Models May Help in Weighing Risks of Rituximab’s Long-term Use in AAV

New statistical models could help to predict the risk of relapse and infection following ongoing rituximab treatment in people with ANCA-associated vasculitis (AAV), a study suggests.

These models may aid in clinical decisions about the relative risks and benefits of continuing to use rituximab beyond its customary two years with these patients, according to the researchers.

The models were described in the study, “Long-term maintenance rituximab for ANCA-associated vasculitis: relapse and infection prediction models” published in Rheumatology.

AAV is caused by antibodies — the eponymous ANCAs (anti-neutrophil cytoplasmic autoantibodies) — that erroneously target the body’s vascular system, leading to increased inflammation in blood vessels.

Rituximab works to kill B-cells, the cells that produce antibodies. By lowering the numbers of these immune cells, it can lessen inflammation in AAV. In the U.S., Europe and elsewhere, rituximab is approved to treat granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), two types of AAV.

Rituximab treatment generally involves an induction period — where comparatively high amounts of the medication are given in a short time to induce disease remission — followed by a lower-intensity period of maintenance treatment, which generally lasts two years.

Because rituximab depletes B-cells, which are important for fighting infections, its continued use can increase the risk of infections. However, stopping treatment raises a risk of AAV relapse.

“In clinical practice, clinicians must weigh up potential relapse and infection risk factors when deciding whether or not an individual patient will benefit from ongoing RTX [rituximab] treatment,” the research team at the University of Cambridge wrote.

“This is the first study to attempt to generate risk prediction models to help guide decision making regarding extended RTX maintenance therapy in AAV beyond a 2-year RTX treatment course,” they added.

Researchers analyzed data for 147 people with GPA or MPA who received a total of four to eight grams of rituximab at Addenbrooke’s Hospital between 2002 and 2018. Most were given a standard treatment protocol consisting of two 1,000 mg doses given two weeks apart (induction treatment), followed by 1,000 mg every six months for two years (maintenance treatment).

Median follow-up time after the last rituximab treatment was 63 months, just over five years. Over those years, 80 of these patients had an AAV relapse, while 88 experienced relevant infections (either one serious infection, or three or more non-serious infections).

Using patient data, the researchers constructed statistical models to assess the risk of relapse or infection. Various statistical tests were used to determine which factors were most appropriate for inclusion in the final models.

The model developed to predict relapse risk was based on seven factors: sex, age, ANCA positivity, ear/nose/throat involvement, dose of prednisolone (an immune-suppressing steroid), concomitant treatment with cyclophosphamide and/or an oral immunosuppressant, and whether the rituximab was originally given to treat new disease or a relapse.

With infection, the predictive model included five factors: sex, structural lung disease, diabetes, levels of IgG (a type of antibody) in the blood, and whether there had been infections during rituximab treatment.

Notably, these statistical models were not well suited to predicting risks in individual patients. However, they could group individuals into high- or low-risk groups accurately.

In the relapse model, the median time to relapse was 72.2 months in the low-risk group, and 29.4 months in the high-risk group. In the infection model, the median time to infection was 74.8 months (low risk) and 29 months (high risk).

Additional analyses that used data available one year after stopping rituximab treatment showed generally consistent results.

“While our models had insufficient power to discriminate risk between individual patients they were able to assign patients into risk groups for both relapse and infection. The ability to identify risk groups may help in decisions regarding the potential benefit of ongoing RTX treatment,” the researchers concluded.

“However, we caution the use of these prediction models until prospective multi-centre validation studies have been performed,” they added.

Rituximab is marketed as Rituxan (by Biogen) in the U.S., Canada, and Japan, and as MabThera (by Roche’s subsidiary Genentech) in Europe.

Recently, biosimilars of rituximab, such as Truxima, Ruxience, and Riabni, have been approved. A biosimilar is a biologic medical product that is similar to another already approved biological medicine, analogous to generics for conventional medicines.