For TNF Response in RA, Weight Matters Save

Patients with rheumatoid arthritis (RA) who were obese were significantly less likely to remain on treatment with tumor necrosis factor (TNF) inhibitors -- but so were those who were underweight, a large, long-term study determined.

Compared with patients with normal weight, patients in obesity class II, whose body mass index (BMI) was 35 to 39.9, had a hazard ratio for shorter drug survival (i.e., the drug's effectiveness, safety, and tolerability) of 1.28 (95% CI 1.06-1.54), while those in obesity class III, whose BMI exceeded 40, had a hazard ratio of 1.67 (95% CI 1.29-2.18), according to Sytske Anne Bergstra, PhD, of Leiden University Medical Center in the Netherlands, and colleagues.

For those in the underweight category, whose BMI was below 18.5, treatment survival also was significantly shorter (HR 1.30, 95% CI 1.07-1.58), the researchers reported online in RMD Open: Rheumatic & Musculoskeletal Diseases.

Because adipose tissue secretes various inflammatory cytokines such as TNF-alpha and interleukins 1 and 6, RA patients with excess adipose tissue might experience higher levels of systemic inflammation independent of their disease activity, rendering them less likely to be treatment responsive, the researchers had speculated.

Indeed, some previous studies have suggested that obese patients with various inflammatory diseases fared worse than their normal-weight counterparts, but the results overall have been inconclusive and some authors have proposed that the reason is not increased inflammation but worse levels of pain.

These prior studies also have been limited in that they excluded the lowest and highest BMIs, generally had follow-up of less than a year, and considered all TNF inhibitors together.

Therefore, to address these shortcomings, Bergstra and co-authors analyzed data from the international observational METEOR registry, which collects information on patient characteristics, disease activity, and treatments in real-world clinical practice.

The current analysis included 5,230 patients with RA starting a first TNF inhibitor who had available data on weight and at least one composite disease activity index such as the Disease Activity Score in 28 joints (DAS28).

Along with the underweight and obesity II and III categories, the study also assessed normal weight, classified as BMI of 18.5 to 24.9; pre-obesity, classified as BMI of 25 to 29.9; and obesity class I, classified as BMI of 30 to 34.9.

The primary outcome was time on the first TNF inhibitor, which was considered a proxy for time to treatment failure.

Almost half of the patients (46%) were in the normal BMI category, and another third (32%) were considered pre-obese. Only 4% of the patients were considered underweight, and 18% were in one of the three obesity categories.

Most patients initiated treatment with etanercept (Enbrel), adalimumab (Humira), or infliximab (Remicade), so only those patients were included in the analysis, the researchers noted.

More than 80% of the patients were women, mean age at the start of the first TNF inhibitor was 54, and duration of symptoms at the time of treatment initiation was 8 years. Mean DAS28 at baseline was 5, and patient pain rated on a visual analog scale was 60. Maximum follow-up time was 13.5 years.

The investigators found that along with the primary outcome, there was no effect difference according to baseline level of pain, suggesting that the association between BMI and response to treatment was unlikely to be pain-specific.

However, the team did observe that the last DAS28 measure before treatment was stopped and was higher among patients with higher BMIs -- "indicating that for patients in the highest BMI categories, the decision to stop treatment was made at higher disease activity levels," Bergstra and co-authors explained.

They added that although information on the reasons for stopping was not available, a high DAS28 at the time of stopping suggests that treatment failure was the main cause, rather than factors such as side effects or costs.

For all three of the included TNF inhibitors, patients in the higher BMI categories had shorter drug survival, but there were differences between the specific agents. For example, compared with normal weight patients, patients in the pre-obesity category starting adalimumab had longer drug survival (HR 0.86, 95% CI 0.75-0.99), while for etanercept, shorter drug survival was seen for obesity class II (HR 1.27, 95% CI 0.98-1.65) and obesity class III (HR 1.79, 95% CI 1.25-2.55).

For infliximab, shorter drug survival was observed for patients in the underweight category (HR 1.82, 95% CI 1.20-2.76) and for those with class II obesity (HR 1.49, 95% CI 0.98-2.26). The reasons for these differences remain unclear, the researchers said.

When they then limited the analysis to the first year of follow-up, when a lack of drug survival could be assumed to reflect primary treatment failure, the results showed shorter survival among patients with obesity class III and those who were underweight.

A possible explanation for the distinctive shorter treatment survival found among underweight patients is that in studies of the effects of obesity, such patients are typically grouped with the normal BMI individuals, Bergstra and co-authors said.

"Our data show that underweight patients are a neglected group that may require customized treatment and may also help to shed light on the relation between body weight and treatment outcomes, because the strongest effects are observed in the underweight and more extreme obesity categories," the researchers wrote.

They concluded that whether interventions such as weight loss programs might improve outcomes among obese patients remains to be determined.

A limitation of the study, the researchers said, was the possibility of bias in treatment decision-making.

Disclosures

The study was supported by Bristol Myers Squibb (BMS).  Bergstra reported no conflicts of interest; one co-author reported financial relationships with BMS and Roche.

Source Reference: Bergstra S, et al "Body mass index and treatment survival in patients with RA starting treatment with TNFα inhibitors; long-term follow-up in the real-life METEOR registry" RMD Open 2020; DOI: 10.1136/rmdopen-2020-001203.