Efficacy and safety of Advanced Combination Treatment in immune-mediated inflammatory disease: A systematic review and meta-analysis of randomized controlled trials

Affiliations

¹ Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada; Gastroenterology and Endoscopy, IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Milan, Italy.
² Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada; Lawson Health Research Institute, London Health Science Center, London, Ontario, Canada.
³ Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
⁴ Division of Gastroenterology & Hepatology, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
⁵ Gastroenterology, Department of Public Health, University Federico II of Naples, Naples, Italy.
⁶ Gastroenterology and Endoscopy, IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Milan, Italy; IBD Unit, Department of Gastroenterology & Digestive Endoscopy, San Camillo-Forlanini Hospital, 00152, Rome, Italy.
⁷ Rheumatology Unit, Internal Medical Services, Hospital Italiano de Buenos Aires, Argentina and Instituto Universitario, Peron 4190 (C1199ABB), CABA, Argentina.
⁸ Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada; Department of Medicine, Division of Rheumatology, Western University, London, ON, Canada.
⁹ Department of Rheumatology, Fondazione Policlinico Universitario A. Gemelli, IRCSS, Catholic University of Sacred Heart, Rome, Italy.
¹⁰ Department of Medicine, Division of Rheumatology, Western University, London, ON, Canada.
¹¹ Department of Gastroenterology, Nancy University Hospital, F-54500, Vandœuvre-lès-Nancy, France; INFINY Institute, Nancy University Hospital, F-54500, Vandœuvre-lès-Nancy, France; Groupe Hospitalier Privé Ambroise Paré - Hartmann Paris IBD Center, 92200, Neuilly sur Seine, France.
¹² Gastroenterology and Endoscopy, IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Milan, Italy.
¹³ Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada; Department of Epidemiology & Biostatistics, Western University, London, Ontario, Canada. Electronic address: vjairath@uwo.ca.

PMID: 39509741
PMCID: PMC12186700 (available on 2025-12-01)
DOI: 10.1016/j.jaut.2024.103331

Meta-Analysis

Efficacy and safety of Advanced Combination Treatment in immune-mediated inflammatory disease: A systematic review and meta-analysis of randomized controlled trials

Virginia Solitano et al. J Autoimmun. 2024 Dec.

. 2024 Dec:149:103331.

doi: 10.1016/j.jaut.2024.103331. Epub 2024 Nov 6.

Affiliations

¹ Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada; Gastroenterology and Endoscopy, IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Milan, Italy.
² Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada; Lawson Health Research Institute, London Health Science Center, London, Ontario, Canada.
³ Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
⁴ Division of Gastroenterology & Hepatology, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
⁵ Gastroenterology, Department of Public Health, University Federico II of Naples, Naples, Italy.
⁶ Gastroenterology and Endoscopy, IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Milan, Italy; IBD Unit, Department of Gastroenterology & Digestive Endoscopy, San Camillo-Forlanini Hospital, 00152, Rome, Italy.
⁷ Rheumatology Unit, Internal Medical Services, Hospital Italiano de Buenos Aires, Argentina and Instituto Universitario, Peron 4190 (C1199ABB), CABA, Argentina.
⁸ Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada; Department of Medicine, Division of Rheumatology, Western University, London, ON, Canada.
⁹ Department of Rheumatology, Fondazione Policlinico Universitario A. Gemelli, IRCSS, Catholic University of Sacred Heart, Rome, Italy.
¹⁰ Department of Medicine, Division of Rheumatology, Western University, London, ON, Canada.
¹¹ Department of Gastroenterology, Nancy University Hospital, F-54500, Vandœuvre-lès-Nancy, France; INFINY Institute, Nancy University Hospital, F-54500, Vandœuvre-lès-Nancy, France; Groupe Hospitalier Privé Ambroise Paré - Hartmann Paris IBD Center, 92200, Neuilly sur Seine, France.
¹² Gastroenterology and Endoscopy, IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Milan, Italy.
¹³ Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada; Department of Epidemiology & Biostatistics, Western University, London, Ontario, Canada. Electronic address: vjairath@uwo.ca.

PMID: 39509741
PMCID: PMC12186700 (available on 2025-12-01)
DOI: 10.1016/j.jaut.2024.103331

Abstract

Objectives: Advanced combination treatment (ACT), defined as a combination of at least 2 biologic agents, a biologic agent and an oral small molecule, 2 oral small molecules drug with different mechanisms of action is a proposed strategy to improve outcomes in patients with immune-mediated inflammatory disease (IMID). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing ACT with monotherapy in patients with select IMIDs.

