麻豆传媒

Add a potentially lower risk of Parkinson's disease (PD) to reasons for giving early anti-tumor necrosis factor (anti-TNF) therapy to patients with inflammatory bowel disease (IBD), a recent database study suggested.

Published in , the analysis found that although IBD patients had an almost 30% higher incidence of PD compared with unaffected controls, early exposure to anti-TNF correlated with an almost 80% reduction in PD incidence in those with IBD.

"These findings support a role for systemic inflammation in the pathogenesis of both diseases," Inga Peter, PhD a genetic epidemiologist at Icahn School of Medicine at Mount Sinai in New York City, and colleagues wrote.

Analyzing healthcare claims in the period 2000-2016 from the Truven Health MarketScan and the Medicare Supplemental database, the investigators found that despite a 28% greater likelihood of PD than in unaffected matched controls, IBD patients given anti-TNF had a 78% reduction in PD incidence rates compared with unexposed patients.

The PD findings were in line with those of a 2016 Taiwanese showing a 35% adjusted increased incidence of PD among IBD patients and underscored the need for these patients to be aware of their heightened susceptibility.

IBD is known to have extraintestinal neurologic manifestations, but these are relatively uncommon and not well studied. And although genetic and pathophysiologic links between IBD and PD have been established, clinical evidence of the association and the potential role of inflammation reduction through anti-TNF is scarce, Peter and associates explained.

Their retrospective study of more than 170 million health-insured lives matched 144,018 adult IBD patients for age, sex, and year of IBD index date with 720,090 unaffected controls. The mean age of both groups was 50.8, and 43.6% overall were men. Geographically, the largest number of participants were from the Northeast or North Central regions of the U.S., followed by the South.

In the overall cohort, 1,796 individuals were identified as having PD, based on at least two diagnoses and at least one PD-related filled prescription. Among IBD patients, there were only two cases of PD in anti-TNF recipients versus 369 in non-recipients.

The adjusted incidence rate ratio of PD in all IBD patients was 1.28 (95% CI 1.14-1.44, P<0.001), and the elevation was evident for both Crohn's disease at 1.26 (95% CI 1.03-1.53, P=0.02) and ulcerative colitis at 1.31 (95% CI 1.14-1.51, P<0.001). In comparison, the adjusted radio in those treated with anti-TNF was 0.22 (95% CI 0.05-0.88, P=0.03), which translated to an incidence rate of 0.08 per 1,000 patient years in treated IBD patients versus 0.76 per 1,000 patient years for untreated IBD patients.

"These findings call into question the notion that existing anti-TNF therapies have limited central nervous system effects because these large molecule drugs do not cross the blood-brain barrier," Peter and co-authors wrote. "Our data suggested the possibility that targeting peripheral TNF is sufficient to reduce neuroinflammation or that the blood-brain barrier may be compromised among patients with IBD such that anti-TNF compounds enter the brain through an already leaky blood-brain barrier."

The researchers called for studies to determine whether the findings might change with differences in clinical features, diet, or lifestyle and whether higher PD susceptibility is confined to carriers with certain genetic mutations.

In an , Abby L. Olsen, MD, PhD, of Brigham and Women's Hospital in Boston, and colleagues stated that such big-data analysis highlights the potential of a new kind of digital prevention trial, offering "exciting evidence in support of the concept of virtual repurposing of old drugs for new benefits."

The editorialists cautioned, however, that while promising in terms of speed and ease, virtual repurposing studies built on preexisting data may face issues of intellectual property rights and commercial drug development and even when using large data sets, might be insufficient to investigate rare diseases and treatments -- for example, that the number of PD cases in the study by Peter et al was relatively small at 371, with only two incident cases in IBD patients receiving anti-TNF.

Olsen et al also noted the large number of IBD cases from the Northeast, where a larger Ashkenazi Jewish population might have conferred more genetic susceptibility and thus confounded the results.

Nonetheless, such data "provide an initial preview into possible drug-phenotype associations in humans, but they need to be kept in perspective, interpreted with caution, complemented with mechanistic studies, and, eventually, tested in clinical trials."

The editorial also acknowledged that the findings mesh with growing genetic and molecular evidence supporting a causal association between the gut, systemic inflammation, and PD.

Among the study's limitations, Peter et al said, were its reliance on claims data, the unavailability of diagnostic clinical criteria used to identify PD cases, and the inability to clinically phenotype patients with IBD who developed PD in terms of disease location, progression, and severity. In addition, lack of access to DNA samples prevented characterizing the mutation status of relevant genes for patients with both IBD and PD. Another limitation was the small number of events in the anti-TNF cohort, which likely contributed to wide confidence intervals despite large effect sizes. Furthermore, the study had no detailed demographic information that can affect both diagnoses, such as race/ethnicity, access to healthcare, smoking, caffeine intake, infections, and head trauma.