Abstract
Importance
The Ritux 3 trial demonstrated the short-term efficacy and safety of first-line treatment with rituximab compared with a standard corticosteroid regimen in pemphigus. No data on the long-term follow-up of patients who received rituximab as first line are available.
Objective
To assess the long-term efficacy and safety of the Ritux 3 treatment regimen.
Design, Setting, and Participants
This 7-year follow-up study of the Ritux 3 trial included patients with pemphigus from 25 dermatology departments in France from January 1, 2010, to December 31, 2015.
Exposure
Patients were initially randomized in the rituximab plus prednisone group or prednisone-alone group.
Main outcomes and measures
The primary outcome was the 5- and 7-year disease-free survival (DFS) without corticosteroids, assessed by Kaplan-Meier curves. Secondary outcomes were occurrence of relapse, occurrence of severe adverse events (SAEs), and evolution of antidesmoglein (Dsg) antibody enzyme-linked immunosorbent assay values to predict long-term relapse.
Results
Of the 90 patients in the Ritux 3 trial, 83 were evaluated at the end of follow-up study visit (44 in the rituximab plus prednisone group; 39 in the prednisone-alone group) with a median (IQR) follow-up of 87.3 (79.1-97.5) months. Forty-three patients (93%) from the rituximab plus prednisone and 17 patients (39%) from the prednisone-alone group had achieved complete remission without corticosteroids at any time during the follow-up. Patients from the rituximab group had much longer 5- and 7-year DFS without corticosteroids than patients from the prednisone-alone group (76.7% and 72.1% vs 35.3% and 35.3%, respectively; P < .001), and had about half the relapses (42.2% vs 83.7%; P < .001). Patients who received rituximab as second-line treatment had shorter DFS than patients treated as first line (P = .007). Fewer SAEs were reported in the rituximab plus prednisone group compared with the prednisone-alone group, 31 vs 58 respectively, corresponding to 0.67 and 1.32 SAEs per patient, respectively (P = .003). The combination of anti-Dsg1 values of 20 or more IU/mL and/or anti-Dsg3 values of 48 or more IU/mL yielded 0.83 positive predictive value and 0.94 negative predictive value to predict long-term relapse.
Conclusions and Relevance
In this secondary analysis of the Ritux 3 trail, first-line treatment of patients with pemphigus with the Ritux 3 regimen was associated with long-term sustained complete remission without corticosteroid therapy without any additional maintenance infusion of rituximab.
Key Points
Question
Is rituximab associated with long-term complete remission without corticosteroid therapy when used as first-line treatment for patients with pemphigus?
Findings
In this long-term evaluation of patients from the Ritux 3 trial with a median follow-up of 7 years, the 5- and 7-year disease-free survival without corticosteroid therapy for those treated with rituximab as first-line treatment were 76.7% and 72.1%, respectively.
Meaning
First-line treatment of patients with pemphigus with the Ritux 3 regimen was associated with long-term complete remission without corticosteroid therapy without any additional maintenance infusion of rituximab.
This cohort study using follow-up data from the Ritux 3 randomized clinical trial examines the association of rituximab treatment with long-term complete remission without corticosteroid therapy when used as first-line treatment for patients with pemphigus.
Introduction
Pemphigus is a rare, life-threatening autoimmune bullous disease affecting the skin and mucosae. It is characterized by pathogenic IgG antibodies (Abs) directed against 2 desmosomal adhesion proteins, desmoglein (Dsg) 1 and Dsg 3 (1-5). The Ritux 3 trial1 showed higher efficacy of a combination of the anti-CD20 monoclonal Ab rituximab with low-dose oral corticosteroids, compared with a standard regimen of corticosteroids alone. Complete remission (CR) without corticosteroids therapy at month (M) 24 was observed in 89% of patients in the rituximab plus prednisone group vs 34% of patients in the prednisone-alone group. Moreover, the rate of severe adverse events (SAEs) in patients receiving the standard regimen of corticosteroids alone was 3-fold higher than in patients from the rituximab plus prednisone group. The Ritux 3 trial1 led to the approval of rituximab in the treatment of moderate to severe pemphigus vulgaris by both the US Food and Drug Administration and the European Medicines Agency.2 The efficacy of rituximab in patients with pemphigus was further supported by a randomized clinical trial showing the superiority of rituximab over mycophenolate mofetil.3
An extension of the Ritux 3 trial was conducted up to month 36 corresponding to 18 months after the last maintenance infusion (month 18) of rituximab. Only 2 of 46 patients in the rituximab plus prednisone group relapsed between months 24 and 36 despite the absence of any additional treatment.1 These results have raised questions about the long-term efficacy of rituximab as first-line treatment in patients with pemphigus. Indeed, although we previously reported a high rate of long-term relapses of 77% when rituximab was used as second-line treatment,4 no data on the long-term follow-up of patients who received rituximab as first-line treatment are currently available. Given the limited number of relapses that occurred between the second and third years following the initiation of rituximab in the Ritux 3 trial, and the regulatory immunological mechanisms that we previously reported in patients maintaining long-term sustained CR after rituximab,4,5,6 we hypothesized that first-line treatment of patients with pemphigus with rituximab, as performed in the Ritux 3 trial, was associated with reduced risk of long-term relapses and thus may increase the rate of sustained CR without corticosteroids compared with second- or third-line treatment with rituximab.4
The primary objective of this study was to assess the 5- and 7-year disease-free survival (DFS) off corticosteroids therapy from the date of achievement of CR without corticosteroids therapy to the end of the follow-up visit. Secondary objectives were assessment of overall relapse rate and occurrence of SAEs. Given the high relapse rate observed in patients initially assigned to the prednisone-alone group and the fact that most of them subsequently received rituximab as second-line treatment, we also compared the DFS of patients initially randomized to receive rituximab (first line) plus prednisone vs that of patients from the prednisone-alone group who received rituximab after they relapsed (second line). Finally, because we previously identified thresholds in anti-Dsg Ab enzyme-linked immunosorbent assay (ELISA) values that predicted early relapse with a high positive predictive value (PPV),7 we similarly assessed the change in anti-Dsg Ab values over time as predictors of long-term relapse.
Methods
Study Design and Patients
The Ritux 3 trial1 was conducted in 25 dermatology departments in France from January 1, 2010, to December 31, 2015. The details of the study have been previously reported.1 To summarize, this study was a 24-month randomized, open-label study that compared the efficacy and safety of rituximab combined with short-term corticosteroids therapy (rituximab plus prednisone group) vs a standard high-dose regimen of oral corticosteroids (prednisone-alone group) as first-line treatment in 90 patients with newly diagnosed pemphigus. Patients in the rituximab plus prednisone group received 1 g of rituximab at day 0 and day 14, then 500 mg at months 12 and 18. All patients who completed the Ritux 3 trial were eligible to participate in this long-term follow-up evaluation. To evaluate the 7-year follow-up of patients, an end of follow-up visit was planned between March 2017 and November 2020 depending on the date at which they had been enrolled in the Ritux 3 trial. All patients provided written informed consent. The study protocol was approved by the CPP Sud Méditerranée 1 Ethics Committee (NCT03790293).
Clinical Assessments
At the end of follow-up visit, the following clinical data were recorded: clinical status (ie, CR without corticosteroids therapy or receiving minimal therapy, partial remission, or relapse) according to the consensus definitions8 that had occurred from the month 36 visit to the end of follow-up visit; number and doses of rituximab infusions administered; and occurrence of SAEs. SAEs were recorded according to the Common Terminology Criteria for Adverse Events.9 We obtained the vital status of patients lost to follow-up via the French National Institute for Statistics and Economical Studies (INSEE) national death register.10
Serological Assessments
Serum samples were collected at the month 36 evaluation and the end of follow-up visit. Measurement of anti-Dsg1 and anti-Dsg3 IgG Abs was performed centrally using ELISA (Euroimmun, Medizinische Labordiagnostika) according to the manufacturer’s instructions, with a positivity threshold of 20 IU/mL.
