Pascal Joly1, Maud Maho-Vaillant2, Catherine Prost-Squarcioni3, Vivien Hebert2, Estelle Houivet4, Sébastien Calbo2, Frédérique Caillot2, Marie Laure Golinski2, Bruno Labeille5, Catherine Picard-Dahan6, Carle Paul7, Marie-Aleth Richard8, Jean David Bouaziz9, Sophie Duvert-Lehembre2, Philippe Bernard10, Frederic Caux3, Marina Alexandre3, Saskia Ingen-Housz-Oro11, Pierre Vabres12, Emmanuel Delaporte13, Gaelle Quereux14, Alain Dupuy15, Sebastien Debarbieux16, Martine Avenel-Audran17, Michel D'Incan18, Christophe Bedane19, Nathalie Bénéton20, Denis Jullien21, Nicolas Dupin22, Laurent Misery23, Laurent Machet24, Marie Beylot-Barry25, Olivier Dereure26, Bruno Sassolas27, Thomas Vermeulin28, Jacques Benichou4, Philippe Musette2. 1. Department of Dermatology, Rouen University Hospital and INSERM U1234, Centre de référence des maladies bulleuses autoimmunes, Normandie University, Rouen, France. Electronic address: Pascal.Joly@chu-rouen.fr. 2. Department of Dermatology, Rouen University Hospital and INSERM U1234, Centre de référence des maladies bulleuses autoimmunes, Normandie University, Rouen, France. 3. Department of Dermatology, University of Paris XIII, Bobigny, France. 4. Department of Biostatistics, Rouen University Hospital and INSERM U1219, Normandie University, Rouen, France. 5. Department of Dermatology, University of Saint Etienne, Saint Etienne, France. 6. Department of Dermatology of Bichat Hospital, University of Paris X, Paris, France. 7. Department of Dermatology, University of Toulouse, Toulouse, France. 8. Department of Dermatology, Assistance Publique des Hopitaux de Marseille, Aix Marseille University, UMR 911, INSERM CRO2, Marseille, France. 9. Department of Dermatology of St Louis Hospital, Paris 7 Sorbonne Paris Cité University, Paris, France. 10. Department of Dermatology, University of Reims, Reims, France. 11. Department of Dermatology, APHP, Henri Mondor Hospital, Créteil, France. 12. Department of Dermatology Dijon University Hospital, Dijon, France. 13. Department of Dermatology, University of Lille, Lille, France. 14. Department of Dermatology, University of Nantes, Nantes, France. 15. Department of Dermatology, University of Rennes, Rennes, France. 16. Department of Dermatology, Centre Hospitalier Lyon Sud; Pierre Bénite, Lyon, France. 17. Department of Dermatology, University of Angers, Angers, France. 18. Department of Dermatology, University of Clermont-Ferrand, Clermont-Ferrand, France. 19. Department of Dermatology, University of Limoges, Limoges, France. 20. Department of Dermatology, Le Mans General Hospital, Le Mans, France. 21. Department of Dermatology, Edouard Herriot Hospital, Lyon Claude Bernard University, Lyon, France. 22. Department of Dermatology, University of Paris V, Paris, France. 23. Department of Dermatology, Brest University Hospital, Brest, France. 24. Department of Dermatology, Tours University Hospital, Tours, France. 25. Department of Dermatology, University of Bordeaux, Bordeaux, France. 26. Department of Dermatology, University of Montpellier, Montpellier, France. 27. Department of Internal Medicine, Brest University Hospital, Brest, France. 28. Department of Medical Information and Informatics, Rouen University Hospital, Rouen, France.
Abstract
BACKGROUND: High doses of corticosteroids are considered the standard treatment for pemphigus. Because long-term corticosteroid treatment can cause severe and even life-threatening side-effects in patients with this disease, we assessed whether first-line use of rituximab as adjuvant therapy could improve the proportion of patients achieving complete remission off-therapy, compared with corticosteroid treatment alone, while decreasing treatment side-effects of corticosteroids. METHODS: We did a prospective, multicentre, parallel-group, open-label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). Eligible participants were patients with newly diagnosed pemphigus aged 18-80 years being treated for the first time (not at the time of a relapse). We randomly assigned participants (1:1) to receive either oral prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 1000 mg of intravenous rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0·5 or 1·0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group). Follow-up was for 3 years (study visits were scheduled weekly during the first month of the study, then monthly until month 24, then an additional visit at month 36). Treatment was assigned through central computer-generated randomisation, with stratification according to disease-severity (severe or moderate, based on Harman's criteria). The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). This study is registered with ClinicalTrials.gov, number NCT00784589. FINDINGS:Between May 10, 2010, and Dec 7, 2012, we enrolled 91 patients and randomly assigned 90 to treatment (90 were analysed; 1 patient withdrew consent before the random assignment). At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38·4-71·7; p<0·0001. This difference corresponded to a relative risk of success of 2·61 (95% CI 1·71-3·99, p<0·0001), corresponding to 1·82 patients (95% CI 1·39-2·60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3-4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1·20 [SD 1·25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0·59 [1·15]; p=0·0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%]). INTERPRETATION: Data from our trial suggest that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events. FUNDING: French Ministry of Health, French Society of Dermatology, Roche.
RCT Entities:
BACKGROUND: High doses of corticosteroids are considered the standard treatment for pemphigus. Because long-term corticosteroid treatment can cause severe and even life-threatening side-effects in patients with this disease, we assessed whether first-line use of rituximab as adjuvant therapy could improve the proportion of patients achieving complete remission off-therapy, compared with corticosteroid treatment alone, while decreasing treatment side-effects of corticosteroids. METHODS: We did a prospective, multicentre, parallel-group, open-label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). Eligible participants were patients with newly diagnosed pemphigus aged 18-80 years being treated for the first time (not at the time of a relapse). We randomly assigned participants (1:1) to receive either oral prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 1000 mg of intravenous rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0·5 or 1·0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group). Follow-up was for 3 years (study visits were scheduled weekly during the first month of the study, then monthly until month 24, then an additional visit at month 36). Treatment was assigned through central computer-generated randomisation, with stratification according to disease-severity (severe or moderate, based on Harman's criteria). The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). This study is registered with ClinicalTrials.gov, number NCT00784589. FINDINGS: Between May 10, 2010, and Dec 7, 2012, we enrolled 91 patients and randomly assigned 90 to treatment (90 were analysed; 1 patient withdrew consent before the random assignment). At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38·4-71·7; p<0·0001. This difference corresponded to a relative risk of success of 2·61 (95% CI 1·71-3·99, p<0·0001), corresponding to 1·82 patients (95% CI 1·39-2·60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3-4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1·20 [SD 1·25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0·59 [1·15]; p=0·0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%]). INTERPRETATION: Data from our trial suggest that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events. FUNDING: French Ministry of Health, French Society of Dermatology, Roche.