Rituximab may raise risks of adverse events in AAV: Study
Serious adverse events, including infections, seen in GPA, MPA patients
Rituximab may be associated with a higher risk of serious adverse events, particularly infections, in people with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).
Time to first serious adverse event, as well as to second and multiple serious adverse events, is significantly shorter for patients treated with rituximab than for those given other immunosuppressive therapies.
These are the findings of real-world study in the U.K. that looked back at long-term safety data from nearly 400 adults with GPA or MPA, the two most common types of ANCA-associated vasculitis (AAV), who were treated with or without rituximab.
“However, these findings should be interpreted with caution as the rituximab patients had been diagnosed … for longer and had received a greater amount of immunosuppression in the past, compared with the patients who had not been treated with rituximab,” the researchers wrote.
The study, “Long-term surveillance study of rituximab originator treated patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA),” was published in Rheumatology Advances in Practice.
Rituximab long-term risks unclear
AAV is a group of autoimmune diseases characterized by inflammation and damage to small blood vessels in several organs. It is commonly triggered by self-reactive antibodies called ANCAs.
Sold as Rituxan in the U.S. and MabThera in Europe, and with available biosimilars, rituximab is approved as an induction and maintenance treatment for GPA and MPA.
It works by killing B-cells, the immune cells responsible for producing not only the antibodies that help the body fight threats, but also the self-reactive antibodies that drive AAV and other autoimmune diseases.
Due to its immunosuppressive effects, rituximab can increase the risk of infections and serious infections. However, “the long-term safety of rituximab remains unclear,” the researchers wrote.
To investigate the long-term risk profile and time to serious adverse events with rituximab versus other immunosuppressive treatments, the team of researchers from Cambridge, U.K., looked back at 15 years of follow-up data from 392 AAV patients treated with or without rituximab.
The patients were 18 and older, and received treatment between 2003 and 2017 at a specialist clinic. All were participating in the UK and Ireland Vasculitis Rare Disease Group registry.
Most patients were diagnosed with GPA (77%), while 23% had MPA. A total of 247 patients (63%) were treated with rituximab, while 145 (37%) were given other treatments (control group). Rituximab was given for a mean of 5.5 years.
Patients given rituximab were generally younger — with a mean age of 58.3, compared with 65.6 for those on other therapies — and had a longer mean disease duration (about two years vs. less than two months).
Prior exposure to certain immunosuppressive treatments (azathioprine, methotrexate, or mycophenolate) was also more frequent in the rituximab group. These patients also had lower levels of immunoglobulins G (IgG), antibodies that help fight infections, and of cells positive for CD19, a marker of B-cell maturation.
Disease activity and severity at study’s entry, as assessed with the Birmingham Vasculitis Activity Score and the Vasculitis Damage Index, were similar between the two groups.
Rates of serious events
Overall, rituximab-treated patients were more likely to experience adverse events (66% vs. 54%) and serious adverse events (54% vs. 49%) than those in the control group. This corresponded to a more than twice higher rate of serious adverse events per 1,000 patient-years (PYs) with rituximab (270 events vs. 129 events).
PYs measure the number of people participating in the study and the length of time they were followed. For example, 1,000 PYs refers to data gathered from 1,000 patients who were followed for one year.
Serious infections, most commonly in the lower respiratory tract, were more frequent in the rituximab group (26% vs. 12%), with a frequency of 84.8 per 1,000 PYs versus 31.6 in the control group.
Rituximab-treated patients were more likely to have low IgG levels requiring reduction or withdrawal of immunosuppressive medications (9% vs. 2%), and low counts of neutrophils, immune cells important to fight bacterial infections (7.3% vs. 1.4%).
There were no major group differences in terms of rates of cancer, cardiovascular events, or kidney insufficiency.
The time to the first serious adverse event or serious infection was significantly shorter for patients treated with rituximab, which was associated with a 55% higher risk of a first serious adverse event and a twofold higher risk of a first serious infection.
Rituximab also significantly increased the risk of a second serious event and of multiple events, by twofold. The rituximab group had a significantly shorter period between serious adverse events relative to the control group.
Further statistical analyses showed that patients treated with rituximab had twice the risk of having a serious infection and nearly twice the risk of additional safety events than those on other treatments.
Since previous studies have not found differences in serious adverse event rates between rituximab and other therapies in AAV patients, the higher rate of such events with rituximab in this analysis “may be attributed to the imbalance in [study’s start] characteristics,” the team wrote.
They also noted that rituximab is currently used as a first-line AAV therapy, meaning that patients may now be less exposed to prior immunosuppressive therapies, which can potentially reduce future adverse events.
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