Hospital for Special Surgery Presents Three Studies Exploring Precision Medicine Approaches to Improve Rheumatoid Arthritis Treatment
Hospital for Special Surgery (HSS) researchers have presented findings from three new studies aimed at improving the assessment of joint inflammation and supporting more personalized treatment decisions for people living with rheumatoid arthritis (RA). The research explores how ultrasound imaging, synovial fluid analysis and molecular profiling of joint inflammation could help physicians better understand differences in disease activity among patients.
Presented at the American College of Rheumatology (ACR) Convergence 2026 in Orlando, Florida, the studies build on previous research suggesting that the biological characteristics of inflammation within the joints may influence how patients respond to different medications. By developing less invasive methods to evaluate these characteristics, investigators hope to reduce the lengthy trial-and-error process associated with RA treatment and move toward more effective precision medicine strategies.
Hospital for Special Surgery (HSS), an academic medical center specializing in musculoskeletal health, has announced research findings from three investigations focused on improving the evaluation and management of rheumatoid arthritis.
The studies were led by Melanie H. Smith, MD, PhD, an HSS rheumatologist who served as the senior author of all three investigations. Smith presented the findings at the annual meeting of the American College of Rheumatology, ACR Convergence 2026, held in Orlando, Florida.
The research addresses an important challenge in rheumatoid arthritis care: identifying which treatment is most likely to work for an individual patient.
For many people diagnosed with RA, finding an effective medication can involve trying multiple therapies over several months or even years. Physicians generally begin with established treatments and adjust the therapeutic approach when patients do not achieve adequate disease control. However, predicting which medication will provide the greatest benefit remains difficult.
HSS investigators are working to improve this process by examining the biological characteristics of inflammation within affected joints. Their research builds on earlier evidence that different patterns of inflammation may be associated with different treatment responses.
The three studies investigate complementary approaches to understanding joint inflammation. The first examines how ultrasound findings correspond with inflammation observed in joint tissue samples. The second evaluates whether synovial fluid, the lubricating liquid found inside joints, can provide information about inflammatory activity and clinical characteristics. The third investigates whether proteins present in synovial fluid can reveal distinct molecular patterns associated with different types of joint inflammation.
Together, these investigations could help establish more accessible methods for identifying the underlying biology of rheumatoid arthritis and supporting individualized treatment decisions.
Addressing the Trial-and-Error Challenge in Rheumatoid Arthritis Treatment
Rheumatoid arthritis is a chronic autoimmune disease in which the immune system mistakenly attacks the synovium, the tissue lining the joints. This abnormal immune response causes inflammation, swelling, stiffness and pain. Over time, persistent inflammation can damage cartilage, bone and other joint structures, potentially resulting in permanent disability.
Although the disease can affect different joints and vary in severity, its biological characteristics are not identical across all patients.
In some individuals, the joint lining contains substantial numbers of immune cells that contribute to inflammation. However, the specific types of immune cells involved may differ from one patient to another. Other patients may experience joint inflammation characterized by different cellular patterns, including cases in which immune cells are less prominent.
These biological differences may influence how patients respond to available treatments.
Currently, physicians commonly begin RA treatment with a first-line medication, often methotrexate, which helps control abnormal immune activity and reduce inflammation.
When methotrexate does not provide sufficient disease control, physicians may consider additional therapies. These frequently include tumor necrosis factor (TNF) inhibitors, which target specific inflammatory pathways involved in rheumatoid arthritis.
However, some patients continue to experience active disease despite treatment with these medications. Although several additional treatment options are available, physicians have limited tools to determine in advance which therapy is most likely to work for a particular patient.
Another challenge is the time required to evaluate treatment effectiveness. It generally takes approximately three months to determine whether a medication is producing an adequate response.
During this period, patients may continue experiencing pain, swelling and inflammation. Persistent disease activity can also increase the risk of irreversible joint damage and other complications.
Untreated or inadequately controlled rheumatoid arthritis is associated with broader health risks, including cardiovascular disease linked to chronic inflammation. The condition can also affect organs outside the joints, including the lungs, where some patients develop interstitial lung disease.
These challenges highlight the need for more accurate methods of evaluating disease activity and identifying the biological characteristics that could guide treatment selection.
Moving Toward Precision Medicine Through Joint Inflammation Assessment
Precision medicine involves selecting treatments based on the distinctive biological characteristics of an individual patient rather than relying exclusively on a standardized treatment sequence.
