Obesity is associated with inferior response to anti-TNF therapy in immune-mediated inflammatory diseases: A systematic review and meta-analysis 714: OBESITY IS ASSOCIATED WITH INFERIOR RESPONSE TO ANTI-TNF THERAPY IN IMMUNE-MEDIATED INFLAMMATORY DISEASES: A SYSTEMATIC REVIEW AND META-ANALYSIS Siddharth Singh1, Antonio Facciorusso2, Abha G. Singh3, Niels Vande Casteele1, Amir Zarrinpar1, Eduardo Grunvald4, Jeffrey R. Curtis5, William J. Sandborn1 1Gastroenterology, University of California San Diego, San Diego, California, United States; 2Gastroenterology, University of Foggia, Foggia, Italy; 3Rheumatology, University of California San Diego, La Jolla, California, United States; 4Medicine, University of California San Diego, La Jolla, California, United States; 5Rheumatology, University of Alabama, Birmingham, Alabama, United States Background: About 10-40% of patients with immune-mediated inflammatory diseases (IMIDs) are obese. Obesity is associated with worse disease activity and accelerated clearance of anti-TNF agents used in the treatment of IMIDs. However, there is limited and conflicting data on whether obesity may be an independent predictor of response to anti-TNF therapy. Hence, we conducted a systematic review with meta-analysis to evaluate the association between obesity and response to anti-TNF therapy in IMIDs. Methods: Through a systematic review of multiple electronic databases and major conferences through November 2016, we identified RCTs or observational studies in adults with inflammatory bowel diseases (IBD), rheumatoid arthritis (RA), spondyloarthropathy (SpA) and psoriatic arthritis (PsA) treated with anti-TNF agents, and reporting clinical remission or response, or need for escalation of therapy, stratified by body mass index (BMI). Primary outcome of interest was failure to achieve remission or response, or need for escalation of therapy, in that hierarchy. We performed a random-effects meta-analysis, comparing obese (BMI≥30kg/m2) vs. normal BMI (<25kg/m2) individuals. Results: We included 22 studies (14 observational, 8 RCTs) (11-50% obese). On pooled analysis, obese patients were almost 2.2-times more likely to fail to achieve clinical remission or response (or need escalation of therapy) (OR, 2.16; 95% CI, 1.64-2.84), with substantial heterogeneity (I2=66%). Each unit increase in BMI was associated with 6% increased risk of failing therapy (OR, 1.06; 95% CI, 1.03-1.10). These effects were consistent across fixed dose anti-TNFs (OR, 1.70; 95% CI, 1.26-2.31; 10 studies) and weight-based dosing (OR, 2.38; 95% CI, 1.43-3.96; 8 studies) [Pinteraction=0.27], suggesting drug exposure-independent effects of obesity. Heterogeneity could be partly explained by study design, with larger effect size in observational studies (OR, 2.64; 95% CI, 1.78-3.91) than RCTs (OR, 1.56; 95% CI, 1.21-1.99) [Pinteraction=0.03]; of note, >90% RCTs of anti-TNF therapy across indications did not reports response rates stratified by weight or BMI, suggesting reporting bias. By disease indication, ankylosing spondylitis (OR, 7.44; 95% CI, 3.94-14.06; 3 studies) and RA (OR, 1.88; 95% CI, 1.53-2.30; 8 studies) had largest effect size; the results did not reach statistical significance for IBD (OR, 1.51; 95% CI, 0.98-2.32; 9 studies). Conclusion: Obesity is an under-reported predictor of inferior treatment response and need for escalation of anti-TNF therapy in IMIDs. This effect may be independent of drug exposure, and was observed with both fixed-dose or weight-based dosing. A thorough evaluation of obesity as a potential effect modifier in clinical trials is warranted. Additionally, targeting obesity may be a potential therapeutic target in obese patients with IMIDs. Singh S, Facciorusso A, Singh AG, et al. Slides compiled by Dr. Cynthia Seow DDW 2017

