Methotrexate helps modify disease course of rheumatoid arthritis: BMJ

Netherlands: Methotrexate, the cornerstone treatment for rheumatoid arthritis (RA), helped to change the course of the disease as evaluated by continuous improvement in MRI-detected inflammation, associated conditions, and impairments. These findings were published in Annals of the Rheumatic Diseases.

Rheumatoid arthritis is the most prevalent autoimmune illness, and it needs long-term therapy to reduce inflammation. Methotrexate is currently used as first-line therapy when arthritis manifests clinically as joint swelling. Disease processes, on the other hand, begin far earlier and become clinically detectable when individuals acquire symptoms. As a result, D. Krijbolder and colleagues proposed that the 'at risk period' of symptoms and subclinical joint inflammation represents a treatment window for irreversibly altering the disease trajectory.

For this study adults with arthralgia clinically suspected of advancing to RA and MRI-detected subclinical joint inflammation were randomly allocated (1:1) to a single intramuscular glucocorticoid injection (120 mg) and a one-year treatment of oral methotrexate (up to 25 mg/week), or placebo injection and placebo tablets, in this double-blind, randomized, 2-year proof-of-concept experiment. Participants were then monitored for another year without study medication.

The primary objective was the occurrence of clinically evident arthritis that lasted at least two weeks. Patient-reported physical functioning, as well as symptoms and workability, were critical secondary goals that were assessed every four months. In addition, the progression of MRI-detected inflammation was investigated. The intention-to-treat analysis included all participants. Two predefined subgroup analyses were carried out. First, studies were limited to patients with a high risk of developing clinical arthritis (PPV 70%). Second, analyses were stratified according to ACPA status.

The key findings of this study were as follows:

1. 236 individuals were randomly allocated to treatment (n=119) or placebo (n=117) from April 16th, 2015 to September 11th, 2019.

2. After 24 months, both groups' arthritis-free survival rates were comparable.

3. During the initial months, physical functioning increased more in the therapy group and stayed better.

4. Similarly, discomfort, morning stiffness, and presenteeism improved with time as compared to placebo.

5. In addition, MRI-detected joint inflammation improved with time.

6. High-risk treatment group participants acquired clinical arthritis later: they developed the endpoint less frequently during therapy, but frequencies returned to normal after 24 months.

7. A similar delayed effect was found in ACPA-positive patients, where 48 and 52% had acquired persistent clinical arthritis after 24 months, respectively.

8. The number of major adverse events was comparable between groups; adverse events were consistent with methotrexate.

"Methotrexate initiated at the pre-arthritis stage of joint symptoms and subclinical inflammation did not prevent clinical arthritis development but modified the disease course as measured by sustained improvement in MRI-detected inflammation, related symptoms, and impairments," wrote the authors. 

In conclusion, these discoveries of long-term disease modification may pave the way for a new therapy landscape in the pre-arthritic period of RA, when limits can be as severe as at the outset of clinical arthritis.

Reference:

Krijbolder D, Verstappen M, van Dijk B, et al, OP0070 INTERVENTION WITH METHOTREXATE IN ARTHRALGIA AT RISK FOR RHEUMATOID ARTHRITIS TO REDUCE THE DEVELOPMENT OF PERSISTENT ARTHRITIS AND ITS DISEASE BURDEN (TREAT EARLIER): A DOUBLE-BLIND, RANDOMISED, PLACEBO-CONTROLLED TRIAL, Annals of the Rheumatic Diseases 2022;81:48-49.