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Preventive treatment with methotrexate benefits pre-RA patients with arthralgia

Presented by
Dr Doortje Krijbolder, Leiden University Medical Center, the Netherlands
EULAR 2022

For the first time, a study demonstrated the benefit of arthralgia treatment with methotrexate before rheumatoid arthritis (RA) is diagnosed. Although the advancement to RA could only be delayed, the burden of disease was significantly reduced in this proof-of-concept study.

The window of opportunity for the treatment of RA is often seen in early disease, as there is ample evidence that effective disease modification with disability reduction or prevention is possible [1,2]. One question that has not been answered yet is whether RA can be prevented in patients with arthralgia who are at risk for RA. “So far, 2 trials have been performed in this phase, but these found no prevention of RA. “This could depend on the chosen treatments or selected outcomes,” stated Dr Doortje Krijbolder (Leiden University Medical Centre, the Netherlands) [1]. The randomised, 2-year proof-of-concept TREAT EARLIER study tested methotrexate versus placebo for reduction of RA development and burden of disease in patients with arthralgia. Included were 236 participants with a clinically suspect arthralgia plus subclinical MRI-detected joint inflammation of the hand or forefoot. They were treated either with 1 sole injection of 120 mg methylprednisolone and subsequent methotrexate (up to 25 mg/week) over 1 year or a placebo substitute. The baseline characteristics showed a mean age of 46.5 years, over 60% were women, and ≥20% were positive for anti-citrullinated protein antibodies (ACPA).

As for the development of persistent clinical arthritis, the overall results did not demonstrate a difference between the groups. The results were also stratified according to high/low risk and ACPA positivity. Dr Krijbolder highlighted that indeed among the high-risk patients, 70% of those on placebo advanced to clinical arthritis. “In the treatment group, this is clearly less at first, with a statistically significant difference at 6 and 12 months, but during the second year this disappeared, so this implicates a delay in arthritis development but no prevention,” she declared. This was similar for the ACPA-positive subgroup.

However, the picture was different when the focus was on pain: the reduction in pain was more pronounced in those on methotrexate (P<0.05) and it not only lasted for the time of therapy but also during the subsequent year of follow-up without medication. Furthermore, a significant and equally persistent decrease in disease burden was observed in measures like morning stiffness, functional impairment, and presenteeism at work, in addition to MRI-detected joint inflammation.

Dr Krijbolder described the results as somewhat counterintuitive since there was a delay in the development of arthritis but no definite prevention. Thus, to further elucidate these results, a post-hoc analysis of the high-risk partakers was executed. “Participants who did not progress to arthritis had an almost complete relief of pain and nearly returned to the normal range of MRI-detected inflammation that can be found in symptom-free controls,” Dr Krijbolder revealed. “Participants who did progress, whether it was early or late during follow-up, clearly had less pain and less MRI-detected inflammation if they were in the treatment group.” Therefore, her take-away was that both non-progressors and progressors were benefiting from this treatment.

“For the first time, we found proof for the concept of disease modification when intervening in pre-RA,” she concluded.

  1. Krijbolder D, et al. Intervention with methotrexate in arthralgia at risk for rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): a double-blind, randomised, placebo-controlled trial. OP0070, EULAR 2022 Congress, 1–4 June, Copenhagen, Denmark.

  2. Burgers LE, et al. RMD Open. 2019;5:e000870.

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