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In the Pipeline-Parkinson's Disease

How Big Data Linked Parkinson's Disease and Inflammatory Bowel Disease

Talan, Jamie

doi: 10.1097/01.NT.0000538944.08078.0d
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Using data from two large databases, researchers found that patients with inflammatory bowel disease and Parkinson's disease shared common variants and a disease mechanism — systemic inflammation. They suggested that a therapy used by IBD patients may be neuroprotective for Parkinson's disease.

Parkinson's disease (PD) and inflammatory bowel disease (IBD) may appear to have little in common but evidence is mounting that the two conditions may share a common biological mechanism: systemic inflammation. This intriguing evidence led scientists at Icahn School of Medicine at Mount Sinai to mine large health insurance databases to see whether there were clinical findings that could back up what scientists are seeing in the laboratory.

Big data sets allowed them to see that PD does track with IBD — including Crohn's disease and ulcerative colitis — and that a common treatment for IBD — anti-tumor necrosis factor (anti-TNF) — substantially cut the risk for PD. The findings were published in the April 23 online edition of JAMA Neurology.

Anti-TNF, a monoclonal antibody that reduces TNF alpha levels but does not cross the blood-brain barrier, reduces systemic inflammation and could offer a new treatment for some patients with PD, the study authors found.

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Inga Peter, PhD, professor of genetics and genomic sciences at Mount Sinai, studies inflammatory bowel disease. She was casting a wide net looking for novel genetic variants in Crohn's disease, turning to a large dataset including Ashkenazi Jews; there is a three- to seven-fold increase of Crohn's among Ashkenazi Jews compared to other ethnic groups.

Dr. Peter and her colleagues identified several previously unreported genetic signals in the leucine-rich repeat kinase 2 (LRRK2) gene for IBD, which is also implicated in PD. Intriguingly, IBD and PD shared the same mutations. The obvious question that emerged from this finding was whether these two conditions occurred together more often than would be suspected by chance — and if so, why?



The researchers turned to the Truven Health MarketScan administrative claims database and the Medicare Supplemental Database and looked for patients who had at least two claims for IBD, a six-month follow-up, and no prior history of PD between 2000 and 2016. They collected data from IBD patients who were prescribed anti-TNF therapy to reduce inflammation due to Crohn's or ulcerative colitis. They also identified individuals with and without IBD who went on to have a diagnosis of Parkinson's and had been prescribed PD medication. The combined databases represented 170 million covered individuals.

The researchers identified 144,018 people with IBD and matched them to 720,090 age-matched and sex-matched controls who were in the claims system during the same time. There were 1,796 people who had at least two PD diagnoses and one filled PD prescription. IBD patients had a 28 percent higher incidence of PD than the control patients (p<.001). Then, they looked at those IBD patients who had received anti-TNF therapy (13,089) and found a 78 percent reduction in the incidence of PD (p=.03) compared to the IBD patients who had not been exposed to the anti-TNF therapy.

This finding suggested that these two conditions share the same inflammatory pathway and that treating IBD with this drug had benefits at significantly reducing the risk for PD, the researchers said.

“We think that a reduction in systemic inflammation contributed to a reduced risk for PD,” said Dr. Peter. “It is important to figure out what is going on.”

The researchers are now looking at patients who were initially diagnosed with PD to see if they are at greater risk of IBD. It is now well accepted that one gene mutation can influence multiple unrelated phenotypes. The most common example is sickle cell anemia and protection against malaria. There is a genetic variant that leads to type 2 diabetes that protects against prostate cancer, too. “What is beautiful about our study is that this is data driven,” said Dr. Peter. “It came together nicely.”

PD patients often present with gut problems (mostly constipation) long before a diagnosable movement disorder, and this study suggests a common thread, Dr. Peter noted. (IBD patients generally have diarrhea and bloody stool.) There have been clinical studies to test whether reducing inflammation would work for slowing down neurodegenerative diseases like Alzheimer's, but the results were not very convincing. It has not been tried in PD.

Dr. Peter suspects that timing of exposure to the anti-TNF medication before the disease is established may be critical. Recent findings on the altered microbiome in PD patients further support the link between these two seemingly unrelated diseases.

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“There have been numerous clues from the literature linking Parkinson's disease and autoimmune disorders,” said Clemens Scherzer, MD, head of the Neurogenomics Laboratory and director of the Brigham & Women's Hospital Precision Neurology Program at Harvard Medical School and Brigham & Women's Hospital. “This finding adds new twists to the story,” said Dr. Scherzer, who wrote an accompanying editorial in JAMA Neurology.

“Most exciting is the clever use of big data to learn about the relationship between these two diseases. It tells us that you can use large population data to have a sneak preview on what drugs might work for certain diseases before spending years studying preclinical models. This allows you to get an initial readout from patients about whether you are on the right track.”

One criticism he had was that the researchers only looked at IBD treatment with anti-TNF. Many IBD patients are treated with other anti-inflammatory agents, “and it would be good to understand whether it was a specific effect or whether other anti-inflammatory drugs would work also,” he said.

Still, Dr. Scherzer added, “it is an exciting finding and shows it is an important new avenue for research to understand the role of anti-TNF in PD.” He said it will be an important next step to test whether this class of drugs can slow the progression of PD.

“The study helped link two very disparate diseases,” added Mark Cookson, PhD, senior investigator at the National Institute on Aging. That anti-TNF seems to reduce the risk for PD suggests that “there may be a way to intervene in PD. The first thing is to replicate the findings,” he added. “It would also be important to understand the genotypes of those patients who were less likely to develop PD after anti-TNF treatment. And finally, what are the signaling properties that underlie these two diseases?”

“It's a very interesting study,” said Kathleen M. Shannon, MD, FAAN, professor and chair of neurology at University of Wisconsin. “This adds fuel to the fire about the role of systemic inflammation in PD.”

She added that there is a big push to identify PD before the obvious clinical signs. Systemic inflammation could be used as a biomarker.

But there are many unanswered questions, she said. “We see PD patients all the time and we should expect to see more cases of IBD, and we don't. At this point, it is hard to go deeper than saying that systemic inflammation is important in PD. And that is important news.”

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•. Peter I, Dubinsky M, Bressman S, et al Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease JAMA Neurology 2018; Epub 2018 Apr 23.
    •. Olsen AL, Riise T, Scherzer CR. Editorial: Discovering new benefits from old drugs with big data—Promise for Parkinson disease JAMA Neurol 2018; Epub 2018 Apr 23.
      © 2018 American Academy of Neurology