Only higher doses do the job properly, according to new analysis of a study previously in the Lancet.
Methotrexate dose is key to preventing subclinical joint inflammation, related symptoms and functional impairments in patients at risk of rheumatoid arthritis, according to a post-hoc analysis of the TREAT EARLIER trial.
Dutch researchers conducted the randomised, double-blind, placebo-controlled TREAT EARLIER trial to evaluate whether early treatment with MTX in patients with clinically suspect arthralgia and MRI-determined subclinical joint inflammation could prevent the development of clinical arthritis or reduce the disease burden.
While the intervention didn’t prevent disease onset, which was the primary outcome, secondary outcomes including pain, physical function and MRI-detected joint inflammation were improved compared with placebo.
The current study, a post-hoc analysis looking at the association of MTX dose and the secondary outcomes, found that “higher MTX doses were associated with larger sustained improvements in subclinical joint inflammation, related symptoms and functional impairments in patients with clinically suspect arthralgia with subclinical joint inflammation,” wrote the authors in the Lancet Rheumatology.
“10mg per week appears to be the minimal dose to achieve a biological effect as measured by reduction of subclinical joint inflammation, while at least 20mg per week is necessary to improve symptoms and functioning,” they wrote.
The proof-of-concept trial randomised 236 patients 1:1 to receive active treatment, comprising a single 120mg intramuscular glucocorticoid injection and up to 25mg oral MTX per week, or placebo injection and pills. Treatment lasted for one year, with follow up continued for a year after the treatment period.
If patients couldn’t tolerate the target 25mg MTX dose, the dose was lowered according to best practice and the number of tablets recorded in a study diary. Dose reductions were due mainly to raised liver panels, gastrointestinal effects or other side effects, or other patient concerns.
In this post-hoc analysis, the mean MTX dose was calculated for the treatment period to examine the relationship between dose and outcomes.
Among the 119 patients in the treatment group, most (57%) took 20mg or more, 30% took 10-20mg and 13% took less than 10mg.
There was a dose-response effect for improvement in MRI-detected joint inflammation, pain, physical functioning (measured by HAQ disability index) and presenteeism. The analysis found no effect of dose on preventing RA, the primary outcome of the original study.
Improvements in MRI-detected joint inflammation were found in doses of over 10mg per week, but clinically relevant changes in pain and HAQ were only found in weekly doses of 20mg or more.
“The association was also observed within the subgroups of patients who were anti-citrullinated-protein antibody positive and had a high (>70%) risk of progression to rheumatoid arthritis, but these results have to be interpreted with caution because of the small patient population,” noted the authors.
The authors point out that the study isn’t “an official dose-finding study” because the original study wasn’t designed to assess dose-dependent efficacy, and the patients weren’t randomised to receive different doses. Most patients kept to the target dose, which meant smaller numbers in the lower-dose groups, limiting statistical power, with potential confounding factors influencing adherence and efficacy.
“Reassuringly, all effect sizes found in the current study show a dose-dependent efficacy, and statistical significance was reached for the higher doses,” wrote the authors.
“Nevertheless, our findings need to be validated, preferably in a randomised trial comparing different methotrexate doses.”
As pointed out after the original study, treating people who may not get the disease with drugs that may cause unpleasant side effects is controversial, especially given the relatively small proportion – less than 20% in this cohort – who do go on to develop RA.
On the other hand, the authors noted that risk prediction has improved a lot since the trial was designed in 2014.
“If temporary treatment in the clinically suspect arthralgia phase is to be implemented in practice, the optimal methotrexate dose depends on the pursued treatment goal and shared decision making on the balance between effectiveness and tolerability,” wrote the authors.
