Using a new research technique, scientists have accurately measured how rheumatoid arthritis patients respond to treatment with the drug adalimumab, one of the most commonly prescribed medications for the condition.
The team's test allowed them to measure levels of a key inflammatory protein that is targeted by the drugs. Their findings, published in the January 30 issue of Science Translational Medicine, could help researchers optimize treatment plans by predicting how future patients might respond to the therapy. The study also yielded surprising insights into the mechanisms of how adalimumab works and raises important questions about how long the drug should be administered to maximize its effectiveness.
Rheumatoid arthritis is a chronic disease that occurs when the immune system attacks the joints, resulting in painful inflammation. If the condition goes untreated, it can eventually damage the cartilage that covers the ends of bones, and it can also attack organs such as the heart and lungs.
The disease is one of the major contributors to disability in the U.S., affecting at least 1.3 million in the country, according to a report by the Arthritis Foundation. It is responsible for significant personal medical expenses, lost wages, and drops in quality of life. A 2010 study found that the condition results in $39.2 billion, measured in 2005 dollars, in total costs each year, and another study revealed that 25% to 50% of all patients become unable to work within 10 to 20 years of follow-up.
Standard treatments for rheumatoid arthritis include drugs that inhibit tumor necrosis factor (TNF), a protein that plays a central role in the body's inflammatory processes. One of these drugs, named adalimumab (Humira), is widely used in the clinic and was the top-selling drug in the U.S. in 2016, according to a report from the QuintilesIMS Institute.
However, researchers have encountered roadblocks in understanding how adalimumab and other TNF inhibitors work and why certain patients respond better than others. It is difficult for scientists to accurately measure concentrations of TNF in patients who are also being treated with TNF inhibitors, according to the study.
"Although the introduction of TNF inhibitors revolutionarily improved the treatment of rheumatoid arthritis, still one third of patients does not respond," said Lea Berkhout, a researcher at Sanquin Research in Amsterdam, the Netherlands and lead author of the new study.
Previous research has demonstrated that the formation of antidrug antibodies — antibodies that the immune system generates in reaction to a drug — is associated with a poorer response to adalimumab. Understanding the mechanisms of antibody formation is therefore critical to improving clinical outcomes, Berkhout said.
"Unraveling these mechanisms might help to optimize current TNF inhibitor therapies, and possibly contribute to avoiding [immune reactions] for future therapies," she said.
To tackle this mystery, Berkhout and the other researchers first created a "drug-tolerant" test that can quantify TNF concentrations during TNF inhibition. Using this test, they analyzed blood samples in three groups of rheumatoid arthritis patients totaling 193 individuals who were treated with adalimumab and tracked how the concentration of TNF in their blood changed over time.
The authors found that circulating TNF concentrations increased 50-fold during the first six months of treatment before reaching a stable concentration. These stable levels then persisted in the majority of the patients for at least two years.
A similar effect was observed in 30 healthy volunteers who received one dose of adalimumab, indicating the concentrations of circulating TNF were not associated with disease activity during treatment, according to Berkhout.
The research team then investigated whether there was any relationship between variations in TNF concentrations and how the patients responded to the drug. They observed that 22% of the patients developed detectable antidrug antibodies during the year-long follow-up. These patients also displayed lower concentrations of TNF after the fourth week of treatment and had a lower chance of disease remission after a year.
These results suggest that monitoring TNF concentrations could help to identify patients who may not respond to adalimumab treatment, Berkhout said.
The fact that circulating TNF concentrations remained high for up to six months after the treatment was discontinued also highlights an important conundrum, according to the authors. They say that the drug's long-lasting nature means it could be exerting effects for months after treatment has stopped, a possibility that is not currently accounted for by clinicians.
"This is relevant when evaluating switch studies, studies aimed at evaluating the success of discontinuing treatments upon reaching remission, and also calls into question the effectiveness of temporarily discontinuing treatment in case of an infection or surgery," Berkhout said.
Even an adalimumab concentration as low as .1 micrograms/milliliter in the circulation was enough to interact with TNF (compared to previously suggested optimal concentrations of 5 micrograms/milliliter) in a portion of the patients. Although further research is necessary to confirm these findings, they indicate that some patients might not need to be exposed to as much of the drug as is currently recommended in standard care, Berkhout said.