Early treatment of at-risk patients fails to prevent RA

4 minute read

But methotrexate and glucocorticoids improved pain, physical functioning and MRI-detected joint inflammation in patients with early signs of rheumatoid arthritis.

Treating people with early signs of rheumatoid arthritis with methotrexate and glucocorticoids did not prevent disease onset.

However, secondary outcomes including pain, physical function and MRI-detected joint inflammation were improved compared with placebo, according to research published in The Lancet.

Researchers in the Netherlands conducted the randomised, double-blind, placebo-controlled TREAT EARLIER trial to evaluate whether early intervention in patients with arthralgia and MRI-determined subclinical joint inflammation could prevent the development of clinical arthritis or reduce the disease burden.

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 methotrexate per week, or placebo injection and pills. Treatment lasted for one year, with follow up continued for a year after the treatment period.

The primary endpoint was development of clinical arthritis that lasted for at least two weeks and met the 2010 rheumatoid arthritis classification criteria or involved two or more joints.

Secondary endpoints, which reflected patient priorities, were physical functioning (measured by HAQ disability index), patient-reported symptoms (joint pain, morning stiffness and fatigue) and work productivity, in particular presenteeism.

At the two-year follow up, the primary endpoint was similar for both groups, with 19% of the treatment group having developed RA, compared with 18% of the placebo group.

However, there were statistically significant differences between the treatment and placebo groups on the secondary endpoints, although the authors stated that the clinical relevance of the differences was unknown.

At the 4-month assessment, physical functioning was improved in the treatment group compared with placebo group, with a mean between-group difference in HAQ of ‑0.09 (95% CI ‑0.16 to ‑0.03; p=0.0042). The difference was maintained during follow up. Pain, morning stiffness of joints and presenteeism showed a similar effect. 

MRI-detected joint inflammation severity was decreased in the treatment group at the 4-month assessment compared to placebo, and the difference was maintained over the two-year period. The mean difference in the sum of synovitis, osteitis and tenosynovitis scores was ‑1.4 points (95% CI ‑2.0 to ‑0.9; p<0.0001).

Adherence was moderate, at only 53% for the treatment group and 75% for the placebo group, which may have contributed to the similar primary outcomes in each group.

Another possible reason for the lack of difference is that most patients weren’t at high risk for progression, with only a third of participants positive for ACPA. The authors noted that risk prediction has improved a lot since the trial was designed in 2014, with risk of progression of more than 70% able to be identified.

Adverse events were similar for both groups, although there were raised liver enzymes and increased gastrointestinal symptoms in the treatment group. Side effects were the main reason given for non-adherence in both groups.

Despite the apparent failure to prevent RA onset, the authors said the trial provided valuable insights into other potential benefits of early treatment with MTX and GC in terms of symptoms and functioning and also severity of the disease in the long term.

“The value of treatment initiation in the at-risk phase could be expressed in the ability to obtain reduction of symptoms and physical impairments, or to maintain normal activities of daily living, including work,” the authors wrote.

“Therefore, this study could open a new treatment landscape for the rheumatoid arthritis field.”

“Future research is needed to assess whether initiation of methotrexate in clinically suspect arthralgia and subclinical joint inflammation leads to a milder long-term disease course, lowers disease activity, reduces the need for biological DMARDs, and increases DMARD-free remission in those who develop clinical arthritis,” they wrote, adding that a five-year follow up is planned.

However, for Melbourne rheumatologist Professor Steve Hall, the side effects of MTX and effects on quality of life, including fatigue and reduced response to vaccine, were something of a deal breaker.

“I don’t think my patients would want to go on long term medication in the absence of a precise diagnosis of disease. If we could be sure that all or most of these people were going to develop RA it would be more compelling,” said Professor Hall, adjunct professor of medicine at Monash University.

“Meanwhile, the therapeutic options we have now have dramatically improved the outcomes for RA, so it may be better to wait and see – and not treat the 80% of people who didn’t need to be treated,” said Professor Hall.

Professor Hall said that a positive outcome of the study is that it provides the suggestion that other more potent drugs, given early in the disease before it becomes clinically evident, may potentially prevent full development of the disease.

“It’s an interesting paper, an indicative paper. But I would be very surprised if it changed practice.”

The Lancet 2022, online 23 July

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