Timing of Rituximab Infusion May Affect COVID-19 Outcomes in AAV Patients

People with ANCA-associated vasculitis (AAV) who receive rituximab treatment may have a higher risk of severe COVID-19 outcomes and should therefore be considered vaccination priorities, a recent case report suggests.

The time since a patient’s last rituximab infusion and their current immunoglobulin level appear to be the most important factors affecting the risk of death from COVID-19 in AAV patients.

The report, “Timing of Rituximab and immunoglobulin level influence the risk of death for COVID-19 in ANCA-associated vasculitis,” was published in the journal Rheumatology.

AAV occurs when self-reactive antibodies, called anti-neutrophil cytoplasm antibodies or ANCAs, cause damage to small blood vessels in various organs. The two most frequently targeted proteins are proteinase 3 (PR3) and myeloperoxidase (MPO).

Rituximab reduces inflammation by killing B-cells, immune cells that produce antibodies. It is used to treat granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), two subtypes of AAV.

Because rituximab depletes B-cells, which are important for fighting infections, its continued use can increase the risk of infections, including infections by the SARS-CoV-2 virus which causes COVID-19.

Recent data from the COVID-19 Global Rheumatology Alliance physician-reported registry identified a strong association between rituximab and worse outcomes in people with rheumatic diseases.

However, the exact timing of rituximab treatment, as well as levels of antibodies and previous immunosuppressive treatments, have not been investigated in this registry.

Researchers at the University of Udine, in Italy, have now reported the case of two AAV patients who had different outcomes to COVID-19 infection, possibly due to differences in the time since their last rituximab infusion and in their immunoglobulin levels.

One, with GPA, became infected 45 days after her last rituximab infusion, never raised antibodies against the virus, and died 25 days later. The second, with MPA, acquired COVID-19 approximately 100 days after her last infusion, had nearly twice the level of immune antibodies as the first patient at the infection’s outset, and recovered, having raised antibodies against the virus.

The first patient was a 73-year-old woman with PR3-positive GPA, who first received rituximab to induce remission and had been using it as maintenance therapy since October 2017. She received her last infusion on Nov. 9, 2020, and was in remission while taking 2.5 mg/day of prednisone equivalent.

Her immunoglobulin G (IgG) level was 456 mg/dL just before her last rituximab dose. IgG is a major component of the immune system that immobilizes pathogens, such as virus particles, and activates other arms of the immune system.

She was diagnosed with COVID-19 via nasal swab on Dec. 24, 2020, 45 days after her last rituximab dose. At that time, her B-cells were depleted from rituximab use and her IgG level was unchanged.

She soon went into severe respiratory failure and was admitted to the intensive care unit on Jan. 10, where she received glucocorticoids, antibiotics, anticoagulants, and oxygen therapy.

She continued to test positive for COVID-19 by nasal swabs and failed to produce appreciable antibodies against the SARS-CoV-2 virus. The patient died on Jan. 17, 25 days following her COVID-19 diagnosis.

The second patient was a 74-year-old woman with MPO-positive MPA. She had been in remission on rituximab since December 2019. Her last rituximab infusion occurred on Aug. 17, 2020, at which time she remained in remission and was taking 5 mg/day of prednisone equivalent.

She received a COVID-19 diagnosis on Nov. 25 — 100 days after her last rituximab dose — because of coming into close contact with a positive COVID-19 case. Her test came back positive, although she never developed COVID-19 symptoms.

At the time of the test, she was B-cell depleted and her IgG level stood at 866 mg/dL.

She received a negative COVID-19 result on Jan. 27, with low levels of anti-SARS-CoV-2 IgG antibodies.

“Timing of [rituximab] and IgG levels were quite different between the two cases, and may have conditioned the final outcome greatly,” the investigators wrote.

“Thus, patients needing [rituximab] require prioritization for SARS-CoV-2 vaccination,” they concluded.

Rituximab was originally sold as Rituxan (by Biogen) in the U.S., Canada, and Japan, and as MabThera (by Roche’s subsidiary Genentech) in Europe, but a number of rituximab biosimilars have also been approved in recent years.