Methotrexate reduces functional burden of disease in patients with arthralgia at-risk of developing rheumatoid arthritis

1. Compared to placebo, methotrexate did not significantly reduce the risk of the development of clinical arthritis in at-risk patients.

2. Methotrexate significantly improved patient-reported symptoms, MRI-detected join inflammation, and physical impairments compared to placebo.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Rheumatoid arthritis (RA) is an autoimmune disease which can cause significant pain, stiffness, and swelling of the joints. While methotrexate is commonly used in the treatment of RA, its use has not been studied in the pre-arthritis phase. The TREAT EARLIER study enrolled patients with arthralgia who were clinically suspected to be at-risk of rheumatoid arthritis by a rheumatologist and had MRI findings of joint inflammation. Patients were randomized to receive either methotrexate or placebo. The study found no significant benefit in the prevention of clinical arthritis in the treatment group compared to the control. However, the treatment group had significantly lower patient-reported symptoms of functional disease burden including pain, morning stiffness and presenteeism. Additionally, MRI-detected joint inflammation was shown to be lower in the treatment group compared to placebo. Serious adverse events were similar between both groups and side effects from methotrexate were consistent with its known safety profile. Despite not being effective at preventing clinical arthritis, methotrexate was shown to have benefit in reducing the burden of disease in patients at-risk of rheumatoid arthritis.

Click to read the study in The Lancet

Relevant Reading: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update

In-Depth [randomized controlled trial]: The TREAT EARLIER trial was run at a single centre in the Netherlands. The study enrolled participants with arthralgia aged 18 years or older at risk of developing rheumatoid arthritis as clinically suspected by a rheumatologist. Subclinical joint inflammation was confirmed by MRI. A total of 236 patients were enrolled and randomly assigned 1:1 to either treatment group (n=119) or placebo group (n=117). Treatment was a single intramuscular glucocorticoid injection of 120 mg methylprednisolone followed by a 52-week course of methotrexate. Dosage was titrated upward to 25 mg methotrexate weekly or the highest tolerated dose. They were followed for one year following treatment and self-reported symptoms every 4 months. The primary outcome was the development of clinical arthritis as defined by the 2010 rheumatoid arthritis classification criteria or involving two or more joints for at least 2 weeks.

During the two-year treatment and follow-up period, the occurrence of clinical arthritis was 19% of the treatment group versus 18% of the placebo group (HR 0.81 [95% CI 0.45 to 1.48]). However, patient-reported symptoms of decreased physical functioning (p=0.0042), pain (p<0.0001), morning stiffness (p<0.0001), and presenteeism (p=0.0007) were significantly lower in the treatment group compared to placebo. MRI-detected joint inflammation was also significantly lower in the treatment group compared to placebo (-1.4 points, -2.0 to -0.9, p<0.0001). Serious adverse events were equal in both groups and adverse events were consistent with the known safety profile of methotrexate.

Image: PD

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