Advanced Combination Therapy in IBD
4 affiliations
- 1Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, 20132 Milan, Italy
- 2Faculty of Medicine and Surgery, Vita-Salute San Raffaele University, 20132 Milan, Italy
- 3Division of Gastroenterology, Department of Medicine, University Hospital, London, ON N6A 5A5, Canada
- 4Department of Epidemiology and Biostatistics, Western University, London, ON N6G 2M1, Canada
Abstract
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic, immune-mediated condition characterized by considerable clinical and biological heterogeneity. Despite major advances in biologic therapies and small molecules, a considerable proportion of patients fail to achieve sustained clinical and endoscopic remission, highlighting the therapeutic ceiling of current treatment strategies. Increasing evidence suggests that treatment failure may result from the activation of multiple, partially overlapping inflammatory pathways that are not adequately controlled by single-agent therapy. Advanced combination therapy (ACT), defined as the concomitant use of two separate advanced targeted agents, either two biologics or a biologic and a small molecule, with complementary mechanisms of action, has emerged as a potential strategy to overcome these limitations, particularly in patients with refractory disease, extraintestinal manifestations, or concomitant immune-mediated inflammatory diseases. This narrative review, based on a PubMed literature search, summarizes the biological rationale, current clinical evidence, safety considerations, and practical applications of ACT in IBD. Available evidence, largely derived from heterogeneous observational studies and phase 2 randomized trials, suggests potential improvements in clinical and endoscopic outcomes in selected patients. However, the incremental benefit over individual targeted therapies has not been consistently demonstrated. Although available studies have not identified a clear increase in short-term serious adverse events, the evidence remains insufficient to establish long-term safety. Important uncertainties persist regarding optimal patient selection, treatment sequencing, duration, de-escalation strategies, and cost-effectiveness. While ACT represents a potentially valuable therapeutic option for selected patients with IBD, its use for active IBD remains largely off-label, and current evidence does not support routine implementation. Larger randomized trials and long-term studies are needed to better define its efficacy, safety, and clinical positioning.
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BibTeX
@article{lisa2026advanced,
title = {{Advanced Combination Therapy in IBD}},
author = {Maria Lisa and Lucia Centanni and Ferdinando D’Amico and Federica Furfaro and Mariangela Allocca and Alessandra Zilli and Tommaso Lorenzo Parigi and Virginia Solitano and Silvio Danese and Vipul Jairath},
journal = {Biomolecules},
year = {2026},
month = nov,
doi = {10.3390/biom16111615},
url = {https://www.mdpi.com/2218-273X/16/11/1615},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Advanced Combination Therapy in IBD
AU - Maria Lisa
AU - Lucia Centanni
AU - Ferdinando D’Amico
AU - Federica Furfaro
AU - Mariangela Allocca
AU - Alessandra Zilli
AU - Tommaso Lorenzo Parigi
AU - Virginia Solitano
AU - Silvio Danese
AU - Vipul Jairath
PY - 2026
DA - 2026/11/06
JO - Biomolecules
DO - 10.3390/biom16111615
UR - https://www.mdpi.com/2218-273X/16/11/1615
AB - Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic, immune-mediated condition characterized by considerable clinical and biological heterogeneity. Despite major advances in biologic therapies and small molecules, a considerable proportion of patients fail to achieve sustained clinical and endoscopic remission, highlighting the therapeutic ceiling of current treatment strategies. Increasing evidence suggests that treatment failure may result from the activation of multiple, partially overlapping inflammatory pathways that are not adequately controlled by single-agent therapy. Advanced combination therapy (ACT), defined as the concomitant use of two separate advanced targeted agents, either two biologics or a biologic and a small molecule, with complementary mechanisms of action, has emerged as a potential strategy to overcome these limitations, particularly in patients with refractory disease, extraintestinal manifestations, or concomitant immune-mediated inflammatory diseases. This narrative review, based on a PubMed literature search, summarizes the biological rationale, current clinical evidence, safety considerations, and practical applications of ACT in IBD. Available evidence, largely derived from heterogeneous observational studies and phase 2 randomized trials, suggests potential improvements in clinical and endoscopic outcomes in selected patients. However, the incremental benefit over individual targeted therapies has not been consistently demonstrated. Although available studies have not identified a clear increase in short-term serious adverse events, the evidence remains insufficient to establish long-term safety. Important uncertainties persist regarding optimal patient selection, treatment sequencing, duration, de-escalation strategies, and cost-effectiveness. While ACT represents a potentially valuable therapeutic option for selected patients with IBD, its use for active IBD remains largely off-label, and current evidence does not support routine implementation. Larger randomized trials and long-term studies are needed to better define its efficacy, safety, and clinical positioning.
SN - 2218-273X
ER -