RA is a chronic disease characterized by inflammation in the synovium, the tissue that covers the inner surface of the joint cavity. Although usually accompanied by joint pain, swelling and deterioration, the level of inflammation varies from patient to patient, potentially requiring customized treatment plans. “What is surprising to us is that there are some patients who have clinical remission, yet continue to experience pain and show radiographic progression of the disease with high levels of synovial inflammation, while others have high disease activity with many swollen and tender joints and little inflammation in the synovial tissue” said Susan M. Goodman, MD, rheumatologist at HSS and principal investigator of the study. She explained that even when standard tests suggest the disease is under control, the joint fluid can still show high levels of inflammation. “By analyzing synovial fluid characteristics, we expected it might give us some insight into the disparity between disease progression and apparent remission,” she added.

The team analyzed samples from 64 patients with RA, 90.6% of whom were women, and with a median age of 65.3 ±11.7 years. The physicians collected synovial fluid samples to analyze and compare with the synovial tissue biopsy counterpart, which defines the inflammatory profile of the disease.

Dr. Goodman and the team measured the total white blood cell count, as well as the percentage of neutrophils, lymphocytes and monocytes in each synovial fluid sample. They then compared those findings to two additional key pieces of clinical information: the patient’s disease activity (such as joint swelling, pain, etc.) and the level of inflammation seen in the tissue.

Their analysis revealed that the total white blood cell count in the synovial fluid did not correlate with disease activity, however, the counting of individual cell types gave insights into tissue inflammation. As such, a higher percentage of neutrophils was associated with increased inflammation in the tissue, while a higher percentage of monocytes was associated with lower inflammation in the tissue.

Because the white blood cell counts in synovial fluid provided distinct and different information from standard disease activity measures and correlated well with tissue inflammation, the team believes it could help guide the selection of personalized anti-inflammatory therapies more efficiently.

“Synovial fluid extraction is already a routine part of care, but until now, it has never been used to analyze disease state in this way,” explained Dr. Goodman. In other words, the approach could be adopted without placing additional burden on healthcare providers.

"It's important that we're gaining new methods of investigating patients with RA,” Dr. Goodman added, “since choosing the appropriate therapy and choosing it in an efficient way is clearly the best way to achieve the best outcomes.”

According to Dr. Goodman, the next phase of this study, led by HSS rheumatologists Melanie H. Smith, MD, MPH, and Dana Orange, MD, MS, will look at both the proteomics and genetics of the cells within the fluid with more molecular and immunologic techniques, with the goal of finding even more clinically relevant and important information.

Poster details

Title: Can synovial fluid features be used to predict synovial tissue pathotype?

Authors: Susan M. Goodman, Michael Parides, Solana Cushing, Daniel Ramirez, Edward DiCarlo, Rebecca B. Blank, Laura Donlin, Anna Helena Jonsson, Amit Lakhanpal, Bella Mehta, Dana Orange, Melanie Smith.

Abstract n°: 2057

Presentation: June 12^th, 2025. 2:45 PM CEST

The study published August 29 in Nature Communications shows that artificial intelligence and machine learning technologies can effectively and efficiently subtype pathology samples from patients with RA.

For this study, Dr. Richard Bell, an Instructor in the HSS Research Institute and Arthritis and Tissue Degeneration Program, and Lionel B. Ivashkiv,  MD, Chief Scientific Officer at HSS teamed up with  Dr. Fei Wang, a professor of population health sciences and the founding director of the Institute of AI for Digital Health (AIDH) in the Department of Population Health Sciences at Weill Cornell Medicine. 

“Our study addresses the analytical bottleneck of pathology research,” Dr. Bell said. “It is very time-consuming and tedious.” “Our tool automates the analysis of pathology slides, which may one day lead to more precise and efficient disease diagnosis and personalized treatment for RA,” said Dr. Wang. “It shows that machine learning can potentially transform pathological assessment of many diseases.”

There are several existing machine learning tools for automatic analysis of pathology slides in oncology. Dr. Wang and his colleagues have been working to expand the use of this technology in other clinical specialties.

Digital Pathology and Precision Medicine in RA

Distinguishing between the three subtypes of RA may help clinicians choose which therapy is most likely to be effective for a particular patient. This personalized medicine approach would represent a breakthrough in the care of patients with RA, and is a major goal of the Research Institute and Division of Rheumatology at HSS, which involves multiple laboratory and clinical investigators. “It’s the first step towards more personalized RA care,” Dr. Bell said. “If you can build an algorithm that identifies a patient’s subtype, you’ll be able to get patients the treatments they need more quickly.”

