Prolonged Impairment of Immunological Memory After Anti-CD20 Treatment in Pediatric Idiopathic Nephrotic Syndrome

Abstract

Anti-CD20 therapy is effective in idiopathic nephrotic syndrome (INS). However, transient or sustained hypogammaglobulinemia predisposing to an increased risk of infectious diseases can follow treatment in some patients. We analyzed the long-term effects of anti-CD20 therapy on immunological memory in 27 frequently-relapsing/steroid-dependent INS pediatric patients after more than 4 years from the first and at least 2 years from the last anti-CD20 infusion. Twenty-one INS children, never treated with anti-CD20 and under an intense oral immunosuppression with prednisone, mycophenolate mofetil, and calcineurin inhibitors were also included as control group. Levels of circulating B-cell subpopulations, total serum immunoglobulins and IgG and memory B cells directed against hepatitis B virus (HBV) and tetanus were determined and correlated with clinical characteristics. Nine patients never relapsed after more than 2 years from the last anti-CD20 administration (5 after the first, 3 after the second, and 1 after the fifth infusion). At last follow-up, most patients showed a complete recovery and normalization of total (27/27), transitional (27/27), and mature-naïve B cells (25/27). However, a sustained and significant reduction of total memory (20/27) and switched memory (21/27) B cells was found in most patients. 11/27 patients showed hypogammaglobulinemia at last follow-up and, among these, four presented with a severe hypogammaglobulinemia (IgG < 160 mg/dl). In contrast, no patient in the control group developed a severe hypogammaglobulinemia. Age at the time of first anti-CD20 administration was positively associated with IgG levels at last follow-up ( p = 0.008); accordingly, younger patients had an increased risk of hypogammaglobulinemia ( p = 0.006). Furthermore, severe hypogammaglobulinemia and delayed switched memory B-cell reconstitution were more frequent in non-relapsing patients. Reduced IgG levels against HBV and tetanus were observed at baseline and further declined at last follow-up. Antigen-specific memory B-cells were induced by re-immunization, but specific IgG titers remained low. In conclusion, anti-CD20 therapy can be disease-modifying in some INS patients. However, a prolonged impairment of immunological memory occurs frequently, independently from the number of anti-CD20 infusions, particularly in younger patients. Re-immunization may be necessary in these patients.

A global antiB cell strategy combining obinutuzumab and daratumumab in severe pediatric nephrotic syndrome

“…This raises concerns over their ability to develop a naïve immune response if infected with a previously unmet pathogen [ 22 ] and supports the need for supplementation of IgG during at least 18 months after treatment in order to prevent severe infections, especially infection by enteroviruses [ 23 ]. Postvaccination serologies after B cell reconstitution and vaccine reimmunization are also mandatory at a distance from B cell repletion, as already suggested after any B cell depletion course in children [ 24 ]. Of note, oral immunosuppressive drugs have been shown to decrease circulating immunoglobulin levels in up to 65% of patients with INS [ 24 ].…”

“…Postvaccination serologies after B cell reconstitution and vaccine reimmunization are also mandatory at a distance from B cell repletion, as already suggested after any B cell depletion course in children [ 24 ]. Of note, oral immunosuppressive drugs have been shown to decrease circulating immunoglobulin levels in up to 65% of patients with INS [ 24 ]. Moreover, oral immunosuppressive drugs, especially when a combination of steroids, CNI and antimetabolites are used, impair all components of immunity, including innate and adaptive immunity, and the T cell–mediated continuous monitoring process by which invading pathogens and tumoral cells are recognized and eliminated.…”

Hypokalemia After Rituximab Administration in Steroid-Dependent Nephrotic Syndrome: A Case Report

“…Early-and late-onset hypogammaglobulinemia, neutropenia, and infections, including bacterial, fungal and viral (new and reactivated) episodes, are also commonly reported in association with rituximab administration (Kronbichler et al, 2017;Colucci et al, 2019). Hyperglycemia and cardiovascular disorders (mostly arrhythmias, hypertension, and hypotension) are associated with the drug administration as well.…”

Effects of Huaiqihuang Granules adjuvant therapy in children with primary nephrotic syndrome

“…[ 10 ], suggesting that circulating IL-18 does not work much in the pathogenesis of PNS and IL-18 expressed in renal tissue in the acute stage may play a role in PNS to some extent. Recent studies have reported that urinary IL-18 can be used as early biomarkers of acute kidney injury [ 11 ] and as a PNS activity index [ 10 ]. After Huaiqihuang Granules treatment for three months, serum levels of IL-18 decreased, suggesting that Huaiqihuang Granules may reduce the expression of IL-18 and reduce damages to renal tissues induced by inflammatory factors, but needing long-term use.…”