Rituximab and novel CD20-blocking agents
Multidrug-resistant patients who are unresponsive to above listed agents – steroids, CNI and MMF – pose a great challenge for nephrologists. Monoclonal antibodies have been investigated as salvage therapy for these patients.
Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody which has been used as an alternative steroid-sparing agent for SSNS patients since the early 2000s and is generally well tolerated. Its main action on immune regulation is through targeting the cell surface antigen CD20 on B lymphocytes and inducing B-cell depletion [
26]. In addition, a non-immune-related mechanism of action has been proposed. RTX reportedly could affect podocyte function through stabilization of sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b), preventing podocyte actin remodelling [
109].
While RTX has been successfully used in patients with FRNS or SDNS in recent years [
110], a comparative study by Topaloglu et al. explored the effects of RTX in children with SSNS (
n = 21) and SRNS (
n = 20) and concluded that RTX had more positive therapeutic effects in patients with SSNS than in those with SRNS [
111].
Although controversial results exist related to its efficacy in SRNS, it has been generally successful in children with SRNS [
60,
112]. Reportedly, approximately 50% of patients with refractory SRNS respond to RTX [
61], showing complete remission in 44% and partial remission in 15% [
9] of cases. Studies with more favourable outcomes report response rates of 63% [
113], 67% [
87] and 80% [
62]. However, contrastingly, non-response rates of 81% [
63] and 71% [
112] were found by other publications. A recent systematic review of RCTs reported remission with RTX in 46% of SRNS (63% with MCD and 39% with FSGS) and sustained remission among responders in up to ~ 94% [
58]. However, an open-label RCT in patients with refractory SRNS by Magnasco et al. demonstrated no additional benefit of RTX over CNI [
63].
There is a recent study by Fujinaga et al. reporting 100% complete remission in children with SRNS receiving RTX [
41]. This study is noteworthy because the authors emphasized the significance of timing of RTX initiation in SRNS patients. In the study, the authors investigated long-term outcomes after early application of RTX in six Japanese children who were unresponsive to a combination of CSA and intravenous methylprednisolone pulses [
41]. The patients had RTX treatment within 6 months of disease onset (median 11 weeks), followed by retrial of high-dose intravenous methylprednisolone (2 mg/kg/d) and oral prednisolone and then switched to maintenance oral immunosuppressants (MMF or CSA). Using this protocol, all six patients achieved complete remission at a median of 158 days and maintained remission (although there were relapses) for a follow-up period of 5.1 years, without developing renal insufficiency [
41]. In the previous open-label RCT in patients with refractory SRNS by Magnasco et al., two standard doses of RTX were not able to induce remission within 3 months after administration [
63]. It is important to note that in the study by Fujinaga, most patients (4/6, 67%) achieved remission after 3 months of RTX administration with repeated doses (one patient required eight doses of RTX until complete remission was achieved) [
41]. The authors suggested that in case of unresponsiveness, repeated administration over a longer period of time can be effective in SRNS. Evidence supports the concept that serum RTX levels may decrease more rapidly in SRNS due to persistent urinary losses [
114,
115]. In that sense, it appears to require more doses in SRNS patients who have uncontrolled proteinuria [
41,
116]. Moreover, the time from diagnosis of SRNS to the first RTX infusion was 2.5 years in the RCT by Magnasco et al. [
63] and 2.2 years in the study by Topaloglu et al. [
111], while it was 11 months in Fujinaga et al.’s study [
41]. It may be speculated that a long-lasting nephrotic state leads to irreversible histologic changes, such as fibrosis and glomerulosclerosis [
41], which results in imperfect response to RTX treatment. This view was supported by an observational study by Kamei et al., in which seven out of ten (70%) SRNS patients responded after repeated doses of RTX followed by intravenous methylprednisolone pulses and an additional oral immunosuppressant [
62]. In this study, the seven patients who received RTX within 6 months of disease onset achieved complete remission, while two patients who had a longer duration of disease (61 and 121 months, respectively) progressed to end-stage kidney disease [
41,
62].
Although rituximab is generally safe and well tolerated in most children, there are potentially serious adverse events that require caution: hypogammaglobulinemia, late-onset neutropenia, hepatitis B reactivation, serious infusion-related adverse events and infections, the latter with potentially fatal outcome with reports of
Pneumocystis jirovecii pneumonia and progressive multifocal leukoencephalopathy [
8,
58,
59,
61,
62,
117,
118]. In the study by Fujinaga et al., although all six patients achieved complete remission, four of the six had hypogammaglobulinemia requiring intravenous immunoglobulins (IVIG), and one of them developed persistent hypogammaglobulinemia demanding regular IVIG treatment (despite re-emergence of B-cells in the blood) [
41]. Such hematologic adverse effects are reported more often and more severely in younger children. In previous studies with SRNS [
41] as well as with SDNS [
119], those patients who developed severe neutropenia and hypogammaglobulinemia were aged under 10 years. In addition, in a Japanese multicentre study involving 114 children, the median age was significantly younger in patients with more severe hematologic adverse effects (6.4 vs. 11.5 years) [
120]. On the other hand, Bonanni et al. reported only 2 cases of severe neutropenia out of 100 Caucasian children with multidrug-resistant nephrotic syndrome who received RTX [
121]. This discrepancy may be explained by the older age of patients in Bonanni’s group (median 9.2 years). Although the mechanisms leading to more complications in younger children are not well understood, younger age appears to be a particular risk factor for these adverse events.
To summarize, although RTX treatment in SRNS may not be as effective as in SSNS, early repeated administration with higher cumulative doses can be efficacious in the management SRNS. Early administration within 6 months of disease onset and a trial of multiple doses followed by methylprednisolone pulses with high-dose prednisolone showed favourable renal outcome. Adverse hematologic effects occur more frequently in children aged under 10.
Ofatumumab
Ofatumumab, a novel humanized anti-CD20 monoclonal antibody, is an alternative to RTX in patients with anti-RTX antibodies or RTX hypersensitivity. It has also been used in patients with resistance to RTX [
64,
67,
68] including cases with post-transplantation RTX-resistant SRNS [
64,
122]. Ofatumumab successfully achieved remission in paediatric SRNS with severe adverse reactions to RTX [
65] and anti-RTX antibodies [
66]. Efficacy of ofatumumab so far is exceptionally positive; its first use reported complete or partial remission in five out of five children with SRNS [
67] and in a more recent study in four out of four children with SRNS who completed ofatumumab treatment [
64]. In the latter study, two patients experienced hypersensitivity to ofatumumab and received desensitization [
64]. In a study with lower doses of ofatumumab, two out of four patients who were resistant to a combination or steroids, CNIs and MMF, achieved remission [
68].
The side effects, however, were more prevalent with ofatumumab than RTX in the study by Bonanni et al. [
121]. They investigated treatment outcomes in steroid- and multidrug-dependent nephrotic syndrome using RTX in 137 and ofatumumab in 37 patients. While treatment efficacy was comparable, infusion reactions, such as skin rash, fever, dyspnoea and late adverse effects, were more frequent in the ofatumumab treatment group [
121]. In this study, immediate infusion reactions were effectively controlled by pretreatment including steroids, antihistamines and paracetamol, and salbutamol was critical for preventing respiratory complications.
In short, ofatumumab is an emerging substitute for RTX-resistant and RTX-hypersensitive patients with multidrug-resistant SRNS, although adverse effects and infusion reactions are more common than following RTX administration. Addition of a beta-mimetic agent in the pretreatment protocol was helpful in controlling respiratory reaction.