Is ‘Difficult-to-Treat’ RA a Lost Cause?

VIENNA — Rheumatologists are still struggling with what to do when multiple state-of-the-art treatments have failed to bring rheumatoid arthritis (RA) under control, reports here indicated.

Analyses of various cohorts from Canada, the U.S., Europe, and Japan all confirmed that something like 20% of RA cases can be classified as “difficult to treat,” according to presentations at the European Alliance of Associations for Rheumatology (EULAR) annual meeting.

That’s a very rough figure. Previous studies have come up with prevalence rates as low as 5% and as high as 35%, depending on how difficult-to-treat RA is defined. In 2021, EULAR published a proposed definition based on three criteria: “failure” of at least two biologics and/or synthetic targeted therapies in patients treated in accordance with published guidelines; signs of active or progressing disease; and “perception” by the patient or the clinician that RA signs and symptoms are “problematic.” But the organization didn’t provide many specifics for determining when, for example, a treatment has failed, or just how a physician should decide that a patient’s status is “problematic.”

In one study discussed here, a researcher from Brigham and Women’s Hospital in Boston described a method used to identify difficult-to-treat patients in her institution’s RA patient population, in which, for instance, patient-reported scores on the RAPID3 instrument defined a “problematic” status. But clearly that was not the only plausible approach.

But however it’s applied, it’s clear that patients classified as difficult-to-treat really do pose a challenge for clinicians. Ladislav Šenolt, PhD, of Charles University in Prague, presented data from a Czech registry of some 8,500 RA patients, of whom 939 had been classified as difficult-to-treat. His group examined outcomes when these patients were put on a new regimen of targeted therapy.

About 85% of this cohort were women, in line with previous observations that female sex is among the risk factors for difficult-to-treat status (women typically account for around 75% of the general RA population). Disease duration averaged 14 years, and most patients were on some type of non-targeted RA medication. Some 60% were using corticosteroids, an indication that their disease was not well controlled. Standard evaluations confirmed that: patients had persistent swollen and tender joints, and Simplified Disease Activity Index (SDAI) scores averaged 29.8. Scores higher than 26 reflect high activity, Šenolt noted.

The new regimen was a tumor necrosis factor (TNF) inhibitor in 533 of these patients; among the rest, 147 went onto an interleukin-6 (IL-6) inhibitor, 133 were given a Janus kinase (JAK) inhibitor, 71 received the B-cell depleting agent rituximab (Rituxan), and 55 were treated with abatacept (Orencia).

Šenolt sought to put a positive spin on the subsequent outcomes. When evaluated after 6 months, just over half of patients given any of these agents — except for abatacept — had achieved either remission or low disease activity (SDAI 3.3 to 11.0). This, he said, was a “high” degree of success. Abatacept appeared less effective, with some 70% still showing moderate or high RA activity.

But the benefits seen at 6 months were not particularly durable, he acknowledged. Close to half of patients on anti-TNF drugs, JAK inhibitors, IL-6 blockers, and abatacept had quit within 2 years. Only rituximab showed good retention (median time on drug was 72 months), and Šenolt said this was likely because the drug is given every 6 months and thus doesn’t require great effort from patients to stick with it.

But another presentation at the EULAR meeting suggested that new frontiers still await. Laura Bucci, MD, of Friedrich-Alexander-Universität in Erlangen, Germany, reported encouraging findings from a pilot trial of the leukemia drug blinatumomab (Blincyto) in difficult-to-treat patients.

Bucci’s group includes Georg Schett, MD, who is well-known for his explorations of “immune reset” approaches in lupus and certain other rheumatologic diseases. Blinatumomab for RA is a variation on this theme. This drug is a bispecific T-cell engager, she explained: while smaller than many monoclonal antibodies, it binds both to the CD19 and CD3 antigens. The effect is to mobilize T cells to kill B cells expressing CD19, which is an anti-tumor mechanism for B-cell malignancies. The researchers hypothesized that the same effect could be exploited to deplete B cells involved in rheumatologic conditions including RA.

Using a blinatumomab dose about one-third of the dose normally used in oncology (so as to minimize cytokine release syndrome and other toxicities), Bucci and colleagues treated six patients with difficult-to-treat RA. Four-day cycles at 9 μg/day were administered during weeks 1 and 3. C-reactive protein and cytokine levels spiked during the first cycle but quickly returned to normal, and remained at normal levels during the second cycle.

By week 12, clinical symptoms in all six patients virtually disappeared, with tender and swollen joint counts falling to near zero and Disease Activity Scores in 28 joints reaching the key threshold of 2.3 or less. Biomarkers such as rheumatoid factor also dropped sharply. Also, for two of three patients who underwent serial synovial biopsies, within-joint B-cell counts hit zero at follow-up, and declined by about 25% in the third patient.

Obviously, such a small, short-term trial proves little. “Controlled studies are necessary,” Bucci said, and the controls should include other anti-B-cell drugs such as rituximab. But the current study shows that the bispecific drug approach “is a promising therapeutic strategy” worth pursuing further, she suggested.

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