Positioning biologics—A case‐based discussion: Ustekinumab

Compared with other autoinflammatory conditions, including rheumatologic and dermatologic diseases, there has been a relative paucity of mechanistically distinct biologic medications for the treatment of inflammatory bowel disease (IBD). The recent approval of ustekinumab (Stelara) in Australia for the treatment of moderate to severe Crohn's disease has been a welcome addition to the biologic armamentarium available to gastroenterologists who treat moderate to severe Crohn's disease. Ustekinumab is a monoclonal IgG1 antibody directed against p40, a subunit shared by both IL-23 and IL-12, which are pro-inflammatory cytokines implicated in the Th17 and Th1 cellular immune responses, respectively. These pathways have been shown to be drivers of inflammation in Crohn's disease.1 The efficacy of ustekinumab in the induction and maintenance of remission in Crohn's disease was demonstrated in the UNITI-1, UNIT-2, and UNITI-IM phase 3 clinical trials.2 Although efficacy was lower in patients who had previously failed anti-TNF therapy, treatment with ustekinumab showed clear superiority compared with placebo. In the clinical cases presented for this session, it is reasonable to consider ustekinumab as a potential treatment strategy. The first clinical case concerned a young male nurse with extensive small bowel Crohn's disease who presented with a stricturing phenotype and required surgery at the time of diagnosis. As noted in Session 1 (Predictors in IBD – Looking in to the Magic Ball), the clinical risk factors present in this case indicate that this patient is at high risk for developing future complications or disability from his disease. In accordance with Australian treatment guidelines, he was treated postoperatively with a course of antibiotics and commenced on a thiopurine but had evidence of active disease recurrence at 6 months indicating the need for an escalation in therapy, as demonstrated in the POCER trial.3 Given that he is a health-care worker and at possible risk of opportunistic infections, he was commenced on vedolizumab; however, after 6 months of therapy, he had persistently active Crohn's disease despite therapeutic levels of azathioprine metabolites. Given the patient's clinical risk factors, a change in therapy is required to gain control of his inflammation, which may otherwise progress to additional serious complications. While the efficacy of any change in therapy is paramount, we must also consider the safety of any new medication introduced. As stated, ustekinumab is efficacious for the treatment of inflammatory Crohn's disease, even in prior biologic non-responders.2 Real-world data published from a multicenter study in Canada, in which ustekinumab had been used off label (before its approval) in patients who had failed one or more anti-TNF therapies, over 50% of patients experienced clinical and objective (endoscopic or imaging) improvement, and ~25% of patients experienced remission at 6 months.4 It should be noted that no intravenous formulation was available in Canada at that time, and all patients had an induction with subcutaneous ustekinumab. In real-world data from the GETAID group in France, similar results were seen in a patient population that consisted entirely of patients who had failed biologics.5 With respect to durability of treatment, ustekinumab appears to be less immunogenic than infliximab and adalimumab with only 2.3% of patients developing anti-drug antibodies in the registration trials,2 which bodes well for the durability of therapy and also raises the possibility of monotherapy with this agent. In this case presentation, we are particularly concerned with the safety of ustekinumab in respect to opportunistic infections and any other serious adverse events, as this patient is young and will likely require biologic therapy for a prolonged period of time. Ustekinumab was initially studied in psoriasis and a prospective registry (PSOLAR) has been tracking adverse events in eligible patients who have been treated with ustekinumab, other biologics, or non-biologic treatments; results indicate that there has been no safety signal observed with respect to infections, cardiovascular events, or malignancy in over 40 000 patient-years of follow up.6 An important caveat to this data is that the dose of ustekinumab commonly used in psoriasis is 45 mg every 12 weeks, significantly lower than the dose used in Crohn's disease. The second clinical scenario concerned a young woman with ileal Crohn's disease, a history of pancreatitis with azathioprine, who is considering having another pregnancy in the future, and travels to areas with endemic tuberculosis. This patient cannot be given immunomodulators, due to the risk of recurrent pancreatitis with thiopurines, and methotrexate is contraindicated in pregnancy, and therefore, combination therapy is not an option. This makes treatment with anti-TNFs, particularly infliximab, problematic due to immunogenicity risks and potential loss of response. As previously mentioned, ustekinumab has shown minimal immunogenicity, even when used as monotherapy, which is reassuring in patients who cannot take immunomodulators such as this patient. In addition, anti-TNF use in patients who live or travel to areas with endemic tuberculosis requires vigilance, because primary infection or reactivation can result in a serious and life-threatening infection without prompt treatment. However, there does not appear to be any increased risk with respect to tuberculosis infection with ustekinumab use during clinical trials or from subsequent registry data. Pregnancy is a special situation for patients with IBD on biologic therapy. Anti-TNF agents have the best safety data with respect to pregnancy, although many guidelines recommend holding treatment in the third trimester in patients who are in sustained remission.7 Ustekinumab is an IgG1 molecule and will therefore crosses the placenta into the fetal blood stream, particularly in the second and third trimesters of pregnancy. Data thus far have been largely reassuring but mainly derived from the dermatology literature, and it is considered generally safe during pregnancy in Crohn's disease.8 As with other biologic agents, due to placental transfer, live vaccination should be avoided in infants during the first 6–12 months of life.7 More data are needed with respect to ustekinumab in pregnancy at the doses used in Crohn's disease, but the existing body of evidence is reassuring. JB has received honorariums and consulting fees from Takeda and Janssen-Cilag.

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