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.

BACKGROUND & AIMS: We sought to assess the association between intra-abdominal visceral adipose tissue (IA-VAT) and response to 3 different biologic drugs in patients with inflammatory bowel disease (IBD) and to investigate its effects on inflammatory cytokine expression, pharmacokinetics, and intestinal microbiota. METHODS: We prospectively enrolled subjects with active IBD initiating infliximab, vedolizumab, or ustekinumab and a healthy control group. Baseline body composition (including IA-VAT as percent of total body mass [IA-VAT%]) was measured using GE iDXA scan. Primary outcome was corticosteroid- free deep remission at weeks 14-16, defined as Harvey Bradshaw Index <5 for Crohn's disease and partial Mayo score <2 for ulcerative colitis, with a normal C-reactive protein and fecal calprotectin. Secondary outcomes were corticosteroid-free deep remission and endoscopic remission (Endoscopic Mayo Score ≤1 in ulcerative colitis or Simple Endoscopic Score for Crohn's disease ≤2) at weeks 30-46. RESULTS: A total of 141 patients with IBD and 51 healthy controls were included. No differences in body composition parameters were seen between the IBD and healthy control cohorts. Patients with higher IA-VAT% were less likely to achieve corticosteroid-free deep remission (P < .001) or endoscopic remission (P = .02) vs those with lower IA-VAT%. Furthermore, nonresponders with high IA-VAT% had significantly higher serum interleukin-6 and tumor necrosis factor at baseline compared with responders and patients with low IA-VAT%. Drug pharmacokinetic properties and microbiota diversity were similar when comparing high and low IA-VAT% groups. CONCLUSIONS: Higher IA-VAT% was independently associated with worse outcomes. This association could be driven at least partially by discrete differences in inflammatory cytokine expression.

Patients With Inflammatory Bowel Diseases and Higher Visceral Adipose Tissue Burden May Benefit From Higher Infliximab Concentrations to Achieve Remission.

INTRODUCTION: In patients with inflammatory bowel diseases (IBDs), high visceral adipose tissue (VAT) burden is associated with a lower response to infliximab, potentially through alterations in volume distribution and/or clearance. Differences in VAT may also explain the heterogeneity in target trough levels of infliximab associated with favorable outcomes. The aim of this study was to assess whether VAT burden may be associated with infliximab cutoffs associated with efficacy in patients with IBD. METHODS: We conducted a prospective cross-sectional study of patients with IBD receiving maintenance infliximab therapy. We measured baseline body composition parameters (Lunar iDXA), disease activity, trough levels of infliximab, and biomarkers. The primary outcome was steroid-free deep remission. The secondary outcome was endoscopic remission within 8 weeks of infliximab level measurement. RESULTS: Overall, 142 patients were enrolled. The optimal trough levels of infliximab cutoffs associated with steroid-free deep remission and endoscopic remission were 3.9 mcg/mL (Youden Index [J]: 0.52) for patients in the lowest 2 VAT % quartiles (<1.2%) while optimal infliximab level cutoffs associated with steroid-free deep remission for those patients in the highest 2 VAT % quartiles was 15.3 mcg/mL (J: 0.63). In a multivariable analysis, only VAT % and infliximab level remained independently associated with steroid-free deep remission (odds ratio per % of VAT: 0.3 [95% confidence interval: 0.17-0.64], P < 0.001 and odds ratio per µg/mL: 1.11 [95% confidence interval: 1.05-1.19], P < 0.001). DISCUSSION: The results may suggest that patients with higher visceral adipose tissue burden may benefit from achieving higher infliximab levels to achieve remission.

Combination Therapy With Immunomodulators Improves the Pharmacokinetics of Infliximab But Not Vedolizumab or Ustekinumab.

BACKGROUND AND AIMS: The aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics. METHODS: This was a prospective cohort study including patients with inflammatory bowel diseases on maintenance doses of infliximab, vedolizumab, or ustekinumab on monotherapy or combination with a thiopurine or oral methotrexate. We collected 6-TGN concentrations, biomarker levels, and clinical and endoscopic disease activity. The primary outcomes were infliximab, vedolizumab, and ustekinumab concentrations as well as anti-drug antibodies (ADAs). RESULTS: A total of 369 patients were recruited (113 infliximab, 133 vedolizumab, and 123 ustekinumab). Patients with 6-TGN levels ≥146 pmol per 8 × 108 red blood cells (RBCs), and those receiving combination therapy with thiopurine or oral methotrexate had significantly higher infliximab concentrations when compared with monotherapy (median levels of 17.4 µg/mL on thiopurine with 6-TGN ≥146 pmol per 8 × 108 RBCs, 17.1 on methotrexate, and 3.9 on infliximab monotherapy; P = .001 for both comparisons). However, there was no association between the use of immunomodulators and 6-TGN concentrations with vedolizumab (median levels of 8.8 on thiopurine with 6-TGN ≥152 pmol per 8 × 108 RBCs, 6.8 on methotrexate, and 10.5 on vedolizumab monotherapy; P > .05 for both comparisons) or ustekinumab median concentrations (median levels of 5.0 on thiopurine with 6-TGN ≥154 pmol per 8 × 108 RBCs, 5.2 on methotrexate and 7.0 on ustekinumab monotherapy; P > .05 for both comparisons). Fourteen (12%) patients had anti-infliximab antibodies, while 1 patient had ADAs in each of the other drug cohorts. CONCLUSIONS: Achieving higher 6-TGN levels or the use of methotrexate improved the pharmacokinetics of infliximab. Conversely, these data do not support the use of combination therapy to augment pharmacokinetics with vedolizumab or ustekinumab.

