Anti-Rituximab Antibodies Occurrence and Clinical Outcomes in Patients With Primary Membranous Nephropathy

Abstract

Introduction: Rituximab is a first-line treatment for primary membranous nephropathy (pMN), with proven efficacy and safety. The use of monoclonal antibodies such as rituximab can lead to the formation of antidrug antibodies that may interfere with the therapeutic response. In pMN, anti-rituximab antibodies (ARAs) have been shown to neutralize the cytotoxicity of rituximab, thereby increasing the risk of relapse of nephrotic syndrome. However, the kinetics of ARAs over time and the effect of ARA titer on prognosis are unclear.

Methods: This retrospective international multicenter study included 74 patients with pMN treated with rituximab. Here we aimed to clarify the correlation between ARAs and clinical outcome, as well as to evaluate the most appropriate timing of ARA detection.

Results: Overall, 35 out of 74 patients (47%) developed ARAs after a median of 9 (interquartile range: 6-12) months following rituximab administration. ARA monitoring at month-9, month-12 and before rituximab readministration identified 88% of patients with ARAs. Clinical remission rate at 6 and 12 months after rituximab administration was significantly lower in patients with ARAs (31% vs. 56%, P = 0.03 and 54% vs. 87%, P = 0.0017, respectively). ARAs were associated with a significantly higher rate of relapse (63% vs. 29%, P = 0.036) and a higher rate of B-cell reconstitution at 6 months (74.2% vs. 50%, P = 0.048). Notably, relapse occurred earlier in patients with ARAs (22 months vs. 32 months, P = 0.01).

Conclusion: The development of ARAs represents one of the most important prognostic factors in pMN, being significantly associated with a reduced remission rate and a higher relapse rate after rituximab therapy. Alternative therapies with obinutuzumab or ofatumumab should be considered for these patients.

Keywords: anti-rituximab antibody; antidrug antibody; immunogenicity; membranous nephropathy; neutralizing antibodies; rituximab.

Graphical abstract

Figure 1

(a) Rate of anti-rituximab antibody positivity in 74 patients with membranous nephropathy and (b) rate of anti-rituximab antibody positivity in 85 rituximab courses from 74 individual patients. The rate of anti-rituximab antibody positivity increases progressively with exposure to subsequent rituximab courses.

Figure 2

Anti-rituximab antibody titer from baseline to 18 months after rituximab infusion in rituximab-naive patients. The dotted line represents ARA negativity, whereas the blue rectangle represents ARA positivity at different time points with the ARA titer specified inside (when available). We considered only those patients with at least 3 out of five 3-monthly ARA assessments. ARA, anti-rituximab antibody; CR, complete remission; NR, no remission; PR, partial remission.

Figure 3

Anti-rituximab antibody titer from baseline to 18 months after rituximab infusion in non–rituximab-naive patients. The dotted line represents ARA negativity, whereas the red rectangle represents ARA positivity at different timepoints with the ARA titer specified inside (when available). We considered only those patients with at least 3 out of five 3-monthly ARA assessments ARA, anti-rituximab antibody; CR, complete remission; NR, no remission; PR, partial remission.

Figure 4

Trend in median anti-rituximab antibody titer from baseline to 18 months after rituximab infusion. Box plot showing the median anti-rituximab antibody titer, both in (a) rituximab-naive patients and (b) non–rituximab-naive patients.