Methotrexate and mortality in patients with

rheumatoid arthritis, a prospective study

Article reviewed - Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. HK Choi, MA Hernan, JD Seeger, JR Robins and F Wolfe.

I chose to comment on this study because it reports for the first time major favourable effects of a commonly used treatment for rheumatoid arthritis not only on the joints but on the number of deaths associated with rheumatoid arthritis. Methotrexate is the most widely used drug for the treatment of rheumatoid arthritis. It is widely used because it is effective and due to the once weekly dosing convenient for patients.

Methotrexate has been shown in studies to improve and maintain mobility, to decrease the symptoms and signs of inflammation such as pain, stiffness, and swelling, and to reduce long-term disability. It is not without its potential serious side-effects but in general shows a good balance of effectiveness compared to adverse effects. It is due to this combination of factors that has lead to Methotrexate being the most widely used drug for the treatment of rheumatoid arthritis in the last decade.

A number of studies in the past ten years particularly have altered the view of rheumatoid arthritis that I was taught as a medical student 25 years ago that rheumatoid arthritis was painful and potentially very destructive of joints but not a disease associated with increased mortality. We now know that this is not the case and that rheumatoid arthritis is associated with an increased death rate. The increase in mortality is similar in size to developing insulin dependant diabetes. Much of the increased mortality is in the form of increased rates of ischaemic heart disease.

Concerns were raised about the possible role of methotrexate in the increased rate of ischaemic heart disease in rheumatoid arthritis by a paper in the Lancet 2000 by a Dutch group ( Landewe et al Lancet 355 1616-7 2000). This suggested that there was an increase in cardiovascular morbidity in patients treated with methotrexate in a retrospective study. The study by Choi et al contains larger numbers of patients and is prospective and reassuringly comes to the opposite conclusions i.e. that the rate of cardiovascular morbidity in rheumatoid arthritis patients treated with methotrexate is reduced. I think this also emphasises the importance of large prospective studies in providing the best quality information. Interestingly other conventional disease modifying drugs, such as gold, sulphasalazine and penicillamine did not modify mortality significantly.

The link between rheumatoid arthritis and ischaemic heart disease is of considerable interest to rheumatologists and cardiologists but is not clearly understood at present. The link appears to be through inflammation and the mechanisms of inflammation. It appears that there is an overlap between the mechanisms of inflammation in joints in rheumatoid arthritis and the inflammation that occurs around the deposits of cholesterol and other fatty materials, which occur in arteries affected by atheroma. The 'spill over' of inflammatory factors form the joints in rheumatoid arthritis may lead to inflammation around the fatty deposits leading to their break-up and release, triggering clotting of blood in the arteries with blockage of blood flow resulting in a heart attack. This is opening up new areas of research which will hopefully be of benefit to not only to patients with rheumatoid arthritis, who suffer ischaemic heart disease, but to sufferers of ischaemic heart disease in general.

In conclusion the paper by Choi et al from Professor Wolfe's team in Kansas provides important and reassuring information about methotrexate the most widely used anti-rheumatic drug for the treatment of rheumatoid arthritis.