Finding Clues to Hard-to-Treat RA 

By Jill Tyrer | June 21, 2023   

When someone is diagnosed with rheumatoid arthritis (RA), they typically are started on a regimen of methotrexate. This conventional synthetic disease-modifying antirheumatic drug (DMARD) has been a treatment mainstay for RA for 35 years. If that doesn’t ease the patient’s symptoms and underlying inflammation, then the doctor will likely add either a biologic drug that blocks tumor necrosis factor (TNF), or prescribe a “triple therapy” of conventional synthetic DMARDs — sulfasalazine, hydroxychloroquine and methotrexate.

Those therapies are life-changing for numerous people living with RA, especially if they receive treatment early enough in the disease process.

But they don’t work for an estimated 20% to 30% of people with RA. For these “refractory” patients, who don’t get adequate relief from typical first-line treatments, there is no proven next step that we know will work. 

“Right now, the dirty truth is it’s a spin of the roulette wheel to figure out the next best therapy for a given patient,” says Daniel Solomon, MD, MPH, professor of medicine at Harvard Medical School and chief of the Section of Clinical Sciences in rheumatology at Brigham and Women’s Hospital. Dr. Solomon has led extensive research in rheumatology and RA treatments.

As part of our commitment to pursue better treatments and quality of life for those living with refractory RA, in 2022 the Arthritis Foundation awarded over $1 million in funding for research focusing on that area, including nearly a half million to Dr. Solomon and his team.

The Arthritis Foundation “is an important funder in the scientific pursuit of improving care of rheumatic diseases, including RA,” says Dr. Solomon, who also serves on the Foundation’s Medical and Scientific Advisory Committee. “I think [the Arthritis Foundation] has been energized over the last several years with a much more vigorous scientific program. I am very thankful that they’ve been able to fund this work, but also to develop a broad palette of really important research areas.”

Targeting Immune Cells

Dr. Solomon is using data collected from his recent TARGET trial, which looked at the effect of either methotrexate and a TNF blocker or triple therapy on cardiovascular disease risk in people with RA. He and his team collected immune cells circulating in the bloodstream before the participants began the therapy when their disease was very active, and at various points during the trial after they went on medication. They were able to see how those circulating immune cells, or peripheral blood mononuclear cells (PBMCs), changed in patients who responded to one treatment or the other versus those who did not respond at all. About 40% to 50% responded to one of the treatments and about 50% to 60% didn’t, Dr. Solomon says.

“The idea is: Can we pick the patients and pick their therapies more intelligently than we currently do by using things we can find in the blood?” he explains. “We need to figure out the circulating biomarkers, circulating blood cells, that might give us an inkling of what’s going on in the joint in patients who are likely to respond or likely to not respond.”

Studies in recent years suggest there are types of cells in the synovium (the tissues lining the joints) that make people more or less likely to respond to certain therapies, Dr. Solomon says. “They’re giving us clues to what kinds of cells we find in the synovium at the joint. We can go look for those cells circulating in the blood, and we can also look for what the function of those cells might be,” he explains. 

With the results of the TARGET trial and funding from the Arthritis Foundation, they can look to see what circulating blood cells were in those who responded to anti-TNF therapies, those who responded to triple therapy, and those who didn’t respond to either. 

Personalizing Therapy

Ultimately, the hope is that in five to 10 years the results of this trial along with others will enable physicians to identify which patients are more likely to get relief from which treatment protocol early on in their disease — before irreversible damage is done.

“There are people across the globe working on similar studies,” Dr. Solomon says.

“The goal is to be able to personalize treatment,” he explains. “Rheumatologists have an algorithm that we use, but it’s as much dictated by insurance and routine as by science. Why do we use methotrexate as first-line therapy? Because we’ve been using it for 35 years. It’s relatively inexpensive. We’re comfortable with the safety of it. And insurance doesn’t let us go to a biologic DMARD right away. 

“But there are patients who are just not going to be responsive to methotrexate. You can say the same for every next agent in the sequence of therapies. So, finding the right drug for the right patient at the right time is always the dictum that we hope we can get closer to with this kind of study.”