Long-term durability of a time-limited methotrexate intervention in patients with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative arthralgia at increased risk for rheumatoid arthritis (TREAT EARLIER): 5-year data from a double-blind, randomised, placebo-controlled trial

Mulligen, EV; Dumoulin, QA; van Steenbergen, HW; Krijbolder, DI; Visser, AW; Böhringer, S; van der Helm-van Mil, AH

doi:10.1016/s2665-9913(26)00109-8

Rheumatoid arthritis

Long-term durability of a time-limited methotrexate intervention in patients with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative arthralgia at increased risk for rheumatoid arthritis (TREAT EARLIER): 5-year data from a double-blind, randomised, placebo-controlled trial

Lancet RheumatolPublished 2 Jul 2026Randomised controlled trial

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Authors' conclusion

ACPA-negative participants had a long-term reduction in inflammatory disease burden and development of rheumatoid arthritis whereas there was no sustained improvement with ACPA-positive participants.

Study context

Population: Adults ≥18 years with clinically suspect arthralgia and subclinical joint inflammation, 13 rheumatology outpatient clinics in the Netherlands; 5-year analysis limited to those at increased predicted RA risk (>10%), stratified by ACPA120 analysed at 5 years
Participants: 236 adults

Comparison: Single IM GC injection then 1-year course of MTX vs placebo
Active treatmentn = 119
Placebon = 117reference
Primary endpoint: Two primary endpoints: disease burden (physical disability, HAQ) and development of RA, by ACPA status
Follow-up: 5 years

Methodological detailsdouble-blind, placebo-controlled, multicentre, 5-year follow-up analysis, stratified for ACPA, 215 (91%) completed 5-year follow-up, Participants and investigators masked for at least 2 years; follow-up 5 years

Double-blind
Placebo-controlled
Multicentre
5-year follow-up analysis
Stratified for ACPA
215 (91%) completed 5-year follow-up
Participants and investigators masked for at least 2 years; follow-up 5 years

Primary result

As reported in the abstract

Physical disability (HAQ), mean difference, by ACPA subgroup (increased risk) · Over 5 years

Active treatment vs PlaceboMean difference (95% CI)P value

ACPA-negative (n=35 vs n=31); sustained improvement

−0.16(−0.29 to −0.04)

P = 0.0082

ACPA-positive; 2-year benefit not sustained

−0.12(−0.26 to 0.03)

P = 0.12

Further findings

Outcome	Active treatment	Placebo	← Lower risk with active treatment ←→ Higher risk with active treatment →	HR	P value
Co-primary: development of RA, ACPA-negative subgroup · Over 5 yearsNNT 4 · intention-to-treat	9%	32%	0.050.21520	0.24 (95% CI 0.07–0.87)	P = 0.018
Co-primary: development of RA, ACPA-positive subgroup · Over 5 yearsIntention-to-treat	58%	65%	0.050.21520	0.75 (CI 0.38–1.49)	P = 0.41
Development of RA, full trial cohort · Over 5 years	22%	27%	0.050.21520	0.79 (95% CI 0.47–1.34)	P = 0.38
			0.050.21520Hazard ratio (log scale)

Outcome	← Lower with active treatment ←→ Higher with active treatment →	Mean difference (95% CI)	P value
Physical disability (HAQ), full trial cohort · Over 5 years	−0.2−0.100.1	−0.06 (−0.14 to −0.05)	P = 0.048
	−0.2−0.100.1Difference (linear scale)

Original publication

Long-term durability of a time-limited methotrexate intervention in patients with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative arthralgia at increased risk for rheumatoid arthritis (TREAT EARLIER): 5-year data from a double-blind, randomised, placebo-controlled trial. Lancet Rheumatol. Published 2 July 2026. doi:10.1016/s2665-9913(26)00109-8

Read the original article ↗

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