Early Methotrexate Can Alter Disease Course in Those At-Risk of Rheumatoid Arthritis

Use of methotrexate in the prearthritis stage of joint symptoms and subclinical inflammation could alter the disease course of clinical arthritis.

Results of the TREAT-EARLIER proof-of-concept study suggest the use of glucocorticoid and methotrexate use in patients with arthralgia at risk of progressing to rheumatoid arthritis did not reduce risk of persistent arthritis but was associated with improvements in inflammation, related symptoms, and impairments.

“Temporary treatment with methotrexate does maybe delay but does not prevent clinical arthritis development. It did, however, induce a sustained reduction in disease burden and MRI-detected inflammation in all at-risk subgroups,” said Doortje Krijbolder, MD, of the Department of Rheumatology at the Leiden University Medical Center. “Therefore, for the first time, we’ve found proof for the concept of disease modification when intervening in ‘pre-RA’.”

With rheumatoid arthritis representing a chronic autoimmune disease, identifying effective prevention strategies can have a significant impact of patient- and population-level health. Hypothesizing intervention during the “at-risk phase” of symptom development might permanently modify disease course, Krijbolder and a team of colleagues designed the current trial as a 2-year, randomized, double-blind, proof-of-concept trial in adult patients with arthralgia clinically suspected of repression to rheumatoid arthritis and MRI-detected subclinical joint inflammation from outpatient rheumatology clinics in the south-west Netherlands.

A total of 236 participants were randomized in a 1:1 ratio to a single 120 mg intramuscular glucocorticoid injection and a 1-year course of oral methotrexate up to 25 mg per week or placebo injection and placebo tablets, with 119 randomized to treatment and 117 randomized to placebo therapy. Per trial protocol, patients were followed for an additional year following the 1-year treatment period. The investigators’ primary outcome of interest was the development of clinically detectable arthritis that persisted for at least 2 weeks. For the purpose of analysis, clinically detectable arthritis was defined as fulfilling the 2010 RA criteria or involving 2 or more joints.

Patient-reported physical functioning, symptoms, and workability were considered secondary outcomes of interested and were measured every 4 months. Investigators noted the course of MRI-detected inflammation was studied and measured using the sum of tenosynovitis, synovitis, and osteitis, scored with the RA-MRI Scoring (RAMRIS) method.

At 2 years, arthritis free survival was similar in both groups (80% vs 82%, HR 0.81 [95% CI, 0.45 to 1.48]), but physical functioning improved more in the treatment-group during the first months and remained better (mean between-group difference over 2 years HAQ, -0.1 [-0.2 to -0.03]; P=.004). Further analysis suggestedpain (-9 on scale 0-100; [95%CI,-12 to -4]; P <.001), morning stiffness (-12 [95%CI -16 to -8]; P <.001), presenteeism (-8% [95%CI -13 to -3%]; P=.001) showed sustained improvement compared to placebo.

In subgroups analyses, investigators found high-risk participants in the treatment group experienced delay in clinical arthritis development, with these participants experiencing the primary outcome less often during treatment phase, but frequencies became similar at 24 months. Investigator pointed out a similar delaying effect was observed in ACPA-positive participants, with 48% and 52% developing clinical arthritis at 24 months.

“Methotrexate, the cornerstone treatment of RA, initiated at the pre-arthritis stage of joint symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as measured by sustained improvement in MRI-detected inflammation, related symptoms and impairments,” wrote investigators. “These findings of sustained disease modification may open up a new treatment landscape in a pre-arthritis phase of RA, where limitations can be just as severe as at the onset of clinical arthritis.”

This study, “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,” was presented at EULAR 2022.