In rheumatoid arthritis, this approach could involve identifying the specific immune-cell populations and molecular pathways responsible for inflammation within a patient’s joints.
Previous research involving biopsies of affected joint tissue has suggested that these biological differences may help predict how patients respond to different medications.
However, obtaining tissue biopsies is not part of routine rheumatoid arthritis clinical practice. The procedure can be invasive, requires specialized expertise and may not be practical for repeated monitoring.
For this reason, Melanie H. Smith and her colleagues are investigating alternative approaches that could provide similar biological information through less invasive and more accessible procedures.
The three studies presented at ACR Convergence 2026 explore whether routinely available ultrasound examinations and joint fluid samples can provide meaningful insights into the underlying inflammatory processes.
The longer-term objective is to develop methods that help physicians understand not only how much inflammation is present but also which biological mechanisms are driving it.
Study 1: Comparing Ultrasound Findings With Joint Tissue Inflammation
The first investigation examined the relationship between ultrasound imaging findings and inflammation identified through the analysis of joint tissue samples.
Ultrasound is already widely used by physicians to diagnose and monitor rheumatoid arthritis. The imaging technique uses sound waves to examine structures within the joints and identify changes associated with inflammation.
Two important ultrasound measurements include:
- Synovial thickening: An increase in the thickness of the joint lining, which can indicate inflammation.
- Increased blood flow: Greater blood circulation within the affected joint, which may reflect active inflammatory processes.
Although these measurements are useful in clinical practice, ultrasound findings do not always correspond directly with the degree or characteristics of inflammation identified through tissue analysis.
To investigate these differences, Smith collaborated with HSS radiologist Ogonna Kenechi Nwawaka, MD, and HSS pathologist Edward DiCarlo, MD.
The researchers worked as part of the Accelerating Medicines Partnership Autoimmune and Immune-Mediated Diseases Network (AMP AIM), a public-private research collaboration focused on advancing the understanding of autoimmune and immune-mediated diseases.
Within a larger research program involving the collection of joint lining tissue from patients with rheumatoid arthritis at different stages of disease, the investigators examined cases with available ultrasound assessments and corresponding tissue inflammation scores.
The analysis revealed that the relationship between ultrasound measurements and tissue inflammation differed depending on the stage of rheumatoid arthritis.
In particular, the correlations between ultrasound findings and tissue inflammation were different when comparing patients with recently diagnosed RA against individuals with long-standing disease that had been difficult to treat.
The researchers also identified differences based on the anatomical location of the examined joint.
For example, ultrasound measurements showed higher blood flow in wrists than in knees. Furthermore, the relationship between increased blood flow and the degree of tissue inflammation was stronger in patients with recently diagnosed rheumatoid arthritis.
These observations suggest that ultrasound measurements should be interpreted in the context of both the affected joint and the stage of disease.
Smith explained that the findings could influence how physicians interpret ultrasound examinations when assessing the underlying inflammatory activity in different patients.
The results also highlight the importance of considering anatomical differences when using imaging measurements to evaluate rheumatoid arthritis.
Although ultrasound provides a convenient, noninvasive method of monitoring joint inflammation, the study suggests that its ability to reflect underlying tissue biology may vary across patient populations and disease stages.
Additional research could help establish more precise approaches to interpreting ultrasound results and determining when imaging findings provide reliable information about the inflammatory processes occurring inside a joint.
Study 2: Using Synovial Fluid to Evaluate Joint Inflammation
The second investigation focused on synovial fluid as a potential source of information about inflammation within the joints.
Synovial fluid is a naturally occurring liquid that lubricates joints, reduces friction between moving surfaces and helps support healthy joint function.
In patients with rheumatoid arthritis and other joint conditions, the characteristics and cellular composition of synovial fluid can change in response to inflammation.
Physicians already collect synovial fluid through a relatively simple procedure called joint aspiration.
During aspiration, a needle is inserted into the affected joint to withdraw excess fluid. The procedure can be performed in an office setting and generally takes only a few minutes.
Physicians may recommend aspiration to relieve swelling and stiffness or to investigate the underlying cause of joint symptoms.
Smith and her colleagues believe that synovial fluid could provide additional information about the biological processes occurring within the joint lining.
According to Smith, the research team is investigating whether information obtained from the fluid can help predict what is happening within the underlying joint tissue.
