Guselkumab and golimumab combination induction therapy in ulcerative colitis results in early local tissue healing that is sustained through guselkumab maintenance therapy
Bibliographic record
Abstract
Introduction: Combination induction therapy with guselkumab (GUS; IL23p19 subunit antagonist) and golimumab (GOL; TNFα antagonist), induced higher rates of clinical remission, endoscopic, histologic outcomes than either monotherapy at Week (W)12 in patients (pts) with ulcerative colitis (VEGA NCT03662542). Data through W38 suggested continued benefit of combination induction after transition to GUS monotherapy at W12. Objectives: We explored early molecular changes in colon tissue in a pt subset at W4 to define mechanistic contributions of each monotherapy and combination which were re-evaluated at W38 to assess potential carry-over of efficacy. Fig. 1 Methodology: Colon biopsies were obtained: baseline (n=195); W4 (n=42 substudy); W38 (n=172). Transcriptional profiles were generated with RNA sequencing (RNAseq). Gene correlation network analysis was applied in conjunction with publicly available single-cell RNAseq data to define biologically relevant bulk and cell type-specific transcriptional modules associated with molecular features of disease. Gene set variation analysis was used to quantitatively assess changes in biologic modules with treatment. Result: At W4, combination induction (n=10) showed significant (p<0.05) decreases in molecular features vs GUS (n=19) and GOL (n=13), including transcriptomic modules representing IL23 pathway, IFN response, inflammatory epithelial and myeloid transcriptional states associated with endoscopic improvement (Mayo endoscopy subscore=0 or 1) (combination 5/11, GOL 1/13; GUS 2/19). Reduction (p<0.05) in inflammatory modules persisted through W38 with combination vs monotherapy induction. Module changes between treatments at W4 indicated stronger correlation between GUS and combination (R=0.8; p=2.2e-16) vs GOL and combination (R=0.52; p=4.1e-12), with processes associated with epithelial and stromal biology, and mucosal inflammation. However, the combination effect on neutrophil/myeloid biology at W4 was more comparable to GOL than GUS, supporting the early role of GOL in targeting innate inflammation. Conclusion: Combination induction with GUS and GOL showed significant reductions in major inflammatory features of disease as early as W4, persisting through W38 with GUS maintenance. Correlative analysis supports GUS as primary driver of tissue healing, with GOL further contributing to innate inflammatory activity, demonstrating differential and complementary mechanisms of action of TNFα and IL23p19 subunit blockade. Publication History Article published online: 26 September 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".