Esophagus to Small Intestine
Lancet Gastroenterol Hepatol. 2023;8(3):215–27
Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn’s disease on combination therapy (SPARE): A multicenter, open-label, randomized controlled trial
Background: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn’s disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. The aim of this trial was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy.
Methods: This multicenter, open-label, randomized controlled trial was performed in 64 hospitals in 7 countries in Europe and Australia. Adult patients with Crohn’s disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomization was stratified according to disease duration before start of first anti-tumor necrosis factor treatment (≤ 2 or > 2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomization website. Treatment was optimized or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analyzing the data were not masked to group assignment. The coprimary end points were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis.
Findings: Between November 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomized and 207 were included in the final analysis (n = 67 in the combination group, n = 71 in the infliximab withdrawal group, and n = 69 in the immunosuppressant withdrawal group). 39 patients had a relapse (8/67 [12%] in the combination group, 25/71 [35%] in the infliximab withdrawal group, 6/69 [9%] in the immunosuppressant withdrawal group). Two-year relapse rates were 14% (95% confidence interval [CI]: 4–23) in the combination group, 36% (95% CI: 24–47) in the infliximab withdrawal group, and 10% (95% CI: 2–18) in the immunosuppressant withdrawal group (hazard ratio [HR] = 3.45; 95% CI: 1.56–7.69; p = 0.003, for infliximab withdrawal vs. combination, and 4.76; 95% CI: 1.92–11.11; p = 0.0004, for infliximab withdrawal vs. immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimized according to protocol, remission was achieved in 25 patients (1/2 in the combination group, 22/23 in the infliximab withdrawal group, and 2/3 in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI: 668–727) in the combination group, 684 days (95% CI: 651–717) in the infliximab withdrawal group, and 706 days (95% CI: 682–730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI: -56–27) between the infliximab withdrawal group and the combination group and -22 days (95% CI: -62–16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). The authors recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (4 in the combination group, 2 in the infliximab withdrawal group, and 1 in the immunosuppressant withdrawal group) and Crohn’s disease exacerbation (3 in the combination group, 4 in the infliximab withdrawal group, and 1 in the immunosuppressant withdrawal group). No death nor malignancy was recorded.
Interpretation: In patients with Crohn’s disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation.