Key Points
Question
What is the clinical relevance of antirituximab antibodies (ARAs) in pemphigus patients treated with rituximab (RTX)?
Findings
In this cohort study of 42 patients with moderate-to-severe pemphigus, ARAs were detected in 13 (31%) patients during the year following the initial cycle of treatment with RTX, and the proportion of patients who achieved sustained complete remission or relapsed was not different whether patients had ARAs. Among these 13 patients with ARAs, 2 patients who had a low serum RTX concentration, an incomplete blood B-cell depletion, and persistent antidesmoglein 3 autoantibodies had a clinical relapse.
Meaning
The study results suggest that ARAs are frequently detected in patients with pemphigus who are treated with RTX and only rarely compromise patients’ outcomes.
Abstract
Importance
The clinical relevance of antirituximab antibodies (ARAs) in patients with pemphigus who are treated with rituximab (RTX) is currently unknown.
Objective
To determine the prevalence of ARAs in patients with pemphigus who are treated with RTX and their association with complete remission (CR) and relapse.
Design, Setting, and Participants
This post hoc analysis of the Ritux3 trial was conducted from January 2010 to December 2015 in 25 dermatology departments in France and included 42 patients with moderate-to-severe pemphigus who were randomized to receive treatment with RTX. Five additional patients were recruited for an ancillary study. The proportions of patients who achieved CR or relapsed after an initial treatment cycle of RTX were compared depending on whether patients had ARAs.
Exposures
Patients were treated with 1000 mg of RTX on days 1 and 15 and 2 maintenance infusions of 500 mg at months 12 and 18.
Main Outcomes and Measures
Rates of relapse and sustained CR at month 36. Levels of ARAs, antidesmoglein 1/3 antibodies, RTX serum concentrations, and peripheral blood CD19+ B-cell frequency were measured.
Results
Of 42 participants with vs without ARAs, the mean (SD) age was 55 (17) years and 56 (17) years, respectively; 25 (59.5%) were women. Antirituximab antibodies were detected in the serum samples of 13 of 42 patients (31%) during the first year. Nine patients who experienced relapse before month 12 were excluded because they received additional infusions and could not be further analyzed. Among the 33 remaining patients, 2 patients (6.1%) experienced relapse after month 12, and 31 (95.9%) maintained a sustained CR until month 36. The rate of sustained CR was not different whether patients had ARAs (11 of 13 [85%]) or not (20 of 20 [100%]) (P = .15). Both groups (ARA+ vs ARA−) also had similar CD19+ B-cell depletion and RTX levels, but patients with ARAs had higher anti–desmoglein 3 antibody (DSG3 Abs) levels compared with those without ARAs (mean [SD], 30.1 [50.9] AU/mL vs 4.0 [4.3] AU/mL; P = .03). The 2 patients with ARAs who experienced relapse after month 12 had an undetectable RTX level, incomplete B-cell depletion, and higher anti-DSG3 Abs level than the 11 patients who maintained a sustained CR with ARAs (RTX mean [SD] concentration, 0 ug/mL vs 12.5 [2.2] ug/mL; P = .03; incomplete B-cell depletion, 2 of 2 vs 4 of 11; P = .19; mean [SD] anti-DSG3 Abs levels, 103.5 [61.5] AU/mL vs 19.5 [11.0] AU/mL; P = .001) or patients without ARAs (mean [SD] RTX concentration, 0 ug/mL vs 13.5 [1.8] ug/mL; P = .02; incomplete B-cell depletion, 2 of 2 vs 5 of 20; P = .09; mean [SD] anti-DSG3 Abs level, 103.5 [61.5] AU/mL vs 4.0 [1.0] AU/mL; P < .001).
Conclusions and Relevance
The results of this cohort study suggest that ARAs are frequently detected in patients with pemphigus who are treated with RTX and generally are not associated with patient outcomes. Only a few patients with the combination of ARAs, low RTX concentration, incomplete B-cell depletion, and persistent serum anti-DSG3 Abs seem at high risk of relapse.
This cohort study examines the prevalence of antirituximab antibodies in patients with pemphigus who are treated with rituximab and their association with complete remission and relapse.
Introduction
Rituximab (RTX), a chimeric monoclonal antibody (Ab) anti-CD20, is approved as a first-line treatment for moderate-to-severe pemphigus vulgaris. Its superiority compared with a conventional regimen of corticosteroids and mycophenolate mofetil has been demonstrated.1,2 The rate of relapse after RTX treatment increases over time. In the Ritux3 trial, around 25% of patients experienced relapse within the first 12 months, and some patients relapsed later on, suggesting the potential interest of maintenance infusions of RTX (NCT00784589). Multiple maintenance infusions have been associated with good clinical outcomes,3 although this systematic retreatment is not completely satisfactory because around 40% of patients do not experience relapse, even in the long term.1,2,4,5
The main factors associated with not achieving CR or relapsing after treatment with RTX are the clinical severity of pemphigus at presentation, a high body mass index, the autoimmune regimen of RTX (vs the lymphoma regimen adapted to a patient’s weight), and the persistence of anti-desmoglein (DSG) Abs 3 months after the initial treatment cycle.5,6 To our knowledge, anti-RTX Abs (ARAs) have rarely been studied in patients with pemphigus and have been occasionally described in patients who did not achieve CR after treatment with RTX,7,8 as in other autoimmune diseases.9,10,11 However, although RTX is now widely used as a first-line treatment for pemphigus vulgaris, to our knowledge, no data are currently available to understand their relevance in the treatment and follow-up of patients with pemphigus who are treated with RTX. The objectives of this study were to evaluate the prevalence of ARAs in patients with pemphigus who were treated with RTX, their association with achievement of sustained CR and occurrence of relapse, and their biological effects.
Methods
This study was reviewed and approved by the ethics committee of Normandie University. The patients provided written informed consent to participate in the study. All patients included in the RTX arm from the Ritux3 trial (NCT00784589) whose serum samples were collected at months 12, 18, and 36 were available for analysis and were included in the present study. Patients were treated according to the Ritux3 regimen, which comprised 1000 mg of intravenous RTX on days 1 and 15 and 2 maintenance infusions of 500 mg at months 12 and 18, which were combined with a short course of prednisone that tapered over 3 to 6 months. Patients were followed until month 36, and their clinical status at month 36 (CR and relapse) was defined according to the consensus statement definition for pemphigus end points.12 A total of 42 patients from the RTX arm of the Ritux3 trial were included in the present study.
We secondarily included 5 patients in an ancillary study to increase the group of patients with relapse to compare the ARA prevalence between relapsing and nonrelapsing patients. These patients were selected according to the following criteria: (1) patients treated with the same first-line RTX regimen as the Ritux3 trial and (2) occurrence of a relapse after the initial treatment cycle of RTX. These 5 patients were selected from a prospective cohort study (unpublished data; Preri, 2022) that included 46 patients who were treated after the end of the Ritux3 trial. The aim of this study was to assess the long-term follow-up of patients with pemphigus who were initially treated with the Ritux3 regimen. This Preri study was approved by the ethics committee of Normandie University. These patients were recruited from 5 different sites in France (Rouen, Toulouse, Marseille, Bordeaux, and Dunkerque). The main baseline clinical characteristics of these patients were not different from those included in the Ritux3 trial. Their serum samples were stored in the skin serum bank of the Rouen University Hospital (Rouen, France).
Serum ARA and RTX concentrations were measured using a commercially available RTX enzyme-linked immunosorbent assay (LISA TRACKER; Theradiag). Anti-DSG1 and anti-DSG3 Abs were measured using the EUROIMMUN Desmoglein test (Medizinische Labordiagnostika). Peripheral blood CD19+ B-cell frequency was evaluated by flow cytometry with a BD LSRFortessa cell analyzer.
The B-cell count was performed just before the maintenance infusions of RTX at months 12 and 18. The concentration of RTX was measured 2 months after these 2 maintenance infusions, at months 14 and 20. A first detection of ARA was performed just before the first maintenance infusion of RTX at month 12 and then at month 36, which corresponded to later period from the last infusion of RTX. In addition, ARAs were measured before month 12 at the time of relapse in 9 patients who experienced relapse early during the first year after the initial treatment cycle of RTX. The calculation of B-cell counts and serum RTX concentrations were performed only in patients who were included in the Ritux3 trial because blood samples from the 5 patients treated after the trial were not collected at the same points.
The ability of ARAs to prevent the binding of RTX to B cells was studied using RTX coupled with fluorescein isothiocyanate to label Epstein-Barr virus (EBV)–immortalized B cells with high expression of CD20. Two serum samples from patients with systemic lupus erythematosus that contained neutralizing anti-idiotype ARA were used as positive controls. The volume of each ARA-containing serum sample used in neutralizing experiments was calculated to contain a neutralizing dose of 5 ng of ARA, which was determined using the 2 positive control serum samples. A BD LSRFortessa cell analyzer was used for data acquisition, and the mean fluorescence intensity of EBV-immortalized B cells was used to determine an arbitrary unit (AU) value using FlowJo software.
Statistical analyses were performed with GraphPadPrism, version 8 (GraphPad Software). The proportion of CR and relapses in patients with or without ARAs was compared using the Fisher exact test. The ARA serum levels and CD19+ B-cell frequencies were compared using the Wilcoxon paired t test. A 1-way analysis of variance with multiple comparisons was used for RTX and anti-DSG3 serum levels. Differences were considered significant at P < .05.
Results
Study Population
Forty-two of the 46 patients (91.3%) assigned to the RTX arm of the Ritux3 trial (NCT00784589) were included in this study. Four patients were excluded because their serum samples were not available. Nine patients (21.4%) experienced relapse during the first year after the initial treatment cycle of RTX. These latter patients could not be further analyzed because they received additional RTX infusions at the time they experienced relapse that prevented the assessment of the proportion of CD19+ B cells and other dosages scheduled in the protocol. Two other patients (4.8%) experienced relapse after month 12 at months 15 and 23, respectively. Five additional relapsing patients (11.9%) treated with the same regimen after the end of the trial were recruited for an ancillary study (eTable in the Supplement). These latter patients were only analyzed to assess the prevalence of ARAs between relapsing and nonrelapsing patients.
Prevalence of ARAs and Clinical Outcomes
These first analyses were completed in patients who were included in the Ritux3 trial. The ARAs were detected at month 12 in 13 of 42 patients (31%), including none of the 9 patients who experienced relapse during the first year of treatment and 13 of the 33 remaining patients (39%) (Table). At month 36, ARAs were detected in 9 patients (27%), including 8 of the 13 who already had ARAs at month 12 and 1 who did not. The mean (SD) serum concentration of ARA decreased from 90 (54) ng/mL at month 12 to 41 (24) ng/mL at month 36, with respective medians of 40.4 ng/mL and 18.0 ng/mL (P = .02) (Figure 1).
Table. Baseline Characteristics and Clinical Evolution of Patients With and Without ARAs at Month 12.
| Characteristics | No. (%) | P value | |
|---|---|---|---|
| With ARAs (n = 13) | Without ARAs (n = 20) | ||
| Age, mean (SD), y | 55 (17) | 56 (17) | .99 |
| Female | 11 (85) | 9 (45) | .03 |
| Male | 2 (15) | 11 (55) | |
| PDAI score, mean (SD) | 30 (26) | 28 (25) | .80 |
| Type of pemphigus | |||
| Foliaceus | 1 (8) | 4 (20) | .33 |
| Vulgaris | 12 (92) | 16 (80) | .33 |
| Mucosal | 4 (33) | 4 (25) | NA |
| Mucocutaneous | 7 (58) | 11 (69) | NA |
| Cutaneous | 1 (8) | 1 (6) | NA |
| Anti-DSG1, mean (SD), AU/mLa | 121 (138) | 253 (328) | .18 |
| Anti-DSG3, mean (SD), AU/mLa | 1093 (1350) | 465 (517 | .11 |
| Incomplete B-cell depletion (CD19+ B cells >0.5%)b | 6 (46) | 5 (25) | .21 |
| Clinical evolution | |||
| Sustained CR until mo 36 | 11 (85) | 20 (100) | .15 |
| Relapse | 2 (15) | 0 | .07 |
Abbreviations: ARA, antirituximab antibody; AU, arbitrary unit; DSG, desmoglein; NA, not applicable; PDAI, pemphigus disease area index.
Measured at baseline using enzyme-linked immunosorbent assay.
Measured at month 18 (6 months after the month 12 infusion of rituximab).
Figure 1. Evolution of Antirituximab Antibody (ARA) Serum Levels From Months 12 to 36 in the 13 Patients With ARAs.
The ARA serum levels were measured by enzyme-linked immunoassay at month 12 following the initial rituximab (RTX) infusion performed at baseline, and at month 36 after the 2 maintenance infusions of RTX at months 12 and 18 (arrows). Relapsing patients are identified in orange. The medians are represented by the horizontal lines.
aP < .05.
Among the 33 patients who were in CR at month 12, 2 patients (6.1%) further relapsed and 31 (93.9%) maintained a sustained CR until month 36. The proportion of patients who maintained a sustained CR until month 36 was not different whether patients had ARAs or not (ARA+: 11 of 13 [85%]; ARA−: 20 of 20 [100%]; P = .15) (Table).
Comparison of Immunological Findings Between Patients With and Without ARAs
CD19+ B-Cell Count
Patients without and with ARAs had a significant decrease in the percentage of CD19+ B cells between months 12 and 18 following the first maintenance infusion of RTX at month 12 from a mean (SD) of 8.6% (7.3%) to 1.8% (4.1%) (P = .001) in patients without ARAs and from 9.6% (7.6%) to 3.5% (4.7%) (P = .04) in patients with ARAs (Figure 2A), with a similar respective mean (SD) δ of −6.95 (4.85) vs −5.63 (8.38) (P = .70). An incomplete CD19+ B-cell depletion at month 18 (defined as CD19+ B cells >0.5%) was observed in 6 of 13 patients with ARAs (46%) compared with 5 of the 20 patients without ARAs (25%) (P = .21) (Table).
Figure 2. Frequency of CD19+ Blood B Cells, Serum Concentration of Rituximab (RTX), and Anti–Desmoglein 3 Antibody (DSG3 Ab) Serum Level in Patients With and Without Antirituximab Antibodies (ARAs).
A, CD19+ B cells in the blood of patients with or without ARAs from month 12 (time of B-cell reconstitution) to month 18 (6 months after the first maintenance infusion of RTX at month 12). B, Serum concentration of RTX at month 14 (2 months after the first maintenance infusion of RTX at month 12) in patients without and with ARAs. C, Anti-DSG3 Ab serum level at month 18 in patients without and with ARAs. Relapsing patients are identified in orange. The positivity threshold of anti-DSG3 Abs is represented by the dotted line at 20 AU/mL.
aP < .001.
bP < .05.
Serum Concentration of RTX and Anti-DSG3 Ab Serum Levels
The mean (SD) RTX serum level measured at month 14 corresponding to 2 months after the first maintenance infusion of RTX at month 12 was not different between patients without and with ARAs (13.4 [6.7] μg/mL vs 10.6 [8.1] μg/mL; P = .36) (Figure 2B). Patients without ARAs had a significantly lower mean (SD) anti-DSG3 Ab serum levels at month 18 than patients with ARAs (4.0 [4.3] AU/mL vs 30.1 [50.9] AU/mL; P = .03) (Figure 2C).
Immunological Findings According to Patients’ Clinical Course (Relapse vs CR)
Prevalence and Serum Concentration of ARAs
As only 2 patients initially included in this study experienced relapse after month 12, to increase the number of patients who experienced relapse, we enrolled 5 additional patients treated with the same regimen. These patients were selected because they experienced relapse more than 1 year after the initial RTX infusion to increase the number of relapsing patients to assess the prevalence of ARAs. The ARAs were detected in 2 of 16 relapsing patients (13%) (2 of 11 patients from the Ritux3 trial and 0 of the 5 additional patients) vs 11 of 31 nonrelapsing patients (35%) (P = .17). The median (range) concentration of ARAs was 45.0 (42.7-47.2) ng/mL in the 2 relapsing patients vs 40.4 (5.9-786.0) ng/mL in the 11 nonrelapsing patients with ARAs (P = .79).
