In the Journals

Studies could shed light on treatment response in RA

Laura Donlin

A pair of studies by researchers at the Hospital for Special Surgery demonstrate that newly discovered subsets of cells found in joint tissue among patients with rheumatoid arthritis, and how they interact, could potentially explain why only certain individuals respond to current treatments, according to a press release.

“Right now, the standard approach for treating patients is a trial and error approach,” Laura Donlin, PhD, of the co-director of the Derfner Foundation Precision Medicine Laboratory at the Hospital for Special Surgery, said in the release. “We try the first-line of medication for 3 months and if it does not work, we try the next one. Sometimes it can take a year or more to find an effective treatment. Meanwhile, the disease progresses to the extent of irreversible damage in some of the cases.”

In the first study, published in Nature Immunology, Donlin and colleagues collaborated within the Accelerating Medicines Partnership in Rheumatoid Arthritis and Lupus Network (AMP RA/SLE), a public-private consortium created by the NIH, to develop a comprehensive map of cells in RA joint tissue, using sequencing technologies.

According to the press release, the researchers found 18 unique cell populations in synovial tissue among 36 patients with RA. Additionally, several of these cell types were present in higher amounts in participants with RA, compared with those in control groups of patients with osteoarthritis. One of these cell populations was a subset of fibroblasts that was found in 15 times greater quantities in tissues from patients with RA, compared with tissues from the control group. According to the release, this fibroblast subset is a major producer of interleukin-6, a major focus among researchers developing medications for RA.

In addition, Donlin and colleagues became the first to identify the presence of a subset of autoimmune-associated B cells in synovial tissue, which were also found in high quantities among patients with RA, the release said.

“Cutting-edge single-cell RNA sequencing technology allowed us to see the complexity of the cell populations in RA tissue for the first time,” Donlin said in the release. “However, determining whether these expanded cell populations are a cause or an effect of the disease, will require further research.”

In the second study, published in Science Translational Medicine, Donlin and colleagues used results from the AMP RA/SLE to discover an abundant subset of macrophages, which they identified as HBEGF+ inflammatory macrophages, in tissue samples from patients with RA. The researchers also tested whether RA medications would impact HBEGF+ inflammatory macrophages, and thus stop the disease at the cellular level. According to the release, although NSAIDs were successful at significantly altering these macrophages, they did not stop TNF responses.

However, an epidermal growth factor receptor (EGFR) inhibitor called AG-1478, an experimental drug developed for cancer, was able to reverse the activity of HBEGF+ inflammatory macrophages.

“Our experiment demonstrated that it is possible to target activity of these cells, but this drug has significant systemic side effects in people,” Donlin said in the release. “Our work sets the stage for developing better drugs in the future that could target the same mechanism but in a more specific fashion.” – by Jason Laday

Disclosures: The researchers report funding from the NIH. Please see the full studies for additional disclosures.

Laura Donlin

A pair of studies by researchers at the Hospital for Special Surgery demonstrate that newly discovered subsets of cells found in joint tissue among patients with rheumatoid arthritis, and how they interact, could potentially explain why only certain individuals respond to current treatments, according to a press release.

“Right now, the standard approach for treating patients is a trial and error approach,” Laura Donlin, PhD, of the co-director of the Derfner Foundation Precision Medicine Laboratory at the Hospital for Special Surgery, said in the release. “We try the first-line of medication for 3 months and if it does not work, we try the next one. Sometimes it can take a year or more to find an effective treatment. Meanwhile, the disease progresses to the extent of irreversible damage in some of the cases.”

In the first study, published in Nature Immunology, Donlin and colleagues collaborated within the Accelerating Medicines Partnership in Rheumatoid Arthritis and Lupus Network (AMP RA/SLE), a public-private consortium created by the NIH, to develop a comprehensive map of cells in RA joint tissue, using sequencing technologies.

According to the press release, the researchers found 18 unique cell populations in synovial tissue among 36 patients with RA. Additionally, several of these cell types were present in higher amounts in participants with RA, compared with those in control groups of patients with osteoarthritis. One of these cell populations was a subset of fibroblasts that was found in 15 times greater quantities in tissues from patients with RA, compared with tissues from the control group. According to the release, this fibroblast subset is a major producer of interleukin-6, a major focus among researchers developing medications for RA.

In addition, Donlin and colleagues became the first to identify the presence of a subset of autoimmune-associated B cells in synovial tissue, which were also found in high quantities among patients with RA, the release said.

“Cutting-edge single-cell RNA sequencing technology allowed us to see the complexity of the cell populations in RA tissue for the first time,” Donlin said in the release. “However, determining whether these expanded cell populations are a cause or an effect of the disease, will require further research.”

In the second study, published in Science Translational Medicine, Donlin and colleagues used results from the AMP RA/SLE to discover an abundant subset of macrophages, which they identified as HBEGF+ inflammatory macrophages, in tissue samples from patients with RA. The researchers also tested whether RA medications would impact HBEGF+ inflammatory macrophages, and thus stop the disease at the cellular level. According to the release, although NSAIDs were successful at significantly altering these macrophages, they did not stop TNF responses.

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However, an epidermal growth factor receptor (EGFR) inhibitor called AG-1478, an experimental drug developed for cancer, was able to reverse the activity of HBEGF+ inflammatory macrophages.

“Our experiment demonstrated that it is possible to target activity of these cells, but this drug has significant systemic side effects in people,” Donlin said in the release. “Our work sets the stage for developing better drugs in the future that could target the same mechanism but in a more specific fashion.” – by Jason Laday

Disclosures: The researchers report funding from the NIH. Please see the full studies for additional disclosures.