Methods: Through a systematic literature search, we identified 10 RCTs (n = 1154) comparing ACT with single agent therapy (monotherapy). The primary outcome was induction of clinical remission. Secondary outcomes were adverse events, serious adverse events, infections, and serious infections. We performed random-effects meta-analysis and used GRADE to appraise certainty of evidence.

Results: Eight out of 10 trials investigated an anti-TNF-α drug (e.g., etanercept, infliximab, golimumab, certolizumab) combined with another biologic (e.g anti-IL-23, anti-integrin, anti-IL-1) or an oral small molecule. There was no significant difference in the likelihood of achieving clinical remission with ACT vs. monotherapy in patients with rheumatoid arthritis (n = 7 RCTs) (RR, 1.75 [95 % CI 0.60-5.13]; moderate heterogeneity (I² = 33 %)] and systemic lupus erythematosus (n = 1) (RR, 1.20 [0.53-2.72]) (GRADE; low certainty evidence). Patients with rheumatoid arthritis in the ACT arm were more likely to experience adverse events (RR, 1.07 [1.01-1.12]) compared to monotherapy. ACT led to higher rates of induction of clinical remission in patients with IBD (n = 2 RCTs) (RR, 1.68 [1.15-2.46]) with minimal heterogeneity (I² = 15 %) (GRADE; low certainty evidence), and no differences in the likelihood of adverse events (RR 0.92 [0.80-1.05]). There were no differences in the risk of infections or serious infections in patients treated with ACT or monotherapy with rheumatological disease or IBD.

Conclusions: ACT did not offer clinical benefit in patients with rheumatological IMIDs and resulted in higher rate adverse events in rheumatoid arthritis. ACT may offer clinical benefit without a clear safety signal in patients with IBD, but further trials are warranted. The variability in ACT regimens across studies limits the generalizability of these findings.

Keywords: Crohn's disease; Design; Dual; RA; SLE; Ulcerative colitis.

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Conflict of interest statement

Declaration of competing interest VS: No relevant disclosures. YY: No relevant disclosures. SS: has received research grants from Pfizer. CM: has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Takeda, Pendopharm, Pfizer, Roche, Sanofi; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Takeda, Pendopharm, and Pfizer; royalties from Springer Publishing; research support from Ferring, Takeda, Pfizer. OMN: has received speaker fees from Janssen, AbbVie, Eli Lilly, Pfizer, Ferring, Alfa Sigma. GF: has received consultancy fees from Takeda, Abbvie, Janssen, Pfizer, Celltrion, Sandoz, Amgen, Ferring, Gilead, Galapagos, BMS. MLAF: has received speaker or advisory board fees from Janssen, Eli Lilly, Abbvie, Asofarma. LB: No relevant disclosure. M-AD: speaker or consultant fees from Novartis, BMS, Janssen, Pfizer, Amgen, Galapagos, AbbVie, UCB, and Eli Lilly. PC reports research grants from UCB, MSD and Pfizer; speaker fees or consultant fees from Pfizer, MSD, Novartis, Bristol Myers Squibb, AbbVie, UCB, Eli Lilly, Gilead and Celgene Corporation. JP: Funding for research: Abbvie, BMS, Eli Lilly & Company, Merck, Roche, Seattle Genetics; UCB consulting relationships: AbbVie, Actelion, Amgen, Bayer, BMS, Eicos Sciences, Eli Lilly & Company, Emerald, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB; Speakers Bureau: UCB. LPB: has received consulting fee from AbbVie, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic Pharma, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax. Received grants from Takeda, Fresenius Kabi, Cell Trion. Speaker fee from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Lilly, Gilead, Viatris, Medac. SD: has received consulting fees from AbbVie, Alimentiv Inc., Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenixa, UCB Inc, and Vifor; and lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer, and Takeda. VJ has received consulting/advisory board fees from AbbVie, Alimentiv Inc (formerly Robarts Clinical Trials), Arena pharmaceuticals, Asieris, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genetech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Reistone Biopharma, Roche, Sandoz, Takeda, Topivert; speaker's fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda.

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Efficacy and safety of Advanced Combination Treatment in immune-mediated inflammatory disease: A systematic review and meta-analysis of randomized controlled trials

Affiliations

Efficacy and safety of Advanced Combination Treatment in immune-mediated inflammatory disease: A systematic review and meta-analysis of randomized controlled trials

Authors

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Abstract

Conflict of interest statement

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