Biologicals and small molecules have revolutionized the medical management of inflammatory
bowel diseases (IBD), yet they are only effective in a proportion of patients, and
their impact on changing the natural history of the disease is still debatable. Recently,
the concept of combining targeted biologics and small-molecule therapies has been
introduced to the treatment of IBD. Dual-targeted therapy (sequential and combined),
which is the combination of two targeted therapies, might be a reasonable choice for
patients to break through the therapeutic ceiling. A recent randomized clinical trial
(VEGA) provided the first controlled evidence that the short-term combination of two
biological agents may lead to superior disease control than either of the agents alone
in patients with ulcerative colitis (UC) without jeopardizing safety. Multiple studies
are underway in both Crohn’s disease and UC. Additionally, real-world evidence is
accumulating in IBD patients receiving combination therapies with concomitant IBD
and extraintestinal manifestations or in patients with medically refractory IBD. Of
note, the majority of these patients were exposed to multiple biological agents earlier
and lost response to at least one of the agents in the combination. This review summarizes
current knowledge regarding this attractive novel therapeutic option in IBD. Clearly,
more controlled data are needed to evaluate optimal timing, efficacy, and mitigation
of safety concerns.