B-Cell Depletion
These experiments could not be performed for the 5 additional patients whose blood samples were not collected 2 months after the RTX infusion. An incomplete B-cell depletion at month 18 was observed in 2 of the 2 relapsing patients with ARAs (100%) vs 4 of 11 nonrelapsing patients with ARAs (36%) (P = .19) and 5 of the 20 nonrelapsing patients without ARAs (25%) (P = .09).
Serum Concentration of RTX and Anti-DSG3 Ab Serum Levels
The mean concentration of RTX measured 2 months after the month 12 infusion of RTX was 0 μg/mL in the 2 relapsing patients with ARAs vs a mean (SD) of 12.5 (2.2) μg/mL in the nonrelapsing patients with ARAs (P = .03) and 13.5 (1.8) μg/mL in the nonrelapsing patients without ARAs (P = .02) (Figure 3A). The mean anti-DSG3 Ab serum levels measured at month 18 were a mean (SD) of 103.5 (61.5) AU/mL in the 2 relapsing patients with ARAs vs 19.5 (11.0) AU/mL in the nonrelapsing patients with ARAs (P = .001) and 4.0 (1.0) AU/mL in the nonrelapsing patients without ARAs (P < .001) (Figure 3B).
Figure 3. Serum Concentration of Rituximab (RTX) and Anti–Desmoglein 3 Antibody (DSG3 Ab) Serum Levels According to the Presence of Antirituximab Antibodies (ARAs) and Patients’ Clinical Courses.
A, Serum concentration of RTX at month 14 (2 months after the first maintenance infusion of RTX at month 12) in relapsing patients with ARAs, nonrelapsing patients with ARAs, and patients without ARAs. B, Anti-DSG3 Ab serum level at month 18 in patients from the same subgroups. The positivity threshold for anti-DSG3 Abs is represented by the dotted line at 20 AU/mL.
aP < .05.
bP < .001.
Neutralizing Ability of ARAs via the Interaction Between the Fab Murine Fragment and CD20
Using flow cytometry, we analyzed the neutralizing ability of ARAs to prevent the binding of the Fab murine fragment to the CD20 on EBV−immortalized B cells. The mean fluorescence intensity of the 2 relapsing patients with ARAs was not different from that of nonrelapsing patients with ARAs and patients without ARAs (these latter serum samples being used as negative controls), with respective mean (SD) values of 19 540 (1204) vs 19 216 (965) (P = .97) and 19 061 (549) (P = .95) (Figure 4), suggesting that the ARAs from the 2 patients who experienced relapse did not have a neutralizing ability.
Figure 4. Evaluation of the Antirituximab Antibody (ARA)–Neutralizing Capacity of the Interaction Between Rituximab (RTX) and Epstein-Barr Virus (EBV)–Immortalized B Cells Expressing CD20.
Mean fluorescence intensity (MFI) of the interaction between the patients’ serum samples and EBV-immortalized B cells expressing CD20 in the 2 relapsing patients with ARAs compared with nonrelapsing patients with ARAs and patients without ARAs as negative controls. The MFI corresponding to a neutralizing capacity of ARAs was determined using 2 positive controls and is represented by the dotted line.
Discussion
The main finding of this cohort study is that ARAs are frequently detected in patients with pemphigus who are treated with RTX because they were detected in 31% of patients, which is very close to the 32% rate recently reported in the PEMPHIX clinical trial.2 Most patients in the present study had a complete depletion of CD19+ B cells after treatment with RTX whether or not they developed ARAs. Indeed, the δ of the relative decrease of CD19+ B cells was very close in both groups (mean [SD], −6.95 [4.85] vs −5.63 [8.38]; P = .70). Accordingly, the serum concentration of RTX measured 2 months after the maintenance RTX infusion was not different whether patients had ARAs (mean [SD], 13.4 [6.7] μg/mL vs 10.6 [8.1] μg/mL; P = .36).
