Rituximab to be used with caution

By Emilio Besada, research fellow at the Bone and joint research group, Institute of Clinical Medicine, University of Tromsø

Rituximab, photo by NIAID

Photo by NIAID

Rituximab (MabThera®) has been used for over a decade to treat blood cells cancer and autoimmune diseases. Experience shows that Rituximab is a very effective and a “remarkably safe” drug. But in theory, Rituximab could increase the risk for infections since it turns off a part of the body’s defence (aka the immune system) against germs by killing B cells from the blood circulation.

Our clinical experience at the University of Tromsø in Norway agrees with the theory: long-term use of Rituximab in patients with Granulomatosis with polyangiitis or GPA increases the risk for severe infections

Revising our judgement about Rituximab

Early in the spring 2011, two patients with GPA, who were doing “remarkably” well with Rituximab, were hospitalized at the intensive care unit for severe pneumonia. By the end of 2011, other patients with GPA on Rituximab had infections. As we reviewed the patients’ medical files, we (re)discovered that some patients developed very low levels of antibodies while receiving Rituximab.

What is going on? B cells produce antibodies. Rituximab kills B cells and its prolonged use results in very low levels of antibodies. Antibodies neutralize and help destroy germs and very low levels of antibodies increase the risk for infections.

Improving patients’ outcome from death to remission

GPA is a severe form of vasculitis, formerly known as Wegener’s granulomatosis. GPA injures blood vessels walls leading to damage. It commonly affects the sinuses, lungs and kidneys, but it can affect almost all organs. It is a fatal disease if left untreated since half of the patients would die during the 6 months following diagnosis.

Conventional treatment with steroids (prednisolone/prednisone), drugs used in transplantation medicine (aka immunosuppressive drugs) and chemotherapy (cyclophosphamide) does not cure the disease, but prevents death and relapses in most patients. Patients feel better under continuous conventional treatment; however they seldom feel good since conventional treatment can also damage organ. Continuous use of high dose of steroids gives weight gain, mood disorders, osteoporosis, diabetes, high blood pressure, cataract and an increased risk for infections. Chemotherapy and immunosuppressive dugs increase the risk for infections and cancers.

On the other hand, Rituximab has slowly revolutionized treatment of patients with GPA. Compared to conventional treatment, Rituximab does not have the same risk for either cancer or infection and patients are able to stop steroids sooner. But since 2011, our expectations regarding Rituximab have become more reasonable.

Learning from experience

In our study, long-term use of Rituximab controlled the disease activity and decreased the risk to relapse by more than 80%. Patients were able to stop their immunosuppressive drugs and to either reduce or stop steroids preventing organ damage due to conventional treatment. In other words, patients got their life back while on Rituximab.

Unexpectedly, a third of the patients had to stop Rituximab after 4 years of treatment mainly due to low levels of antibodies and infections.

But the most important finding is that only a distinctive group of patients develops infections while using Rituximab. Patients at risk for infections are over the age of 60; they have a reduced kidney function and had received a lot of chemotherapy.

Is Rituximab a Faustian choice?

Rituximab works very well in patients with GPA and patients on Rituximab should not be afraid to use it. But patients are not equal and some will develop low levels of antibodies and infections during long-term Rituximab use. Therefore we need to adapt the treatment dose and duration according to each patient. The treatment goals are equal for all patients: to control the disease, to limit organ damage and infections risks. There is no Faustian choice: Rituximab achieves most of these goals, when used with caution.

E-mail Emilio Besada
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