Up to 250,000 rheumatoid arthritis sufferers could benefit from a drug “that can halt the disease in its tracks”, according to The Daily Telegraph. The newspaper featured a front-page report on a study of 755 patients which found that adding the drug rituximab to the standard drug treatment for rheumatoid arthritis (methotrexate) stopped joint damage in 30.5% of people after six months. By contrast, only 12.5% of those using the standard treatment had no progression in joint damage.
The results of this trial show promise for rituximab in treating early active rheumatoid arthritis, but the research has only been presented at a scientific conference and therefore has some limitations. Results presented at conferences are often preliminary and may change when the study is fully completed and analysed. In addition, this trial will not yet have had its methods and results reviewed by independent experts in the field, which is normally part of the publication process.
Rheumatoid arthritis is a long-term condition. As this trial only lasted for one year, the longer-term effectiveness and safety of this treatment will also require further study.
The research was conducted by Professor Peter-Paul Tak and colleagues from universities and medical centres in Holland, the US, Germany and Sweden and by the companies Roche Products Ltd (manufacturers of MabThera rituximab), Genentech Inc and Synarc Inc.
Specific sources of funding for the study were not reported but most of the researchers received research grants from and/or acted as consultants for Roche, or worked for Roche or the other commercial organisations involved. The research was presented at the Annual European Congress of Rheumatology 2009.
The study was a randomised controlled trial which looked at the effects of adding rituximab to methotrexate for treatment of early rheumatoid arthritis.
The researchers enrolled people with early rheumatoid arthritis whose symptoms were ongoing. They included those who met a number of criteria, such as not having previously taken methotrexate, having had the disease for less than four years, having a certain level of swelling and tenderness of their joints and testing positive for rheumatoid factor (a protein present in people who have rheumatoid arthritis).
A total of 755 eligible participants were randomly assigned to receive either methotrexate plus a placebo, methotrexate plus two 500mg doses of rituximab, or methotrexate plus two 1,000mg doses of rituximab. Methotrexate was started at 7.5mg a week and increased to 20mg a week by week eight. Rituximab was given by gradual injection into a vein on days one and 15 of the of the study.
Patients had the severity of their rheumatoid arthritis assessed through calculation of a “Disease Activity Score” (DAS28). This gives a score from one to 10 which measures the “activity” of the disease, including the severity of a number of symptoms (number of tender and swollen joints) and other markers of disease severity and general health.
Participants with a DAS28 score of 2.6 or more at week 24 received a second course of rituximab treatment. Those whose DAS score was less than 2.6 received a second course of rituximab if and when their score increased to 2.6 or more.
The main outcome that the researchers were interested in was X-ray evidence of changes in the appearance of joints. A number of secondary outcomes were also of interest, including change in DAS28 score and various other criteria, such as a 70% reduction in the number of swollen and tender joints, plus a reduction of 70% in three of the following five factors: physician global assessment of disease, patient global assessment of disease, patient assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in Health Assessment Questionnaire score (the ACR70 criteria).
Of the 755 people randomised, 715 (95%) had X-ray data available. At the start of the study, participants had experienced rheumatoid arthritis for an average of 0.9 years.
Compared to a combination of methotrexate and placebo, the combination of the higher dose of rituximab and methotrexate reduced the change of joint appearance seen in X-rays and also increased the proportion of patients with no change of joint appearance in X-rays. The lower dose of rituximab plus methotrexate was not found to significantly affect the change of joint appearance in X-rays.
Adding either dose of rituximab to methotrexate improved clinical outcomes, such as improvement in ACR70 response and major improvement in clinical symptoms, compared with adding placebo.
Around 10% of people in each group (methotrexate plus either dose of rituximab or methotrexate alone) experienced serious adverse effects. Three deaths occurred, all of which were in the placebo plus methotrexate group.
The researchers concluded that combining the higher dose of rituximab with methotrexate “significantly improved clinical outcomes” and “inhibited joint damage” compared with methotrexate alone. They say that the lower dose of rituximab “significantly improved clinical, but not radiological [X-ray], outcomes”.
The researchers used the most appropriate study design, a randomised controlled trial, to investigate the effects of rituximab in rheumatoid arthritis. While their initial results show some promise, there are some important limitations to consider:
For these reasons, results presented at conferences should be considered as preliminary until the research has been fully published in a peer-reviewed scientific journal. There are additional points that must be considered when interpreting coverage of this study:
An important part of the evaluation of any new drug is the assessment of its cost relative to any improvements in effectiveness compared to the best alternative. The National Institute of Clinical Evidence is charged with assessing how any additional benefits of this drug and any extra cost of using it in combination with methotrexate would compare to currently funded treatments.
The results of this analysis, due in June 2010, will be of great interest to both the drug companies involved and those people with rheumatoid arthritis.