Statistical Analysis
The patients’ characteristics were described according to the initial randomization in the Ritux 3 trial (rituximab plus prednisone group vs prednisone-alone group) using mean (SD) or median (IQR) for quantitative variables, and percentages for categorical variables. Survival distributions were estimated using the Kaplan-Meier method, with comparisons between subgroups performed using the log-rank test. DFS was calculated from the date of disease control obtained in the Ritux 3 trial to the earliest of the following dates (whether patients were still receiving corticosteroids or not receiving corticosteroids therapy): date of first relapse, date of last evaluation for patients who did not relapse, date of death, or date of last available evaluation for patients who were lost to follow-up. DFS without corticosteroids therapy was calculated from the date of achievement of CR without corticosteroids therapy to the earliest occurrence among these dates.
To assess the value of anti-Dsg1 and anti-Dsg3 Abs collected at month36 in predicting occurrence of long-term relapses and determine optimal cutoff values, receiver operating characteristic (ROC) curve analyses were performed. Fisher exact test was used to compare randomization groups for qualitative variables and Student t test or Mann-Whitney nonparametric tests as appropriate were used for quantitative variables. All statistical tests used 2-sided .05 level as significance threshold. All analyses were performed with SAS statistical software (version 9.4; SAS Institute).
Results
Patient Characteristics
Among the 90 patients randomized in the Ritux 3 trial, 83 patients (92%) (44 [96%] from the rituximab plus prednisone group and 39 [89%] from the prednisone-alone group) were evaluated at the end of follow-up visit (Figure 1). Overall, the median (IQR) time of follow-up was 87.3 (79.1-97.5) months. Patients’ characteristics at the end of follow-up visit including their clinical status (CR without therapy, CR receiving minimal therapy, partial remission, active disease) are displayed in Table 1.
Figure 1. Flow Chart of Patients Included in the Ritux 3 Trial.
CR indicates complete remission.
aAt the last evaluation, these patients were in CR without corticosteroid therapy.
bAt the last evaluation, these 3 patients had relapsed and had active disease.
Table 1. Clinical and Immunological Features of Patients Who Attended the End of Follow-Up Visit.
| Characteristic | Rituximab plus prednisone group (n = 44)a | Prednisone-alone group (n = 39)b |
|---|---|---|
| Age, mean (SD), y | 61.5 (15.1) | 60.9 (12.8) |
| Time of follow-up, median (IQR), mo | 87.3 (79.2-97.8) | 88.3 (79.1-95.3) |
| Clinical status, No. (%) | ||
| CR without therapy | 40 (91) | 28 (72) |
| CR receiving minimal therapy | 1 (2) | 4 (10) |
| Partial remission | 0 | 1 (3) |
| Active disease | 3 (7) | 6 (15) |
| Sera with positive anti-Dsg3 antibodies, positive/total tested sera (%) | 8/35 (23) | 10/32 (31) |
| Positive sera in patients in sustained CR off corticosteroid therapy/total tested sera | 2/22 (9) | 0/5 |
| Sera with positive anti-Dsg1 antibodies, positive/total tested sera | 3/35 (9) | 4/32 (13) |
| Positive sera in patients with sustained CR off corticosteroid therapy/total tested sera | 1/22 (5) | 1/5 (20) |
Abbreviations: CR, complete remission; Dsg, desmoglein; IQR, interquartile range.
Two patients did not attend the extension study visit and remained in CR without corticosteroid therapy at the date of the last information available.
Five patients did not attend the extension study visit, 3 of whom had relapsed by the last information available.
Disease-Free Survival and Relapses
Rituximab Plus Prednisone Group
From the date of disease control to the end of follow-up visit, 19 patients from the rituximab plus prednisone group had at least 1 relapse, with a total of 35 relapses: 7 patients had their first relapse after month 36, and 12 patients had relapsed before month 36 including 5 patients who had a new relapse after month 36 (Figure 1, gray boxes). Thus, among the 45 of 46 patients who achieved disease control during the Ritux 3 trial, the overall relapse rate at the end of this study was 42.2% (n = 19/45; 95% CI, 27.7%-57.8%), and the 5- and 7-year DFS of patients both still receiving corticosteroids and not receiving corticosteroids was estimated at 64.4% and 62.2%, respectively (Figure 2).
Figure 2. Kaplan-Meier Estimates of Disease-Free Survival (DFS) of Patients Both Still Receiving Corticosteroids and Without Corticosteroids .
