Obesity and response to anti-tumor necrosis factor-α agents in patients with select immune-mediated inflammatory diseases: A systematic review and meta-analysis.

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prednisone 2 endocrinologydiseasesdrugs
Etanercept 2 endocrinologydiseasesdrugs
hyperlipidemia 1 endocrinologydiseases
metabolic syndrome 2 endocrinologydiseases
obesity 52 endocrinologydiseases

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Etanercept 22763 index; CDAI = Crohn’s disease activity index; CS = corticosteroids; CZP = Certolizumab pegol; ETN = Etanercept ; hfPGA = hand/feet physician global assessment; IFX = Infliximab; IM = Immunomodulators; MTX = Methotrexate;
Etanercept 36369 protein; CS = corticosteroids; CZP = Certolizumab pegol; ESR = Erythrocyte sedimentation rate; ETN = Etanercept ; EULAR = European League Against Rheumatism; hfPGA = hand/feet physician global assessment; IFX = Infliximab;
prednisone 17133 Group 3: initial combination therapy,with the COBRA scheme: MTX, sulfasalazine and tapered highdose prednisone (N = 133), vs. Group 4: a combination of MTX and IFX 3mg/kg IV every 8 weeks (N = 128)Only group 4:
prednisone 25335 3m; 10.6% (variables adjusted for: age, sex, disease duration, prior DMARDs, DAS28, concurrent MTX or prednisone , smoking, RF, other comorbidities)Age: 61 (12)Sex: 23%Steroids: 31.6%INFLAMMATORY BOWEL DISEASESGuerbau,
Select Disease Character Offset Disease Term Instance
hyperlipidemia 34039 activity (variables adjusted for: age, sex, disease duration, concomitant methotrexate, smoking, diabetes, hyperlipidemia , hypertension, ESR, CRP, baseline disease activity)BMI<30 vs. BMI ≥30Age: 51 (13) vs. 52 (10)Sex:
metabolic syndrome 33048 ProspectiveAnti-TNF: 330 (Psoriatic arthritis)BMI, mean (SD): Metabolic syndrome– 28.5 (4.5); No metabolic syndrome – 26.4 (3.8); Exposure categories: BMI≥30 vs. BMI<30Failure to achieve minimal disease activity,
metabolic syndrome 33264 activity, 24 months; 52.2% failed to achieve minimal disease activityAge: Metabolic syndrome– 47 (9); no metabolic syndrome – 47 (9)Sex: 45%; 46%Steroids: NRIannone, 2013[[28]]Italy, 2006–11; RetrospectiveADA: 42;ETN: 48;IFX:
obesity 2208 5/2018Publication date (collection): /2018AbstractObjectivesWe sought to evaluate the association between obesity and response to anti-tumor necrosis factor-α (TNF) agents, through a systematic review and meta-analysis.MethodsThrough
obesity 3048 confidence interval (CI).ResultsBased on 54 cohorts including 19,372 patients (23% obese), patients with obesity had 60% higher odds of failing therapy (OR,1.60; 95% CI,1.39–1.83;I2 = 71%). Dose-response relationship
obesity 3842 anti-TNF agents in patients with select immune-mediated inflammatory diseases. A thorough evaluation of obesity as an effect modifier in clinical trials is warranted, and intentional weight loss may serve as adjunctive
obesity 3984 trials is warranted, and intentional weight loss may serve as adjunctive treatment in patients with obesity failing anti-TNF therapy.Data AvailabilityAll relevant data are within the paper and its Supporting
obesity 4147 data are within the paper and its Supporting Information files.IntroductionThe global prevalence of obesity is rising, with one in 10 people across the world being classified as obese.[[1], [2]] In the United
obesity 5358 associated with accelerated clearance, resulting in lower trough concentrations.[[20]–[22]] Additionally, obesity , particularly visceral fat, independently contributes to higher systemic inflammatory burden.[[23],
obesity 5518 contributes to higher systemic inflammatory burden.[[23], [24]] Several observational studies have shown that obesity may be a negative prognostic marker in patients with rheumatic diseases,[[11], [25]] and variably and
obesity 5786 agents in obese patients.[[26]–[33]]Hence, we sought to systematically review the association between obesity and response to anti-TNF agents across selected IMIDs, and examine whether the effect varies across
obesity 7568 also excluded studies in which the exposure categories did not include any patients with overweight or obesity patients (for example, BMI <20 vs. ≥20kg/m2).[[35]] When there were multiple publications from the
obesity 8632 keywords was used to search for observational studies (S2 Text) and RCTs (S3 Text) reporting impact of obesity on response to anti-TNF therapy. Two authors independently reviewed the title and abstract of studies
obesity 11151 alternative therapy, and/or need for surgery).In order to evaluate stability of the association between obesity and response to anti-TNF therapy, and examine potential sources of heterogeneity, we performed several
