Off-Label Rescue Therapy and Surgery
Though the armamentarium of IBD therapies has expanded greatly over the past 2 decades, and will continue to do so for the foreseeable future, there are still a limited selection of therapies available to patients. Patients who have failed anti-TNF therapy, and subsequently fail vedolizumab and/or ustekinumab, have limited options. These options include clinical trials, off-label small molecule rescue therapy, and surgery. Patients who are felt to require any of these options should be referred to a tertiary center for evaluation by a gastroenterologist specializing in the treatment of IBD and/or a colorectal surgeon specializing in the surgical management of IBD.
Tacrolimus
Tacrolimus, a macrolide calcineurin inhibitor, has been studied as a small molecule therapy for IBD, though not in randomized controlled trials. There is biological plausibility for its use as a disease modifying agent. Mucosal T cells in subjects with active Crohn’s disease have been found to express increased levels of mRNA encoding IL-2, and tacrolimus acts primarily by reducing IL-2 production [25]. The largest observational cohort evaluating the use of tacrolimus, published by Thin et al, included patients with both ulcerative colitis (n = 24) and Crohn’s disease (n = 11) who had moderate to severely active IBD. All patients had failed dose-optimized thiopurine therapy, 89% had primary nonresponse or secondary loss of response to at least one anti-TNF agent, and 74% were either steroid-refractory or steroid-dependent at the time tacrolimus was started. With close monitoring, they targeted a tacrolimus trough of 8–12 ng/mL. At 30 days, 66% had a clinical response, and 40% were in clinical remission. At 90 days, 60% had a clinical response, and 37% were in clinical remission. At 1 year, 31% had a clinical response, and 23% were in clinical remission. Of those in clinical remission at 1 year, 88% were either off of steroids or on less than 5 mg of prednisone per day. Renal impairment was seen in 25% of patients, including severe renal impairment in 11%, requiring drug cessation. Infectious complications were seen in 9% of patients. Headaches, tremor, and pancreatitis were also observed, though less commonly. The majority of patients ultimately had a surgical intervention, particularly if they were steroid-refractory at baseline, but the time to surgery was delayed in those who achieved a response or remission in the first 90 days of tacrolimus therapy. The authors suggested that while tacrolimus may lack clear long-term benefit in patients with medically refractory IBD, a therapeutic trial should be considered in select patients with the goal of medical and nutritional optimization before surgical intervention [26].
Cyclosporine
Cyclosporine, which also exerts its effect by inhibiting IL-2 production, has an established role in the management of severe ulcerative colitis. Data from randomized, placebo-controlled trials, along with numerous open label observational studies, have shown that intravenous cyclosporine can induce remission and potentially obviate the need for urgent/emergent colectomy in steroid-refractory patients who are hospitalized with severe ulcerative colitis [27,28]. Its use in maintenance therapy remains controversial, however. Older observational data suggest that even among those who have an initial clinical response to cyclosporine induction, 33% will undergo colectomy by 1 year, and 88% will undergo colectomy by 7 years [27). Though the concomitant administration of a thiopurine may delay the need for colectomy [29,30], cyclosporine seems to be, at best, a temporizing therapy for patients with severe ulcerative colitis. Studies on the use of cyclosporine for the induction of remission in Crohn’s disease have been less robust, as have studies on the use of cyclosporine for the maintenance of remission in Crohn’s disease [31]. Dose-dependent toxicity also remains a concern, particularly when being considered as maintenance therapy. Though some observational data suggest that the absolute risks of serious side effects from maintenance cyclosporine are small, cyclosporine is still generally avoided as a maintenance therapy [30].
Mycophenolate Mofetil
Mycophenolate mofetil (MMF), which inhibits both B and T cell proliferation by inhibiting de novo purine synthesis, has been studied in both Crohn’s disease and ulcerative colitis. Studies have been small, observational, and heterogeneous. On the whole, they suggest that MMF does have some efficacy, but it is not necessarily more effective than azathioprine and may have a slightly increased risk of side effects [32]. Given that the side effects of MMF include diarrhea, and an IBD-like enterocolitis (MMF-induced colitis) when given to subjects without an established diagnosis of IBD, it is likely best to avoid using the drug in patients with IBD [33].
Surgery
Finally, when medical management has failed, or when fibrostenotic and/or penetrating complications of inflammatory bowel disease are present, surgery should be considered. Surgery can provide a cure in patients with ulcerative colitis, and can induce remission in patients with Crohn’s disease. Managing IBD medications around the time of surgery is always challenging. Multiple large, retrospective cohort studies have suggested that the risk for postoperative infectious complications, anastomotic leaks, and thrombotic complications do not differ between those who receive anti-TNF therapy within several months of surgery and those who do not. Nevertheless, some surgeons may prefer to time elective surgery halfway between doses of anti-TNF therapy. Additionally, there is some data to suggest that patients who are on both thiopurines and anti-TNF agents have an increased risk of postoperative complications compared to those who are on anti-TNF agents alone [34].