 The technology may provide new insights into the disease by detecting unexpected tissue changes that humans might miss. By saving pathologists time on subtyping, the tool may also decrease the cost and increase the efficiency of clinical trials testing treatments for patients with different subtypes of RA. “This work represents an important advance in analyzing RA tissues that can be applied for the benefit of patients” Dr. Ivashkiv said.

 Pathologists currently manually classify arthritis subtypes using a rubric to identify cell and tissue characteristics in biopsy samples from human patients—a slow process that adds to the cost of research and may lead to inconsistencies between pathologists.

 The team first trained its algorithm on RA samples from one set of preclinical models, optimizing its ability to distinguish tissue and cell types in the sample and sort them by subtype. They validated the tool on a second set of samples. The tool also yielded new insights into treatment effects in the models, such as reduced cartilage degradation within six weeks of administering commonly used RA treatments.

Then, they deployed the tool on patient biopsy samples from the NIH-supported Accelerating Medicines Partnership Rheumatoid Arthritis research consortium, of which HSS is a major participating site in research led by Laura Donlin, PhD, scientist and co-director of the HSS Precision Medicine Program and rheumatologist Susan  M. Goodman, MD. The new digital pathology approach could effectively and efficiently type human clinical samples. The researchers are now validating the tool with additional patient samples and determining the best way to incorporate this new tool into pathologists’ workflows.

 The team is working to develop similar tools for evaluating osteoarthritis, disc degeneration and tendinopathy.

The research reported in this story was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of General Medical Sciences, and the National Institute on Aging, all part of the National Institutes of Health, through grant numbers R21AR071670, R01AI175212, UH2AR067690, UC2AR081025, F30AG076326, T32GM007356, AR046713, AR050401, R01AR078268, UC2AR081025, UL1TR001866 and R01AR056702.

Researchers at HSS and other institutions have noted that women with knee osteoarthritis report more pain than men, but the reason for this difference has been unclear. “Others have speculated that women tend to delay surgery more than men, but when we looked in our database, that wasn’t true,” said HSS rheumatologist Dana Orange, MD, MS, assistant professor at The Rockefeller University and senior author of the study. “We studied synovial tissue removed at the time of total knee arthroplasty to look for a biological reason that may explain the difference in reported pain between sexes.”  

Synovial tissue lines the knee joint and produces fluid that helps the joint move. It can become inflamed as osteoarthritis progresses. Pathologists at HSS have been generating data on different types of cells found in synovial tissue, including mast cells, which are also found in many other tissues throughout the body and are commonly known for producing inflammatory chemicals called histamines during allergic reactions and asthma. Basic research by other scientists has suggested a link between mast cells and osteoarthritis progression and pain.

Dr. Orange and colleagues, including HSS rheumatologist Bella Mehta, MBBS, MS, lead author of the study, studied joint tissue obtained from 96 women and 61 men who underwent total knee replacement at HSS. They counted the number of cells for more than a dozen cell types typically found in synovial tissue and examined synovial fluid and blood using a high-powered microscope. They also evaluated patient-reported pain outcomes collected with two validated surveys. “At HSS, we were in a unique position to conduct this research because we have synovial tissues collected from patients with end-stage osteoarthritis undergoing arthroplasty and expert musculoskeletal pathologists who systematically grade tissue samples for 13 characteristics,” Dr. Mehta said.  

The investigators discovered that synovial tissue from women had significantly more mast cells, 63 per sample area, compared to 46 in tissue from men, on average. They also found higher levels of a byproduct of mast cells called tryptase in synovial tissue from women than men, providing further evidence of increased mast cell activity. No other differences in synovial tissue between sexes were observed. Finally, as expected, women reported worse pain than men on both surveys.

“We hope our findings encourage other researchers to start thinking about biological factors that may contribute to sex differences in patient-reported pain in knee osteoarthritis,” Dr. Orange said.

Authors: Bella Mehta, MBBS, MS, Edward F. Dicarlo, MD, Miguel Otero, PhD, Peter K. Sculco, MD, Mark P. Figgie, MD, Susan M. Goodman, MD (HSS), Fei Wang, PhD (Weill Cornell Medicine), Eun Kyung Song, PhD (Stanford University School of Medicine), Dana Orange, MD, MS (HSS and The Rockefeller University).