.16; 95% CI, 1.52-33.74; P = .01). Systemic glucocorticoids and intravenous immunoglobulins were associated with a decreased risk of infections (adjusted OR, 0.40; 95% CI, 0.18-0.88; P = .02). No significant difference in 6-week mortality was found between treatment groups. CONCLUSIONS AND RELEVANCE: This cohort study noted differences in treatment strategies for SJS/TEN in Europe; the findings suggest the need for prospective therapeutic studies to be conducted and registries to be developed.
IMPORTANCE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug reactions associated with a high rate of mortality and morbidity. There is no consensus on the treatment strategy. OBJECTIVE: To explore treatment approaches across Europe and outcomes associated with the SJS/TEN disease course, as well as risk factors and culprit drugs. DESIGN, SETTING, AND PARTICIPANTS: A retrospective pan-European multicenter cohort study including 13 referral centers belonging to the ToxiTEN ERN-skin subgroup was conducted. A total of 212 adults with SJS/TEN were included between January 1, 2015, and December 31, 2019, and data were collected from a follow-up period of 6 weeks. MAIN OUTCOMES AND MEASURES: Risk factors for severe acute-phase complications (acute kidney failure, septicemia, and need for mechanical ventilation) and mortality 6 weeks following admission were evaluated using a multivariable-adjusted logistic regression model. One tool used in evaluation of severity was the Score of Toxic Epidermal Necrolysis (SCORTEN), which ranges from 0 to 7, with 7 the highest level of severity. RESULTS: Of 212 patients (134 of 211 [63.7%] women; mean [SD] age, 51.0 [19.3] years), the mean (SD) body surface area detachment was 27% (32.8%). In 176 (83.0%) patients, a culprit drug was identified. Antibiotics (21.2%), followed by anticonvulsants (18.9%), nonsteroidal anti-inflammatory drugs (11.8%), allopurinol (11.3%), and sulfonamides (10.4%), were the most common suspected agents. Treatment approaches ranged from best supportive care only (38.2%) to systemic glucocorticoids (35.4%), intravenous immunoglobulins (23.6%), cyclosporine (10.4%), and antitumor necrosis factor agents (3.3%). Most patients (63.7%) developed severe acute-phase complications. The 6-week mortality rate was 20.8%. Maximal body surface area detachment (≥30%) was found to be independently associated with severe acute-phase complications (fully adjusted odds ratio [OR], 2.49; 95% CI, 1.21-5.12; P = .01) and SCORTEN greater than or equal to 2 was significantly associated with mortality (fully adjusted OR, 10.30; 95% CI, 3.82-27.78; P < .001). Cyclosporine was associated with a higher frequency of greater than or equal to 20% increase in body surface area detachment in the acute phase (adjusted OR, 3.44; 95% CI, 1.12-10.52; P = .03) and an increased risk of infections (adjusted OR, 7.16; 95% CI, 1.52-33.74; P = .01). Systemic glucocorticoids and intravenous immunoglobulins were associated with a decreased risk of infections (adjusted OR, 0.40; 95% CI, 0.18-0.88; P = .02). No significant difference in 6-week mortality was found between treatment groups. CONCLUSIONS AND RELEVANCE: This cohort study noted differences in treatment strategies for SJS/TEN in Europe; the findings suggest the need for prospective therapeutic studies to be conducted and registries to be developed.