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Do methotrexate and other treatment agents protect rheumatic patients against dementia?

Can conventional rheumatism drugs halve the risk of dementia in patients with rheumatoid arthritis? A large cohort study data hints at this and gives a particular protective potential for methotrexate.

Evidence of positive MTX side effects investigated

Can conventional rheumatism drugs halve the risk of dementia in patients with rheumatoid arthritis? A large cohort study data hints at this and gives a particular protective potential for methotrexate.

To go into detail at this point that rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease would be to carry owls to Athens. The fact that other organs and structures such as the heart, lungs, and blood vessels are affected by the inflammatory processes in addition to the joints is worth taking a closer look at. In this way, RA clearly illustrates the negative effects of systemic inflammation.

As with RA, biomarkers also indicate inflammatory events in dementia. Various inflammatory markers such as tumor necrosis factor (TNF) alpha, interleukin-6 and 12, endothelin-1 and resistin are elevated in both diseases. In RA-relevant cytokines such as TNF-alpha, there is also an association between serum levels and the progression of dementia.

A large patient cohort in the UK was evaluated

The conventional disease-modifying antirheumatic drugs (cDMARDs) used in RA therapy control disease activity, reduce the extent of joint erosion and improve patients’ quality of life. Methotrexate (MTX) also reduces the rate of cardiovascular events in patients with RA. Accordingly, cDMARDs could also protect against dementia and possibly be therapeutically effective if inflammatory processes play a role.

To what extent such an association exists between the intake of cDMARDs and the development of dementia, the authors of this publication examined a large cohort of patients with newly diagnosed RA. They were registered in the "UK Clinical Practice Research Datalink" database, which is representative of the total population of the UK with 6.5 million patients.

The proportion of cDMARD users has increased over the years

In the period 1995-2011, 11,772 patients with incident RA were identified, of whom 8,312 (71%) became cDMARD users. Their share rose from 63.5% in 1995 to over 80% in 2009. cDMARD users were younger at the time of RA diagnosis, smoked more frequently and consumed regular alcohol but had fewer comorbidities. After adjustment for corresponding influencing factors, 3,876 cDMARD users and 1,938 corresponding non-users were included in the evaluation. Among cDMARD users, 61% received MTX and 39% received another cDMARD.

Dementia risk halved

Dementia was a rare event with a frequency of 2% within 15 years. However, due to a large number of patients, a significant difference between the two groups was found. After five years, cDMARD users had a dementia rate of 0.5% versus 1.6% compared to non-users. After 15 years, the difference was 1.5% versus 3.0% (HR: 0.60; 95% CI: 0.42-0.85). For the first time, there was a significant difference after three years. The effect was independent of the use of non-steroidal antirheumatic drugs such as ibuprofen, which according to data from a cohort study had a positive effect on cognitive abilities.

Central or peripheral effect, still an open question

MTX (HR: 0.52; 95% CI: 0.34-0.82), which only penetrates the blood-brain barrier in relatively small amounts, showed the strongest protective effect. Nevertheless, it can have a therapeutic effect in the brain, for example given its effective results in certain brain tumors. Whether the MTX doses used in rheumatotherapy are sufficient for central efficacy, or whether the protection against dementia is based on a peripheral effect, cannot be said. In Alzheimer's dementia, however, there is increasing evidence that peripheral inflammatory processes are involved.

In view of their results, the publication authors suggest randomized, controlled trials to test the therapeutic potential of cDMARDs in dementia. They also propose to review their own results in further large cohort studies.

Judge A, Garriga C, Arden NK, et. al. Protective effect of antirheumatic drugs on dementia in rheumatoid arthritis patients. Alzheimers Dement (NY) 2017; 3: 612-621.