Serum trough levels of infliximab are not associated with peripheral arthralgia activity in patients with inflammatory bowel disease.

BACKGROUND: Infliximab is an efficacious therapy for inflammatory bowel disease and may play a role in management of some extraintestinal manifestations. While higher trough levels of infliximab are associated with higher rates of disease remission, the association between trough levels of infliximab and arthralgia activity characterised as an extraintestinal manifestation has yet to be defined. OBJECTIVE: We aimed to assess the association between serum trough levels of infliximab and peripheral arthralgia activity in patients with inflammatory bowel disease. DESIGN: In this cross-sectional study, we identified patients with inflammatory bowel disease on infliximab therapy with known history of arthralgias attributed to an extraintestinal manifestation. Collected variables included disease phenotype, medications (such as thiopurines or methotrexate), Harvey Bradshaw Index, partial Mayo score, C reactive protein, trough levels of infliximab and anti-infliximab antibodies. The primary outcome was active patient-reported arthralgia. RESULTS: Out of 267 patients included, 65 (24.4%) had active arthralgias at the time the trough level of infliximab was measured. No significant differences in trough levels were seen between those patients with and without arthralgias. Patients on combination therapy with methotrexate or thiopurines or those with detectable anti-infliximab antibodies were not more likely to have inactive arthralgias (OR 0.99, 95% CI 0.57 to 1.74, p=0.99 and OR 1.94, 95% CI 0.9 to 4.1, p=0.09, respectively). CONCLUSIONS: This study suggests that although therapeutic drug monitoring of infliximab can have a role in the management of Crohn's disease and ulcerative colitis, it does not seem to be useful in managing arthralgias associated with inflammatory bowel disease.

Correction to: Vedolizumab Concentrations Are Associated with Long-Term Endoscopic Remission in Patients with Inflammatory Bowel Diseases.

The original version of the article unfortunately contained a couple of errors. In 'methods' section, in 'Outcomes' subsection, the sentence 'Endoscopic remission was defined as an SESCD ≤ 2 in patients with CD and an EMS ≤ 2 in UC patients while off corticosteroids.'

Higher Trough Vedolizumab Concentrations During Maintenance Therapy are Associated With Corticosteroid-Free Remission in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Vedolizumab is an anti-α4ß7 biologic approved for ulcerative colitis [UC] and Crohn's disease [CD]. We aimed to examine the association of maintenance vedolizumab concentrations with remission. METHODS: We performed a cross-sectional multi-centre study of inflammatory bowel disease [IBD] patients on maintenance vedolizumab. A homogeneous mobility shift assay [HMSA] was used to determine trough serum concentrations of vedolizumab and anti-drug antibodies [ATVs]. The primary outcome was corticosteroid-free clinical and biochemical remission defined as a composite of clinical remission, normalized C-reactive protein [CRP] and no corticosteroid use in 4 weeks. Secondary outcomes included corticosteroid-free endoscopic and deep remission. Vedolizumab concentrations were compared between patients in remission and with active disease. Logistic regression, adjusting for confounders, assessed the association between concentrations and remission. RESULTS: In total, 258 IBD patients were included [55% CD and 45% UC]. Patients in clinical and biochemical remission had significantly higher vedolizumab concentrations [12.7 µg/mL vs 10.1 µg/mL, p = 0.002]. Concentrations were also higher among patients in endoscopic and deep remission [14.2 µg/mL vs 8.5 µg/mL, p = 0.003 and 14.8 µg/mL vs 10.1 µg/mL, p = 0.01, respectively]. After controlling for potential confounders, IBD patients with vedolizumab concentrations >11.5 µg/mL were nearly 2.4 times more likely to be in corticosteroid-free clinical and biochemical remission. Only 1.6% of patients had ATVs. CONCLUSIONS: In a large real-world cohort of vedolizumab maintenance concentrations, IBD patients with remission defined by objective measures [CRP and endoscopy] had significantly higher trough vedolizumab concentrations and immunogenicity was uncommon.

Vedolizumab Concentrations Are Associated with Long-Term Endoscopic Remission in Patients with Inflammatory Bowel Diseases.

BACKGROUND: The aim of this study was to assess the relationship of serum vedolizumab concentrations (SVC) during induction and endoscopic remission in patients with inflammatory bowel diseases (IBD) after 52 weeks of therapy with vedolizumab. We also sought to assess the incidence of antibody to vedolizumab (ATV) formation, the effect of ATV on drug pharmacokinetics and efficacy, and identify variables associated with SVC through the first 30 weeks of treatment. METHODS: This is a prospective cohort study of patients with active IBD initiating standard therapy with vedolizumab. Collected variables included demographics, clinical disease activity, biomarkers, pre-infusion SVC, and ATV measured at weeks 2, 6, 14, 22, and 30. Primary outcome was steroid-free endoscopic remission at week 52. RESULTS: Fifty-five patients were included. Patients that achieved steroid-free endoscopic remission by week 52 had higher SVC at weeks 2, 6, 14, 22, and 30, but only achieved statistical significance at weeks 2 and 6. Only 3 out of the 55 study subjects (5.5%) had detectable ATV through the follow-up. Overall, there were a positive correlation between SVC and serum albumin and a negative correlation with C-reactive protein, fecal calprotectin, and body mass. Vedolizumab concentrations ≥ 23.2 mcg/ml at week 2 were associated with endoscopic remission at week 52 (OR 8.8 [95% CI 2.6-29.7], p < 0.001). CONCLUSIONS: Vedolizumab concentrations during induction were associated with endoscopic remission at week 52. Interventional studies looking into improved efficacy with higher drug exposure are warranted.