For some people with rheumatoid arthritis (RA), finding the most effective medication turns into a lengthy trial-and-error experiment that can last months or even years. Three new studies by Hospital for Special Surgery (HSS) investigators seek to lay the groundwork for more-efficient treatment by improving options for assessing inflammation in joints.

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Melanie H. Smith, MD, PhD, HSS rheumatologist and senior author of all three studies, presented this research at the annual meeting of the American College of Rheumatology, ACR Convergence 2026, in Orlando, Florida.

“If I had active rheumatoid arthritis and my rheumatologist told me, ‘We’re going to try this medication and we’ll know in three months if it worked,’ I wouldn’t be very happy,” Dr. Smith says. “In general, patients understand this is what we have right now. But I think we can do better.”

For Dr. Smith and others in her field, better means using a person’s distinctive biological characteristics to guide treatment decisions — an approach known as precision medicine. To make this possible, they are building on previous research showing that differences in inflammation in patients’ joints can predict how they will respond to treatment.

Why Better Methods Are Needed for Evaluating Inflammation

In RA, the immune system mistakenly attacks the lining of the joints, causing painful inflammation and, if left untreated, leading to damage. But the disease doesn’t look the same for everyone. In some cases, this tissue contains high numbers of immune cells, which drive inflammation. But the identity of those immune cells can differ from person to person. Meanwhile, others don’t have immune cells in their joint lining.

While there is no cure for RA, medications can alleviate symptoms and protect joints. When someone is diagnosed, physicians typically start off on a first-line medication, typically a drug called methotrexate. If that isn’t adequate, they move on to a second-line option, often drugs called TNF inhibitors. But some patients continue to struggle with the disease.

At this point, more medications are available, but physicians have limited ability to predict which is most likely to be effective. What’s more, it takes about three months to know if a medication is effective, further lengthening the process.

In the meantime, not only do the symptoms continue, but the patient also faces the possibility of permanent damage to the joint, along with other risks that accompany untreated RA. These include cardiovascular disease linked to chronic inflammation and non-joint manifestations, such as interstitial lung disease.

Studies of samples, or biopsies, from affected joints suggest that analyzing this tissue could help determine the best strategy for treating the individual patient. However, biopsies are not collected as part of clinical practice. Dr. Smith and her colleagues are working to get similar insight into joints through less invasive, more accessible means.

Study 1: Aligning the Results of Ultrasounds and Tissue Samples

Physicians routinely use noninvasive ultrasound scans to diagnose and monitor RA. This technology relies on soundwaves to look for thickening of the joint lining and increases in blood flow to the joint, both signs of the disease. However, in certain cases, when researchers compare a patient’s ultrasound results to an analysis of inflammation in tissue samples, the findings don’t match up.

As part of the Accelerating Medicines Partnership® Autoimmune and Immune-Mediated Diseases Network (AMP® AIM) consortium, a public-private partnership that studies autoimmune diseases, Dr. Smith, along with HSS radiologist Ogonna Kenechi Nwawaka, MD and HSS pathologist Edward DiCarlo, MD, examined these discrepancies.

As part of a larger study where researchers collected joint lining tissue from RA patients in different stages of disease, Dr. Smith and colleagues examined cases where there were joint ultrasound as well as joint lining tissue inflammation scores. They found that the two ultrasound measurements correlated with tissue inflammation differently when comparing those patients with recently diagnosed RA to those patients with long-standing RA that has been difficult to treat.

The location of the joint mattered too. The amount of blood flow as measured by the ultrasound was higher in wrists than knees. This blood flow was more strongly associated with the degree of tissue inflammation in patients with recently-diagnosed RA.

“These results can influence our thinking about how well an ultrasound from a particular joint in a patient at a specific stage of disease represents the underlying inflammation,” Dr. Smith says.

Study 2: Linking Synovial Fluid to Clinical Characteristics

While ultrasounds are already part of clinical practice, the other studies focused on developing an entirely new way to assess joint inflammation using synovial fluid, the lubricating liquid inside the joints.

