We first describe the use of obinutuzumab to overcome the challenge of multidrug-dependent FRSDNS that relapses despite B-cell depletion after rituximab, sustained remission with reasonable side effect profiles.

Mounting evidence has shown the efficacy of rituximab in NS through restoring B- and T-cell immune homeostasis directly and indirectly [2]. Earlier reports demonstrated that NS relapses often occurred after total B-cell reconstitution [2]. Nonetheless, there is no substantial temporal relationship between total B-cells and relapse. Recent studies reveal that memory B-cells, a subset of the B-cell lineage, is closely associated with relapse [2]. Our patient experienced NS relapses, despite undetectable circulating levels of total and memory B-cells (< 0.05%), following two distinct courses of rituximab. This observation had been described by Sato et al., where 7% patients relapsed during B-cell depletion post-rituximab [1]. This phenomenon is thought to indicate that mechanistic pathways other than B-cell immunity are implicated in a subset of children with NS. Importantly, there is currently no effective treatment for this therapeutic dilemma.

Obinutuzumab is a type II anti-CD20 monoclonal antibody that is associated with a more profound depletion of B-cells and their subsets in both blood and tissue. In our patient, the last two courses of rituximab were ineffective, and the relapse-free periods were short—between 1 and 5 months—even in the presence of triple maintenance immunosuppression acting on the T-cell immunity. We speculate that in our patient, rituximab did not deplete memory B-cells residing within tissue and secondary lymphoid organs, such as lymph nodes and spleen [3], which continued to produce pathogenic circulating factors. The use of obinutuzumab enables more effective suppression of circulating factors, thereby achieving sustained disease remission. While measurements of anti-nephrin antibodies and anti-rituximab antibodies were unavailable in our locality, assessment of these biomarkers would have helped to better understand the case. One potential confounder was the use of concomitant triple immunosuppression, although the patient also received triple immunosuppression during the last course of rituximab, with trough tacrolimus levels comparable to that during obinutuzumab therapy. Following obinutuzumab, the family opted to continue triple immunosuppressants since previous relapses were associated with the development of acute kidney injuries and our patient had significant corticosteroid toxicities. Recently, Dossier et al. reported their experience in treating FRSDNS with obinutuzumab [4]. Of the 41 children with rituximab-refractory FRSDNS receiving obinutuzumab, 92% and 68% subjects were in sustained remission at 12 and 24 months. The study, however, did not include children who relapsed during circulating B-cell depletion.

Safety profiles appear to be acceptable in our patient. Apart from prolonged hypogammaglobulinemia of very low levels, there was no clinical infection and other reported adverse events. Hypogammaglobulinaemia occurs in 14–58% children treated with rituximab for NS [5]. In concordance with the aforementioned report on obinutuzumab [4], our patient developed significantly low levels of IgM, while IgG showed a gradual increment over time. Of note, our patient also had low levels of IgG prior to obinutuzumab which might contribute to the development and perpetuation of hypogammaglobulinemia [5]. Reduction of IgM levels has also been reported in up to 46% of patients treated with rituximab for various childhood conditions [6]. Importantly, low IgM levels may potentially contribute to infections [6]. Intravenous immunoglobulin replacement was not prescribed in our case, since only 1% of hypogammaglobulinaemia episodes develop infection [5], and current recommendations do not support substitution for asymptomatic hypogammaglobulinaemia. Furthermore, intravenous immunoglobulin contains only a minimal amount of IgM, which limits its use for preventing infections. The use of a prophylactic antibiotic is recommended for 3–6 months following anti-CD20 therapy [2]. Co-trimoxazole was given for 6 months, according to the departmental protocol, in our patient to prevent Pneumocystis jirovecii infection. In view of the longer duration of B-cell depletion with obinutuzumab, it is justifiable to extend its use until B-cell repopulation. While obinutuzumab appeared to be a feasible therapeutic option in this specific clinical setting, the decision to prescribe obinutuzumab should be excised with caution due to potential risk of severe infection, particularly in the presence of pre-existing hypogammaglobulinemia and concomitant immunosuppression.

In conclusion, obinutuzumab could be a viable option to achieve durable remission, more profound/complete B-cell depletion and corticosteroid-sparing effects in patients with rituximab-refractory NS who relapse despite circulating B-cell depletion. Future trials are required to establish the role of obinutuzumab in this difficult-to-treat disease.