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COPENHAGEN -- Methotrexate helped high-risk individuals with aching and inflamed joints, but who didn't yet have overt rheumatoid arthritis (RA), avoid that diagnosis for close to 2 years in a randomized trial, a researcher said here.

Half of those judged to be at least 70% likely to eventually develop RA and treated with methotrexate for 1 year were still RA-free at month 16, whereas half of a placebo group received an RA diagnosis within 4 months, said Doortje Krijbolder, MD, of Leiden University in The Netherlands.

In addition, pain was significantly reduced almost immediately with methotrexate relative to placebo in the , she reported at the European Alliance of Associations for Rheumatology (EULAR) annual meeting -- even among those at relatively lower risk of eventually developing overt RA.

But Krijbolder emphasized that methotrexate wasn't a cure. At the 2-year study's end, most high-risk participants had clinical RA irrespective of treatment.

Methotrexate, of course, is the backbone treatment for RA. While the drug is somewhat toxic, physicians have wondered whether early disease-modifying therapy could alter the subsequent clinical course in patients showing joint pain and inflammation without an obvious external cause.

To answer that question, TREAT EARLIER was conceived in 2014, eventually enrolling 236 patients in southwestern Netherlands seen for painful joints who did not meet standard criteria for persistent clinical arthritis (affecting at least two joints for 2 consecutive weeks or longer). Their characteristics were typical of early RA: mean age 46, about two-thirds women, with symptoms first noticed about 6 months previously. Roughly 30% showed elevations in C-reactive protein and were positive for rheumatoid factor; about one-quarter were positive for anti-citrullinated protein antibodies (ACPA).

Participants were assigned 1:1 to the placebo or active-treatment groups, with the latter consisting of oral methotrexate at up to 25 mg/week, along with a single injection of 120-mg methylprednisolone. Both groups received these treatments for 1 year, with an additional year of follow-up.

Across all patients, only a slight delay in eventual RA diagnosis was seen with the active treatment. However, the intervention was clearly helpful in staving off clinical RA in two high-risk subgroups: those at least 70% likely to develop overt RA, based on autoantibody positivity and MRI-evaluated joint inflammation; and those positive specifically for ACPA.

In the latter group, the delay was a bit shorter mainly because ACPA-positive individuals receiving placebo were slower to develop clinical RA compared with placebo recipients in the risk ≥70% subgroup. By month 12, for example, about 60% of the ACPA-positive patients receiving placebo still did not qualify for an RA diagnosis, versus about 75% of those assigned to methotrexate.

The active therapy was more clearly effective with regard to secondary endpoints -- pain, morning stiffness, functional impairment, and ability to work -- and this was true regardless of risk factors for overt RA. Moreover, the benefits from methotrexate relative to placebo persisted right to the end of follow-up.

For example, mean morning stiffness scores on a 100-point scale declined in the methotrexate group from 50 at baseline to just over 30 at month 24; with placebo, scores fell only slightly. A similar pattern was seen for functional impairment as evaluated with the . A smaller difference between active treatment and placebo was seen for "presenteeism" -- about 10 points on a 100-point scale -- but it was still statistically significant and was maintained throughout follow-up.

Perhaps the most provocative effect was in objective joint inflammation, assessed via MRI. Virtually no change was seen in the placebo group (again, irrespective of baseline risk factors), whereas a clear reduction was apparent at month 4 in the active-treatment group, maintained at exams repeated at months 12 and 24. On the other hand, inflammation was not totally abolished, even in those who didn't ultimately progress to overt RA.

Krijbolder also acknowledged that the early start to disease-modifying treatment came with toxicity. She said 27% of the methotrexate group discontinued early, and about three-quarters were because of adverse effects. In comparison, 19% of the original placebo group quit in the first year.

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