Earlier research conducted by Smith and her colleagues compared synovial fluid samples with tissue specimens obtained from patients with rheumatoid arthritis undergoing knee replacement surgery.
The findings, previously described in ACR Open Rheumatology, suggested that a synovial fluid white blood cell count of at least 1,400 cells per microliter could indicate a high level of inflammation within the joint lining tissue.
The new study expanded on this observation by examining medical records associated with 1,927 joint aspirations.
Of these procedures, 744 were performed in patients with rheumatoid arthritis.
The analysis found that 62% of patients with RA had synovial fluid white blood cell counts that met or exceeded the 1,400 cells-per-microliter threshold associated with high inflammation.
The researchers also examined aspiration findings from patients with other joint conditions.
Most patients with osteoarthritis demonstrated relatively low levels of inflammation in their synovial fluid. In contrast, nearly all patients with septic arthritis, a joint infection, had high levels of inflammation.
These findings suggest that synovial fluid analysis may help distinguish different inflammatory patterns associated with joint diseases.
Synovial Fluid Inflammation Associated With Blood Markers and Treatment Changes
The researchers also investigated whether synovial fluid inflammation was associated with other clinical characteristics among patients with rheumatoid arthritis.
Their analysis identified several notable relationships.
Patients whose synovial fluid samples met the threshold for high inflammation tended to have higher levels of systemic inflammatory markers, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).
Both ESR and CRP are commonly used in clinical practice to assess inflammation throughout the body. Elevated levels can indicate increased inflammatory activity, although they are not specific to rheumatoid arthritis.
The study also found that patients with highly inflammatory synovial fluid were more likely to undergo changes to their rheumatoid arthritis medication relatively soon after joint aspiration.
This observation suggests that synovial fluid analysis could provide clinically relevant information about disease activity and potentially help physicians assess whether existing treatment strategies are adequately controlling inflammation.
Interestingly, the investigators did not find a correlation between the degree of synovial fluid inflammation and patient-reported pain.
This finding reinforces the complexity of rheumatoid arthritis symptoms.
Pain experienced by patients does not necessarily correspond directly with the amount of inflammation measured in a joint. Other factors, including structural damage, changes in pain processing and additional biological mechanisms, may contribute to symptom severity.
Smith emphasized that inflammation is only one component of the processes influencing pain and symptoms in rheumatoid arthritis.
The distinction is important because patients with similar inflammatory measurements may experience different levels of discomfort, while some individuals may report substantial pain even when measurable inflammatory activity is relatively limited.
Repeated Joint Aspirations Support Potential Clinical Feasibility
The second study also examined whether joint aspiration could be a practical method for repeated assessment of inflammation.
Among the patients with rheumatoid arthritis included in the analysis, 131 underwent repeated aspirations.
The investigators considered this observation supportive of the potential feasibility of using aspiration to monitor joint inflammation over time.
The researchers also found that synovial fluid inflammation measurements from different joints in the same patient produced similar results.
This finding could have important implications for clinical practice.
For example, the knee is generally more accessible for aspiration than smaller joints in the fingers. If fluid collected from one accessible joint can provide information about inflammatory patterns in other joints, physicians may eventually be able to obtain broader insights into a patient’s disease biology without needing to sample multiple joints.
However, further research will be needed to determine how consistently synovial fluid findings from one joint represent inflammation throughout the body and whether this approach can reliably guide treatment decisions.
Study 3: Identifying Molecular Differences Between High and Low Inflammation
The third investigation explored the molecular characteristics of synovial fluid and their relationship with inflammation in joint tissue.
While the second study focused primarily on clinical characteristics and white blood cell counts, this investigation examined the proteins present in synovial fluid samples collected from patients with rheumatoid arthritis undergoing joint replacement surgery.
The researchers also analyzed tissue specimens obtained from the same patients during surgery.
By comparing the molecular composition of synovial fluid with the characteristics of the corresponding joint tissue, the team aimed to identify proteins associated with different inflammatory patterns.
The analysis revealed distinct molecular signatures between samples associated with highly inflamed and less inflamed joint tissue.
Synovial fluid from patients with highly inflamed joint lining tissue contained proteins produced by inflammation-associated immune cells, particularly macrophages and monocytes.
Macrophages and monocytes play important roles in immune defense and inflammatory responses. However, their activity can also contribute to chronic inflammation and tissue injury when immune regulation becomes abnormal.
