Intensive treatments deliver good long-term results

The COBRA-Slim treatment is as effective as more complex treatments for high-risk patients with early RA

Rheumatoid arthritis is a chronic inflammatory disease that affects a person’s joints, and may cause pain and disability. Rheumatoid arthritis can affect people of all ages, but it most often starts between the ages of 30 and 50 – although this can depend on where you live. Rheumatoid arthritis is more common in women than men.

CareRA was a controlled trial that compared the effectiveness of different treatment schemes in people with early rheumatoid arthritis. It included the so-called “COBRA-Slim scheme” which uses initial methotrexate and short-term glucocorticoid (steroid), followed by treat-to-target adaptations. The results up to 2 years showed that COBRA-Slim was just as effective, but better tolerated and more cost-effective than the more complex schemes. CareRA-plus is a follow-up study that looks at outcomes of the treatment schemes over a longer period.

The authors wanted to find out how effective the treatment schemes used in CareRA would be over a longer time period.

The CareRA-plus study looked at 252 people with rheumatoid arthritis. Everyone had been diagnosed within the past 3 years, and had started treatment with a disease-modifying antirheumatic drug (often shortened to DMARD) in the previous CareRA study.

The original CareRA study was a randomised controlled trial. This means that people were assigned by chance to the treatment groups. Using chance in this way means that the groups are similar and allows the treatments under investigation to be compared objectively.

Before being allocated to a particular treatment in CareRA, people were classed as being either low- or high risk, depending on the presence of risk factors. These ‘prognostic factors’ give an indication of how well a person’s disease will respond to treatment.

People in the high-risk group were randomised to one of three remission induction schemes:

1. “COBRA-Classic” (initial combination of methotrexate plus sulfasalazine)
2. “COBRA-Slim” (methotrexate on its own)
3. “COBRA-Avant-Garde” (initial combination of methotrexate plus leflunomide).

Everyone at high-risk also started their COBRA scheme with a short course of oral prednisone (a steroid
medicine), which was then gradually removed (sometimes referred to as ‘bridging therapy’).
People in the low-risk group were randomised to one of two schemes:

1. The same COBRA-Slim scheme as people in the high-risk group with initial steroid
2. “Tight Step-up”, where they received methotrexate on its own without any steroids.

Everyone who completed CareRA could carry on in the long-term CareRA-plus study. This was an observational follow-up study assessing disease activity and functionality. These outcomes were measured every 6 months for a further 3 years to see if there was a need to change treatment over time.

The main finding was that people in the high-risk group had similar and sustained effectiveness profiles over 5 years for the COBRA-Slim scheme compared to high-risk people who started with DMARD combinations and glucocorticoid bridging (COBRA-Classic or COBRA-Avant-Garde).

For people in the low-risk group, starting a COBRA-Slim scheme was more effective over 5 years than a
conservative tight step-up from methotrexate without glucocorticoids.
Only about 1 in 6 patients ever used glucocorticoids chronically for more than 6 months, and only about 1 in 5 patients started taking a biologic treatment over 5 years.

No. However, the results confirm and expand on the conclusions of the initial CareRA trial. These results also support findings about the sustained effectiveness of COBRA schemes seen in other trials, and confirm the EULAR recommendations. However, the exact details of the COBRA-Slim scheme used in this study were slightly different from those used in other trials, so that part is new. For example, in CareRA, the COBRA-Slim scheme did not require people to start a biologic therapy without first trying DMARD combination therapy if their disease activity was not well controlled, as was the case in another trial called COBRA-Light.

In CareRA-plus, treatment choice was made at the discretion of the rheumatologist. It is possible that this could have resulted in bias in treatment decisions, which would have influenced differences in outcomes between the groups. However, the authors note that the proportions of people who needed to intensify their DMARD treatment during the 5-year follow-up period were comparable between groups. It is therefore unlikely there were differences that could have influenced the comparison in the high-risk population.

Another possible limitation is that analyses in the group of people without factors of poor prognosis were based on a limited population. However, people at low risk are not often looked at separately, and their evaluation in studies is not often planned as it was in CareRA, which can be considered a strength of the study.

Despite the high response rates, there was a subgroup of people who could not achieve the desired target with any of the intensive treatment regimens tested. Since early response can predict the future course of a person’s disease activity, this could be used as a way to select people who need quicker treatment intensification, for instance with a biologic or targeted DMARD. The findings from this study have contributed to the set up the CareRA 2020 trial, which is now underway.

If you have early rheumatoid arthritis, you may be started on a COBRA-Slim treatment. Most people who
receive this treatment get rapid and stable relief of their symptoms, and can achieve sustained disease control.

If you have any concerns about your disease or its treatment, you should talk to your doctor.

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Date prepared: July 2021
Summary based on research article published on: 2 April 2021
From: Stouten V, et al. Five-year treat-to-target outcomes after methotrexate induction therapy with or without other csDMARDs and temporary glucocorticoids for rheumatoid arthritis in the CareRA trial. Ann Rheum Dis 2020;80:965–973. doi:10.1136/annrheumdis-2020-219825

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