Functional Molecular Network Analysis Enables Prediction of Response to Vedolizumab Therapy in Anti-TNF Refractory IBD Patients

Eftekhari, Pierre; Louis, François; Rotoiu, Claudia; Räth, Timo; Atreya, Raja

doi:10.1093/crocol/otaa037

Cited by 6 publications

(3 citation statements)

References 46 publications

(43 reference statements)

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“…Molecular studies have shown some evidence on predictors of response to vedolizumab, but these have been carried out in small numbers. 7 Although there have been studies into predictors of primary response to induction therapy, there have been limited investigations into predictors of sustained response during maintenance therapy. Previous studies of sustained remission have mainly focused on tumor necrosis factor inhibitor (TNFi) therapies or been conducted in pediatric cohorts.…”

Section: Introductionmentioning

confidence: 99%

Predictors of Sustained Response With Tofacitinib Therapy in Patients With Ulcerative Colitis

Sandborn

Armuzzi

Liguori

et al. 2021

Inflammatory Bowel Diseases

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Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We evaluate baseline characteristics as predictors of sustained response and remission in patients with ulcerative colitis receiving tofacitinib maintenance therapy. Methods Patients with clinical response following OCTAVE Induction 1 and 2 entered OCTAVE Sustain and were rerandomized to receive tofacitinib 5 or 10 mg twice daily or placebo. Baseline characteristics were stratified by week 52 efficacy endpoints (remission, sustained remission, clinical response, sustained clinical response). Associations between baseline characteristics and efficacy endpoints were evaluated using logistic regression analyses. Results Overall, 170 of 487 (34.9%) patients were in remission at week 52. In multivariable modeling, endoscopic subscore at baseline of OCTAVE Induction 1 and 2 (2 vs 3; odds ratio [OR], 1.60; 95% confidence interval [CI], 1.06-2.44]), partial Mayo score (<2 vs ≥2; OR, 1.92; 95% CI, 1.27-2.90), and age (per 10-years; OR, 1.19; 95% CI, 1.02-1.39) at baseline of OCTAVE Sustain (following 8 weeks’ tofacitinib induction therapy) were associated with higher odds of remission at week 52. Oral corticosteroid use (OR, 0.63; 95% CI, 0.42-0.96) and C-reactive protein (per unit; OR, 0.94; 95% CI, 0.89-0.99) at baseline of OCTAVE Sustain were associated with reduced likelihood of remission at week 52. In general, opposite associations were observed for time to loss of response. Conclusion Patients with greater clinical improvement after 8 weeks of tofacitinib induction therapy are more likely to maintain response or remission with tofacitinib regardless of dose received during maintenance, highlighting the importance of a robust response to induction therapy.

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Section: Introductionmentioning

confidence: 99%

Predictors of Sustained Response With Tofacitinib Therapy in Patients With Ulcerative Colitis

Sandborn

Armuzzi

Liguori

et al. 2021

Inflammatory Bowel Diseases

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“…In our cohort, patients with UC with previous exposure to anti-TNF or VDZ, but not both, frequently achieved clinical remission and response rates compared with those with previous exposure to both anti-TNF and VDZ. Previous studies have reported that patients with UC who were nonresponders to VDZ following failure to respond to anti-TNF antibody had higher levels of serum IL-6 30 and mucosal infiltration of eosinophils 31 than those who were responders to VDZ following failure to respond to anti-TNF antibody. Previous studies have indicated that eosinophilia led to the release of Th2-related cytokines, including IL-5 and IL-13, which are suggested to be associated with disease severity and complicated UC course.…”

Section: Discussionmentioning

confidence: 95%

Effectiveness and Persistency of Ustekinumab Treatment for Ulcerative Colitis: A Phoenix retrospective Cohort Study