obesity 12251 approaches. First, we limited analysis to studies reporting the association between 2 or more categories of obesity against a reference category, and compared as nominal groups. For example, for studies using WHO-defined
obesity 36793 response to anti-TNF therapyOn meta-analysis, across included IMIDs and across all anti-TNF agents, obesity was associated with 60% higher odds of failure of index anti-TNF therapy (OR, 1.60; 95% CI, 1.39–1.83),
obesity 38078 Fig).[[32], [33], [42], [54], [81]–[84]]10.1371/journal.pone.0195123.g002Fig 2Association between obesity and response to anti-TNF therapy–dose-response relation, with comparison of patients in the 3rd tertile
obesity 39373 [49]–[52], [60], [61], [63], [65]–[67], [77], [78], [80]] No significant association was observed between obesity and response to anti-TNF therapy in patients with IBD based on 16 studies, with 3,130 patients (median
obesity 40925 subcutaneously. Hence, route and dosing scheme could not be evaluated independently. Patients with obesity treated with both weight-based dosing regimens (16 studies; OR, 1.69 [1.26–2.27], I2 = 67%) (Panel
obesity 41598 weight-based dosing = 0.28).Exposure categories and outcome definitionStudies comparing patients with obesity with either non-obese (16 studies, OR, 1.70 [1.32–2.20])[[26], [29], [31]–[33], [42], [45], [47],
obesity 41932 [57], [59], [60], [64], [67], [68], [75], [78]] patients consistently reported a negative effect of obesity on response to therapy; in contrast studies with exposure categories of only overweight vs. non-overweight
obesity 42283 0.42).[[33], [44], [54], [55], [61], [62], [72], [74], [76]] Based on outcome definition, the effect of obesity was more pronounced in studies that used validated definitions of clinical remission or response (based
obesity 43403 [49]–[51], [53], [55], [61]–[64], [68], [70], [74], [76]–[78], [80]]On meta-regression, prevalence of obesity in included studies modestly but significantly affected summary estimate (p = 0.06), with smaller effect
obesity 43566 summary estimate (p = 0.06), with smaller effect size observed in studies with lower prevalence of obesity (Panel A in S4 Fig); prevalence of outcome did not affect summary estimate (p = 0.54) (Panel B in S4
obesity 44790 select IMIDs treated with anti-TNF agents, we made several key observations related to the influence of obesity on response to anti-TNF therapy. First, we observed that obesity was associated with a 60% higher odds
obesity 44855 observations related to the influence of obesity on response to anti-TNF therapy. First, we observed that obesity was associated with a 60% higher odds of failing anti-TNF therapy as compared to non-obese and normal
obesity 45608 <10% of eligible RCTs reported results stratified by baseline BMI. Our findings of negative impact of obesity on treatment response to anti-TNF agents suggests that obesity is a negative prognostic factor and treatment
obesity 45671 BMI. Our findings of negative impact of obesity on treatment response to anti-TNF agents suggests that obesity is a negative prognostic factor and treatment effect modifier that must be considered in clinical trial
obesity 46029 in levels of cytokines, chemokines and adipokines.[[6]] Besides its direct impact on inflammation, obesity can also modify pharmacokinetics of anti-TNF and other biologic agents. Population pharmacokinetic studies
obesity 46643 unbound targets “sop up” antibody, serving as a sink.[[85]] This may explain why patients with obesity treated even weight-based regimens such as infliximab, had inferior response to therapy.Comparison with
obesity 46848 therapy.Comparison with other studiesOur findings expand on prior observations on the potentially negative impact of obesity on overall treatment response in patients with RA and psoriasis. However, these prior studies included
obesity 47191 impact across different diseases, and with different anti-TNF agent. Though we had hypothesized that obesity would negatively impact response to anti-TNF therapy across all selected diseases, we did not observe
obesity 47665 is likely that in IBD patients, this local mesenteric fat plays a more important role than systemic obesity . Additionally, dose of infliximab and adalimumab approved in patients with IBD is higher than that for
obesity 47990 also explain this finding–severe IBD is likely to result in weight loss and misclassification of obesity , whereas, severe rheumatic diseases would likely impact physical activity, promote sedentary lifestyle
obesity 48119 rheumatic diseases would likely impact physical activity, promote sedentary lifestyle and contribute to obesity . Alternatively, it is possible that our observation in IBD patients is biased. Most studies in IBD patients
