TREAT EARLIER Study - Is MTX Intevention in Pre-Clinical RA Warranted? Save

Management of arthralgias before a certified rheumatoid arthritis (RA) diagnosis is challenging - should one use DMARD therapy before clinically evident synovitis in a preemptive effort to avoid or forestall the diagnosis or damage of RA? A novel study has shown that MTX initiated in subclinical, pre-diagnosed, arthralgia patients did not prevent the development of inflammatory arthritis, but did appear to modify the disease course (compared to placebo), as shown by serial MRI.

The TREAT EARLIER study was a randomised, double-blind, placebo-controlled, proof-of-concept-trial at the Leiden University Medical Centre, that enrolled adults with arthralgia for >12 weeks, seropositivity and clinically suspected of progressing to rheumatoid arthritis and MRI-detected subclinical joint inflammation. Patients were randomized (1:1) to receive to a single intramuscular glucocorticoid injection (120 mg) and a 1-year course of oral methotrexate (up to 25 mg/week), or placebo (single injection and PBO tablets for 1 year). Follow-up continued for 1 year after the end of the 1-year treatment period. The primary endpoint was development of inflammatory arthritis (fulfilling the 2010 rheumatoid arthritis classification criteria or involving two or more joints) that persisted for at least 2 weeks.

A total of 236 were enrolled (2015-2019) and randomized. After 2 years, achieving the primary endpoint (RA) was similar between the groups (19% MTX group vs 18% PBO group; hazard ratio 0·81, 95% CI 0·45 to 1·48).

Yet there were differential responses that improved in the first 4 months and remained better than in the placebo group over 2 years; including:

• Health Assessment Questionnaire disability index: –0·09, 95% CI –0·16 to –0·03; p=0·0042)
• Pain (scale 0–100): mean between-group difference: –8, 95% CI –12 to –4; p<0·0001)
• Morning stiffness (–12, –16 to –8; p<0·0001)
• Presenteeism (–8%, –13 to –3; p=0·0007)
• MRI-detected joint inflammation (–1·4 points, –2·0 to –0·9; p<0·0001)
• All favored the MTX treated patients compared to the placebo group.

The number of serious adverse events was equal in both groups; adverse events were consistent with the known safety profile for methotrexate.

Similar to the PROMPT study, early use of MTX in pre-clinical or undifferentiated arthralgia patients did not change the primary outcome of developing future RA. Yet, these data show that several measures were improved over the long term suggesting some degree of disease modification. 

But is this enough improvement in some (but not key) parameters to warrant DMARD intervention in the earliest stages of disease?