January 2024

RHEUMATOLOGY

DEFINING RHEUMATOID ARTHRITIS SUBTYPES MAY IMPROVE TREATMENTS

Featuring: Arthur M. Mandelin, MD, PhD, Harris R. Perlman, PhD
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​By profiling the inflammatory cells types in joint tissue biopsy samples, scientists have characterized six subtypes of rheumatoid arthritis, an approach that could help physicians tailor more effective treatment strategies for patients based on their specific disease type, according to findings published in Nature.

“This study attempts to more deeply characterize rheumatoid arthritis, because only a deep understanding of how the disease works will allow us to make better-informed decisions and come up with the best possible research plans,” said Arthur Mandelin, MD, PhD, associate professor of Medicine in the Division of Rheumatology and a co-author of the study.

Rheumatoid arthritis is a chronic autoimmune disease that causes joint inflammation and damage over time. According to recent estimates from the World Health Organization, approximately 18 million people worldwide live with the disease, and more than half are women.

While no cure for rheumatoid arthritis currently exists, some drugs and, in more severe cases, surgery can help slow disease progression and reduce symptom burden. Knowing whether a patient will respond to a drug, however, has remained a guessing game, according to Mandelin.

​“The current method – believe it or not – is simple trial and error, backed up by only the vaguest hints regarding what kind of patient might do better on a given drug. Incredible amounts of time and money are wasted every year on rheumatoid arthritis treatments that ultimately fail, for reasons that are not yet known,” Mandelin said.

In the current study, investigators examined synovium (joint lining tissue) samples from 79 adult patients with rheumatoid arthritis. Using single-cell RNA-sequencing and surface protein data coupled with the tissue samples, the investigators developed a single-cell atlas of rheumatoid arthritis synovial tissue including more than 314,000 cells. This allowed the investigators to then determine what types of inflammatory cells were present in each sample.

“This is important because different rheumatoid arthritis drugs target different inflammatory cells,” Mandelin said.​
Representative synovial tissue fragments from each of the CTAPs
Representative synovial tissue fragments from each of the CTAPs. Top row: haematoxylin and eosin (H&E) staining. Middle row: immunofluorescence microscopy for CD3, CD34, CD68, CD90, CLIC5 and HLA-DR. Bottom row: immunofluorescence microscopy for CD3, CD20 and CD138.

The investigators were able to categorize the synovium samples into six groups called cell-type abundance phenotypes (CTAPs). Each CTAP group was characterized based on the types of inflammatory cells most abundant in the synovium of each patient, which were determined by identifying specific cell surface markers, such as increased T- and B-cells or reduced lymphocytes, and RNA expression.

The findings demonstrate the potential future clinical utility of CTAPs for predicting treatment response and non-response for certain rheumatoid arthritis drugs.
According to Mandelin, the findings also support the possibility of providers tailoring a patient’s drug regimen to their specific type of disease based on their CTAP group.

“Reassuringly, while the CTAP classification process used in this paper was very involved and complicated, it was found that simpler methods which have been used to analyze these tissue samples in the past do correctly categorize the synovium most of the time. Therefore, if it turns out that a rheumatoid arthritis patient’s CTAP grouping does someday have clinical meaning, it will probably be possible to analyze a synovial sample using these less complicated assays in order to determine a given patient’s CTAP group,” Mandelin said.

Harris Perlman, PhD, chief of Rheumatology in the Department of Medicine and the Mabel Greene Myers Professor of Medicine, was also a co-author of the study.

This work was supported by the Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network.

This study was recognized by NAIMS in the Spotlight on Research on December 11, 2023: Study Identifies Subtypes of Inflammation in People with Rheumatoid Arthritis | NIAMS (nih.gov)

This article was originally published in the Feinberg School of Medicine News Center on January 4, 2024. 
Arthur M. Mandelin, MD, PhD, associate professor of Medicine in the Division of Rheumatology, was a co-author of the study published in Nature.
​Harris R. Perlman, PhD, Chief of Rheumatology, the Mabel Greene Myers Professor of Medicine at Northwestern Medicine

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