Tofacitinib Is Safe and Effective When Used in Combination With Infliximab for the Management of Refractory Ulcerative Colitis

Gilmore, Robert; Hilley, Patrick; Srinivasan, Ashish; Choy, Matthew C; Grace, Josephine A; Cruz, Peter P De

doi:10.1016/j.cgh.2020.07.046

Cited by 7 publications

(3 citation statements)

References 4 publications

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“…Four small studies totaling 21 individuals were treated with a combination of anti-TNF therapy with tofacitinib for partially or non-responsive IBD (Tables 1 , 3 ). The first reported case of combining anti-TNF with tofacitinib included five patients treated with infliximab in combination with tofacitinib for a minimum of 90 days [ 36 ]. All five patients demonstrated a partial response to intensified infliximab dosing following a median total of eight months.…”

Section: Resultsmentioning

confidence: 99%

Efficacy and Safety of Dual Targeted Therapy for Partially or Non-responsive Inflammatory Bowel Disease: A Systematic Review of the Literature

et al. 2023

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Background Dual targeted therapy (DTT) has emerged as an attractive therapeutic option for select patients with active inflammatory bowel disease (IBD) who are unable to achieve remission with biologic or small molecule monotherapy. We conducted a systematic review of specific DTT combinations in patients with IBD. Methods We conducted a systematic search of MEDLINE, EMBASE, Scopus, CINAHL Complete, Web of Science Core Collection, and Cochrane Library to identify articles related to the use of DTT for the treatment of Crohn Disease (CD) or ulcerative colitis (UC) published before February 2021. Results Twenty-nine studies were identified comprising 288 patients started on DTT for partially or non-responsive IBD. We identified 14 studies with 113 patients receiving anti-tumor necrosis factor (TNF) and anti-integrin therapies (i.e., vedolizumab and natalizumab), 12 studies with 55 patients receiving vedolizumab and ustekinumab, nine studies with 68 patients receiving vedolizumab and tofacitinib, five studies with 24 patients receiving anti-TNF therapy and tofacitinib, six studies with 18 patients receiving anti-TNF therapy and ustekinumab, and three studies with 13 patients receiving ustekinumab and tofacitinib. Conclusion DTT is a promising approach to improve IBD treatment for patients with incomplete responses to targeted monotherapy. Larger prospective clinical studies are needed to confirm these findings as is additional predictive modeling to identify the patient subgroups most likely to require and benefit from this approach. Supplementary Information The online version contains supplementary material available at 10.1007/s10620-023-07837-0.

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Section: Resultsmentioning

confidence: 99%

Efficacy and Safety of Dual Targeted Therapy for Partially or Non-responsive Inflammatory Bowel Disease: A Systematic Review of the Literature

et al. 2023

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“…Recent retrospective studies by Gilmore et al. ( 71 ) and Hilley et al. ( 72 ) reported that all patients with refractory UC who showed a partial response to a single biologic agent remained on biologics/tofacitinib combination therapy.…”

Section: Discussionmentioning

confidence: 99%

Precision therapy for ulcerative colitis: insights from mitochondrial dysfunction interacting with the immune microenvironment

Zhang,

Fan,

Bai

et al. 2024

Front. Immunol.

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BackgroundAccumulating evidence reveals mitochondrial dysfunction exacerbates intestinal barrier dysfunction and inflammation. Despite the growing knowledge of mitochondrial dysfunction and ulcerative colitis (UC), the mechanism of mitochondrial dysfunction in UC remains to be fully explored.MethodsWe integrated 1137 UC colon mucosal samples from 12 multicenter cohorts worldwide to create a normalized compendium. Differentially expressed mitochondria-related genes (DE-MiRGs) in individuals with UC were identified using the “Limma” R package. Unsupervised consensus clustering was utilized to determine the intrinsic subtypes of UC driven by DE-MiRGs. Weighted gene co-expression network analysis was employed to investigate module genes related to UC. Four machine learning algorithms were utilized for screening DE-MiRGs in UC and construct MiRGs diagnostic models. The models were developed utilizing the over-sampled training cohort, followed by validation in both the internal test cohort and the external validation cohort. Immune cell infiltration was assessed using the Xcell and CIBERSORT algorithms, while potential biological mechanisms were explored through GSVA and GSEA algorithms. Hub genes were selected using the PPI network.ResultsThe study identified 108 DE-MiRGs in the colonic mucosa of patients with UC compared to healthy controls, showing significant enrichment in pathways associated with mitochondrial metabolism and inflammation. The MiRGs diagnostic models for UC were constructed based on 17 signature genes identified through various machine learning algorithms, demonstrated excellent predictive capabilities. Utilizing the identified DE-MiRGs from the normalized compendium, 941 patients with UC were stratified into three subtypes characterized by distinct cellular and molecular profiles. Specifically, the metabolic subtype demonstrated enrichment in epithelial cells, the immune-inflamed subtype displayed high enrichment in antigen-presenting cells and pathways related to pro-inflammatory activation, and the transitional subtype exhibited moderate activation across all signaling pathways. Importantly, the immune-inflamed subtype exhibited a stronger correlation with superior response to four biologics: infliximab, ustekinumab, vedolizumab, and golimumab compared to the metabolic subtype.ConclusionThis analysis unveils the interplay between mitochondrial dysfunction and the immune microenvironment in UC, thereby offering novel perspectives on the potential pathogenesis of UC and precision treatment of UC patients, and identifying new therapeutic targets.

