Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial

Laharie D, et al.

Lancet 2012 · PMID 23063316 (PubMed, opens in a new tab) · doi 10.1016/S0140-6736(12)61084-8 (full paper, opens in a new tab)

Figure 1. Treatment failure by day 98, ciclosporin minus infliximab. Failure meant no response at day 7, relapse between days 7 and 98, no steroid-free remission at day 98, a severe adverse event stopping treatment, colectomy or death. The square is the difference; the line is its 95% CI.

Data for this figure: Difference, percentage points (95% CI). Left of the null line: Favours ciclosporin. Right: Favours infliximab.
Outcome	Ciclosporin	Infliximab	Estimate (confidence interval)	P
Treatment failure, Primary endpoint · day 98 (primary)	60% (35/58)	54% (31/57)	+6 (95% CI −7 to 19)	P=0.52

The interval runs from 7 points fewer to 19 points more failures with ciclosporin: no difference was shown, but equivalence was not tested.

Source: Laharie 2012, abstract (intention to treat).

Structured abstract

BackgroundCiclosporin and infliximab were both used to avoid colectomy in acute severe UC refractory to IV steroids, but they had not been compared head to head in a randomised trial.

MethodsParallel, open-label, randomised controlled trial at 27 European centres. 115 patients. Primary endpoint: Treatment failure by day 98: no clinical response at day 7, relapse between days 7 and 98, no steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death.

ResultsPrimary result. Treatment failure 60% (35/58) with ciclosporin vs 54% (31/57) with infliximab; absolute risk difference 6% (95% CI −7 to 19); P=0.52

Take-homeCiclosporin and infliximab perform similarly as rescue therapy for steroid-refractory acute severe UC, in the short and long term.

Table 1. Trial at a glance

Patients	115
Population	Adults with acute severe UC (Lichtiger score >10) after an unsuccessful course of high-dose IV steroids; naive to ciclosporin and infliximab
Comparison	Ciclosporin 2 mg/kg/day IV for 1 week, then oral to day 98, vs infliximab 5 mg/kg on days 0, 14 and 42; azathioprine started at day 7 in responders in both arms
Drugs	ciclosporin, infliximab, azathioprine
Classes	Calcineurin inhibitor, Anti-TNF
Published	Laharie D, et al. Lancet 2012;380:1909–15.

Key points

Severe adverse events: 16% (9) with ciclosporin vs 25% (14) with infliximab.
Long-term follow-up (median 5.4 years; PMID 28053054): colectomy-free survival at 5 years 61.5% (ciclosporin) vs 65.1% (infliximab); P=0.97.
By 5 years, 57.1% of patients first treated with ciclosporin had received infliximab; only 4 infliximab patients later switched to ciclosporin.

Limitations

Open-label and small.
A non-significant difference in a small trial does not prove the drugs are equivalent.
Both arms used azathioprine maintenance, which may not suit patients already failing a thiopurine.

Commentary

Context. CYSIF is the European counterpart of the UK CONSTRUCT trial (PMID 27595142). Both reached the same conclusion: no meaningful efficacy difference between the two rescue drugs. The authors concluded that treatment choice should be guided by physician and centre experience.

Teaching point. Ciclosporin works as a bridge to thiopurine maintenance, so it suits thiopurine-naive patients. Infliximab can itself be continued as maintenance.

Journal club

PopulationAdults with acute severe UC (Lichtiger score >10) after an unsuccessful course of high-dose IV steroids; naive to ciclosporin and infliximab

InterventionCiclosporin 2 mg/kg/day IV for 1 week, then oral to day 98,

ComparisonInfliximab 5 mg/kg on days 0, 14 and 42; azathioprine started at day 7 in responders in both arms

Primary outcomeTreatment failure by day 98: no clinical response at day 7, relapse between days 7 and 98, no steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death

Design

Parallel, open-label, randomised controlled trial at 27 European centres. 115 patients.

Primary result. Treatment failure 60% (35/58) with ciclosporin vs 54% (31/57) with infliximab; absolute risk difference 6% (95% CI −7 to 19); P=0.52

Validity and applicability

Open-label and small.
A non-significant difference in a small trial does not prove the drugs are equivalent.
Both arms used azathioprine maintenance, which may not suit patients already failing a thiopurine.

Where it sits now

Ciclosporin and infliximab perform similarly as rescue therapy for steroid-refractory acute severe UC, in the short and long term.

ACTIVE (2025): After a steroid-responsive episode of acute severe UC in a thiopurine- and biologic-naive patient, starting infliximab plus azathioprine reduced 1-year treatment failure compared with azathioprine alone.
PREDICT-UC (2024): In steroid-refractory acute severe UC, a 10 mg/kg first infliximab dose or an accelerated schedule was not better than standard 5 mg/kg dosing.
TACOS (2024): Adding tofacitinib to IV steroids improved day-7 response in acute severe UC in one small single-centre trial; promising, but not yet standard care.
CONSTRUCT (2016): In steroid-refractory acute severe UC, infliximab and ciclosporin are equally effective rescue therapies; choose by local experience, patient factors and the maintenance plan.

Questions for discussion

The 95% CI runs from −7 to +19 points. Would a difference that size change your choice of rescue drug, and what sample size would have ruled it out?
Both arms started azathioprine in responders. How does this design apply to a patient already failing a thiopurine?
By 5 years most ciclosporin patients had received infliximab. What does that say about ciclosporin as a bridge?

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