Early treatment prevents rheumatoid arthritis in a subgroup of patients

6 July 2026

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Rheumatoid arthritis does not develop overnight. By the time a diagnosis is made, inflammation has often been present for some time, even though it is not yet visible on the outside. Ideally patients at risk for RA are recognized and treated in this at-risk phase in order to prevent progression to clinically apparent disease. New research shows that this approach can improve outcomes in ACPA-negative patients and may even prevent rheumatoid arthritis.

Professor Annette van der Helm

Rheumatoid arthritis starts even long before swollen joints appear

Rheumatoid arthritis usually develops slowly. People may have painful or stiff joints and find it hard to get going in the morning. Yet there are no visible swollen joints. Doctors refer to this early stage as “clinically suspect arthralgia,” or CSA. This means there are symptoms consistent with early-stage rheumatoid arthritis, even though the characteristics swollen joints required for the diagnosis of RA, are still absent.

Previous research has shown that people who are diagnosed and treated early are less likely to suffer permanent joint damage and are more likely to achieve remission.

It was precisely this early intervention stage that served as the starting point for the TREAT EARLIER trial, a joint initiative of LUMC and Erasmus MC, in which all hospitals in the southwest of the Netherlands participated. “We know that the disease process in inflammatory rheumatism can already be underway for some time before we can detect it externally,” says rheumatologist and principal investigator Annette van der Helm-van Mil. “But during the early phase, we do already see changes in the blood and in the joints when we use advanced imaging modalities such as MRI. In fact, this is the time interval when you want to help people.”

From monitoring to early treatment

People with early symptoms usually see their primary care physician first, and only a small number of them are referred to a rheumatologist. Within that group, the specialist identifies signs of very early rheumatoid arthritis (and thus CSA) in only a few patients.

Until recently, the standard approach was to monitor these patients over time. Only when the disease became clearly visible, with swollen and inflamed joints, would doctors make a diagnosis and start treatment, often with methotrexate. “You could say that we often don’t start treatment until the disease has already been progressing for some time,” says van der Helm-van Mil.

The TREAT EARLIER trial set out to examine what happens when people with early symptoms are treated immediately. Using MRI scans, researchers were able to detect joint inflammation that was not yet visible or detectable by physical examination. Study participants received a single anti-inflammatory injection, followed by one year of methotrexate or placebo after which treatment was stopped and they were followed for another five years. “The goal was not to give long-term medication, but to see whether a short course of treatment at the right moment could have long-lasting effects,” says van der Helm-van Mil.

Different cause hence different treatment

Some people have ACPA antibodies in their blood, while others do not. Internationally, the group without these antibodies receives less attention because the diagnosis is more difficult to make. It is sometimes questioned whether a diagnosis of rheumatoid arthritis (RA) can be made with confidence in the absence of ACPA. However, nearly half of people with early-stage rheumatoid arthritis are ACPA-negative and do not have ACPA antibodies, even though they do have chronic joint inflammation. This underscores the need for studies to enhance outcomes for this group of patients with RA.

It is precisely in this group that the study shows early treatment can make a real difference. Only 9 percent of ACPA-negative patients eventually developed rheumatoid arthritis after treatment, compared to 32 percent in the placebo group. This means that by treating four people early, you can prevent one case of rheumatoid arthritis on average.

These patients also experienced fewer symptoms, such as pain and morning stiffness. “We’re not only seeing less disease, but also that people feel better over the long term. Some even become completely symptom-free,” says van der Helm-van Mil.

In contrast, early treatment was less effective in people with ACPA antibodies. While many experienced temporary relief, it did not prevent rheumatoid arthritis in the long term.

“I still see this as a hopeful and important finding,” van der Helm-van Mil adds. “If the disease develops in different ways in patients with or without autoantibodies, it makes sense that different treatment strategies are needed to intercept with the development of these two subsets of the disease.”

TREAT EARLIER trial offers new perspective

This study shows that early treatment can make a real difference, but only for the right group of patients. For people without autoantibodies but who do show signs of inflammation on an MRI, this opens up the possibility of something that was hardly conceivable until recently: not only fewer symptoms, but possibly even the prevention of rheumatoid arthritis.

For people with autoantibodies, early treatment is less effective evaluated over the course of five years, and further research is needed to explore other approaches.

Meanwhile, the researchers are continuing to work on early diagnosis in the most pragmatic way possible. The goal remains clear: to identify the disease earlier, treat patients more effectively, and prevent symptoms from developing into a chronic disease. The TREAT EARLIER trial offers hope and the prospect that this is possible.

More information

This study was funded by NWO and ReumaNederland and was recently published in The Lancet Rheumatology.