Rituximab Use in Children Not Likely to Raise Serious Infection Risk
Prolonged low levels of immunoglobulin antibodies as a result of rituximab treatment did not increase the likelihood of serious infections in children with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) — the two most common forms of ANCA-associated vasculitis (AAV).
This was according to a post-hoc analysis of children enrolled in the Phase 2a PePRS clinical trial of the B-cell depleting therapy.
“These findings indicate that repeated peripheral B-cell depletion with rituximab did not increase [serious infection] risk over time, despite prolonged low [immunoglobulins],” the researchers wrote. “Vigilance is recommended in monitoring for [serious infection] in pediatric patients with prolonged low immunoglobulin levels during or after rituximab treatment.”
The study, “Evaluation of Serious Infection in Pediatric Patients with Low Immunoglobulin Levels Receiving Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis,” was published in the journal Rheumatology and Therapy.
Rituximab is an antibody-based therapy that acts by lowering the levels of immune antibody-producing B-cells, serving to dampen the inappropriate immune responses seen in AAV and other autoimmune conditions. An approved therapy, it was originally marketed by Roche as Rituxan in the U.S., with biosimilars now available.
Results from the Phase 2a PePRS clinical trial (NCT01750697) showed that children with MPA and GPA safely achieved disease remission within 18 months of beginning treatment with rituximab, leading to its approval in the U.S. and Europe for children with both forms of AAV who were at least 2 years old.
The use of immunosuppressive therapies such as rituximab can lead to hypogammaglobulinemia — an inability of the immune system to make proper amounts of antibodies called immunoglobulins (Igs), specifically IgG and IgM subtypes. Igs are an important part of the body’s defense system, and when depleted may raise the risk of serious infections.
Researchers now examined data from the PePRS trial to evaluate the risk of serious infections in children who had low IgG or IgM levels after being treated with rituximab.
The trial consisted of a six-month remission induction phase, in which children ages 2–17 with MPA or GPA received four weekly rituximab intravenous (in the vein) infusions while being tapered off glucocorticoid treatment. All had at least one year of follow-up, lasting up to 4.5 years in some children.
After six months, children could receive further rituximab infusions or other immunosuppressants according to their doctor’s instructions.
The trial enrolled 25 children, including 19 with GPA and six with MPA. Eighteen had newly diagnosed disease whereas seven had relapsing disease.
As expected, B-cell levels were depleted with rituximab treatment. Six patients whose B-cell levels remained depleted underwent an extended safety follow-up to monitor levels until they returned to normal or to levels recorded before starting with rituximab.
IgG and IgM were measured in patients’ serum — the liquid component blood — every four to 12 weeks throughout the study, and patients were monitored for serious infections during follow-up.
An overall decline in median IgG and IgM levels was observed throughout rituximab’s use, with both IgG and IgM reaching their lowest levels at month two of treatment. IgG levels returned to normal between nine and 12 months after the study’s start, whereas IgM remained below normal for up to 18 months.
Overall, 22 children experienced prolonged low IgG and/or IgM for at least four months during the study. Of these, three had low IgG, four had low IgM, and 15 had both low IgG and IgM.
During the overall study period lasting up to 4.5 years, 105 infections were reported among 23 patients, most of which were not serious. The most frequently reported infections were influenza and lower respiratory tract infections.
Nine serious infections were reported in seven children, all of whom had prolonged low IgG and/or IgM levels. All children who experienced serious infections had a history of steroid or immunosuppressant use, either before or during the study period. All but one of these infections, a serious bacterial eye infection that developed within two months of the last rituximab infusion, resolved without complications.
Three children were given intravenous immunoglobulin to clear these infections.
Statistical analyses found no increased risk of serious infection with prolonged low levels of either IgG or IgM, and the number of rituximab infusions or participation in the safety follow-up were not associated with infections.
The team noted the these results are limited by the fact that the PePRS trial was not originally designed to assess infections as an outcome, and that it lacked a comparative placebo group.
Nonetheless, “most of the observed laboratory abnormalities of prolonged low immunoglobulin were asymptomatic, and there was no increase in the number of [serious infections] over time, through the extended [safety follow-up], or with increasing rituximab treatments,” the researchers wrote.
“Most [serious infections] could be treated, had a favorable outcome, and were consistent with the safety profile in adult patients with GPA/MPA receiving rituximab,”