Synovial fluid is already routinely withdrawn from joints through an in-office procedure called an aspiration. Physicians sometimes perform this simple procedure, which takes only a few minutes, to relieve swelling and stiffness. The fluid they extract has “untapped potential,” according to Dr. Smith.

“The question is whether or not we can use information from the synovial fluid to predict what’s going on in the tissue,” she says.

Previously, Dr. Smith was part of a team that compared synovial fluid to tissue samples from RA patients undergoing knee replacement surgery. Their analysis, described in ACR Open Rheumatology, suggested that having a white blood cell count of 1,400 or more per microliter of synovial fluid indicates a high level of inflammation in the joint lining tissue.

The new study followed up by looking at medical records associated with 1,927 aspirations, including 744 from patients with RA. Sixty-two percent of the RA patients crossed the 1,400 threshold to be considered highly inflammatory. Most osteoarthritis patients had a low-level inflammation, while nearly everyone with septic (infected) arthritis had a high level.

The researcher’s analysis of the aspirations from RA patients showed that those patients with aspirations that qualified as highly inflammatory shared certain characteristics: they had higher blood inflammatory markers (ESR and CRP) and were more likely to change their RA medication not long after having had an aspiration. Interestingly, the degree of synovial fluid inflammation did not correlate with patient reported pain.

“In rheumatoid arthritis, there’s much more that goes into pain and symptoms than just the degree of inflammation,” Dr. Smith says.

Their analysis also supported aspiration as a potential means for assessing joints — 131 RA patients had repeated aspirations, implying that they tolerated the procedure well. Meanwhile aspirations from different joints on the same person returned similar results, suggesting that fluid from one joint, such as the knee, which is relatively easy to aspirate, may be used to assess other joints, like the much smaller ones in the fingers.

Study 3: A Distinct Molecular Pattern in High Versus Low Inflammation

In the second study of synovial fluid, the team looked closely at proteins within the samples removed from RA patients who received joint replacements. They also examined joint tissue from the same patients removed during the surgery.

A distinct pattern emerged: Those with highly inflamed joint lining tissue had proteins made by inflammation-producing immune cells, such as macrophages and monocytes, in their synovial fluid. Meanwhile, fluid associated with the low-inflammation samples contained proteins made by cells called fibroblasts, which build and repair tissue. Heightened activity by fibroblasts is likely responsible for the buildup of fibrous tissue, equivalent to scarring, that can occur in RA.

This finding builds on previous research identifying a certain type of patient who has high levels of fibroblasts but lacks immune cells in their tissue. These patients may have painful, swollen joints and tend to struggle to find an effective medication.

The pattern the team uncovered adds to growing evidence that the fluid could stand in for a tissue sample when assessing inflammation, according to Dr. Smith. Over time, she foresees refining the predictions based on synovial fluid, moving beyond the level of inflammation to the type of immune cells present in the joint lining.

“If the patients have only, for example, one kind of immune cell, maybe we know this medication over here would be better. But if they have mostly another kind of cell, this other medication would be preferred,” she explains. “We want to start thinking about precision medicine.”

About HSS

HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the 17th consecutive year), No. 3 in rheumatology by U.S. News & World Report (2026-2027), and the best pediatric orthopedic hospital in NY, NJ and CT by U.S. News & World Report “Best Children’s Hospitals” list (2026-2027). HSS is the worlds most awarded hospital in orthopedics by Newsweek each year since the “World’s Best Specialized Hospitals” survey was introduced in 2020. Founded in 1863, the Hospital has the lowest readmission rate in the nation, and among the lowest infection and complication rates. HSS was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center six consecutive times. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State, as well as in Florida. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. In addition, more than 200 HSS clinical investigators are working to improve patient outcomes through better ways to prevent, diagnose, and treat orthopedic, rheumatic and musculoskeletal diseases. The HSS Education Institute is a trusted leader in advancing musculoskeletal knowledge and research for physicians, nurses, allied health professionals, academic trainees, and consumers in more than 165 countries. The institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally. www.hss.edu.

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