Which factors predict sustained RA remission with MTX or ETN monotherapy?

Following the switch from combination therapy to monotherapy, rheumatoid arthritis (RA) patients with overall lower disease activity (LDA) have higher odds of achieving and remaining in Simplified Disease Activity Index (SDAI) remission/LDA, suggests a study.

In addition, rheumatoid factor (RF)-negative status and lower patient global assessment of disease activity (PtGA) scores predict an increased likelihood of remaining in remission/LDA with methotrexate (MTX) or etanercept (ETN) monotherapy.

“Understanding factors associated with a patient achieving remission while on therapy for RA is important to predict how well an individual patient will do,” the investigators said.

This phase III, multicentre, randomized controlled study enrolled 371 patients with RA on MTX plus ETN, of whom 253 entered 48-week double-blind period after sustaining remission (SDAI ≤3.3) through a 24-week run-in period. These patients were then randomly assigned to receive MTX monotherapy, ETN monotherapy, or continue combination therapy.

The investigators identified the baseline factors associated with remission or LDA at the end of both periods via multivariate logistic regression analysis.

Factors for remission

After adjusting for potential confounders, the following factors correlated with achieving SDAI remission at the end of the run-in period: younger age, longer duration of MTX treatment, and less severe clinical disease variables. [J Rheum 2023;50:1114-1120]

Furthermore, maintaining remission/LDA at the end of the double-blind period correlated with lower PtGA, lower C-reactive protein, RF negativity, longer RA duration in the MTX arm, shorter duration of ETN treatment, and lower magnesium.

“Serum magnesium level is emerging as a potential risk factor in RA, though this connection is not yet understood,” the investigators said. “It is unclear whether magnesium levels influence the disease or vice versa.”

In earlier studies, researchers have shown that magnesium could reduce inflammatory cytokine production. In addition, moderate doses of magnesium (184‒446 mg/day) was found to be associated with the lowest prevalence of RA, but lower or higher levels correlated with higher prevalence. [J Immunol 2012;188:6338-6346; BMJ Open 2020;10:e039640]

“The role of magnesium in retaining good disease control warrants further exploration,” the investigators said. “These results may help guide clinicians in deciding whether to discontinue MTX or ETN in a patient with RA in sustained remission on a combination of ETN and MTX.”

Early treatment

One way of achieving optimal outcomes is early treatment of disease. Based on previous studies, patients who reach remission are also more likely to sustain it, and those with shorter RA duration have greater chances of attaining remission. [Clin Exp Rheumatol 2012;4(Suppl 73):S35-38; J Rheumatol 2014;41:2161-2166; Int J Rheum Dis 2018;21:1977-1985]

“Our findings align with this in that shorter duration of RA (≤5 yrs) in the MTX arm was significantly associated with increased odds of maintaining remission/LDA (p=0.003),” the investigators said.

The American College of Rheumatology and the European Alliance of Associations for Rheumatology conditionally recommend continuation of all disease-modifying antirheumatic drugs (DMARDs) at their current dose over a dose reduction.

“However, patients with RA who persist in remission may consider tapering their therapy, provided that a therapeutic dose of at least one DMARD is maintained, the investigators said. [Ann Rheum Dis 2020;79:685-699; Arthritis Care Res 2021;73:924-939]