The researchers observed a different pattern in synovial fluid associated with low-inflammation tissue samples.
These samples contained proteins produced by fibroblasts, specialized cells responsible for building, maintaining and repairing connective tissue.
Fibroblasts play an essential role in normal tissue repair. However, excessive or abnormal fibroblast activity can contribute to the accumulation of fibrous tissue, a process comparable to scarring.
In rheumatoid arthritis, this type of tissue remodeling may contribute to joint stiffness, structural changes and persistent disease-related symptoms.
The molecular differences identified in the study provide additional evidence that rheumatoid arthritis involves multiple biological pathways and that patients may have different underlying mechanisms contributing to joint inflammation and damage.
Fibroblast-Associated Disease Patterns Could Explain Differences in Treatment Response
The third study also builds on previous research identifying a distinct group of rheumatoid arthritis patients who have elevated fibroblast activity but relatively few immune cells within their joint tissue.
These patients may continue experiencing painful and swollen joints despite having a different inflammatory profile from individuals whose disease is primarily driven by immune-cell activity.
Such differences could help explain why some patients do not respond adequately to conventional treatments that primarily target immune-mediated inflammatory pathways.
If a patient’s disease is driven by a particular immune-cell population, a medication targeting that pathway may provide meaningful benefits.
However, when fibroblast-associated processes play a more prominent role, the same medication may be less effective.
The molecular patterns identified through synovial fluid analysis could therefore provide a starting point for identifying different biological subtypes of rheumatoid arthritis.
Rather than relying exclusively on conventional clinical measurements, physicians may eventually be able to use information about the proteins and cellular pathways present in joint fluid to better characterize an individual’s disease.
Smith believes that synovial fluid could potentially serve as a less invasive alternative to joint tissue biopsies for understanding the biological processes responsible for inflammation.
The research team hopes to refine these assessments over time, moving beyond measuring the overall degree of inflammation toward identifying the specific immune cells and molecular mechanisms involved.
Building a Foundation for More Personalized RA Treatments
The three HSS studies collectively support a broader research strategy focused on improving how physicians evaluate rheumatoid arthritis.
The first study demonstrates that ultrasound measurements may have different relationships with tissue inflammation depending on the patient’s disease stage and the joint being examined.
The second study suggests that synovial fluid white blood cell counts could provide useful information about joint inflammation and may be associated with systemic inflammatory markers and subsequent treatment changes.
The third study identifies distinct protein patterns associated with immune-cell-driven inflammation and fibroblast-related tissue remodeling.
Together, these findings suggest that combining imaging assessments with synovial fluid analysis and molecular profiling could provide a more detailed understanding of rheumatoid arthritis.
Such information could eventually help physicians distinguish patients based on the biological mechanisms driving their disease.
This may support a shift away from the current treatment approach in which patients often move through several medications before finding an effective option.
In a future precision medicine model, clinicians could potentially evaluate a patient’s joint inflammation profile and select therapies based on the immune cells or molecular pathways most closely associated with the disease.
For example, patients with inflammation primarily associated with one type of immune cell might benefit from a medication targeting that particular pathway, while patients with a different cellular profile could require an alternative treatment strategy.
Smith emphasized that the goal is to begin moving toward this type of individualized treatment selection.
Although the three studies represent important investigative steps, additional research will be required before these methods can be routinely used to guide medication selection in clinical practice.
The findings need further validation in larger and more diverse patient populations. Researchers will also need to determine how accurately synovial fluid measurements and molecular signatures predict responses to specific rheumatoid arthritis treatments.
Future investigations may examine whether combining ultrasound findings, synovial fluid cell counts and protein analysis can improve patient classification and help physicians identify the most appropriate therapies earlier in the disease course.
The research could also contribute to better monitoring strategies by providing less invasive ways to evaluate changes in joint inflammation over time.
For patients, more accurate assessment methods could eventually reduce the time spent trying different medications and help limit the consequences of persistent disease activity.
The studies presented at ACR Convergence 2026 highlight the importance of understanding the biological differences underlying rheumatoid arthritis rather than treating the condition as a single, uniform disease.
Through continued investigation of ultrasound imaging, synovial fluid biomarkers and molecular characteristics of joint tissue, Hospital for Special Surgery researchers aim to advance precision medicine approaches that could make rheumatoid arthritis treatment more targeted, efficient and responsive to individual patient needs.
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.