Combination therapy with cortisone most effective for early rheumatoid arthritis

3 May 2021

UZ Leuven researchers have shown that a combination therapy of methotrexate and cortisone is the optimal start treatment for patients with early rheumatoid arthritis, regardless of the severity of their prognosis. These are the results from a 5 year trial in various Flemish rheumatology centres. The approach is currently the start treatmet is all centres involved and is also included in the newest European guidelines for rheumatology.

"We saw that 70% of patients reached a remission status only after eight weeks with the COBRA Slim treatment, thus controlling their disease for a longer period of time", according to prof. dr. Patrick Verschueren.

The CareRA trial followed more than 300 patients with rheumatoid arthritis in ten Flemish rheumatology centres over a period of five years.

Prof. dr. Patrick Verschueren, principal investigator of the trial and rheumatologist at UZ Leuven: “We've known for a while that it is recommended to have an immediate, powerful approach for early rheumatoid arthritis in order to get the disease under control quickly and on a permanent basis. For this reason we have developed an intensive combination therapy some years ago, together with our Dutch colleagues. We called it COBRA, which stands for ‘Combinatietherapie Bij Reumatoïde Artritis’. The CareRA trial aimed to solve a number of unanswered questions: can we strategically alleviate the heavy combination treatment without losing any efficacy? And what is the importance of cortisone in the starting treatment?”

Milder version of the classic combination therapy

To examine this, the team set up a randomised, controlled trial. The patients were first subdivided depending on the expcted severity of their disease: with a high or low risk of a bad prognosis. After that they were randomly divided in groups that received different treatment schedules. The researchers compared the classic COBRA, consisting of a cocktail of various medication and a high dose of cortisone, with a milder version consisting with only methotrexate and a lower dose of cortisone (the so-called 'COBRA Slim'). In patients with a low risk, the COBRA Slim treatment was compared to the traditional step-by-step approach without cortisone, where the antirheumatic medication is adapted gradually until the desired improvement is reached.

In patients with a high risk of a bad prognosis, the outcome measurement showed that the COBRA Slim treatment turned out to be as efficacious as the heavier treatments with more more side effects. In the low risk groups, the treatment worked even better and quicker than the step-by-step approach without cortisone.

Prof. dr. Verschueren: “We saw that, with the COBRA Slim treatment, 70 % of patients reached a remission status, thus keeping their disease under control for a longer period of time. The milder combination therapy with a lower dose of cortisone turns out to be the recommended start treatment for all patients with early rheumatoid arthritis. Today it is the gold standard at UZ Leuven and many other rheumatology centres. Our approach is also endorsed by the European rheumatology association, and has been included in their guidelines.”


The fact that the first treatment includes cortisone is sometimes cause for criticism, because it is a hormone that can have a number of side effects. However, the researcers stress that, for early rheumatoid arthritis, cortisone can be very beneficial. It is anti-inflammatory, therefore eases the pain quickly and will fight the disease itself, whereas classic antirheumatic medication only start off working slowly.

"We think of cortisone as an important weapon to buy time. It helps limit the damage to the joints as well as the psychosocial consequences of the disease, until the antirheumatic medication such as methotrexate catches on", prof. dr. Verschueren says. “Because we deal with this strategically, within a striclty outlined time frame, the side effects are relatively limited and we've even found that cortisone use in our patients is lower in the long run.”

Wider framework

The CareRA trial is part of a wider framework of various trials which also involves GPs, nursing specialists, patient associations and patients. For instance there is attention for the effect of the treatment on psychosocial welfare, the quality of life and patients' integration in society. It also includes a pharmaco-economic section that compares the different treatments. From these related trials we learn that most patients have a very positive experience with the COBRA Slim treatment. In addition, the therapy is cheap and cost-efficient, because it can be applied worldwide.

For a minority of the patients, the COBRA Slim approach is not sufficient and need to scale up to more heavy treatment schedules with other medication. In an ongoing follow-up trial with the support of the KCE, the Leuven team examines whether early use of the new generation of so-called 'biological' and 'targeted synthetic' antirheumatic drugs is more appropriate in these cases. They are also looking into future biomarkers that can help predict what therapy will be most suitable for each individual patient.

About rheumatoid arthritis

An estimated 1 in 100 people are affected by rheumatoid arthritis and is one of the most common types of rheumatism. It's a chronic auto-immune disease, characterised by inflammation of joints and tendons. For most patients it means taking lifelong medication to keep the disease under control.

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Last edit: 4 May 2021