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Systemic inflammatory diseases involving tumor necrosis factor (TNF) increased the risk of Alzheimer's disease, but that risk was reduced in patients who used anti-TNF biologics, an analysis of 56 million adults' electronic health records showed.

While rheumatoid arthritis increased Alzheimer's risk, it was reduced in patients taking etanercept (Enbrel), adalimumab (Humira), or infliximab (Remicade), according to Rong Xu, PhD, of Case Western University in Cleveland, and co-authors.

Similarly, people taking etanercept and adalimumab for psoriasis also had their risk of Alzheimer's reduced, the researchers reported in a manuscript on the preprint server .

These findings show the power of combining expert knowledge with big data analytics, Xu said. "Retrospective clinical studies using very large databases of patient electronic health records have high potential in uncovering risk associations among complex diseases and potential novel drug repurposing opportunities, as in this example where anti-TNF drugs might have a new use in Alzheimer's disease and associated dementia," she told 名媛直播.

The findings also reinforce the concept that late-onset Alzheimer's may have multiple causes, added study author Mark Gurney, PhD, chief executive officer of Tetra Therapeutics in Grand Rapids, Michigan. "In this subset of patients, TNF produced in the body is an important risk factor for Alzheimer's disease and is of the same magnitude as genetic risk factors such as APOE4," Gurney told 名媛直播.

The analysis comes after years of speculation about how anti-inflammatory drugs might affect cognition. A phase II published in 2015 showed positive trends but no significant changes in cognition, behavior, or global function. Yet, observational data suggests there might be a link: a 2016 nested case-control study found that the in rheumatoid arthritis patients taking etanercept, and earlier this year, the Washington Post reported that Pfizer had insurance claims data showing that .

The new research "adds further weight to the growing evidence that people who have diseases carrying a systemic inflammatory component have an increased risk of developing Alzheimer's disease," said Clive Holmes, MRCPsych, PhD, of the University of Southampton in England, who was not involved with the study.

"Furthermore, it clearly suggests that drugs that target peripheral inflammation -- in particular, TNF inhibitors -- have the potential to substantially reduce the risk of developing Alzheimer's disease," Holmes told 名媛直播. "Only a large randomized placebo-controlled clinical trial will definitively answer this question, but it is a question that clearly needs answering."

This retrospective case-control study looked at electronic health records of 56 million unique adult patients from 360 hospitals and 317,000 providers, identifying patients with rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. Patients diagnosed with more than one inflammatory disease were excluded from the study.

The analysis compared a diagnosis of Alzheimer's disease as an outcome measure in patients who received at least one prescription for a TNF-blocking agent (etanercept, adalimumab, and infliximab) or for methotrexate. A patient was considered "taking a medication" if at least one outpatient prescription for the medication had been written. Patients were included in the study if they were treated with a single TNF blocker but excluded if treated with two or more TNF-blocking drugs.

Alzheimer's risk was increased in adults with the following diagnoses (all P <0.0001):

• Rheumatoid arthritis: adjusted OR 2.06, 95% CI 2.02-2.10

• Psoriasis: adjusted OR 1.37, 95% CI 1.31-1.42

• Ankylosing spondylitis: adjusted OR 1.57, 95% CI 1.39-1.77

• Inflammatory bowel disease: adjusted OR 2.46, 95% CI 2.33-2.59

• Ulcerative colitis: adjusted OR 1.82, 95% CI 1.74-1.91

• Crohn's disease: adjusted OR 2.33, 95% CI 2.22-2.43

Rheumatoid arthritis patients treated with etanercept (adjusted OR 0.34, 95% CI 0.25-0.47), adalimumab (adjusted OR 0.28, 95% CI 0.19-0.39), or infliximab (adjusted OR 0.52; 95% CI 0.39-0.69) had a reduced risk of Alzheimer's. Methotrexate also reduced Alzheimer's disease risk, especially for patients who had a prescription history for both a TNF blocker and methotrexate.

Psoriasis patients treated with etanercept (adjusted OR 0.47; 95% CI 0.30-0.73) or adalimumab (adjusted OR 0.41, 95% CI 0.20-0.76) also had a reduced risk for Alzheimer's disease.

Sex or race did not affect the results, but younger patients showed greater benefit from a TNF blocker than older patients, the researchers observed.

The study had several limitations, Xu and co-authors noted. Electronic health record quality or misdiagnoses may have affected outcomes. While the analysis suggests a potential therapeutic benefit of TNF-blocking agents in Alzheimer's, it did not look at prevention or address how disease severity might influence results.

"The anti-TNF biologics are powerful drugs that can cause severe side effects," Gurney said. "Further studies are necessary to understand their potential in treating or preventing Alzheimer's disease in patients who do not have rheumatoid arthritis, psoriasis, or other inflammatory diseases as risk factors for Alzheimer's disease."

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