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Dosing for arthritis drug may be too slow

Friday 7 November 2008

Dosing for common rheumatoid arthritis drug may be too slow

Researchers at the University of Otago Christchurch have completed a study which indicates that current approaches for treating rheumatoid arthritis may be too slow to control the onset of joint damage associated with the disease.

Methotrexate is the most commonly used drug in the treatment of rheumatoid arthritis. However, the exact way in which it works is unclear. The researchers measured the active forms of methotrexate in blood cells in patients starting and stopping treatment and found that it takes much longer than initially thought for the drug to reach steady blood levels.

“Certainly our research raises some serious questions about current methotrexate dosing regimens when starting the drug,” explains rheumatologist Dr Lisa Stamp. “At this stage it looks as though larger doses, more rapid dose escalation, or possibly administration by injection under the skin may lead to more rapid accumulation in the blood and potentially earlier disease control”.

Approximately 1% of New Zealanders suffer from rheumatoid arthritis, many of whom are in constant pain and even crippled by the disease because of joint damage. Methotrexate is normally taken orally and binds to and inhibits several important enzymes, playing a role in a number of inflammatory pathways and thus limiting or controlling joint inflammation and subsequent damage.

Dosing normally starts at low levels, based on ‘response to treatment’, with increasing amounts until the disease is controlled. But valuable time may be lost with this method, resulting in unnecessary joint damage.

“One of the reasons why application of methotrexate has been based on ‘response to treatment’ is that there are a number of possible side-effects from this drug including nausea. However injecting under the skin may get around this problem,” says Dr Stamp.

The study measured methotrexate polyglutamates (active forms of the drug) in red blood cells in 10 patients who were beginning treatment and 10 who were stopping. In those patients starting treatment the median time until the methotrexate concentrations were nearly stable was 27.5 weeks.. For those patients stopping treatment it took 15 weeks for the drug to be undetectable in their red blood cells, which may relate to the lifespan of red blood cells of about 120 days.

The researchers conclude that it may be necessary to consider either injecting the drug or rapidly increasing oral doses, in order to reach optimum stable levels much earlier, to improve the beneficial effects on joint damage.

This study has been published in the November issue of Arthritis and Rheumatism. It was funded by the Health Research Council of New Zealand and Arthritis New Zealand.


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