Rituximab found as effective as cyclophosphamide in AAV children
International study data show both therapies induce disease remission
Treatment with rituximab in children with ANCA-associated vasculitis (AAV) is at least non-inferior to the use of cyclophosphamide at inducing disease remission or low disease activity among pediatric patients, according to data from a large international observational study.
The researchers noted that rituximab treatment was associated with greater rates of hospitalization due to infection or drug-related causes relative to cyclophosphamide. However, these differences did not reach statistical significance.
The study findings, while “not powered appropriately to determine whether rituximab or cyclophosphamide was superior in achieving remission-induction … should serve to satisfy some of the questions regarding the efficacy of rituximab in pediatric AAV,” the team wrote.
Overall, according to the researchers, “the results of this study will assist pediatric rheumatologists with clinical decision making as well as to help guide future comparative effectiveness studies within this patient population.”
The study, “Comparing Rituximab and Cyclophosphamide in Induction Therapy for Childhood-Onset ANCA-Associated Vasculitis: An ARChiVe registry-cohort study,” was published in the journal Arthritis Care & Research.
Significantly more US children treated with rituximab vs. cyclophosphamide
AAV is a collection of rare autoimmune diseases in which self-reactive antibodies, called ANCAs, wrongly target immune cells known as neutrophils, causing them to become overly active. These overly active neutrophils bind to the cells lining blood vessels, leading to blood vessel inflammation and damage.
Depending on the organ or tissue where blood vessel damage occurs, AAV can cause many different symptoms, including poor kidney function, breathing difficulties, nerve damage-related symptoms, and congestion.
Standard AAV treatment consists mainly of immunosuppressive therapies. Remission-induction treatment typically combines glucocorticoids with cyclophosphamide or rituximab.
Cyclophosphamide, sold as Cytoxan and others and with generics available, has historically been used for AAV off-label. Originally developed as a cancer therapy, it works by killing immune cells.
Despite being very effective at inducing remission, cyclophosphamide comes with severe side effects, such as infections and infertility, when used long-term, “limiting the extent of treatment particularly in teenagers and young adults in their childbearing years,” the researchers wrote.
Rituximab, sold as Rituxan in the U.S. and MabThera in Europe, with biosimilars available, was approved more than a decade ago in the U.S. for treating granulomatosis with polyangiitis and microscopic polyangiitis (MPA), the two most common types of AAV. Specifically promoting the death of antibody-producing immune B-cells, the therapy is believed to cause fewer side effects than cyclophosphamide.
In the adult patients, several studies have shown rituximab’s non-inferiority relative to cyclophosphamide. However, given that AAV rarely occurs in children, there is scant data on the use of cyclophosphamide versus rituximab in pediatric AAV patients. Children with the disease typically are treated based on information collected from studies on adult patients.
This is the largest study to date comparing induction regimens in pediatric patients with these diseases.
Now, an international team of researchers examined the outcomes of 104 pediatric AAV patients who received induction treatment with cyclophosphamide — 48 children or 46% — or rituximab, used for 45 children, or 43%. A combination of the two medications was used for 11 patients, or 11% of the children.
“This is the largest study to date comparing induction regimens in pediatric patients with these diseases,” the team wrote.
The children had a median age of 14 at diagnosis. All were participating in A Registry of Childhood Vasculitis (ARChiVe), an international registry established in 2007. Most lived in North America (72%), and were diagnosed with GPA (81%); the remaining 19% had MPA.
Children in the U.S. were significantly more likely to receive rituximab or the combination treatment for induction compared with other countries (74% vs. 42%). Also, rates of kidney disease were significantly lower in the rituximab group (76%) compared with the cyclophosphamide group (94%) and the combination therapy group (91%).
Rituximab treatment in children linked to greater rates of hospitalization
A total of 90 children were followed for one year, while 42 had data from a two-year follow-up visit.
The study’s main goal was to assess whether rituximab results in non-inferior rates of disease remission or low disease activity relative to cyclophosphamide, as assessed with the Pediatric Vasculitis Activity Score (PVAS). Disease remission was classified as a PVAS score of zero, while low disease activity was classified as a PVAS score of up to two.
The results showed that a comparable proportion of rituximab-treated children achieved remission or low disease activity compared with the cyclophosphamide group (64% vs 62%).
Comparably high proportions of children in both groups achieved at least a 75% reduction in PVAS score (80% vs. 85%) or a 50% or greater reduction in PVAS score (89% vs. 96%), indicating lessened disease severity with treatment.
The researchers noted that patients who received rituximab had a significantly lower median glucocorticoid dose compared to the cyclophosphamide-treated group (0.13 vs. 0.3 mg/kg per day).
Further statistical analyses also confirmed rituximab’s non-inferiority relative to cyclophosphamide.
Compared with the cyclophosphamide group, rituximab-treated patients were more likely to experience hospitalization for drug- or infection-related causes (22% vs. 10%), as well as multiple hospitalizations (11% vs. 2%). Still, these group differences did not reach statistical significance.
There also were no significant group differences in terms of disease-related damage after one year of treatment.
“Our findings are consistent with adult studies demonstrating non-inferiority of rituximab compared to cyclophosphamide for induction therapy in AAV,” the researchers wrote, also adding that “a significant number of adult studies have shown rituximab to be superior to cyclophosphamide in achieving remission.”
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