The DFS survival curves were calculated by taking into account the 44 patients (97.8%) from the rituximab plus prednisone group and the 43 patients (97.7%) from the prednisone-alone group who achieved disease control during the Ritux 3 trial. The orange curve indicates those who were initially randomized in the rituximab plus prednisone group and the blue curve the prednisone-alone group.
Forty-three patients (93.5%) achieved CR without corticosteroids at any time during the study. The 5- and 7-year DFS without corticosteroids therapy were estimated at 76.7% and 72.1%, respectively (Figure 3). Importantly, none of the 25 patients who achieved CR without corticosteroids in the Ritux 3 trial and continued to receive CR without corticosteroids until the end of follow-up visit, had any additional infusion of rituximab after the last infusion scheduled in the Ritux 3 regimen at month 18. Only 9 out of the 19 patients who relapsed were re-treated with additional infusions of rituximab.
Figure 3. Kaplan-Meier Estimates of Disease-Free Survival (DFS) Without Corticosteroid Therapy.
The DFS estimates without corticosteroid survival curves were calculated by taking into account the 43 patients (93.5%) from the rituximab plus prednisone and the 17 patients (38.6%) from the prednisone-alone group who achieved complete remission off corticosteroid therapy. The orange curve indicates patients initially randomized to the rituximab plus prednisone group and the blue curve the prednisone-alone group.
Prednisone-Alone Group
From the date of disease control to the end of follow-up visit, 36 patients from the prednisone-alone group had at least 1 relapse (including 3 patients who were lost to follow-up after they relapsed and did not attend the end of follow-up visit), with a total of 116 relapses: 5 patients had their first relapse after month 36, and 31 relapsed before month 36, including 16 patients who had a new relapse after month 36 (Figure 1, blue boxes). Thus, among the 43 of 44 patients who achieved disease control, the overall relapse rate was 83.7% (n = 36/43; 95% CI, 69.3%-93.2%) and the 5- and 7-year DFS rates were estimated at 23.3% and 20.9%, respectively (Figure 2).
Seventeen patients (38.6%) from the prednisone-alone group achieved CR without corticosteroids. The 5- and 7-year of DFS without corticosteroids therapy were estimated at 35.3% and 35.3%, respectively (Figure 3).
Intergroup Comparisons
Patients from the rituximab plus prednisone group had much longer DFS than those from the prednisone-alone group (P < .001) (Figure 2). In addition to the fact that a higher number of patients from the rituximab group achieved CR without corticosteroids than those in the standard prednisone group (93.5% vs 38.6%), patients from the rituximab plus prednisone group also had a much longer DFS without corticosteroids therapy than those from the prednisone-alone group (P < .001) (Figure 3). Patients initially treated with rituximab plus prednisone had a 2-fold lower relapse rate than patients from the prednisone-alone group (42.2% vs 83.7%, P < .001). The mean number of relapses per patient from the rituximab group and the prednisone-alone group were 1.84 and 3.2, respectively (P = .045).
Efficacy of Rituximab as Second-Line Treatment
To assess the efficacy of rituximab as first-line vs second-line treatment, we compared the DFS from the first rituximab infusion to the end of the study between patients initially assigned to the rituximab plus prednisone group (first line) and 23 patients in the prednisone-alone group who were treated secondarily with rituximab after they relapsed. Fourteen of these 23 patients (60.9%; 95% CI, 38.5%-80.%) experienced a new relapse. The 2- and 3-year DFS rates were 39.2% and 17.4%, respectively, which was significantly lower than the 2- and 3-year DFS of patients who received rituximab as first-line treatment estimated at 75.6% and 75.6% (P = .007) (eFigure 1 in Supplement 1).
Severe Adverse Events
Two patients died during the study, both after month 36: 1 patient died from stroke in the rituximab plus prednisone group, and 1 patient died from Pseudomonas aeruginosa septic shock in the prednisone-alone group. From baseline to the end of the study, 31 and 58 SAEs were recorded in the rituximab plus prednisone group and the prednisone-alone group, respectively, corresponding to 0.67 and 1.32 SAEs per patient, respectively (P = .003). Most of these SAEs occurred during the first 3 years of the Ritux 3 trial,1 with 27 and 53 SAEs in the rituximab plus prednisone group and in the prednisone-alone group, respectively (Table 2). From month 36 to the end of the study, 7 patients from the rituximab plus prednisone group and 23 from the prednisone-alone group were treated or re-treated with rituximab after they relapsed. Four SAEs (1 death, 2 pneumonia, and 1 neutropenia) and 5 SAEs (1 death, 1 Achilles tendon rupture, and 3 flares needing an inpatient hospital stay) were reported in these groups, respectively. Importantly, no additional SAE occurred in the 25 patients from the rituximab plus prednisone group who maintained a sustained CR without any therapy from the last infusion of rituximab at month 18 to the end of the study.
