‘Double negative’ B cells may predict abatacept response in rheumatoid arthritis
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SCOTTSDALE, Ariz. — Patients with rheumatoid arthritis who had a decrease in a certain type of B cell that fails to express immunoglobulin D and CD27 saw clinical improvement with abatacept, according to data presented here.
Gregg Silverman, MD, of the New York University School of Medicine, who presented the data at the Basic and Clinical Immunology for the Busy Clinician symposium, added that these findings could push the field closer to personalized care.
“The question is often what drug in what person,” he said. “How can we use this to identify who will best respond to an agent and who will not? We are getting closer.”
According to Silverman, abatacept (Orencia, Bristol Myers Squibb) blocks the bidirectional cd80/86-cd28 signaling circuit.
“The question was whether or not breaking the circuit would have an effect on B cells, and, if that was the case, which B cells would be affected,” he said. “This was something that had not been appreciated.”
In an attempt to answer that question, Silverman and William Rigby, MD, conducted the Rheumatoid Arthritis Memory B Cells and Abatacept (RAMBA) trial, a single-open label study to evaluate immunologic response in adults who had been treated with IV abatacept. Eligible participants were naïve to biologic therapies.
Among the 21 enrolled patients, 17 had complete data available at 6 months’ follow-up.
Patients were treated with a standard regimen of abatacept, which was administered every 2 weeks through the first month, and monthly thereafter. Treatment was then withdrawn to determine flare rates.
“What we found was that we had a very high rate of clinical responders — 16 out of 18 patients — which was actually higher than in the pivotal trials for the approval of the drug,” Silverman said.
This outcome was assessed using the Clinical Disease Activity Index (CDAI), which does not include laboratory markers, according to Silverman.
“The patients, in general, got better. Only four out of 17 patients who withdrew flared,” he said. “This was fascinating.”
However, Silverman stressed that the point of the study was not just to determine the efficacy of abatacept.
“We wanted to know how this drug really works,” he said. “The devil is in the details.”
One important result from an analysis of antibodies to citrullinated protein antigens (ACPA) showed that responders demonstrated decreases in autoantibodies.
The researchers gathered data for approximately 140,000 individual cells from patients with RA at baseline, and then at 3 and 6 months after treatment. Samples were also taken at 9 months, after patients had ceased treatment.
“What it really is about is single-cell RNA sequencing,” Silverman said. “What does a cell want to do? What can it do?”
Although the findings included information about CD-4 positive cells, monocytes, natural killer cells and others, Silverman was primarily concerned with B cells.
Specifically, the focus was on a subset of so-called “double negative” cells, which are those that that undergo class switching but do not express immunoglobulin D and the memory marker CD27, according to Silverman.
“We found a suspect that could be very important for rheumatoid arthritis that was not previously known,” he said. “We found that clinical responders had distinct drops that were clinically significant over time, while in non-responders they actually went up.”
A decrease in double negative cells correlated with clinical improvement, Silverman added. “As treatment progressed, you could even see particular B cell clones rapidly disappearing with abatacept treatment,” he said. “It really is B-cell targeted.”
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Silverman G. Inside the Brain of Abatacept: Multi-Omics Dissection of How it Works to Halt RA Pathogenesis. Presented at Basic and Clinical Immunology for the Busy Clinician, Feb. 17-18, 2024; Scottsdale, Arizona (hybrid meeting).
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