1st-course Rituximab Found to Not Trigger Antibodies in AAV Patients

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A first course of rituximab is sufficient to trigger the development of anti-rituximab antibodies in patients with systemic lupus erythematosus (SLE) but not in those with ANCA-associated vasculitis (AAV), a study found.

The researchers had thought that rituximab might have similar effects in patients with SLE and AAV — both autoimmune diseases. However, the results of this study showed “the striking difference” in the occurrence of anti-drug antibodies, or ADAs, triggered by rituximab treatment across the two patient groups.

“After first rituximab cycle, no AAV patients were ADA-positive compared to 37.8% of the SLE patients,” the researchers wrote.

The study, “First exposure to rituximab is associated to high rate of anti-drug antibodies in systemic lupus erythematosus but not in ANCA-associated vasculitis,” was published in Arthritis Research & Therapy.

Rituximab is approved for use in AAV as both an induction therapy, to push the condition into remission, and a maintenance therapy, when it is used to keep patients in remission. It works by depleting B-cells, a type of immune cell that produces antibodies and is overactive in AAV and other autoimmune diseases.

The therapy is available under the brand name Rituxan in the U.S., as MabThera in Europe, or as biosimilars across the world.

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Despite being unapproved for lupus treatment, rituximab also is used off-label in SLE, an autoimmune disease characterized by widespread inflammation and tissue damage.

Some people develop antibodies against rituximab as the result of an unwanted immune response, and this may limit the efficacy and safety of the treatment. However, there are limited data on the development of anti-rituximab antibodies in particular patient groups.

Now, a team of researchers in Sweden looked at how common it is for patients with AAV or SLE to develop such antibodies and how they may affect the efficacy and safety of rituximab treatment.

The study included 22 AAV patients — 10 men and 12 women — with a median age of 62 and a median disease duration of 1.5 years. Among the patients, 15 had granulomatosis with polyangiitis (GPA), six had microscopic polyangiitis (MPA), and one had eosinophilic granulomatosis with polyangiitis (EGPA).

The most common rituximab treatment regimen given to these patients was 1 gram taken two weeks apart (in 59% of them, 13 patients). Just under half (10 patients; 45.4%) also received cyclophosphamide as part of their treatment.

A total of 66 SLE patients (60 women) also were involved in the study. These participants were younger, with a median age of 36.3, and had their disease longer, with a median duration of 7.9 years. The most common rituximab treatment regimen was 375 milligrams per square meter of body surface area once weekly for four weeks in 38 patients (57.6%). Methylprednisolone was prescribed for 37 (56.1%) of these patients, and 36 (54.5%) also were receiving cyclophosphamide.

After the first course of rituximab treatment, none of the AAV patients developed anti-rituximab antibodies, the data showed.

This was in contrast with the SLE patients, among whom 25 (37.8%) developed antibodies at a median of six months after the start of rituximab treatment. Those who developed antibodies were a median 10 years younger (34 vs. 44.3 years), and had more active disease and with shorter duration (4.14 vs. 9.19 years) than those who did not. Most cases (22) occurred in patients receiving rituximab for lupus nephritis, or an inflammation of the kidneys.

Despite overall reduction of SLE disease activity, as measured using a tool called SLEDAI-2K, patients who developed antibodies against rituximab had a higher SLEDAI-2K score (6 vs. 4) and a greater proportion of B-cells (4% vs. 0.5%) at six months follow-up than those who did not.

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According to the scientists, these findings mean that the development of antibodies may affect the efficacy of rituximab in these patients.

After the second course of rituximab treatment, three antibody-positive SLE patients (25%) had immediate reactions to rituximab infusion, and two (16.7%) experienced serum sickness, or extreme sensitivity to rituximab, characterized by a fever, rash, and joint inflammation or pain. Serum sickness also was reported in one antibody-negative patient (5.2%), while no immediate infusion reactions were reported in this group upon treatment.

Next, to look for naturally occurring anti-rituximab antibodies, the researchers used blood samples from 41 AAV patients and 62 SLE patients who had never been treated with rituximab. One AAV patient and three SLE patients had positive yet very low levels of anti-rituximab antibodies.

“The presence of naturally occurring antibodies,” the researchers wrote, may reflect “the presence of a remarkably broad antibody repertoire.”

Overall, the findings suggest that the development of anti-rituximab antibodies is common among SLE patients, calling attention to the need for anti-rituximab antibody “screening before retreatment and survey of immediate and late-onset infusion reactions,” the researchers wrote.

However, “such phenomenon appears not to be of greater relevance for AAV,” they added.

The team noted that “rituximab is routinely used for ANCA-associated vasculitis.”