— Exact mechanism remains speculative, however
by John Gever, Contributing Writer, MedPage Today May 1, 2023

Individuals with seropositive rheumatoid arthritis (RA) were at almost double the risk for developing Parkinson’s disease within a median of about 4 years of follow-up, Korean insurance claims data indicated.

Parkinson’s disease was diagnosed at a rate of 1.2% in patients with RA and autoantibodies commonly linked to the disease, compared with just over 0.6% in non-RA controls (adjusted HR 1.95, 95% CI 1.68-2.26), according to Jihun Kang, MD, PhD, of Sungkyunkwan University School of Medicine in Seoul, and colleagues.

But no significant association was seen for patients with clinical RA lacking the autoantibodies (aHR 1.20, 95% CI 0.91-1.57), the researchers reported in JAMA Neurology.

Other findings, too, complicated the interpretation. For example, use of biologic drugs for RA such as adalimumab (Humira) seemed to negate the association with Parkinson’s disease. As well, the link was stronger for premenopausal versus postmenopausal women. Kang and colleagues had no explanation for either of these findings, and could only speculate on possible mechanisms to account for the overall increased risk for Parkinson’s disease in RA in their study.

At the same time, this isn’t the first study to find a connection, though it may be the largest. The researchers cited studies going back some 25 years that suggested a linkage between the systemic inflammation that develops in RA and the pathologic processes underpinning Parkinson’s. More recently, a claims study from Taiwan, with some 34,000 rheumatic disease patients, found a 37% higher rate of Parkinson’s than in a control group.

The new study tracked about 55,000 RA patients (three-quarters with seropositive RA) and 273,000 non-RA controls matched for age and sex; both groups were enrolled in South Korea’s national insurance program from 2000 to 2017, with follow-up through 2019. Mean age was about 59 and 75% were women. In the RA group, 290 cases of Parkinson’s disease were diagnosed during the median 4.3 years of follow-up (interquartile range 2.6-6.4), versus 803 among controls.

Clinical and demographic parameters in individuals with seropositive RA did differ in some respects from those with seronegative disease, including age, alcohol use, obesity, and smoking status. Similar differences were seen between the RA patients as a whole and the control group. But Kang and colleagues adjusted for these variables in their statistical models.

“[I]mpairment in autophagic pathways, which normally remove damaged or abnormally modified proteins, might be a shared pathologic process of the two conditions,” the researchers suggested as a potential explanation for the association. They noted that some earlier studies had implicated impaired autophagy as a mechanism in generating anti-cyclic citrullinated peptide antibodies. RA marked by these autoantibodies is, in some ways, a different clinical entity than seronegative RA, with different trajectories and outcomes in the natural history. Meanwhile, Kang and colleagues wrote, the same process “is a well-demonstrated pathogenesis in the development of PD [Parkinson’s disease] and other neurodegenerative diseases.”

But despite the lack of certainty about how RA may make people more vulnerable to Parkinson’s, the researchers did offer a solid clinical takeaway: “The study findings suggest that physicians who care for patients with RA should be aware of the elevated risk of PD and prompt referral to a neurologist should be considered at onset of early motor symptoms of PD in patients with RA without synovitis.”

Limitations to the study included the reliance on administrative data and its retrospective nature. Also, the data did not include some important potential confounders such as occupational exposure to neurotoxic agents or family histories. And the control group included individuals whose healthcare encounters were merely for check-ups and thus were conceivably healthier than others, “such that issues of generalizability might be raised,” the researchers noted.