High anti-TNF Failure Rates with Obesity Save

A meta-analysis has suggested that obesity is an under-reported predictor of inferior response to tumor necrosis factor blockade (anti-TNF) in a range of inflammatory immune-mediated inflammatory diseases (IMIDs), with the results showing a 60% risk of impaired response to anti-TNF across several IMIDs. Surprisingly, however, inflammatory bowel disease (IBD) appeared to be the exception to the obesity-response effect.

Reporting in PLoS One, researchers led by Siddharth Singh, MD, of the University of California San Diego, wrote, "A thorough evaluation of obesity as an effect modifier in clinical trials is warranted, and intentional weight loss may serve as adjunctive treatment in patients with obesity failing anti-TNF therapy."

Obesity, which is linked to systemic inflammation, is thought to increase the risk of Crohn's disease, rheumatoid arthritis (RA), and psoriasis, and as many as 50% of patients with IMIDs are obese.

Last year, Singh and colleagues reported that obesity might contribute to the pathogenesis of IBD through dysbiosis, mucosal barrier dysfunction with bacterial translocation, and activation of adipocytes.

Obesity is associated with rapid clearance of biologic agents, resulting in low trough concentrations, and could result in suboptimal response to biologics, the researchers noted, so treating obesity could be an adjunct target in IBD patients.

The new meta-analysis identified phase II and III randomized controlled trials (RCTs) and observational cohort studies in publications from 1946 to 2017 that used infliximab, adalimumab, certolizumab pegol, golimumab, and etanercept for IBD, RA, spondyloarthropathies, psoriasis, and psoriatic arthritis (PsA).

The primary outcome measures were failure to achieve clinical remission or to respond to treatment and the need for treatment modification. The authors noted that fewer than 10% of the identified RCTs stratified outcomes by body-mass index (BMI), and most reported BMI as above or below a median rather than at the extreme ends of the BMI spectrum, bolstering the concern that obesity could be an under-reported risk factor for poor response.

The final analysis was based on almost 20,000 patients from 54 cohorts in 50 studies – 16 in IBD, 22 in psoriasis/PsA, 10 in RA, and six in spondyloarthritis. Studies included patients from 34 observational cohorts (n=13,336) and 20 from RCTs (n=6,036). Almost a quarter (23%) of the 19,372 patients were obese, and these individuals had a 60% higher odds of failure of therapy, for an odds ratio (OR) of 1.60 (95% CI 1.39±1.83, I2 71%).

Dose-response relationships by weight emerged: for obese versus normal BMI, the OR was 1.87 (1.39±2.52); and for overweight versus normal BMI, the OR was 1.38 (1.11±1.74, P=0.11). Each increase of 1 kg in BMI was associated with a 6.5% higher odds of failure (OR 1.065, 1.043±1.087).

The BMI effect was consistent across all dosing regimens and routes, study designs, exposure definitions, and outcome measures.

As for the response discrepancy for IBD, Singh and co-authors explained that this disease entails a unique, locally restrictive form of visceral adipose tissue known as creeping fat, in which mesenteric fat hyperplasia is limited to areas of the inflamed bowel. "It is likely that in IBD patients, this local mesenteric fat plays a more important role than systemic obesity," and infliximab and adalimumab doses tend to be higher for IBD than for other IMIDs.

"Even though the current meta-analysis found no consistent association between obesity and response to anti-TNF therapy in IBD, most studies in patients with IBD were small and failed to adjust for important covariates," Singh told MedPage Today. "Additionally most studies focused on infliximab, which is administered in a weight-based dosing regime, and some newer studies in patients with IBD suggest a negative impact of obesity on response to anti-TNF therapy."

Asked for his perspective, Edward V. Loftus, Jr., MD, of the Mayo Clinic in Rochester, Minn., who was not involved with the research, called obesity "a new hot topic in IBD."

"We still don't completely understand the interaction between obesity and IBD, but we know that obesity can complicate surgery," he said.

Loftus said he expected to see a difference with weight-based dosing of infliximab, and found the lack of difference interesting. "So this is not just a simplistic [finding] of bigger size and larger distribution area."

He cautioned that the list of RCTs in the analysis was relatively small and that RCTs are exclusionary and unrepresentative of real-world patients with comorbidities: "We need to look at a bigger sample size in large observational studies. This chapter on obesity and IBD has not been fully written, and as gastroenterologists, we should still be counseling our patients to restrict caloric intake and increase physical activity as ways to combat obesity."

Added Singh: "In treating our obese patients with IBD, we should be proactive in closely monitoring response and we should have a low threshold for drug monitoring and treatment escalation." He and his co-authors suggested that obesity may offer a therapeutic opportunity in IMIDs, either through dosing adjustment by body weight or through directly targeting the obesity itself.

Regarding study limitations, the team cited the focus only on anti-TNF biologics, especially weight-based infliximab treatment, inter-study heterogeneity, and the lack of stratification by presence or absence of obesity, which may have led to reporting bias. In addition, most studies did not account for potential confounders such as steroid use and baseline disease activity, both of which influence exposure and outcome, and neither did the studies address obesity-related factors such as depression and fibromyalgia, which may contribute to inferior therapeutic response.

Singh and two co-authors reported relationships with various companies including Pfizer, AbbVie, Takeda, Illumina, and UCB.