Y-ECCO Literature Review: Joana Roseira
Joana Roseira
Higher intra-abdominal visceral adipose tissue mass is associated with lower rates of clinical and endoscopic remission in patients with inflammatory bowel diseases initiating biologic therapy: Results of the Constellation Study
Yarur A, Bruss A, Moosreiner A, et al.
Gastroenterology 2023;165:963–75
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Introduction
Despite an expanding therapeutic arsenal, a considerable proportion of patients with Crohn's Disease (CD) and Ulcerative Colitis (UC) fail to achieve or sustain therapeutic responses [1, 2]. Mechanisms contributing to this failure, particularly with respect to biologic therapy, are only partially understood [3]. Uncovering the mechanisms behind loss of response may help to enhance the efficacy of existing treatment options or to develop alternative options for the future.
Some investigations have noted an association between obesity, high intra-abdominal visceral adipose tissue (IA-VAT) mass and unfavourable outcomes in individuals with Inflammatory Bowel Disease (IBD). However, these observations have been constrained by their methodology and have to date focused only on patients having treatment with anti-tumour necrosis factor alpha (anti-TNF-α) agents [4–6], limiting their scope.
The Constellation Study by Yarur and colleagues aimed to investigate the relationship between IA-VAT in patients with IBD and the response to biologic drugs with multiple different mechanisms of action.
Methods
The Constellation Study was a prospective observational cohort study conducted at Froedtert and the Medical College of Wisconsin. It explored the association between IA-VAT in patients with IBD and response to three biologic medications (infliximab, vedolizumab and ustekinumab). Potential pathways through which IA-VAT may adversely influence outcomes were also explored, including assessment of pharmacokinetics, expression of cytokines and the gastrointestinal microbiota.
Adult IBD patients initiating these treatments, with both clinical and endoscopic activity, underwent body composition assessments at baseline, and IA-VAT was measured using dual-energy X-ray absorptiometry scans. IA-VAT percentage, a key metric for analysing IA-VAT burden, was categorised as 'high' or 'low' based on the study population's median IA-VAT percentage score.
The primary outcome was steroid-free deep remission (SFDR) at weeks 14–16 [defined by a Harvey-Bradshaw Index <5 or a partial Mayo score <2 and normal biomarkers (CRP ≤0.5 µg/dL and faecal calprotectin ≤150 µg/g)]. Secondary outcomes were SFDR at weeks 30–32 and endoscopic remission (defined by Simple Endoscopic Score for CD ≤2 or partial Mayo score ≤2) at weeks 30–46.
Key findings and discussion
A total of 141 patients (79 with CD and 62 with UC) were included in the study.
1. IA-VAT percentage was a negative predictor for therapeutic outcomes. Rates of SFDR post induction (weeks 14–16) and during maintenance (weeks 30–32) and endoscopic remission were significantly lower among patients with a high IA-VAT percentage, irrespective of the drug or disease type. Multivariable models revealed associations: Higher IA-VAT percentage (OR 0.4), previous biologic exposure (OR 3.499) and higher drug levels (OR 2.97) were independently associated with treatment failure at weeks 14–16, while lower drug levels at weeks 30–32 and high IA-VAT percentage were independent predictors for failure at weeks 30–32 (OR 0.26 and 0.25, respectively).
2. Similar pharmacokinetic properties of biologic drugs were noted, irrespective of IA-VAT percentage. Comparable drug pharmacokinetic properties were observed between patients with high and low IA-VAT percentages. Despite an association between drug levels and efficacy, no correlation was found between baseline IA-VAT percentage and drug levels of infliximab, vedolizumab or ustekinumab. These findings suggest that adjusting drug levels based on IA-VAT burden may not overcome lower effectiveness in patients with higher IA-VAT percentage.
3. Potential link between IA-VAT percentage and distinct inflammatory pathways. Patients with a high IA-VAT percentage who failed to achieve the outcomes of interest exhibited elevated serum levels of interleukin-6 and TNF-α compared to responders and those with a lower IA-VAT percentage. Indeed, IA-VAT percentage was positively correlated with IL-6 and TNF-α but negatively correlated with IL-13. Limitations included a small sample size, preventing subgroup analysis by IBD phenotype or individual biologic drugs. Also, cytokine expression in tissue from visceral fat may have differed from serum levels.
4. Limited impact of IA-VAT percentage on microbial diversity. Faecal microbiome analyses were conducted in 93 people, including 41 patients with IBD selected at random from this cohort and 52 healthy control volunteers. The authors replicated lower levels of alpha and beta diversity amongst patients with IBD compared to healthy volunteers. Although patients with a higher IA-VAT percentage did have enrichment of certain species such as Eubacterium(hallii group), Bacteroides and Blautia, it is of note that IA-VAT differences did not significantly influence the microbial diversity of patients with IBD.
Conclusions
In summary, Yarur and colleagues demonstrated an association between high IA-VAT percentage burden and lower response rates to infliximab, vedolizumab and ustekinumab in both CD and UC. The observed significant variations in serum interleukin-6, TNF-α and IL-13 levels when stratifying patients based on high or low IA-VAT burden underscore the clinical relevance of visceral adipose tissue in IBD. Interestingly, IA-VAT burden does not seem to impact drug pharmacokinetics or microbiota. Future investigations into the underlying mechanisms of these correlations, particularly the potential role of cytokine overexpression, are warranted. Interventions to reduce IA-VAT burden and extension of these findings to small molecule therapies represent critical areas for further research.
References
- Danese S, Vermeire S, Zhou W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet 2022;399:2113–28.
- Barberio B, Gracie DJ, Black CJ, et al. Efficacy of biological therapies and small molecules in induction and maintenance of remission in luminal Crohn’s disease: systematic review and network meta-analysis. Gut 2023; 72:264–74.
- Dalal SR, Cohen RD. What to do when biologic agents are not working in inflammatory bowel disease patients. Gastroenterol Hepatol (N Y) 2015;11:657–65.
- Singh S, Proudfoot J, Xu R, et al. Impact of obesity on short- and intermediate-term outcomes in inflammatory bowel diseases: Pooled analysis of placebo arms of infliximab clinical trials. Inflamm Bowel Dis 2018;24:2278–84.
- Ding NS, Malietzis G, Lung PFC, et al. The body composition profile is associated with response to anti-TNF therapy in Crohn’s disease and may offer an alternative dosing paradigm. Aliment Pharmacol Ther 2017;46:883–91.
- Gu P, Chhabra A, Chittajallu P, et al. Visceral adipose tissue volumetrics inform odds of treatment response and risk of subsequent surgery in ibd patients starting antitumor necrosis factor therapy. Inflamm Bowel Dis 2021;28:657–66.
Joana Roseira - Short Biography
Joana Roseira completed her Gastroenterology and Endoscopy training in 2021 and currently serves as a Gastroenterology assistant at Algarve University Hospital Center in Southern Portugal. Alongside her clinical role, she is undertaking a PhD on histopathological evaluation in IBD. Joana is actively engaged in the activities of international (ECCO) and national (GEDII) IBD societies, and she is one of the members of the young committee of the Portuguese IBD group (Y-GEDII). Joana recently assumed the role of UEG Journal Trainee Editor, specifically overseeing the IBD section.