Table 2. Severe Adverse Events Associated With Treatment Strategies Reported From Baseline to the End of the Study.
| Severe adverse event | Group | |||
|---|---|---|---|---|
| Rituximab plus prednisone | Prednisone alone | |||
| Baseline to 36 | Month 36 to end of study | Baseline to month 36 | Month 36 to end of study | |
| Infectionsa | 5 | 2 | 5 | 0 |
| Cardiovascular disordersb | 3 | 0 | 7 | 0 |
| Musculoskeletal disorders | 8 | 0 | 15 | 1 |
| Diabetes and endocrine disorders | 6 | 0 | 11 | 0 |
| Neurological disorders | 0 | 0 | 3 | 0 |
| Psychiatric disorders | 2 | 0 | 4 | 0 |
| Major weight gain (>10 kg) | 0 | 0 | 4 | 0 |
| Ocular disorders (cataract) | 0 | 0 | 2 | 0 |
| Biological abnormalitiesc | 1 | 1 | 1 | 0 |
| Flare needing an inpatient stay | 0 | 0 | 0 | 3 |
| Death | 0 | 1 | 0 | 1 |
| Otherd | 2 | 0 | 1 | 0 |
| Total | 27 | 4 | 53 | 5 |
Pneumonia, septicemia, septic arthritis, urinary tract infection, herpes, spondylodiscitis, or chorioretinitis.
Angina, myocardial infarction, thrombosis, pulmonary embolism, or cardiac failure.
Hypokalemia, neutropenia, liver cytolysis.
Skin atrophy and ear, nose, and throat carcinomas.
Predictive Factors of Long-Term Relapse After First-Line Rituximab Treatment
Finally, we calculated the thresholds for anti-Dsg1 and anti-Dsg3 Abs, which could predict the occurrence of long-term relapse (from month 36 to the end of the study) in patients who received rituximab as first-line treatment. Based on ROC curve analysis, an anti-Dsg1 ELISA value of 4 IU/mL yielded a PPV of 0.73 and a negative predictive value (NPV) of 0.88, whereas a cutoff of 48 IU/mL for anti-Dsg3 yielded a PPV of 0.90 and an NPV of 0.91 (eFigure 2 in Supplement 1). Since the Euroimmun ELISA assay is calibrated for anti-Dsg1 values higher than 20 IU/mL, we used this cutoff proposed by the manufacturer in ROC curve analyses. A combination of ELISA values of anti-Dsg1 Ab of 20 or more IU/mL and/or of anti-Dsg3 Ab of 48 or more IU/mL at month 36 yielded a PPV of 0.83 and a NPV of 0.94 to predict long-term relapse.
Among the 22 patients who maintained sustained CR off corticosteroids therapy until the end of the study and had serological evaluation at the end of follow-up visit, 19 (86%) had persistent negative anti-Dsg1 and anti-Dsg3 Abs from month 18 to the end of follow-up visit.
Discussion
This long-term evaluation of the Ritux 3 trial essentially showed that, after a median follow-up of 7.3 years, the relapse rate in patients initially randomized in the rituximab plus prednisone group was 2-fold lower than that of patients in the prednisone-alone group (42.2% vs 83.7%; P < .001), demonstrating the superiority of rituximab over a standard corticosteroids regimen, both in the short term and the long term. Specifically, the 72.1% 7-year DFS rate without corticosteroids therapy observed in the present study was much higher than previously reported in patients who had second- or third-line treatment.11,12,13,14 Moreover, it must be underlined that these patients who maintained sustained CR off corticosteroids therapy did not have any additional maintenance infusion of rituximab from the last 500-mg infusion of rituximab at month 18 (end of the Ritux 3 regimen) to the end of the study. In particular, the fact that nearly two-thirds of patients maintained sustained CR without corticosteroids therapy without any additional infusion of rituximab for a long duration does not support the use of multiple systematic maintenance infusions of rituximab, which have been proposed to maintain sustained CR.17 In addition, the fact that the rate of DFS without corticosteroids did not change much from 76.7% after 5 years to 72.1%, after 7 years, suggests that most of these patients will not further relapse. This high rate of sustained CR without corticosteroids is consistent with the long-term disappearance of anti-Dsg Abs, which was observed in 86% of these patients. As expected, no SAE associated with immunosuppression was observed in patients who sustained CR without any therapy until the end of the study, whereas only 4 SAEs (1 case of stroke, 2 pneumonia, and 1 case of neutropenia) were observed in patients who relapsed and were re-treated with rituximab.