Introduction Background Methods About 10–40% of patients with an immune-mediated inflammatory disease (IMID) are obese Includes inflammatory bowel disease (IBD), rheumatoid arthritis, spondylosing arthropathy, psoriasis, psoriatic arthropathy Obesity is associated with worse disease activity Non-linear association between weight and drug clearance Accelerated clearance of anti-TNF agents in obese patients Methods Systematic review with meta-analysis to evaluate the association between obesity and response to anti-TNF therapy in IMIDs stratified by body mass index (BMI) Primary outcome: Failure to achieve remission or response, or need for escalation of therapy Stratified by BMI ≥30 kg/m2 (obese) vs BMI <25 kg/m2 (normal BMI)

55 studies (32 observational, 23 RCTs); 16,479 patients Population: 11–50% obese Failure to achieve remission/response, or need for escalation of therapy Effect of obesity (55 studies) Effect size, OR 95% CI Obese (BMI ≥30 kg/m2) 1.55 1.36–1.77 Weight-based anti-TNF 1.72 1.25–2.36 Fixed-dose anti-TNF 1.38 1.22–1.56 Substantial heterogeneity (I=66%) [Pinteraction=0.27], suggesting drug exposure-independent effects of obesity. Heterogeneity could be partly explained by study design, with larger effect size in observational studies (OR, 2.64; 95% CI, 1.78-3.91) than RCTs (OR, 1.56; 95% CI, 1.21-1.99) [Pinteraction=0.03]; of note, >90% RCTs of anti-TNF therapy across indications did not reports response rates stratified by weight or BMI, suggesting reporting bias. Anti-TNF: anti-tumour necrosis factor; OR: odds ratio; RCT: randomized controlled trial

Results 55 studies (32 observational, 23 RCTs); 16,479 patients Population: 11–50% obese Dose–response relationship (17 studies) Effect size, OR 95% CI Overweight (BMI 25–30 kg/m2) vs normal weight 1.38 1.16–1.66 Obese (BMI ≥30 kg/m2) vs normal weight 1.70 1.33–2.18 Disease type Effect size, OR 95% CI IBD (19 studies) 1.13 0.92–1.39 Psoriasis/psoriatic arthritis (19 studies) 1.50 1.24–1.82 Spondylosing arthropathy (6 studies) 4.19 1.73–10.15 Substantial heterogeneity (I=66%) [Pinteraction=0.27], suggesting drug exposure-independent effects of obesity. Heterogeneity could be partly explained by study design, with larger effect size in observational studies (OR, 2.64; 95% CI, 1.78-3.91) than RCTs (OR, 1.56; 95% CI, 1.21-1.99) [Pinteraction=0.03]; of note, >90% RCTs of anti-TNF therapy across indications did not reports response rates stratified by weight or BMI, suggesting reporting bias. OR: odds ratio; RCT: randomized controlled trial

Results: Subgroup analyses OR (95% CI) Obesity and failure to achieve remission/response Superior Inferior 0.5 1 2 5 10 Subgroups Categories (no. of studies) OR Lower limit Upper limit Study design RCTs (23) 1.46 1.26 1.70 Observational (32) 1.65 1.38 1.98 Diseases Rheumatoid arthritis (11) 1.83 1.54 2.17 IBD (19) 1.13 0.92 1.39 Psoriasis/psoriatic arthritis (19) 1.50 1.24 1.82 Spondyloarthropathies (6) 4.19 1.73 10.15 Outcome definition Disease activity indices (41) 1.77 2.14 Failure of therapy (14) 1.19 1.00 1.41 Exposure comparators Obese vs. non-obese (12) 1.92 1.36 2.71 Obese vs normal BMI (15) 1.99 1.48 2.68 Overweight vs normal BMI (9) 0.83 1.86 Dosing type Weight-based dosing (15) 1.72 1.25 2.36 Fixed dose (28) 1.22 1.56

Conclusions Conclusions Implications for clinical practice Obesity is associated with inferior response to anti-TNF therapy in immune- mediated inflammatory disease Implications for clinical practice The effect on IBD is less clear Currently insufficient data to guide choice of treatment (weight-based vs fixed dosing, type of therapy) Further studies needed in the IBD population Subgroup analyses of CD vs UC (differing involvement of mesenteric fat) Prospective studies