Anti-TNF Therapies Reduce Alzheimer Risk in RA, Psoriasis, Early Study Says

The question of whether anti—tumor necrosis factor (anti-TNF) therapy has a role in reducing Alzheimer disease (AD) arose publicly earlier this year, when a report indicated that unpublished drug company data showed that etanercept cut AD risk by 64%.

Likewise, a recent preliminary study (although not peer reviewed), examined whether adults treated with etanercept as well as 2 anti-TNFs—etanercept, adalimumab, and infliximab, as well as methotrexate—had similar effects, despite the fact that it has been believed that the drugs would not be able to cross the blood-brain barrier.

In these latest findings, the researchers said that for a subset of patients, it appears that systemic inflammation contributes to risk for AD through a pathological mechanism involving TNF. Their results showed that inflammatory diseases involving TNF are linked with increased AD risk, particularly patients with rheumatoid arthritis, inflammatory bowel disease, or Crohn disease. For patients with RA or psoriasis, anti-TNF agents led to a reduced AD risk.

Noting that an earlier 2016 study found that the relative risk of AD in patients with RA using etanercept was lower, the researchers sought to test the idea that that systemic inflammation involving TNF is associated with increased AD risk, but one that could be mitigated with an anti-TNF drug.

The retrospective study used the IBM Watson Healthcare Explorys Cohort Discovery platform, which contains electronic health records (EHR) from patients with private insurance, Medicare, and Medicaid. The database contains the de-identified data of nearly 56 million unique patients, age 18 or older, from 26 healthcare systems in all 50 states in the United States from 1999 to 2018. The authors examined data for patients with RA, psoriasis, and other inflammatory diseases who had received at least 1 prescription for 1 of the 3 anti-TNF drugs, or methotrexate, which is often the first therapy tried for autoimmune conditions before moving on to biologics or biosimiliars.

RA increased the risk for AD (adjusted odds ratio [AOR] = 2.06; 95% confidence interval [CI], 2.02-2.10, P <.0001) as did psoriasis (AOR = 1.37; 95% CI, 1.31-1.42, P <.0001), ankylosing spondylitis (AOR = 1.57; 95% CI, 1.39-1.77, P <.0001), inflammatory bowel disease (AOR = 2.46; 95%, 2.33-2.59, P <.0001), ulcerative colitis (AOR = 1.82; 95% CI, 1.74-1.91, P <.0001), and Crohn disease (AOR = 2.33; 95% CI, 2.22-2.43, P <.0001).

The risk for AD in patients with RA was reduced by treatment with etanercept (AOR = 0.34; 95% CI, 0.25-0.47, P <.0001), adalimumab (AOR = 0.28; 95% CI, 0.19-0.39, P < .0001), and infliximab, AOR = 0.52; 95% CI, 0.39-0.69, P <.0001).

Methotrexate also cut AD risk (AOR = 0.64; 95% CI, 0.61-0.68), P <.0001), but additionaal risk reduction was achieved in patients with a prescription history for both an anti-TNF drug and methotrexate.

Etanercept and adalimumab also reduced the risk for AD in patients with psoriasis: AOR = 0.47; 95% CI, 0.30-0.73 and AOR= 0.41, 95% CI, 0.20-0.76, respectively.

Younger patients benefitted more from a anti-TNF drug than did older patients; there was no effect by gender or race.

AD, which has no cure, is one of the most common causes of dementia, which is expected to cost the country as much as $1.1 trillion by 2050 and affect 15 million people, according to the Alzheimer’s Association.

Plaque deposits of amyloid-β peptide in the brain and tangles of intraneuronal deposits of hyperphosphorylated tau protein build up in the hippocampus and associational cortex, which control executive function, over many years. A growing base of evidence indicates that TNF may trigger wayward microglia, a type of macrophage in the brain, and contribute to an inflammatory environment, contributing to the AD disease process.

Earlier this year, The Washington Post reported that etanercept, sold as the blockbuster rheumatoid arthritis drug Enbrel by Amgen within the United States and by Pfizer in other territories, appeared to reduce the risk of Alzheimer disease by 64% when Pfizer researchers analyzed hundreds of thousands of insurance claims. The researchers urged the company to conduct a clinical trial to see if the effect was real, but after several years of discussion, Pfizer opted not to pursue that path, deeming that it held little chance of success. Both Pfizer and Amgen denied that the decision was tied to commercial reasons.