Weight loss is a strong predictor of death in rheumatoid arthritis, with the greatest risk of death in low body mass index patients who were previously obese.

“Our study is the first to demonstrate a strong and independent association between recent weight loss, as opposed to BMI per se, and risk of subsequent death in patients with RA. These observations represent an important step in explaining the ‘obesity paradox’ observed in this disease,” Dr. Joshua F. Baker and his colleagues wrote in a study published online May 4 in Arthritis & Rheumatology (doi:10.1002/art.39136).

Although obesity is associated with a higher incidence of a number of diseases, including cardiovascular disease, diabetes, and certain cancers, several epidemiologic studies in the elderly and chronic disease states have reported that overweight patients may have lower mortality than normal-weight patients.

More recent evidence, however, suggests that weight loss due to the development of chronic illness is a significant confounder and may explain the seemingly protective effect of obesity on mortality. Studies that fail to consider weight loss that occurs in chronic illnesses such as RA are likely to underestimate causal associations between greater weight and death, noted Dr. Baker, a rheumatologist at the University of Pennsylvania, Philadelphia, and the Philadelphia VA Medical Center.

To unravel the “obesity paradox” in RA, the investigators examined multiple BMI measures over time and date of death for 1,674 patients with rheumatologist-diagnosed RA in the Veterans Affairs Rheumatoid Arthritis registry. The annualized rate of change in BMI was determined from the slope of BMI over time over all available visits in the preceding 13 months. Cox multivariable proportional hazard models assessed associations between BMI measures and mortality.

At enrollment, the average duration of RA was 7.4 years, average C-reactive protein was 0.8 mg/dL, average BMI was 28.5 kg/m², and maximum BMI was 33.3 kg/m². The cohort’s average age was 63.5 years and 91% were male.

Among the 1,674 patients, there were 312 deaths in 9,183 person-years of follow-up. The median follow-up was 5.5 years, and the median interval between visits was 105 days.

A modest decline in BMI of ≥1 kg/m² over the preceding observation period was associated with an increased risk of death before and after adjustment for multiple potential confounders, including demographics, comorbidities, BMI, smoking, and RA therapies (hazard ratio, 1.99; P < .001), Dr. Baker reported.

This remained significant in a subsample of observation periods after further adjustment for C-reactive protein and physical function (HR, 1.81; P < .001).

The analysis revealed a dose-dependent increase in the risk of death based on the annualized rate of decrease in BMI, he noted.

A loss of less than 2 kg/m² of BMI per year did not have an increased risk of death in the subsequent observation period after multivariable adjustment (HR, 1.12; P = .4). In contrast, a loss of 2-3 kg/m² of BMI per year increased the risk of death by about 1.5 times (HR, 1.65; P = .02) and a loss of more than 3 kg/m² per year was associated with the greatest risk of death (HR, 2.49; P < .001).

“This observation supports the common dogma that more rapid weight loss is a poor prognostic sign, while slower changes should be less alarming,” the authors wrote.

In multivariable models, maximum BMI was not associated with risk of death (HR, 1.00; P = .80).

In models including both current and maximum BMI, however, a lower current BMI and greater maximum BMI category were each independently associated with a greater risk of death, Dr. Baker and his associates reported.

Among patients with a similar maximum BMI, a low current BMI of less than 20 kg/m² is associated with a greater risk of death (HR, 3.82; P < .001). Similarly, among patients with a similar current BMI, those with an obese maximum BMI over 30 kg/m² were at an increased risk of death (HR, 2.22; P = .001).

This suggests that a patient with a low BMI at a given visit and a history of BMI in the obese range is at a dramatically increased risk of death, compared with a normal-weight patient with a consistently normal weight (HR, 8.52; P < .001), the authors reported.

Overall, the observations do not support a biologically protective role of obesity in RA and support close monitoring of patients with RA who demonstrate unintentional weight loss, they concluded.

“The next steps in this area are to understand more specifically how body composition may change over time in the disease and how this may tie in with the observations here with weight loss and the obesity paradox,” Dr. Baker said in an interview. “In general, I think it is important to understand how weight and body composition changes themselves impact long-term outcomes such as comorbid disease, fractures, cardiovascular disease, and death.”

The VARA registry is supported by the Nebraska Arthritis Outcomes Research Center at the University of Nebraska Medical Center and by the Veterans Affairs Health Services Research and Development Program of the Veterans Health Administration. The investigators were supported by awards from the VA, a Rheumatology Research Foundation Investigator Award, and the National Institute of Arthritis and Musculoskeletal and Skin Disorders.

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