Trial Shows RA Can Be Stopped at Preclinical Stage

MILAN -- One year of treatment with abatacept (Orencia) kept "preclinical" rheumatoid arthritis (RA) from becoming clinical in most patients showing signs of imminent onset, a researcher reported here.

In a phase IIb randomized trial involving patients at high risk for developing RA, only seven of the 110 assigned to abatacept had gone on to develop clinical arthritis after 1 year, compared with 30 of 103 in a placebo group (HR 0.20, P=0.0002), according to Andrew Cope, MD, MBBS, of King's College London.

But the effect didn't last after abatacept was stopped at the 1-year mark, he told attendees at the European Alliance of Associations for Rheumatology (EULAR) annual meeting. During the following year, 20 more patients in the abatacept group developed clinical arthritis, as did another eight in the placebo group.

Although the abatacept regimen maintained a significant advantage for the full 2 years (HR 0.61, P=0.003), the Kaplan-Meier curves for arthritis-free survival were quickly converging near the end, making it seem likely that the abatacept group would catch up with additional follow-up.

At the same time, there were no particular safety problems seen with abatacept, and thus no obvious reason why the regimen could not have been continued longer.

Stopping RA before it really gets going has long been a goal for rheumatologists. Many studies have supported early aggressive treatment once RA is diagnosed. Starting biologic therapy without a formal RA diagnosis, however, has never been recommended.

Nevertheless, some patients show up at arthritis clinics with a few painful joints and other features such as RA-related serum biomarkers that suggest progression to full-blown RA is likely. Wouldn't it be good to find out whether aggressive treatment at that stage, in this population, would keep them from going down that road?

That's exactly what Cope and colleagues thought about a decade ago, registering the current trial called Arthritis Prevention in the Pre-clinical Phase of RA with Abatacept (APIPPRA) in 2014. They picked abatacept because, the group explained in a 2019 description of the protocol, "it targets immune reactions early in the chain of events leading to inflammation in RA. It functions by interrupting the interaction between T cells and antigen-presenting cells, attenuating the co-stimulatory signals required for T-cell activation, differentiation and effector responses," thereby resulting "in downstream immunomodulatory effects on other inflammatory cells of the immune system."

The researchers recruited patients from 31 sites in the U.K. and the Netherlands. To be eligible, participants had to show joint pain but no synovitis, plus either test positive for anti-citrullinated protein antigen (ACPA) antibodies and for rheumatoid factor (RF), or show high levels of ACPA antibodies (more than three times the upper limit of normal for the assay used) without RF. The primary endpoint was development of clinically apparent arthritis in at least three joints or diagnosis of RA according to standard criteria.

Mean patient age was about 48, and three-quarters were women. Most had a history of smoking, but fewer than one-third consumed more than five alcoholic drinks a week. Baseline pain scores averaged about 24 on a 100-point scale. Almost all participants met the threshold for high ACPA antibody levels.

While the preventive effect seen in the primary analysis wasn't durable across the entire sample, Cope pointed out that it appeared more so in one very-high-risk subgroup: 49 patients who had some level of IgG ACPA antibodies and who were also positive for a series of other biomarkers, including RF, IgA ACPA antibodies, anti-carbamylated protein antibodies, and anti-acetylated peptide antibodies. In this set, only about 10% of those who had taken abatacept progressed to clinical arthritis by the end of 2 years, versus 50% of those assigned to placebo.

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