A one-year course of methotrexate significantly reduces inflammatory disease burden and new rheumatoid arthritis diagnoses among ACPA-negative arthralgia patients at risk of the autoimmune condition, five-year trial data suggest.
But the same couldn’t be said for ACPA-positive patients who showed no durable improvements with treatment over placebo at last follow-up despite recording benefits in the earlier years of the randomised controlled trial.
Dr Elise van Mulligen
Writing in the Lancet Rheumatology [link here], the researchers led by epidemiologist Dr Elise van Mulligen of Leiden University Medical Centre in the Netherlands said their results implied that at-risk arthralgia patients might require different treatment strategies depending on their ACPA status.
Methotrexate, the low-cost gold-standard RA treatment, benefited ACPA-negative individuals on “multiple fronts”, they added, and demonstrated a “unique opportunity” to reduce the burden of patients with the ACPA-negative subtype.
The TREAT EARLIER trial involved 236 patients with clinically suspect arthralgia and subclinical inflammation recruited from rheumatology clinics in the Netherlands. Patients were randomly assigned to a single intramuscular glucocorticoid injection (methylprednisolone 120 mg) and a 1-year methotrexate course (up to 25 mg/week) or placebo (single injection and tablets for 1 year).
The intention-to-treat population consisted of 120 participants (mean age 48, 60% female) at increased predicted risk of RA, of whom 66 were ACPA-negative (treatment 35; placebo 31) and 54 were ACPA-positive (treatment 31; placebo 23).
Physical disability measured with the Health Assessment Questionnaire disability index (HAQ; range 0–3) was used as a proxy for burden of disease.
Findings
Among ACPA-negative patients, the latest 5-year results showed a sustained and clinically relevant improvement in physical disability in the treatment group versus the placebo group (mean between-group difference –0.16 [95% CI –0.29 to –0.04], p=0.0082).
Three (9%) of 35 participants in the treatment group developed RA versus 10 (32%) of 31 in the placebo group (hazard ratio [HR] 0.24 [95% CI 0.07 to 0.87], p=0.018), corresponding to a number needed to treat of four.
Importantly, the RA diagnoses occurred only in the first year for the treatment group, whereas they occurred even into the fifth year for the placebo group.
For ACPA-positive patients, the previously reported benefit in disability over 2 years in the treatment group versus the placebo group was not maintained over 5 years (mean difference –0.12 [–0.26 to 0.03], p=0.12).
In ACPA-positive participants, 18 (58%) of 31 in the treatment group developed RA versus 15 (65%) of 23 in the placebo group (HR 0.75 [0.38–1.49], p=0.41).
Among secondary findings, morning stiffness improved over 5 years in treated ACPA-negative participants versus those in the placebo group, but not among the ACPA-positive participants. Pain significantly improved for all treatment groups.
Elaborating on their findings, the researchers said methotrexate was effective at suppressing inflammation at the chronic stage of disease, but might not be as useful in permanently altering the underlying mechanisms of ACPA-positive RA.
“The so-far unidentified pathological mechanisms essential for ACPA-positive arthralgia and subclinical inflammation developing into rheumatoid arthritis might not have been targeted, or the effect might not have been permanent. It is also possible that chronicity has already developed in the risk stage of arthralgia and subclinical inflammation, preventing complete reversal of the disease process.
“Ultimately, these findings might contribute to different treatment strategies for ACPA-positive and ACPA-negative individuals with arthralgia who are at risk for rheumatoid arthritis,” the researchers concluded.