Progress Slow in Development of Useful Biomarkers for Rheumatoid Arthritis Treatment

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LONDON—Josef Smolen, MD, chair of rheumatology at the University of Vienna and former president of the European League Against Rheumatism (EULAR), expressed a “personal disappointment” in the development of useful biomarkers in the treatment of rheumatoid arthritis (RA).

Even though a good portion of his life’s work has been researching biomarkers to help with targeting therapies, he lamented that the field has been full of promises that have mostly ended up dashed.

“We have to do better, from my perspective,” said Dr. Smolen, speaking in a scientific debate at the 2016 EULAR Annual Congress. His debate counterpart—Ronald van Vollenhoven, MD, PhD, director of the Amsterdam Rheumatology and Immunology Center—was not particularly effusive about the progress of RA biomarkers, either, but painted a brighter picture.

Dr. Smolen said the hopes for biomarkers have been high.

“We want to predict what’s going on,” he said. “We want to predict new treatment targets. … We want to predict bad outcome; we want to predict response to therapy. We want to know who will respond to which agents having four biological principals, plus jakinibs,” which all yield essentially similar results.

He pointed to the example of IL-17 inhibitors. Those who don’t respond to anti-tumor necrosis factor drugs tend to have increased levels of IL-17.

“What happens if we use IL-17 inhibitors, especially in patients who fail TNF inhibitors?” Dr. Smolen said. But the results, even in these patients, were disappointing.¹

“IL-17 looks like a biomarker of chronic inflammation, its levels are even elevated in patients who are inadequate responders to TNF inhibitors,” Dr. Smolen said. “But it fails as a target.”

Failed Potential Biomarkers

The list of potential biomarkers that have produced similarly dashed hopes is a long one, among them the IL-2 receptor, CD4 cells, IL-12 and IL-23.

“All of these have failed as therapeutic targets, even though we would have sworn that each one of them would bring a new era into rheumatoid arthritis treatment,” Dr. Smolen said.

The result is that, for the past 20 years, the field has relied on the same old markers: mainly swollen joint count, C-reactive protein, rheumatoid factor and anti-citrullinated protein antibody.

MBDA

One of the latest attempts to use biomarkers—the 12-component multiple biomarker disease activity score (MBDA), which is approved by the FDA for monitoring disease activity—has been called into question by some studies.

A 2016 study looked at data from the AMPLE trial of abatacept vs. adalimumab. The response graphs using DAS28-CRP are superimposable for the two drugs. But using the MBDA, adalimumab shows a greater effect, Dr. Smolen noted.