The dramatic but transient depletion of blood B lymphocytes may unlikely be directly responsible for this high rate of sustained CR. Indeed, it has been suggested that the emergence of transitional regulatory B cells secreting IL-10 could participate in the mechanisms of prolonged remission.15,16,17 Moreover, we recently reported a decrease in autoreactive follicular T helper cells, which might explain the blockage of Dsg-specific B lymphocytes isotype switching, which may be responsible for prolonged disappearance of anti-Dsg IgG secreting B cells, and disappearance of circulating anti-Dsg Abs in most patients in sustained CR, as observed in the present study.5
The findings of this study also suggest that patients should be monitored to detect those who are at high risk of relapse. We previously reported7 the interest of monitoring anti-Dsg Abs after the initial cycle of rituximab to predict the occurrence of early relapses in patients who had an insufficient decrease of anti-Dsg Abs 3 months after the first infusions. In the present study, we observed that a reincrease in anti-Dsg1 and anti-Dsg3 Abs yielded very high PPV (83%) for the occurrence of relapse, suggesting the possibility of re-treating with rituximab only those patients whose serum anti-Dsg ELISA values became higher than the thresholds that we determined. Furthermore, the 94% NPV yielded by these thresholds allows confidence while not re-treating patients whose anti-Dsg Abs are lower than the thresholds, corresponding to the majority of patients treated as first line with the Ritux 3 regimen. We are currently conducting a randomized clinical trial to test this strategy of re-treating patients with a high risk of relapse based on the ELISA values of anti-Dsg Abs to prevent the occurrence of clinical relapses and to prevent patients from having to take corticosteroids again (NCT05898308).
Limitations
This study has some limitations. Seven patients (7.8%) did not attend the end of follow-up visit, which may be considered rather low for such a long-term follow-up. Given this low number and the fact that the baseline characteristics of these patients were not clearly different from those of patients included in this study (eTable in Supplement 1), it is unlikely that they could have significantly biased the results. Serum samples used to predict the occurrence of relapses were collected at month 36, suggesting that a closer monitoring of anti-Dsg Abs every 4 to 6 months might provide higher accuracy to predict the occurrence of relapses.
Conclusion
Overall, this study showed that the first-line treatment of patients with pemphigus with rituximab was associated with sustained CR without corticosteroids therapy up to 7 years after the start of treatment, without any additional maintenance infusions of rituximab. It also suggests the possibility of identifying patients with a high risk of relapse based on ELISA values of anti-Dsg Abs to re-treat only these latter patients to prevent the occurrence of relapse.
eTable 1. Baseline characteristics of patients who attended the end of follow-up visit, and those who were lost of follow-up before this end of follow-up visit
eFigure 1. Kaplan-Meier estimates of disease-free survival of patients who received rituximab as first-line treatment (blue curve) versus second-line treatment (red curve)
eFigure 2, Receiver operating characteristic (ROC) curves to predict long-term relapse on anti-desmoglein 1 and 3 antibody levels from month 36 to the extension study visit
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Baseline characteristics of patients who attended the end of follow-up visit, and those who were lost of follow-up before this end of follow-up visit
eFigure 1. Kaplan-Meier estimates of disease-free survival of patients who received rituximab as first-line treatment (blue curve) versus second-line treatment (red curve)
eFigure 2, Receiver operating characteristic (ROC) curves to predict long-term relapse on anti-desmoglein 1 and 3 antibody levels from month 36 to the extension study visit
Data Sharing Statement