Study suggests that anti-tumor necrosis factor inhibitors may reduce the risk of developing Alzheimer's disease in patients with rheumatoid arthritis.
Alzheimer’s disease (AD) has a devastating effect on patients’ and caregivers’ lives and poses a huge financial burden to the healthcare system. So far, no effective therapy or cure is available, but an intriguing study presented at the 2010 Annual Scientific Sessions of the American College of Rheumatology suggests that anti-tumor necrosis factor (TNF) inhibitors used to treat rheumatoid arthritis (RA) appear to reduce the risk of developing AD among RA patients.
“One obstacle to developing a treatment for Alzheimer’s disease is that it is a pathological diagnosis made at autopsy of patients’ brains. It is currently a diagnosis of exclusion. We wanted to study anti-TNF inhibitors because the TNF protein is involved in developing AD and it is also involved in RA. In AD, TNF levels are elevated and elevated TNF correlates with progression of disease. We were interested in the association between AD and RA based on TNF,” said Richard C. Chou, MD, PhD, Dartmouth Medical School in Lebanon, NH.
The study was based on a large claims database for a commercially insured cohort of 8.5 million adults throughout the US. A subcohort of 42,193 patients with a pre-existing diagnosis of RA was identified, and a nested, case-control study was conducted in cases and matched controls. Exclusions were psoriatic arthritis, inflammatory bowel disease, previous stroke, or previous AD. Cases (165 individuals with newly diagnosed AD) were matched with up to 10 controls (total of 1333 controls) who did not have a prior diagnosis of AD and were free of AD during the drug exposure assessment period. Cases and controls were matched for age, gender, duration of drug exposure assessment period, and methotrexate treatment. Exposure to three commonly used anti-TNF inhibitors (infliximab, etanercept, and adalimumab) and to rituximab was measured.
Treatment with an anti-TNF inhibitor was associated with a 56% reduction in the risk of developing AD (P=.023 in an unadjusted analysis). The risk of developing AD was independent of exposure to sulfasalazine, prednisone, or rituximab. The reduced risk of developing AD in patients with RA and anti-TNF therapy remained the same (56%) after adjusting for known risk factors for AD. Chou said that diabetes mellitus, coronary artery disease, peripheral vascular disease were significantly associated with an increased risk of AD in patients with RA (P=.004, P=.0284,and P = .0248, respectively).
He explained that all three anti-TNF agents as a group reduced the risk of AD in patients with RA by 56%. Then the investigators looked at each of these agents separately, and it appeared that most of the risk reduction was driven by etanercept. “Etanercept significantly reduced the risk of developing AD in patients with RA by around 70% [P=.024], “ he stated.
There are two major differences between etanercept and the other anti-TNFs, he explained. Etanercept binds to TNF and is a smaller molecule than the two monoclonal antibodies (infliximab and adalimumab), and he suggested that it may be able to cross the blood-brain barrier more easily.
“These results showing a risk reduction of AD with anti-TNF therapy in patients with RA should encourage further research,” Chou said. After his group publishes their study, they plan to analyze the mechanisms of anti-TNF therapy. Further studies will show whether anti-TNF agents can reduce the risk of AD in other populations.