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“…Pediatric patients hospitalized for UC require additional therapies to further decrease colectomy rates. Tofacitinib, either in combination, sequentially, or alternatively to infliximab following corticosteroid‐failure, has recently been shown to decrease colectomy rates among adult patients with ASUC (13,14,17,29). The present study represents the first evidence that tofacitinib may also provide benefit in preventing colectomy among hospitalized pediatric patients with refractory UC.…”

Section: Discussionmentioning

confidence: 99%

Tofacitinib Salvage Therapy for Children Hospitalized for Corticosteroid- and Biologic-Refractory Ulcerative Colitis

Constant

Baldassano

Kirsch

et al. 2022

Journal of Pediatric Gastroenterology &Amp; Nutrition

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Objectives: Colectomy rates following acute severe ulcerative colitis have plateaued around 20% despite intravenous corticosteroid and intensified anti-tumor necrosis factor (TNF) biologic dosing. Recent studies have shown tofacitinib to provide additional benefit in further decreasing colectomy rates among hospitalized adult patients with corticosteroid- and anti-TNF-nonresponsive ulcerative colitis. Pediatric data describing the effectiveness of tofacitinib for this indication does not yet exist. We aimed to describe the treatment courses and colectomy-free survival among pediatric patients treated with tofacitinib while hospitalized for refractory ulcerative colitis. Methods: We performed a retrospective single-center cohort study of consecutive hospitalized pediatric patients initiating tofacitinib for refractory ulcerative colitis from 2018 to 2021. The primary outcome was 90-day colectomy-free survival. Secondary outcomes included colectomy-free clinical remission, corticosteroid independence, colectomy-free tofacitinib drug-persistence, tofacitinib-related adverse events, and postoperative complications. Baseline characteristics and details of the timing and positioning of therapies utilized during hospitalization were described. Outcomes were described using counts, percentages, and Kaplan-Meier curves. Results: Eleven patients met inclusion criteria. All patients demonstrated nonresponse to both intravenous corticosteroids and anti-TNF therapy prior to tofacitinib initiation. Median hospitalization length was 22 days and mean maximum pediatric ulcerative colitis activity index during hospitalization was 68. Eight of 11 patients remained colectomy-free at 90 days following hospital admission and 6 remained colectomy-free over median 182-day follow-up, including 4 of whom remained on tofacitinib. Conclusions: Tofacitinib may represent a new treatment option for hospitalized pediatric patients with corticosteroid- and anti-TNF-nonresponsive ulcerative colitis. Future research is essential in determining the optimal positioning of these therapies.

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Tofacitinib Is Safe and Effective When Used in Combination With Infliximab for the Management of Refractory Ulcerative Colitis

Cited by 7 publications

References 4 publications

Efficacy and Safety of Dual Targeted Therapy for Partially or Non-responsive Inflammatory Bowel Disease: A Systematic Review of the Literature

Efficacy and Safety of Dual Targeted Therapy for Partially or Non-responsive Inflammatory Bowel Disease: A Systematic Review of the Literature

Precision therapy for ulcerative colitis: insights from mitochondrial dysfunction interacting with the immune microenvironment

Tofacitinib Salvage Therapy for Children Hospitalized for Corticosteroid- and Biologic-Refractory Ulcerative Colitis

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