Biologics should be compared to the highest possible dose of methotrexate

Some drugs work better at higher doses. Traditionally, studies designed to show that biologic drugs are better than methotrexate have not used the highest possible dose of methotrexate to compare against.

Rheumatoid arthritis is a chronic inflammatory disease that affects a person’s joints, causing pain and disability. It can also affect internal organs. Rheumatoid arthritis is more common in older people, but there is also a high prevalence in young adults, adolescents and even children, and it affects both men and women. Methotrexate is a disease-modifying antirheumatic drug (also called a DMARD). Methotrexate is often considered to be the anchor drug in the treatment of rheumatoid arthritis, and it is recommended as the first drug to be used in people with the disease. The dose of methotrexate should be gradually increased according to a person’s disease activity, and it tends to work better at higher doses. Methotrexate is usually first tried as an oral pill, but if the disease continues to be active then methotrexate can be given as an injection instead, which help to get more of the drug into your system where it is needed. Methotrexate should be taken once a week and the maximum dose usually does not exceed 25 mg each week. New drugs with biologic activity (called biologics or bDMARDs) have been developed for the treatment of rheumatoid arthritis, and many studies have concluded that they are better than methotrexate. For a fair comparison, studies designed to show that biologics are better should use methotrexate at its highest possible dose.

The authors wanted to see whether studies showing how well biologics work have used an appropriate dose of methotrexate to compare against.

This study did not involve patients or people with rheumatoid arthritis. It was carried out by performing a literature search.

A systematic review aims to identify all the published evidence on a particular topic and draw it together into one summary. The authors used major electronic databases to search for trials and studies that compared a biologic drug with methotrexate in people with rheumatoid arthritis who had not used methotrexate previously. The search gave a long list of 3276 articles. Two independent reviewers determined which studies had to be included; 13 had the correct type of information and were included in the review.

The authors found that all studies except one had used only oral methotrexate. In addition, the maximum weekly dose used in the studies was 15 mg when given as an injection, and 20 mg when given as an oral pill, even when people continued to have high disease activity. It is possible to use up to 25 mg of methotrexate every week. Therefore the main finding was that the maximum dose of methotrexate was not reached in these studies, and this may have affected the results in favour of the biologic drugs.

It has been shown in other areas of medicine that studies often use less good drugs or suboptimal doses to compare against, which gives an advantage to the new drug being studied. This is the first time that a study has looked at this effect in the studies of biologic drugs in rheumatoid arthritis.

The authors are aware that not all people in the studies would have needed or been able to take the maximum dose of methotrexate, but they think that the studies should have been designed so that people could take 25 mg as an injection if needed, rather than stopping at 20 mg of oral methotrexate.

No more studies are planned, but the authors hope that these results will influence the design of future studies of new drugs in rheumatoid arthritis.

If you have rheumatoid arthritis, this article suggests that it is important to be aware that although biologics are helpful in people who do not respond to traditional drugs, you may also be able to control your disease by taking the highest possible dose of methotrexate, or by taking it in a different way. It is very important that you do not increase your methotrexate dose yourself without taking medical advice. If you have any concerns about your disease or your medication, you should speak to your doctor.

EULAR recommendations for management. Available at: cfm

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Date prepared: September 2016

Summary based on research article published on: 18 April 2016

From: Durán, J. et al. Methotrexate dosage as a source of bias in biologic trials in Rheumatoid Arthritis: a Systematic Review. Ann Rheum Dis 2016;75:1595–98.

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