Importantly, the presence of ARAs was not strongly associated with the rate of sustained CR, which was achieved by 85% and 100% of patients with or without ARAs, respectively. Moreover, the frequency and concentration of ARAs decreased with subsequent maintenance infusions of RTX, which suggests that the presence of ARAs was not a contraindication to further infusions of RTX, as previously observed in patients with optic neuromyelitis.13 We also did not note an association between the presence of ARAs and occurrence of infusion-related reactions, as previously suggested in a patient with pemphigus.8
This study’s immunological and clinical findings support the fact that despite their frequency, ARAs are only rarely associated with the evolution of disease in patients with pemphigus who are treated with RTX. Only a few patients with the combination of ARAs and a low serum concentration of RTX that was followed by an incomplete B-cell depletion and persistence of anti-DSG3 Abs seemed at high risk of relapse. Incomplete B-cell depletion after treatment with RTX and low RTX concentrations have also recently been identified as predictors of relapse in patients with membranous nephropathy14 and systemic lupus erythematosus.15 Two studies have suggested that the efficacy of ARAs might depend on the ratio of RTX and ARA serum levels, thus being predictive of relapse.15,16 In the present study, we did not find a difference in the concentration of ARAs between the 2 patients who experienced relapse and those who did not (47.2 and 42.7 ng/mL vs 40.4 ng/mL), although these 2 subpopulations were quite limited. To increase the number of relapsing patients, we included in the ancillary study 5 patients who experienced relapse after having been treated with the Ritux3 regimen after the end of the clinical trial. We did not observe a higher prevalence of ARAs in relapsing patients compared with nonrelapsing patients, suggesting that ARAs are only rarely responsible for the occurrence of relapses.
To further analyze the neutralizing ability of ARAs, we studied their capacity to inhibit the interaction of the Fab murine fragment with the CD20 using flow cytometry. We did not find a direct interaction between the ARAs and the binding site of RTX. However, other mechanisms of action have been described, including the interaction with the Fc portion of the RTX, which prevents the complement dependent cytotoxic effects, and the formation of immune complexes between ARAs and RTX, thus increasing the clearance of RTX.17,18 This latter mechanism might explain the undetectable RTX serum levels observed in patients who had functional ARAs.16 It was previously shown that a clinical response after RTX retreatment was observed when the dose of RTX infused exceeded that of circulating ARAs, leading to a detectable serum level of RTX despite the consumption of RTX by ARAs. Thus, the efficacy of ARA might be associated with the dose of RTX infused, and consequently the ratio between ARA and RTX serum levels.16 The decrease of ARAs with additional RTX infusions that we observed in the present study suggests that they might be produced by short-lived plasma cells, which are generated by CD20+ memory B cells, these latter being eliminated by further infusions of RTX.
Limitations
The main limitation of this study is that only 2 patients experienced a late relapse after the initial treatment cycle of RTX, which on one hand is a major therapeutic outcome, but on the other hand decreased the power of the statistical comparisons. We could not precisely determine the mechanism of action of the ARAs in the 2 patients who experienced a relapse with ARAs. Despite the fact that ARAs did not directly interfere with the binding between RTX and the CD20 molecule, the combination of an undetectable RTX serum level, an incomplete B-cell depletion, and persistent high titers of anti-DSG3 Abs suggested that ARAs were functional in these 2 patients. Finally, the B-cell frequency was evaluated by flow cytometry using an anti-CD19 and not an anti-CD20 monoclonal Ab. Some studies showed that RTX could mask and down-modulate the expression of CD20 on B cells.19 It has also been reported that a CD20 polymorphism could impair the efficacy of RTX, although to our knowledge such a polymorphism has not been observed in patients with pemphigus.20 However, because CD19 and CD20 are coexpressed on B cells, we used an anti-CD19 monoclonal Ab as a marker of B cells.
Conclusion
Overall, this post hoc analysis of the Ritux3 trial showed that although ARAs are frequently detected in patients with pemphigus who are treated with RTX, they generally do not affect the disease course of patients with pemphigus nor contraindicate the use of further maintenance infusions of RTX. Few patients with the combination of ARAs, an undetectable RTX serum level, an incomplete B-cell depletion, and a persistence of high levels of anti-DSG3 Abs seem at high risk of relapse. However, because the number of patients included was relatively small, prospective studies encompassing more patients are needed to properly address this question.
eTable. Clinical and Serological Characteristics of the 5 Patients With Relapse From the Ancillary Study
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Supplementary Materials
eTable. Clinical and Serological Characteristics of the 5 Patients With Relapse From the Ancillary Study