BY JAMIE TALAN
An analysis of prescription information from the Medicare database found that older people who have taken immunosuppressant therapies, including corticosteroids and inosine monophosphate dehydrogenase (IMDH) inhibitors, have a reduced risk of developing Parkinson's disease (PD). The epidemiological study was published in the May 31 open-access journal, Annals of Clinical and Translational Neurology.
Brad A. Racette, MD, FAAN, the Robert Allan Finke professor of neurology at Washington University School of Medicine, first became interested in the role of immunosuppressants while working on a study to develop a predictive model of Parkinson's disease. In that 2017 study in Neurology, he and colleagues mapped out 536 predictors for their model and identified several inflammatory diseases associated with a lower risk of PD. They decided to go back to the Medicare database and see whether there is a relationship between any of the medications people take for these inflammatory conditions that could protect them against developing PD.
STUDY METHODS, FINDINGS
This new analysis of prescription drug use was conducted on the same Medicare sample but focused on those who had signed on to the federal prescription drug program (Medicare Part D.) Using a case-control design, the scientists collected information on the class of medications and the medications people were taking.
The sample included Medicare beneficiaries between 60 and 90 years old in 2009. The scientists had prescription data on 48,295 Parkinson's patients and 52,324 controls. They collected information on everyone who had at least one prescription drug claim between 2008 and 2009. They identified seven immunosuppressant drug classes and 26 specific medications in those classes that had been prescribed between 2008–2009, prior to PD diagnosis.
The categories, according to the report, included calcineurin inhibitors (cyclosporine, tacrolimus); IMDH inhibitors (azathioprine, leflunomide, mycophenolate); dihydrofolate reductase inhibitors (methotrexate); biologics (abatacept, adalimumab, anakinra, certolizumab, etanercept); corticosteroids (prednisone, prednisolone, methylprednisolone, dexamethasone, cortisone, hydrocortisone); and miscellaneous (hydroxychloroquine, sulfasalazine, mesalamine, interferon beta-1a, thalidomide, lenalidomide, glatiramer acetate, fingolimod, and dimethyl fumarate). Other immunosuppressants were used too infrequently to be included in the analyses.
They also performed a secondary analysis in which they ignored immunosuppressant use that occurred in the 12 months prior to the PD diagnosis date or control reference date. They assumed that recent exposure would not be associated with PD risk.
The researchers found that two of the six classes of immunosuppressants were associated with a lower risk of PD: corticosteroids (RR = 0.80) and IMDH inhibitors (RR = 0.64). They looked for confounding diagnoses from the ICD-9/CPT codes and did not find any that altered the risk for PD.
All IMDH inhibitors were consistently associated with a lower risk of PD. Mycophenolate was associated with the lowest risk of PD (RR = 0.55). The corticosteroids most strongly associated with PD were those used commonly for long-term immunosuppression: prednisone (RR = 0.81) and dexamethasone (RR = 0.76).
People who were exposed to corticosteroids between 12 and 24 months before a diagnosis had a 20 percent reduced risk of Parkinson's. Those taking IMDH inhibitors had a 40 percent reduced risk of Parkinson's.
Dr. Racette and his colleagues said that "IMDH inhibitors appeared to be the most strongly protective, although the relative risk for medications within this class were imprecise because these medications were used infrequently." He said that they couldn't rule out the possibility that the protective effects from corticosteroids were not due to a history of smoking, which has also been shown to throw off a protective signal. Corticosteroids are often used to treat smoking-related pulmonary conditions.
The researchers are calling for more research to confirm the findings and determine whether it would be prudent to test these medications for any neuroprotective effects in PD. The immunosuppressants come with serious side effects with long-term use.
"These findings provide more evidence that the immune system is involved in PD," said Dr. Racette. "Targeting the immune system could modify the risk of PD and possibly even PD progression. "We would like to understand how these drugs work to protect against the disease."
The scientists pointed out limitations of the epidemiological study. "Since Medicare provides insurance coverage for the elderly US population, we could not estimate the risk of PD in relation to these immunosuppressants in younger patients. We were also limited to a relatively narrow window of exposure and have to assume that patients took these medications for extended periods during their lives, limiting our ability to make causal inference and to conduct analyses that consider cumulative dose. While this assumption of long-term use may be true for IMDH inhibitors, it is probably less true for corticosteroids, which are used more episodically for numerous conditions."
The study was supported by the Michael J. Fox Foundation, the National Institute of Environmental Health Sciences, the National Institute of Neurological Disorders and Stroke, the American Parkinson Disease Foundation, and the Center for Pharmacoepidemiology Research and Training at the University of Pennsylvania Perelman School of Medicine.
"The paper is quite thought provoking," said David Eidelberg, MD, FAAN, professor and head of the Feinstein Center for Neurosciences at The Feinstein Institute for Medical Research, part of Northwell Health in New York. "While localized inflammatory responses have been noted in many pathological studies of PD, the issue remains whether these are central to the disease process or merely an epiphenomenon of neurodegeneration of varied origin. Dr. Racette's provocative study provides interesting evidence in support of the former hypothesis. While replication is needed, his observations accord well with other findings."
"The study will stimulate discussion, but it could be misinterpreted," said Malú G. Tansey, PhD, professor of physiology at Emory University School of Medicine. "There is a difference between immunosuppression and anti-inflammation. It looks like this study includes people who have mostly been taking corticosteroids. More than 300 people were on combination therapies, and it is hard to tease out what specifically may be related to a reduced risk for Parkinson's."
"The findings suggest that corticosteroids and immunosuppressive drugs may be a good strategy to protect the brain against Parkinson's, but these drugs have serious risks," Dr. Tansey said.
She noted that the immune system ages, "and rather than immunosuppressing an aging individual, it would be much more beneficial to try to restore or normalize immune function to a younger functioning state. While it looks like immunosuppression is associated with a reduced risk for Parkinson's, it would be worrisome to use immunosuppressive regimens in an elderly population because it could leave them open to opportunistic infections."
LINK UP FOR MORE INFORMATION:
Racette BA, Gross A, Vouri SM, et al. Immunosuppressants and risk of Parkinson disease. Ann Clin Transl Neurol 2018; Epub 2018 May 31.
Nielsen SS, Warden MN, Camacho-Soto A, et al. A predictive model to identify Parkinson disease from administrative claims data. Neurology 2017; 89(14): 1448-1456.