Ando,

Fujiya,

Ueno

et al. 2024

Crohn's &Amp; Colitis 360

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Background Real-world data regarding ustekinumab (UST) for ulcerative colitis (UC) particularly in biologics-naïve patients is currently limited. This study aimed to elucidate the real-world effectiveness and safety of UST for UC. Methods Overall, 150 patients with UC treated with UST from March 2020 to January 2023 were enrolled across seven referral hospitals. To assess the clinical efficacy and persistence of UST, retrospective analyses were conducted from weeks 8 to 56. Predictive factors concerning the response and persistence of UST were examined through univariate and multivariate analyses. Results Of the 150 patients, 125 received UST for remission induction, including 36% biologics-naïve. The response and remission rates were 72.8% and 56.0% at week 8 and 73.2% and 63.4% at week 56, respectively. Biologics-naïve patients represented higher response and remission rates at week 8 (84.4% and 73.3%) than those with biologics exposure (66.2% and 46.2%). Patients with prior antitumor necrosis factor (anti-TNF) and vedolizumab (VDZ) exposure had relatively lower response and remission rates (34.5% and 24.1%, respectively). The 1-year cumulative persistence rate was 84.0%. Multivariate analysis revealed that the chronic continuous type and prior anti-TNF and VDZ exposure were negative predictive factors for week 8 responsiveness. Clinical response at week 8 was a predictor of 1-year persistence. Adverse event incidence remained notably low at 6.4%. Conclusion This study highlights the safety and effectiveness of UST as an induction and maintenance therapy for UC. Chronic continuous type and previous anti-TNF and VDZ exposure negatively contributed to short-term effectiveness, whereas short-term effectiveness provided good persistency.

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“…Previous studies have shown that elevated mucosal OSM transcripts were associated with increased inflammatory activity and failure of anti-TNF therapy. 25,26 In a recent study in patients treated with a monoclonal antibody against MaDCAM-1, a significant association was demonstrated between OSM gene expression in inflamed mucosal biopsies and treatment efficacy, although a predictive value of pretreatment expression of OSM was not reported. 18 Despite the aforementioned differences, our current work and those previous studies show the feasibility of pretreatment profiling of patients subjected to biological therapies and the potential for discovering mucosal signatures with predictive value for subsequent response to treatment.…”

Section: Discussionmentioning

confidence: 99%

Response to Anti-α4β7 Blockade in Patients With Ulcerative Colitis Is Associated With Distinct Mucosal Gene Expression Profiles at Baseline

Gazouli

Dovrolis

Bourdakou

et al. 2021

Inflammatory Bowel Diseases

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Background Improving treatment outcomes with biological therapy is a demanding current need for patients with inflammatory bowel disease. Discovery of pretreatment prognostic indicators of response may facilitate patient selection and increase long-term remission rates. We aimed to identify baseline mucosal gene expression profiles with predictive value for subsequent response to or failure of treatment with the monoclonal antibody against integrin α4β7, vedolizumab, in patients with active ulcerative colitis (UC). Methods Mucosal expression of 84 immunological and inflammatory genes was quantified in RNA extracted from colonic biopsies before vedolizumab commencement and compared between patients with or without response to treatment. Significantly differentiated genes were further validated in a larger patient cohort and within available public data sets, and their functional profiles were studied accordingly. Results In the discovery cohort, we identified 21 genes with a statistically significant differential expression between 54-week responders and nonresponders to vedolizumab. Our validation study allowed us to recognize a “core” mucosal profile that was preserved in both discovery and validation cohorts and in the public database. The applied functional annotation and analysis revealed candidate dysregulated pathways in nonresponders to vedolizumab, including immune cell trafficking, TNF receptor superfamily members mediating noncanonical NF-kB pathway, in addition to interleukin signaling, MyD88 signaling, and toll-like receptors (TLRs) cascade. Conclusions Nonresponse to vedolizumab in UC is associated with specific pretreatment gene-expression mucosal signatures and dysregulation of particular immunological and inflammatory pathways. Baseline mucosal and/or systemic molecular profiling may help in the optimal stratification of patients to receive vedolizumab for active UC.

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Functional Molecular Network Analysis Enables Prediction of Response to Vedolizumab Therapy in Anti-TNF Refractory IBD Patients

Cited by 6 publications

References 46 publications

Predictors of Sustained Response With Tofacitinib Therapy in Patients With Ulcerative Colitis

Predictors of Sustained Response With Tofacitinib Therapy in Patients With Ulcerative Colitis

Effectiveness and Persistency of Ustekinumab Treatment for Ulcerative Colitis: A Phoenix retrospective Cohort Study

Response to Anti-α4β7 Blockade in Patients With Ulcerative Colitis Is Associated With Distinct Mucosal Gene Expression Profiles at Baseline

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