Comparable Long-Term Outcomes of Cyclosporine and Infliximab in Patients With Steroid-Refractory Acute Severe Ulcerative Colitis: A Meta-Analysis

Abstract

Background: In steroid-refractory acute severe ulcerative colitis (ASUC), cyclosporine (CYS) or infliximab (IFX) may be considered as a second-line alternative to avoid colectomy. There are short-term data reported, but until now, there is no meta-analysis regarding long-term outcomes of CYS and IFX in patients with ASUC. Aim: To compare long-term efficacy and safety of CYS and IFX in a meta-analysis. Methods: Three electronic databases (PubMed, Embase, Cochrane Central Register of Controlled Trials) were searched for studies which compared CYS vs. IFX in adults with ASUC. Long-term colectomy-free rate from 1 to 10 years during CYS or IFX therapy was collected, last updated up to 22nd May 2019. Primary outcome was long-term colectomy-free rate, secondary outcomes were adverse events (AE), serious adverse events (SAE), and mortality. Long-term colectomy-free survival and safety measures were pooled with the random-effect model. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. Results: Data from 1,607 patients in 15 trials were extracted. In the first 3 years, pooled OR for colectomy-free survival was higher with IFX than with CYS (OR = 1.59, 95% CI: 1.11-2.29, p = 0.012; OR = 1.57, 95% CI: 1.14-2.18, p = 0.006; and OR = 1.75, 95% CI: 1.08-2.84, p = 0.024; at 1, 2, and 3 years, respectively). However, the significant difference remained undetected from the fourth year of follow-up and in subgroup of RCTs (OR = 1.35, 95% CI: 0.90-2.01, p = 0.143; OR = 1.41, 95% CI: 0.94-2.12, p = 0.096; and OR = 1.34, 95% CI: 0.89-2.00, p = 0.157; at 1, 2, and 3 years, respectively). No significant difference was detected regarding adverse events, serious adverse events and mortality between the groups. The neutral associations proved to be underpowered with trial sequential analysis. Conclusion: However observational studies show IFX as a better choice, according to the RCTs, choosing either CYS or IFX as rescue therapy for ASUC, the long-term outcomes are not different, although further large RCTs are warranted.

Keywords: colectomy; cyclosporine; infliximab; meta-analysis; steroid-refractory; ulcerative colitis.

Figure 1

Results of the trial sequential analysis of the risks of 1 year colectomy-free rate. The required sample size of 1,502 patients was estimated using α = 0.05 (two-sided) and ß = 0.02 (power of 80%). Crossing of the constructed cumulative Z-curves (blue) and the two-sided Z = 1.96 provides a traditionally significant result. To obtain reliable evidence, crossing of the trial sequential monitoring boundaries (red) is needed. In the case of 1 year colectomy-free rate outcome, the cumulative Z-curve (blue) did not crossed the conventional boundary and neither the trial sequential monitoring boundary nor the required sample size line was surpassed.

Figure 2

Results of the trial sequential analysis of the risks of adverse events. The required sample size was calculated with α = 0.05 (two-sided) and ß = 0.02 (power of 80%). Although cumulative Z-curve (blue) reached the conventional boundary, it did not cross through. Number of participants (385) did not reach the information size (749) and the cumulative Z-curve does not cross the monitoring boundary either.

Figure 3

Results of the trial sequential analysis of the risks of serious adverse events. The required sample size was calculated using α = 0.05 (two-sided) and ß = 0.02 (power of 80%). The cumulative Z-curve (blue) did not cross the monitoring boundary (red) and not reached the required information size (4,325 patients). There is insufficient information about the evidence of significance.

Figure 4

PRISMA flowchart.

Figure 5

Odds ratios of colectomy-free survival with infliximab (vs. cyclosporine) in the first, second, and third year in steroid-refractory acute severe ulcerative colitis.

Figure 6

Odds ratios of colectomy-free survival with infliximab (vs. cyclosporine) between the fourth and tenth year in steroid-refractory acute severe ulcerative colitis.

Figure 7

Odds ratios of studies evaluating adverse events, serious adverse events, and mortality during infliximab treatment compared to the cyclosporine group in steroid-refractory acute severe ulcerative colitis.

Figure 8

Risk of bias in (A) RCTs and in (B) non-randomized studies.