Are antidrug antibodies reducing the effectiveness of rheumatoid arthritis treatment?

By Dr. Chinta SidharthanReviewed by Sophia CoveneyJul 17 2023

In a recent study published in JAMA Network Open, researchers examined the association between antidrug antibodies, such as those against the monoclonal antibodies targeting tumor necrosis factor (TNF) and interleukin-6 receptor, and the response to treatments for rheumatoid arthritis such as biologic disease-modifying antirheumatic drugs (bDMARDs).

Background

Biologic drugs used in rheumatology, often called bDMARDs, are used as second-line treatment options for rheumatoid arthritis. Still, they often have a low retention rate with approximately only half the patients continuing the treatment after two years.

One factor that makes these bDMARDs ineffective and reduces their concentration is the development of antibodies against these biologic drugs.

A European study investigated the development of antibodies against biological drugs across cohorts of patients with multiple sclerosis, Crohn's disease, rheumatoid arthritis, and ulcerative colitis. It reported that using antibiotics and immunosuppressants lowered the risk of antidrug antibody development.

In patients with rheumatoid arthritis, the use of methotrexate was also linked to a decrease in the development of anti-drug antibodies. However, the impact of anti-drug antibodies on various bDMARDs used to treat rheumatoid arthritis remains unclear.

About the study

In the present study, the researchers used the multi-center data from the European Anti-Biopharmaceutical Immunization study for the rheumatoid arthritis cohort, which spanned 27 recruiting centers across four countries in Europe, namely, the United Kingdom (U.K.), France, the Netherlands, and Italy.

Participants were eligible for the study if they were above the age of 18, were diagnosed with rheumatoid arthritis, and their physician had decided to initiate treatment with rituximab (a CD20 inhibitor), tocilizumab (a monoclonal antibody targeting interleukin-6 receptor), and TNF inhibitors such as infliximab, etanercept, and adalimumab.

Previous treatment with similar drugs, current pregnant or breastfeeding status, and an inability to follow the study protocols were grounds for exclusion. Protocol visits were conducted every three months for 18 months, and C-reactive protein scores were used during each visit to evaluate disease activity.

Serum samples were also collected during each visit to assess the levels of antidrug antibodies against all the bDMARDs, and drug concentrations of the TNF inhibitors.

Routine biological tests were conducted, such as erythrocyte sedimentation rate, alanine aminotransferase, creatinine levels, aspartate aminotransferase, and blood cell counts. Data on medical history, body mass index (BMI), history of autoimmunity in the family, concomitant treatments, and tobacco use and exposure were also obtained.

Electrochemiluminescence was used to measure the binding antidrug antibodies. Bridge enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of etanercept, while the levels of infliximab and adalimumab in the serum were also measured using ELISA.

The detection of antidrug antibodies at least once during one of the protocol visits between the first and the twelfth month was defined as antidrug antibody positivity. Furthermore, they were subdivided into transient-positive and persistent-positive groups based on whether the patients had a negative status for antidrug antibodies after subsequent tests.

The European League Against Rheumatism (EULAR) response after one year of therapy for rheumatoid arthritis was the primary objective. In contrast, the EULAR response at six months and at different time points between six months and 18 months, along with drug levels during each protocol visit were the secondary objectives of the study.

Results

The results reported that antidrug antibodies were associated with a decreased response to bDMARDs in patients with rheumatoid arthritis. The study found that in rheumatoid arthritis patients, antibodies against TNF inhibitors, tocilizumab, and rituximab were high.

Furthermore, the clinical response after one year of therapy to all bDMARDs, especially the monoclonal antibodies against TNF, was inversely associated with the levels of antidrug antibodies.

The multivariable analysis also revealed that rheumatoid factor, BMI, and antidrug antibody levels had independent inverse associations with the response to therapy for rheumatoid arthritis.

The results from the pharmacokinetic analyses also indicated that the concentrations of infliximab and adalimumab were significantly lower in the patients with a positive antidrug antibody status. Furthermore, methotrexate concentration was inversely associated with persistent-positive status for antidrug antibodies.

Conclusions

Overall, the findings reported that the response to bDMARDs in rheumatoid arthritis patients was significantly lowered by the generation of antidrug antibodies. The results suggested that personalized management and monitoring of antidrug antibody levels should be considered for patients with rheumatoid arthritis.