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

Virginia Solitano; Yuhong Yuan; Siddharth Singh; Christopher Ma; Olga Maria Nardone; Gionata Fiorino; Maria Laura Acosta Felquer; Lillian Barra; Maria-Antonietta D'Agostino; Janet Pope; Laurent Peyrin-Biroulet; Silvio Danese; Vipul Jairath

doi:10.1016/j.jaut.2024.103331

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

J Autoimmun. 2024 Nov 6:149:103331. doi: 10.1016/j.jaut.2024.103331. Online ahead of print.

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
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.

Publication types

Review