Assessing the Complex Interplay Between Metabolic Dysfunction and Rheumatoid Arthritis

Though metabolic disruption can have significant long-term adverse outcomes for people with rheumatoid arthritis (RA), more work is needed to understand the relationship and the potential benefits of RA therapy, a new review argues.¹

Corresponding author Joshua F. Baker, MD, MSCE, of the University of Pennsylvania’s Perelman School of Medicine, and colleagues noted that people with RA appear to be at a higher risk of types 1 and 2 diabetes, metabolic syndrome, and hypertension, among other metabolic conditions. The reasons, they wrote, “include those related to energy overabundance and excess adiposity, as well as those related to inflammation and high energy use, resulting in a complex picture.”

The complex interplay between RA and metabolic health can have a significant impact on morbidity and mortality and thus deserves attention, authors of a new review argued. | Image credit: 9nong - stock.adobe.com

In the new review article, which was published in the journal Arthritis Care & Research, they outline the ways systemic inflammation and other disease complications can lead to metabolic disturbances.

Baker and colleagues noted that people with RA tend to have higher body mass indexes (BMIs) than the general population. They also tend to have higher average levels of visceral fat, they said. Yet, in patients with severe RA, cachexia appears to lead to significant loss of visceral fat, they noted. And while it is normal for adults to gain weight in middle age and lose it later in life, the investigators said people with RA who experience “weight cycling” are more likely to have cardiovascular events.²

“These observations may be the result of direct metabolic or proinflammatory effects of weight fluctuation, as has been suggested in some mouse studies, or may be related to changes in health status and the accumulation of comorbidity,” they wrote.¹

Higher BMI also conjures the specter of diabetes. Baker and colleagues said studies evaluating whether RA disease activity might lead to insulin resistance have been inconclusive. Interestingly, though, there is also evidence that RA therapy might affect diabetes risk. A 2011 study suggested that patients with RA who were taking tumor necrosis factor inhibitors or hydroxychloroquine had a lower adjusted risk for diabetes than patients with RA who took other nonbiologic disease-modifying anti-rheumatic drugs (DMARDs).³

Lastly, Baker and colleagues looked at how inflammation affects circulating lipids and blood pressure. In terms of lipids, the investigators noted that hyperlipidemia is a well-known risk factor for cardiovascular disease, but they added that low levels of low-density lipoprotein in people with RA have paradoxically been associated with higher rates of cardiovascular disease.

The authors said several studies have evaluated how RA therapies affect lipid levels and cardiovascular risk, including trials designed to help clinicians understand when to initiate lipid-lowering therapy. They said RA-specific risk prediction tools have not yet proven useful. Still, they said, “it seems rational to consider those with high disease activity and severity as particularly high risk, even when their risk is low by traditional standards.”

Systemic inflammation also appears to be linked with hypertension, they noted, though the links have not yet been fully elucidated. In RA, the evidence linking hypertension and inflammation appears to be even more clear, though the investigators said that few studies have looked at how DMARDs might affect that association.

Baker and colleagues concluded that there is ultimately a complex interplay between RA and the clinical assessments of metabolic health. However, they said these issues can have a significant impact on morbidity and mortality and thus deserve attention.

“Although current evidence does not support metabolic targets for treatment, they represent an important potential off-target benefit that should be considered by clinicians,” they concluded.

References

1. Barry S, Sheng E, Baker JF. Metabolic consequences of rheumatoid arthritis. Arthritis Care Res (Hoboken). Published online April 2, 2025. doi:10.1002/acr.25537
2. Baker JF, Reed G, Kremer J. Weight fluctuation and the risk of cardiovascular events in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2022;74(2):229-235. doi:10.1002/acr.24469
3. Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA. 2011;305(24):2525-2531. doi:10.1001/jama.2011.878