Safety of Sequential Biological Therapy in Inflammatory Bowel Disease

Results From a Tertiary Referral Centre

Annick Moens; Nasim Sadat Seyed Tabib; Vera Ballet; João Sabino; Séverine Vermeire; Marc Ferrante


Aliment Pharmacol Ther. 2022;56(2):271-281. 

In This Article

Abstract and Introduction


Background: Biologicals represent the cornerstone of treatment for moderate-to-severe inflammatory bowel diseases (IBD). Many patients cycle between biologicals when encountering loss of response or adverse events. Aim: To assess the occurrence of serious infections and malignancies with exposure to several (classes of) biologicals.

Methods: We performed a retrospective cohort study in a tertiary referral centre including consecutive IBD patients exposed to adalimumab, infliximab, ustekinumab or vedolizumab between 1996 and 2019. All serious infections and malignancies, as well as potential confounders, were accounted for.

Results: In total, 1575 patients were included with a median (interquartile range) follow-up of 10 (6–16) years and a duration of biological therapy of 71 (39–112) months. Incidence rates of serious infections were 3.4 per 100 patients' years (PY) in the post-biological setting. Serious infections after biological exposure were associated with systemic steroids in monotherapy (hazard ratio 2.96 [95% confidence interval 1.78–4.93], p < 0.0001), combination therapy of systemic steroids and a biological (2.44 [1.37–4.34], p = 0.002), female gender (1.25 [1.04–1.51], p = 0.02), and prior serious infections in the pre-biological setting (1.42 [1.03–1.96], p = 0.03). Malignancy rates were 1.06 per 100PY in the post-biological setting and increased with older age at biological initiation (1.04 [1.02–1.05], p < 0.0001). The risk for serious infections or malignancies was independent of type and number of biologicals to which the patient was exposed.

Conclusion: This study shows that the sequential use of biological therapy in IBD does not seem to convey an overall higher risk of serious infections or malignancies, but that underlying more refractory disease seems to increase this risk.


Inflammatory bowel diseases (IBD) are chronic relapsing and remitting diseases necessitating long-term medical treatment. Biological therapies have been introduced 20 years ago and nowadays represent the cornerstone of treatment for moderate-to-severe diseases. Early introduction of these molecules is advocated to quickly achieve remission and halt disease progression.[1,2] However, 30%–40% of patients fail to show initial response (primary non-responders) and over time, another 30%–40% of patients lose response often related to immunogenicity (secondary loss of response).[3] In addition, biologicals used in the treatment of IBD block a specific target that plays a crucial role in the pathogenesis of IBD. Yet, these targets are not only involved in IBD pathogenesis but also have important physiological roles with regard to the protection of the host against invading pathogens and the protection against tumour development.[4,7] Previous studies showed that there seems to be an increased risk for Mycobacterium tuberculosis (TB) infections.[4,5] In addition, anti-TNF therapy has been linked to an increased risk for lymphoma as well as melanoma skin cancer.[8,10] Regarding UST, a higher risk for Salmonella, non-TB Mycobacteria and mucocutaneous Candida infections has been suggested, but could not yet be confirmed in humans.[6] For UST, no increased risk of lymphoma has been demonstrated in IBD patients. In addition, in psoriasis patients treated with UST, no increased risk of skin cancer, lymphoma or solid organ tumours could be established.[11,12] No papers exist regarding the risk for specific cancers with VDZ, and an increased risk for opportunistic infections could also not be shown.[13] Not only these adverse events but also intolerance linked to these molecules lead to treatment cessation in a proportion of patients. This therefore results in many patients cycling from one biological therapy to another and becoming exposed to various biological classes throughout their disease course.[14,18] More importantly, there is no information on the potential safety risks associated with the consecutive and cumulative use of several biologicals over time. It is questioned if prolonged medical therapy with switching between biological classes and thus sequentially affecting different pathways may be more detrimental, or in analogy to thiopurines,[19] there might still be a risk for certain malignancies after withdrawal of biological therapies. Therefore, we assessed the occurrence of serious infections and malignancies in a large single-centre tertiary referral cohort with exposure to several classes of biological agents.