Efficacy and Safety of Simultaneous Treatment With Two Biologic Medications in Refractory Crohn's Disease

Edward Yang; Nicola Panaccione; Natalie Whitmire; Parambir S. Dulai; Niels Vande Casteele; Siddharth Singh; Brigid S. Boland; Angelina Collins; William J. Sandborn; Remo Panaccione; Robert Battat


Aliment Pharmacol Ther. 2020;51(11):1031-1038. 

In This Article

Materials and Methods

Patient Population

Data were reviewed from patient records at the University of California, San Diego (La Jolla, California) and University of Calgary (Calgary, Alberta). Data were extracted from patients with Crohn's disease who had started a combination of two different biologics between January 1, 2007 and December 31, 2018. At the University of California, San Diego, we utilised a program, "SlicerDicer", in the electronic medical record (Epic Systems Corporation), that permits identification of all patients with overlapping dates of biologic prescriptions or medication documentation, regardless of duration. Subsequently, individual chart review was performed to confirm patients received dual biologic therapy. At the University of Calgary, all patients starting dual biologic therapy for any duration were identified prospectively and the data were extracted retrospectively. No patient was started on dual biologic therapy for an indication other than Crohn's disease, such as rheumatologic or dermatologic diseases. Biologics searched include permutations for combinations of adalimumab, infliximab, certolizumab, golimumab, vedolizumab, natalizumab and ustekinumab. Chart review and data extraction were performed on each potential combination (EY and NP).

Data regarding demographics, disease phenotype, prior biologic therapies (prior response, dosing and failures), prior medications (corticosteroids, immunomodulators and antibiotics), prior surgeries, presence of fistulas, laboratory data and adverse events were obtained thorough chart review. Endpoints were assessed at the time of endoscopic evaluation closest to 1 year of treatment with DBT or at the time of treatment failure.

Approach to Combining Biologics

All therapeutic trials consisted of two biologic medications which included vedolizumab, ustekinumab or a TNF-antagonist paired with each other. In all therapeutic trials, patients were receiving therapy with a single biologic agent, and the second biologic was added on. Documented infusion of the second concomitant biologic medication was considered the start dates for DBT. Therapeutic drug monitoring was utilised in the majority of cases as standard of care at our institutions—this includes reasons for biologic failure (such as primary nonresponse, secondary nonresponse, immunogenicity and pharmacokinetic or mechanistic failure) and dose-escalated regimens.


The primary outcome was endoscopic improvement during maintenance therapy, defined as either > 50% reduction in Simplified Endoscopic Score-Crohn's disease (SES-CD) or explicitly stated on the endoscopy report by an inflammatory bowel disease specialist. Other outcomes included endoscopic remission (SES-CD < 3 or clear stated), clinical response (Crohn's disease–patient-reported outcome-2 score [PRO-2] reduced by 8), clinical remission (PRO2 < 8) and adverse events.[23,24] Need for surgery was considered treatment failure for all endoscopic and clinical outcomes. Per-patient analysis was repeated using the most recent therapeutic trials. PRO-2 scores were calculated using standardised forms routinely given to patients, or from records if clearly stated.[23,24]

Statistical Analysis

Data analysis included descriptive statistics computed for continuous variables (means and SD). Percentages were used for categorical variables. Between-groups comparisons were performed using chi-squared, Fishers exact test, t test or Wilcoxon rank testing, as appropriate. P -values ≤ 0.05 were considered significant. All analyses were done using STATA SE 15.1 (StataCorp).


All authors had access to study data, reviewed and approved the final manuscript. Study protocol and materials were approved by the institutional review boards at University of California, San Diego and the University of Calgary.