obesity 48398 median weight, and did not include patients at extreme categories of BMI, where the negative impact of obesity may be more pronounced. On meta-regression, effect estimates were smaller in studies with lower prevalence
obesity 48516 more pronounced. On meta-regression, effect estimates were smaller in studies with lower prevalence of obesity . Five studies in IBD patients were reported only as abstracts, putting them at high risk of bias (though
obesity 49765 observational studies, but participants in RCTs were not stratified based on presence or absence of obesity . Most of the included studies did not account for several potential confounding factors including steroid
obesity 50019 of which influence exposure and outcome. Additionally, factors that may be intrinsically related to obesity , such as depression, fibromyalgia, etc., may confound this association between obesity and inferior
obesity 50106 intrinsically related to obesity, such as depression, fibromyalgia, etc., may confound this association between obesity and inferior clinical response to therapy. While sensitivity analysis using the adjusted data had little
obesity 50579 overall analysis, which was partly explained by difference in outcome definition and prevalence of obesity in included cohorts, as well as different types of diseases. It is important to note that a stronger
obesity 51459 agents and small molecules. This was done to minimize conceptual heterogeneity. Negative impact of obesity on response to other therapies has been observed, and merits detailed evaluation.Implications for clinical
obesity 51611 observed, and merits detailed evaluation.Implications for clinical practiceWhile the negative impact of obesity in patients with psoriasis is well-known, our observations that obesity uniformly results in inferior
obesity 51683 practiceWhile the negative impact of obesity in patients with psoriasis is well-known, our observations that obesity uniformly results in inferior response to anti-TNF therapy across all rheumatic diseases that we studied
obesity 51992 practice, physicians may consider aggressive treatment and close proactive monitoring in patients with obesity treated with anti-TNF agents such as empirically using higher dose of anti-TNF agent in obese patients,
obesity 52300 increase drug concentration and decrease risk of immunogenicity. Clinical trialists should consider obesity as a potential effect modifier and consider obesity as a stratification variable; at the very least,
obesity 52352 immunogenicity. Clinical trialists should consider obesity as a potential effect modifier and consider obesity as a stratification variable; at the very least, stratified analysis by baseline BMI should be performed
obesity 52517 stratified analysis by baseline BMI should be performed and consistently reported. Finally, the presence of obesity may offer a potential therapeutic intervention, either through adjusting biologic dosing for body weight
obesity 52664 intervention, either through adjusting biologic dosing for body weight or through directly targeting the obesity itself for treatment in patients with select IMIDs with a multi-disciplinary approach. Small RCTs and
obesity 52985 intentional weight loss on treatment response to anti-TNF agents.[[88]–[90]]ConclusionIn conclusion, obesity is associated with inferior response to anti-TNF therapy in patients with rheumatic diseases, but not
obesity 53630 warranted to confirm this association. If this effect is consistent, interventional studies targeting obesity should be explored for difficult-to-treat obese patients with select IMIDs.Supporting informationS1
obesity 54156 file.S1 TableRisk of bias assessment.(DOCX)Click here for additional data file.S1 FigAssociation between obesity measured as per unit increase in body mass index and response to anti-TNF therapy.(TIFF)Click here for
obesity 54314 and response to anti-TNF therapy.(TIFF)Click here for additional data file.S2 FigAssociation between obesity and response to anti-TNF therapy–Subgroup analyses based on anti-TNF dosing regimen: (A) weight-based
obesity 54531 dosing, and (B) fixed dose therapies.(TIFF)Click here for additional data file.S3 FigAssociation between obesity and response to anti-TNF therapy–Subgroup analyses based on study design: (A) RCTs, and (B) observational
obesity 54746 studies.(TIFF)Click here for additional data file.S4 FigMeta-regression based on (A) prevalence of obesity , and (B) prevalence of outcome.(TIFF)Click here for additional data file.S5 FigFunnel plot to evaluate

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