Inflammatory markers were reduced in patients with persistent joint pain and other markers for incipient rheumatoid arthritis (RA), as was progression to formal RA diagnosis, after a 6-month course of abatacept (Orencia) in a placebo-controlled trial.

While 35% of controls were diagnosed with RA while on treatment in the trial, called ARIAA, only 8% of the abatacept group were (P=0.002), according to Georg Schett, MD, of Friedrich-Alexander Universität Erlangen-Nürnberg in Germany, and colleagues.

Inflammation as quantified in MRI scans was also significantly improved with abatacept: 51% of those receiving the drug versus 24% of the placebo group (P=0.012) showed some degree of lessening a full year after stopping the erstwhile prophylactic treatment, the researchers reported in The Lancet.

It's the second such study to demonstrate that what might be called preclinical or pre-RA can be stopped, at least for a while, with abatacept. At the European Alliance of Associations for Rheumatology (EULAR) annual meeting, a different group reported from a similar study that, in patients with pre-RA, abatacept taken for 1 year reduced risk of a formal RA diagnosis by 80%. (The final peer-reviewed report from that study, APIPPRA, also appeared this week in The Lancet.)

Blocking further development of joint pathology in patients with early signs of RA has long been a goal in rheumatology. Many studies have supported early aggressive treatment once RA is diagnosed, but starting biologic therapy without a formal RA diagnosis has never been recommended.

Why abatacept and not one of the many other targeted therapies available for RA? Schett and colleagues explained that the idea behind ARIAA (and APIPPRA) was that overactive T cells are an early driver of RA pathology, and that abatacept is unique among RA drugs in targeting this pathway. Abatacept is a CTLA4-Fc fusion protein that "is a powerful inhibitor of T-cell co-stimulation by monocytes and B cells, thereby blunting adaptive immune responses," the researchers wrote.

Patients enrolled in ARIAA had a history of joint pain, but no joint swelling either previously or at screening. They did, however, have to show subclinical synovitis, tenosynovitis, or osteitis in the dominant hand. It was not required to have blood biomarkers for RA such as rheumatoid factor, but most did.

Among the 98 patients randomized, mean age was about 50 and more than two-thirds were women. Participants were assigned in equal numbers to 6 months of injections with abatacept or placebo. The primary outcome measure was the responder rate for MRI-quantified hand joint inflammation at 6 months, but patients were then followed for 1 year beyond this point for this as well as clinical outcomes.

This evaluation indicated that 57% of patients on abatacept showed improvement, compared with 31% of the placebo group (P=0.014). These percentages shrank a bit during subsequent follow-up to month 18, but the difference remained substantial and statistically significant.

At month 18 in the trial, 35% of the abatacept group and 57% of those assigned to placebo had progressed to full-blown RA, suggesting that the treatment effect wasn't durable after dosing ended. On the other hand, as in APIPPRA, safety problems were minimal -- serious adverse events were numerically less common than in the placebo group -- such that continuing the therapy indefinitely could be considered.

Schett and colleagues were heartened to find that the 6-month course of abatacept "not only improves some symptoms and MRI signs of inflammation associated with this pre-disease state but also inhibits progression to clinical disease in a sustained manner."

"Therefore, these data provide new possibilities for earlier preventive interventions in rheumatoid arthritis," they concluded.

In an accompanying commentary, Annette van der Helm-van Mil, MD, PhD, from Erasmus Medical Centre, Rotterdam and Leiden University Medical Centre in the Netherlands, largely agreed. But she observed that the prospects for preventing RA permanently remain uncertain. "Many autoantibody characteristics appear to be matured at arthralgia presentation," she wrote. "It is unknown whether the point-of-no-return for developing chronic RA has been passed."

She also suggested that progression to full-on RA isn't the best outcome on which to focus. Instead, van der Helm-van Mil offered, what's needed is "a disease inflammation activity score for the [pre-RA] arthralgia phase."

Then, she argued, "further trials can establish the most efficacious and cost-effective treatment strategy."