Exploratory analysis of the TREAT EARLIER trial: is the efficacy of temporary methotrexate treatment dose-dependent?

The TREAT EARLIER trial 1 Krijbolder DI Verstappen M van Dijk BT et al. Intervention with methotrexate in patients with arthralgia at risk of rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): a randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet. 2022; 400: 283-294 Summary Full Text Full Text PDF PubMed Scopus (31) Google Scholar showed sustained improvement in MRI-detected subclinical joint inflammation and related joint symptoms after a 1-year methotrexate course in patients with both clinically suspect arthralgia and subclinical joint inflammation. Discussions are ongoing regarding whether pharmacological treatment has a place in individuals at risk of rheumatoid arthritis and if advancing the current first-line rheumatoid arthritis treatment (methotrexate) for a limited period to the clinically suspect arthralgia phase is beneficial. Crucial to this discussion is whether patients with clinically suspect arthralgia require the same dose of methotrexate as that which is currently prescribed to patients with rheumatoid arthritis. 2 Visser K Katchamart W Loza E et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis. 2009; 68: 1086-1093 Crossref PubMed Scopus (440) Google Scholar Therefore, we studied the relationship between methotrexate dose and treatment efficacy in patients with clinically suspect arthralgia who used methotrexate in the TREAT EARLIER trial. 1 Krijbolder DI Verstappen M van Dijk BT et al. Intervention with methotrexate in patients with arthralgia at risk of rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): a randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet. 2022; 400: 283-294 Summary Full Text Full Text PDF PubMed Scopus (31) Google Scholar Despite being commonly used in rheumatoid arthritis, the evidence on optimal dose of methotrexate is scarce, as illustrated by the literature overview presented in the appendix (pp 9–10). Two double-blind randomised dose-finding trials were done in patients with rheumatoid arthritis more than three decades ago, which included 56 patients (46 in the study by Furst and colleagues 3 Furst DE Koehnke R Burmeister LF Kohler J Cargill I Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol. 1989; 16: 313-320 PubMed Google Scholar and ten in the study by Seideman 4 Seideman P Methotrexate—the relationship between dose and clinical effect. Br J Rheumatol. 1993; 32: 751-753 Crossref PubMed Scopus (57) Google Scholar ). On the basis of these data and general clinical experience in patients with rheumatoid arthritis, we hypothesised that in clinically suspect arthralgia there is also an association between methotrexate dose and effectiveness in improving subclinical joint inflammation, joint pain, functional impairment, and work-related impairment.