GOOD NEWS, MOSTLY, ON PREVENTING RHEUMATOID ARTHRITIS
BARCELONA -- Aggressive treatment for patients who look like they may soon develop rheumatoid arthritis (RA) appears very effective for certain patients, according to long-term data presented here from the placebo-controlled TREAT EARLIER trial.
Five years after taking methotrexate for 12 months, 90% of patients with clinically suspect arthralgia (CSA) -- and, importantly, who initially tested negative for anti-citrullinated protein antibodies (ACPA) -- never went on to full-blown RA, according to Hanna van Steenbergen, MD, PhD, of Leiden University in the Netherlands, speaking at the European Alliance of Associations for Rheumatology's (EULAR) annual meeting.
Among ACPA-negative patients randomized to placebo in the trial, about one-third developed RA during follow-up. Comparing those trajectories for a "number needed to treat" calculation, van Steenbergen said treating four ACPA-negative CSA patients with this 12-month methotrexate course would prevent one case of RA.
Meanwhile, while the early methotrexate therapy seemed to help ACPA-positive patients while they were taking the drug, RA diagnoses ramped up immediately after it ended. Within a few months, Kaplan-Meier survival curves for the treatment and placebo groups were superimposed.
These data show "different treatment strategies are needed for ACPA-positive and ACPA-negative at-risk patients," she said.
Similar, though perhaps less encouraging, long-term results were reported in a companion presentation at EULAR from a placebo-controlled trial called ARIAA, in which CSA patients took the biologic drug abatacept (Orencia) or placebo for 6 months. Primary results had shown that significantly fewer patients had gone on to full RA 12 months after completing the abatacept course.
Now, with up to 9 years of follow-up, Koray Tascilar, MD, of Friedrich-Alexander-Universität in Erlangen, Germany, said that this preventive effect gradually vanished. The active treatment group still showed a significant advantage over placebo at year 5, but 2 years later, cumulative RA rates were identical at about 75%.
Even before then, it appeared that staying on treatment was key to keeping RA at bay. RA diagnoses in the abatacept group spiked dramatically from months 6 to 12 in the trial: about 20% of the group were diagnosed with RA during that short period after treatment ended.
Tascilar did point out that, even though this approach to prevention fell short, it wasn't devoid of benefit. He noted that abatacept "still provided, on average, 10 additional RA-free months" relative to placebo.
Moreover, the data allowed some insights into patients' baseline characteristics correlating with RA risk. In particular, CSA patients presenting with "more pain, more [systemic] inflammation, and worse health-related quality of life" were significantly more likely to develop RA. (Unfortunately, the ARIAA research team did not examine ACPA serology at baseline and therefore could not determine whether it mattered in the same way as it did in TREAT EARLIER.)
Neither EULAR nor the American College of Rheumatology (ACR) have formal guidelines for treating CSA. Only last month, the two organizations published a joint paper on risk stratification for CSA (with van Steenbergen as first author), which will help clinicians in deciding therapy but provides no direct recommendations. In practice, most patients are advised to try such remedies as over-the-counter medications, heat and/or ice, and physical therapy, and to have their symptoms monitored closely for progression.
While methotrexate isn't an entirely benign drug, it seems likely that clinicians will look more kindly on it for CSA patients testing negative for ACPA. A formal EULAR/ACR recommendation, though, will surely require additional studies.
TREAT EARLIER Follow-Up Details
Patients were enrolled in the original trial if they had a small number of painful and/or stiff joints and MRI evidence of subclinical inflammation, both insufficient to warrant an RA diagnosis. A total of 236 were randomized to placebo or methotrexate for 12 months.
Out of this group, van Steenbergen and colleagues analyzed 120 who were considered at high risk for progression because of increased baseline joint inflammation on MRI. These included 54 ACPA-positive and 66 ACPA-negative patients. Their ages were similar (mean 49 vs 47) but fewer of those in the former category were women (57% vs 72%). Baseline tender joint counts averaged two and four (out of 68 joints) in the ACPA-positive and ACPA-negative groups, respectively. Mean scores for disability on the Health Assessment Questionnaire were 0.7 and 0.8, respectively.
In addition to RA development during follow-up, van Steenbergen and colleagues also tracked physical disability. These data, too, showed stark differences according to baseline serology. In the ACPA-positive group, no difference between active treatment and placebo was ever seen. The ACPA-negative patients, however, saw significant improvement over time if they had received methotrexate, whereas those on placebo showed no substantial change.
As well, CSA resolved entirely by year 5 for a significant number of ACPA-negative patients: about 15% of those randomized to placebo and 40% of the methotrexate group. Overall among seronegative patients, self-reported morning stiffness scores declined by a mean of 21 points out of 100, and pain by 9 points out of 100.
ARIAA Follow-Up Details
A total of 98 patients were originally randomized in equal numbers to the 6-month course of abatacept or placebo. Eligibility criteria were similar to those of TREAT EARLIER. Enrollment proceeded gradually, with the first patient dosed in 2014 and the last in late 2019. Median follow-up was 5.3 years. The current analysis was based on data as of November 2024.
Mean patient age was about 50 at randomization, and some three-quarters were women.
At month 18, when the primary analysis was taken, just under half of the sample had progressed to overt RA. During subsequent follow-up, 25 additional RA diagnoses were made, of which 17 were in the abatacept group.
While patients with increased baseline pain, self-reported disability, and erythrocyte sedimentation rates were more likely to develop RA, Tascilar reported that joint inflammation on MRI did not seem to predict progression to RA.
He also noted several questions that could be addressed in future studies. Could patients who develop RA after a course of preventive treatment show milder disease or respond better to subsequent therapy? And could a preventive treatment minimize subsequent structural damage?
TREAT EARLIER was funded by the Dutch research organization ZonMw.
ARIAA was funded by Innovative Medicine Initiative and German and EU government grants.
Van Steenbergen declared she had no relevant financial interests.
Tascilar reported a relationship with Novartis.
