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


Patients with longstanding Crohn's disease often fail multiple biologic therapies and require surgical resections. As remission rates of individual biologics are low and limited further options exist, combining biologics may be a reasonable alternative to avoid disease progression and recurrent surgery. However, limited evidence on this approach exists. We report the largest study to date assessing the efficacy and safety of concomitant use of two (dual) biologic therapies in refractory Crohn's disease. This study reflects a high-risk population, with a large majority having a stricturing or penetrating phenotype and a high prevalence of perianal disease. Objective endoscopic outcomes were achieved in significant proportions of patients and endoscopic scores decreased significantly. Furthermore, objective documentation of fistula resolution existed in many patients. This is consistent with clinical remission rates, PRO-2 reductions and objective reductions in CRP. Three adverse events (13%) were recorded.

Overall, the preliminary evidence on the efficacy of DBT in this study appears promising. This is particularly evident when considering the limited available therapeutic options in this cohort of refractory Crohn's disease patients. In these patients, 91% had undergone prior surgical resections and the median number of previously failed biologics was 4. In addition, the severe and treatment-refractory disease phenotype described in our cohort is not uncommon in other tertiary academic medical centres. Thus, when considering the range of previously failed medical and surgical therapies in patients with refractory and high-risk Crohn's disease, an endoscopic improvement rate of 43% may imply a significant beneficial effect of this regimen. Additionally, the proportion of patients remaining on dual biologic therapy at 1 year was similar to the endoscopic response rate. Although there was no preliminary signal, adverse event rates were comparable to previous TNF-antagonist data.[25–27]

Previously, pooled data using small case series and case reports in inflammatory bowel disease patients treated with DBT included 10 Crohn's disease patients, with a majority having received vedolizumab and a TNF antagonist.[20] Although prior small case series had similar adverse event rates to this study, endoscopic data were generally lacking.[18,19] In contrast, this study significantly increase available data on this topic in patients with severe- and high-risk Crohn's disease phenotypes.

Although a study limitation was its retrospective design, objective endoscopic and biomarker endpoints were evaluated and patient reported outcomes were assessed. Adverse events were documented for a long duration, and the therapeutic impact of a diverse range of biologic combinations and dosing was assessed. While a possibility exists that patients started on dual biologic therapy for very short durations were not captured in this study, all patients receiving DBT were identified using either software from electronic medical records or prospective identification of patients, to permit identification of all patients with overlapping dates of biologic prescriptions or medication documentation, regardless of duration. Additionally, chart review was performed to confirm patients received dual biologic therapy. Lastly, data were not collected for patients in whom DBT was recommended, but not initiated.

The ideal approach to selecting dual biologic regimens remains to be determined. Vedolizumab or ustekinumab may be ideal adjunct therapies in DBT regimens due to their favourable safety profile.[12,13,21,22] For this reason, most patients in our study received vedolizumab, and the most frequently used pairing was with ustekinumab. One consideration is an individualised approach that incorporates reasons for prior biologic failures, such as utilising biologics with prior response (secondary nonresponse without immunogenicity) in addition to targeting an alternative untreated inflammatory pathway while avoiding biologics that have previously caused immunogenicity. While we did not find a significant difference in endoscopic response rates in this study when comparing prior reasons for biologic failure or alternate inflammatory targets, this study was not designed to detect this difference. Another consideration may be that the patients in our cohort had a high median number of previously failed biologic agents, which limits therapeutic choices from a mechanistic standpoint.

In summary, DBT was associated with clinical, biomarker and endoscopic improvements in a highly selective cohort with refractory Crohn's disease who have failed multiple biologics. While our findings appear promising, additional real world reports and randomised controlled trial data will assist in determining the efficacy and safety of DBT in refractory Crohn's disease.