Claire Mignard1, Maud Maho-Vaillant1, Marie-Laure Golinski1, Pierre Balayé2, Catherine Prost-Squarcioni3, Estelle Houivet2, Sé Bastien Calbo1, Bruno Labeille4, Catherine Picard-Dahan5, Maria Polina Konstantinou6, Guillaume Chaby7, Marie-Aleth Richard8, Jean-David Bouaziz9, Sophie Duvert-Lehembre10, Emmanuel Delaporte10, Philippe Bernard11, Frédéric Caux3, Marina Alexandre3, Saskia Ingen-Housz-Oro12, Pierre Vabres13, Gaëlle Quereux14, Alain Dupuy15, Sébastien Debarbieux16, Martine Avenel-Audran17, Michel D'Incan18, Christophe Bédane19, Nathalie Bénéton20, Denis Jullien21, Nicolas Dupin22, Laurent Misery23, Laurent Machet24, Marie Beylot-Barry25, Olivier Dereure26, Bruno Sassolas27, Jacques Benichou2, Pascal Joly1, Vivien Hébert1. 1. Centre de référence des maladies bulleuses auto-immunes, Department of Dermatology, Rouen University Hospital, Normandie University, INSERM U1234, Rouen, France. 2. Department of Biostatistics and Clinical Research, Rouen University Hospital, Rouen, France. 3. Centre de référence des maladies bulleuses auto-immunes, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris, Department of Dermatology, University of Paris 13, Bobigny, France. 4. Department of Dermatology, University of Saint Etienne, Saint Etienne, France. 5. Department of Dermatology, Bichat Hospital, University of Paris X, Paris, France. 6. Department of Dermatology, University of Toulouse, Toulouse, France. 7. Department of Dermatology, University of Amiens, Amiens, France. 8. Assistance Publique des Hôpitaux de Marseille, Department of Dermatology, Aix Marseille University, UMR 911, INSERM CRO2, Marseille, France. 9. Department of Dermatology, St Louis Hospital, Paris 7 Sorbonne Paris Cité University, Paris, France. 10. Department of Dermatology, University of Lille, Lille, France. 11. Department of Dermatology, University of Reims, Reims, France. 12. Department of Dermatology, Assistance Publique-Hôpitaux de Paris, Henri Mondor Hospital, Créteil, France. 13. Department of Dermatology, Dijon University Hospital, Dijon, 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.
Abstract
Importance: Rituximab and short-term corticosteroid therapy are the criterion standard treatments for patients with newly diagnosed moderate to severe pemphigus. Objective: To examine factors associated with short-term relapse in patients with pemphigus treated withrituximab. Design, Setting, and Participants: This post hoc analysis of a randomized clinical trial (Comparison Between Rituximab Treatment and Oral Corticosteroid Treatment in Patients With Pemphigus [RITUX 3]) conducted from January 1, 2010, to December 31, 2015, included patients from 20 dermatology departments of tertiary care centers in France from the RITUX 3 trial and 3 newly diagnosed patients treated according to the trial protocol. Data analysis was performed from February 1 to June 30, 2019. Exposure: Patients randomly assigned to the rituximab group in the RITUX 3 trial and the 3 additional patients were treated with 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. Main Outcomes and Measures: Baseline (pretreatment) clinical and biological characteristics (Pemphigus Disease Area Index [PDAI] score, ranging from 0-250 points, with higher values indicating more severe disease) and changes in anti-desmoglein (DSG) 1 and anti-DSG3 values as measured by enzyme-linked immunosorbent assay during the 3 months after rituximab treatment were compared between patients with disease relapse and those who maintained clinical remission during the first 12 months after treatment. The positive and negative predictive values of these factors were calculated. Results: Among 47 patients (mean [SD] age, 54.3 [17.0] years; 17 [36%] male and 30 [64%] female) included in the study, the mean (SD) baseline PDAI score for patients with relapsing disease was higher than that of the patients with nonrelapsing disease (54 [33] vs 28 [24]; P = .03). At month 3, 7 of 11 patients with relapsing disease (64%) vs 7 of 36 patients with nonrelapsing disease (19%) had persistent anti-DSG1 antibody values of 20 IU/mL or higher and/or anti-DSG3 antibody values of 130 IU/mL or higher (P = .01). A PDAI score of 45 or higher defining severe pemphigus and/or persistent anti-DSG1 antibody values of 20 IU/mL or higher and/or anti-DSG3 antibody values of 130 IU/mL or higher at month 3 provided a positive predictive value of 50% (95% CI, 27%-73%) and a negative predictive value of 94% (95% CI, 73%-100%) for the occurrence of relapse after rituximab. Conclusions and Relevance: The findings suggest that initial PDAI score and changes in anti-DSG antibody values after the initial cycle of rituximab might help differentiate a subgroup of patients with high risk of relapse who might benefit from maintenance rituximab infusion at month 6 from a subgroup of patients with low risk of relapse who do not need early maintenance therapy. Trial Registration: NCT00784589.
RCT Entities:
Importance: Rituximab and short-term corticosteroid therapy are the criterion standard treatments for patients with newly diagnosed moderate to severe pemphigus. Objective: To examine factors associated with short-term relapse in patients with pemphigus treated with rituximab. Design, Setting, and Participants: This post hoc analysis of a randomized clinical trial (Comparison Between Rituximab Treatment and Oral Corticosteroid Treatment in Patients With Pemphigus [RITUX 3]) conducted from January 1, 2010, to December 31, 2015, included patients from 20 dermatology departments of tertiary care centers in France from the RITUX 3 trial and 3 newly diagnosed patients treated according to the trial protocol. Data analysis was performed from February 1 to June 30, 2019. Exposure: Patients randomly assigned to the rituximab group in the RITUX 3 trial and the 3 additional patients were treated with 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. Main Outcomes and Measures: Baseline (pretreatment) clinical and biological characteristics (Pemphigus Disease Area Index [PDAI] score, ranging from 0-250 points, with higher values indicating more severe disease) and changes in anti-desmoglein (DSG) 1 and anti-DSG3 values as measured by enzyme-linked immunosorbent assay during the 3 months after rituximab treatment were compared between patients with disease relapse and those who maintained clinical remission during the first 12 months after treatment. The positive and negative predictive values of these factors were calculated. Results: Among 47 patients (mean [SD] age, 54.3 [17.0] years; 17 [36%] male and 30 [64%] female) included in the study, the mean (SD) baseline PDAI score for patients with relapsing disease was higher than that of the patients with nonrelapsing disease (54 [33] vs 28 [24]; P = .03). At month 3, 7 of 11 patients with relapsing disease (64%) vs 7 of 36 patients with nonrelapsing disease (19%) had persistent anti-DSG1 antibody values of 20 IU/mL or higher and/or anti-DSG3 antibody values of 130 IU/mL or higher (P = .01). A PDAI score of 45 or higher defining severe pemphigus and/or persistent anti-DSG1 antibody values of 20 IU/mL or higher and/or anti-DSG3 antibody values of 130 IU/mL or higher at month 3 provided a positive predictive value of 50% (95% CI, 27%-73%) and a negative predictive value of 94% (95% CI, 73%-100%) for the occurrence of relapse after rituximab. Conclusions and Relevance: The findings suggest that initial PDAI score and changes in anti-DSG antibody values after the initial cycle of rituximab might help differentiate a subgroup of patients with high risk of relapse who might benefit from maintenance rituximab infusion at month 6 from a subgroup of patients with low risk of relapse who do not need early maintenance therapy. Trial Registration: NCT00784589.