MADRID – Measuring the formation of antibodies against biologic agents has no real value in daily practice as their presence or absence does not really change how patients are likely to be treated, Johannes W.J. Bijlsma, MD, observed at the European Congress of Rheumatology.
Consider a female patient who is 59 years old, diagnosed with rheumatoid arthritis (RA) in 2014, he said. She was being treated with methotrexate at a dose of 20 mg with additional glucocorticoids, initially given at a dose of 10 mg, reduced to 5 mg after 2 years, and then stopped. The patient experiences a disease flare, however, and for various other reasons is given a tumor necrosis factor inhibitor (TNFi). She does well initially but then has another flare, so would there be any point of measuring anti-drug antibodies (ADAbs) as this point? Not really, Dr. Bijlsma suggested, as the same decision to change the biologic agent would probably result if ADAbs were detected or not.
“If I do not measure them, I decide to change the biological. If I measure them and they are present, I change the biological, and if they are absent, I still change the biological,” said Dr. Bijlsma, professor and head of the department of rheumatology and clinical immunology at University Medical Center Utrecht (the Netherlands).
Following the European League Against Rheumatism (EULAR) recommendations for biologic disease-modifying antirheumatic drug (bDMARD) use (Ann Rheum Dis. 2017;76:960-77) would then mean that the first bDMARD, in this case adalimumab (Humira), would be replaced by another biologic with a different mechanism of action or a second TNFi.
“The immune response is always there,” Dr. Bijlsma said. It does not matter what or how it is administered, introducing any foreign protein, humanized or not, will instigate some kind of immune reaction, he said. The extent to which an immune reaction is raised might vary between biologic agents, but it will be there. He cited a review paper (Rheumatology [Oxford]. 2016;55:210-20) showing that the mean estimated occurrence of ADAbs in patients with RA ranges from 0.6% with the interleukin-6-targeting agent tocilizumab (Actemra) to 30% with infliximab (Remicade).
Measuring the level of ADAbs becomes problematic when considering that different biologics will induce different levels of immune response. The level of detection also will be dependent on which of three current types of assays are used. In addition, “humanization of biological agents is not the key point in preventing anti-drug antibodies,” Dr. Bijlsma said, pointing out that the prevalence of ADAbs against adalimumab did not appear to by any lower than ADAbs against infliximab.
Preventing ADAbs can be achieved by co-administering methotrexate or alternating the treatment schedule, Dr. Bijlsma said. Treatment with methotrexate, which is usually continued when patients start a biologic, “diminishes the immune response,” he noted. Indeed, while 50% of patients who are not treated with this conventional DMARD develop ADAbs, only 14%-35% develop them while taking methotrexate, depending on the dose used.
It is likely to be more useful in clinical practice to measure individual patients’ drug trough levels than to measure ADAb levels, he suggested, with dosing continued or adjusted accordingly for each patient. Using drug trough levels to personalize adalimumab treatment has been tested (Ann Rheum Dis. 2015;74:361-8) using a theoretical algorithm based on whether patients achieve a EULAR response at 6 months. If they do achieve a EULAR response and drug trough levels are between 5 and 12 mg/L or greater than 12 mg/L, then adalimumab treatment should continue. However, if the trough levels fall below 5 mg/L, there is probably no point in continuing treatment and this TNFi should be stopped. If patients do not respond and drug testing shows a trough level above 5 mg/L, then a switch to infliximab might be advantageous, while a trough level below this threshold could indicated that a TNFi with a lower immunogenic potential such as etanercept might be a better choice.
Using drug trough levels is still very much research based right now and is not ready for clinical practice just yet, but the theory is that it could help decide if patients should continue, stop, or perhaps switch their biologic, Dr. Bijlsma said.
Dr. Bijlsma spoke about these issues in a video interview at the congress.
Dr. Bijlsma has worked with many of the pharmaceutical companies that produce biologic agents for the management of rheumatic diseases but had no specific disclosures in relation to his comments.