First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.
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.


RESULTS
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%]).


CONCLUSIONS
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.


BACKGROUND
French Ministry of Health, French Society of Dermatology, Roche.
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.
Pascal
P
Joly
Department of Dermatology, Rouen University Hospital and INSERM U1234, Centre de référence des maladies bulleuses autoimmunes, Normandie University, Rouen, France.
Maud
M
Maho-Vaillant
Department of Dermatology, University of Paris XIII, Bobigny, France.
Catherine
C
Prost-Squarcioni
Department of Dermatology, Rouen University Hospital and INSERM U1234, Centre de référence des maladies bulleuses autoimmunes, Normandie University, Rouen, France.
Vivien
V
Hebert
Department of Biostatistics, Rouen University Hospital and INSERM U1219, Normandie University, Rouen, France.
Estelle
E
Houivet
Department of Dermatology, Rouen University Hospital and INSERM U1234, Centre de référence des maladies bulleuses autoimmunes, Normandie University, Rouen, France.
Sébastien
S
Calbo
Department of Dermatology, Rouen University Hospital and INSERM U1234, Centre de référence des maladies bulleuses autoimmunes, Normandie University, Rouen, France.
Frédérique
F
Caillot
Department of Dermatology, Rouen University Hospital and INSERM U1234, Centre de référence des maladies bulleuses autoimmunes, Normandie University, Rouen, France.
Marie Laure
ML
Golinski
Department of Dermatology, University of Saint Etienne, Saint Etienne, France.
Bruno
B
Labeille
Department of Dermatology of Bichat Hospital, University of Paris X, Paris, France.
Catherine
C
Picard-Dahan
Department of Dermatology, University of Toulouse, Toulouse, France.
Carle
C
Paul
Department of Dermatology, Assistance Publique des Hopitaux de Marseille, Aix Marseille University, UMR 911, INSERM CRO2, Marseille, France.
Marie-Aleth
MA
Richard
Department of Dermatology of St Louis Hospital, Paris 7 Sorbonne Paris Cité University, Paris, France.
Jean David
JD
Bouaziz
Department of Dermatology, Rouen University Hospital and INSERM U1234, Centre de référence des maladies bulleuses autoimmunes, Normandie University, Rouen, France.
Sophie
S
Duvert-Lehembre
Department of Dermatology, University of Reims, Reims, France.
Philippe
P
Bernard
Department of Dermatology, University of Paris XIII, Bobigny, France.
Frederic
F
Caux
Department of Dermatology, University of Paris XIII, Bobigny, France.
Marina
M
Alexandre
Department of Dermatology, APHP, Henri Mondor Hospital, Créteil, France.
Saskia
S
Ingen-Housz-Oro
Department of Dermatology Dijon University Hospital, Dijon, France.
Pierre
P
Vabres
Department of Dermatology, University of Lille, Lille, France.
Emmanuel
E
Delaporte
Department of Dermatology, University of Nantes, Nantes, France.
Gaelle
G
Quereux
Department of Dermatology, University of Rennes, Rennes, France.
Alain
A
Dupuy
Department of Dermatology, Centre Hospitalier Lyon Sud; Pierre Bénite, Lyon, France.
Sebastien
S
Debarbieux
Department of Dermatology, University of Angers, Angers, France.
Martine
M
Avenel-Audran
Department of Dermatology, University of Clermont-Ferrand, Clermont-Ferrand, France.
Michel
M
D'Incan
Department of Dermatology, University of Limoges, Limoges, France.
Christophe
C
Bedane
Department of Dermatology, Le Mans General Hospital, Le Mans, France.
Nathalie
N
Bénéton
Department of Dermatology, Edouard Herriot Hospital, Lyon Claude Bernard University, Lyon, France.
Denis
D
Jullien
Department of Dermatology, University of Paris V, Paris, France.
Nicolas
N
Dupin
Department of Dermatology, Brest University Hospital, Brest, France.
Laurent
L
Misery
Department of Dermatology, Tours University Hospital, Tours, France.
Laurent
L
Machet
Department of Dermatology, University of Bordeaux, Bordeaux, France.
Marie
M
Beylot-Barry
Department of Dermatology, University of Montpellier, Montpellier, France.
Olivier
O
Dereure
Department of Internal Medicine, Brest University Hospital, Brest, France.
Bruno
B
Sassolas
Department of Medical Information and Informatics, Rouen University Hospital, Rouen, France.
Thomas
T
Vermeulin
Department of Biostatistics, Rouen University Hospital and INSERM U1219, Normandie University, Rouen, France.
Jacques
J
Benichou
Department of Dermatology, Rouen University Hospital and INSERM U1234, Centre de référence des maladies bulleuses autoimmunes, Normandie University, Rouen, France.
Philippe
P
Musette
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010392:Pemphigus / Q000188:drug therapy*; D011239:Prednisolone / Q000008:administration & dosage* / Q000009:adverse effects; D011446:Prospective Studies; D000069283:Rituximab / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
D000069283:Rituximab; D011239:Prednisolone