From the Guidelines
For a patient with Crohn's disease who has failed both infliximab (Remicade) and adalimumab (Humira), I recommend switching to ustekinumab (Stelara) as the next line of treatment. This recommendation is based on the most recent and highest quality study available, which suggests that ustekinumab is effective in inducing and maintaining clinical remission in patients with moderate to severe Crohn's disease who have failed anti-TNF therapy 1. Ustekinumab is administered with an initial IV infusion (based on weight, approximately 6 mg/kg), followed by 90 mg subcutaneous injections every 8 weeks.
Key Considerations
- Before switching therapies, it's essential to confirm treatment failure through objective measures like endoscopy, imaging, or fecal calprotectin, and rule out complications like strictures or abscesses that might require surgical intervention.
- Check for anti-drug antibodies, as dose intensification might help if the patient has low drug levels without antibodies.
- Ustekinumab targets IL-12/23, providing a different mechanism of action than TNF inhibitors (infliximab and adalimumab).
Alternative Options
- If ustekinumab is not effective, consider vedolizumab (Entyvio) as an alternative, which blocks gut-specific α4β7 integrin.
- Other options, such as tofacitinib (Xeljanz) or risankizumab (Skyrizi), may also be considered, but the evidence for these agents is less robust compared to ustekinumab 1.
Evidence Summary
The AGA clinical practice guidelines recommend the use of ustekinumab over no treatment for the induction and maintenance of remission in adult outpatients with moderate to severe Crohn's disease who have failed anti-TNF therapy 1. The Canadian Association of Gastroenterology also suggests ustekinumab as a conditional recommendation for patients who fail to achieve or maintain clinical remission with anti-TNF-based therapy 1.
From the Research
Management of Crohn's Disease After Failure of Infliximab and Adalimumab
- The management of a patient with Crohn's disease who has failed treatment with Infliximab and Humira (adalimumab) involves several considerations, including the use of alternative therapies and the potential for reintroduction of previously used medications 2.
- A study published in the Journal of Crohn's & Colitis found that reintroducing Infliximab after successive failure of Infliximab and Adalimumab can be feasible and clinically efficient, particularly in patients who received co-immunosuppression during both treatments 2.
- The efficacy and safety of Adalimumab for the treatment of Crohn's disease in patients who have failed Infliximab treatment have been evaluated in a systematic review, which found that Adalimumab can be an effective treatment for these patients, with response and remission rates ranging from 29 to 83% during induction and 31 to 59% during maintenance therapy 3.
Alternative Therapies
- Infliximab maintenance therapy has been shown to be effective in patients with fistulizing Crohn's disease, with a significant reduction in the time to loss of response compared to placebo maintenance 4.
- The use of concomitant immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate may result in improved outcomes due to a reduction in the frequency of human anti-chimeric antibody formation, acute infusion reactions, and a reduced risk of delayed hypersensitivity-like reactions and formation of antinuclear antibodies 5.
Considerations for Treatment
- Patients with evidence of active infection should not receive Infliximab until the infection is adequately treated, and all patients should be screened for tuberculosis prior to initiating Infliximab therapy 5.
- Pretreatment with diphenhydramine (and in selected cases of acetaminophen and, rarely, corticosteroids) is recommended in patients with a history of infusion reactions and patients at risk for delayed hypersensitivity-like reactions 5.