EXITUC and CD · Positioning and de-escalation
Withdrawal of antitumour necrosis factor in inflammatory bowel disease patients in remission: a randomised placebo-controlled clinical trial of GETECCU
Gisbert JP, et al.
Gut 2025 · PMID 39794921 (PubMed, opens in a new tab) · doi 10.1136/gutjnl-2024-333385 (full paper, opens in a new tab)
| Endpoint | Continue anti-TNF | Stop (placebo) | Difference |
|---|---|---|---|
| Sustained clinical remission, 12 months (primary endpoint) | 84% (59/70), 95% CI 74–92 | 76% (53/70), 95% CI 64–85 | P=0.2; the trial was powered to detect an 18-point difference |
| Faecal calprotectin above 250 µg/g, End of follow-up · lower is better | 13% (8/59), 95% CI 6–25 | 33% (17/52), 95% CI 20–47 | P=0.01 |
| Significant endoscopic lesions, End of follow-up · lower is better | 8.5% (5/59), 95% CI 2.8–19 | 19% (11/59), 95% CI 9.6–31 | P=0.1; endoscopy was not the primary endpoint and the trial was not powered for it |
Clinical remission barely differed, but raised calprotectin and significant endoscopic lesions were each more than twice as common after stopping; only the calprotectin difference was significant.
Source: Gisbert 2025, full text (PMC11874338), Results: Sustained clinical remission, Biochemical relapse and Endoscopic relapse. Remission is intention to treat; calprotectin and endoscopy are observed values in the patients tested.
Structured abstract
BackgroundPatients in long-term remission on an anti-TNF plus an immunomodulator often ask to stop the anti-TNF; earlier withdrawal trials gave conflicting results, and many of their patients were left on no immunomodulator.
MethodsQuadruple-blind, placebo-controlled, multicentre randomised trial (33 Spanish IBD units); 12 months; enrolment closed at 140 of a planned 200. 140 patients. Primary endpoint: Sustained clinical remission at 12 months.
ResultsPrimary result. 84% (59/70; 95% CI 74–92) continuing anti-TNF vs 76% (53/70; 64–85) on placebo; P=0.2 (no significant difference).
Take-homeIn carefully selected patients in deep remission who stay on an immunomodulator, stopping the anti-TNF did not significantly reduce 1-year sustained remission, but calprotectin rose more often; withdrawal is an option to discuss, not a default.
| Patients | 140 |
|---|---|
| Population | Adults with Crohn's disease or UC in clinical remission for at least 6 months on standard-dose infliximab (86–87%) or adalimumab plus an immunomodulator (mostly thiopurines), with no significant endoscopic lesions (and no significant MR enterography lesions in ileal Crohn's disease). Perianal indication and previous resection excluded. |
| Comparison | Continue anti-TNF (n=70) vs switch to matching placebo (n=70); all continued the immunomodulator |
| Drugs | infliximab, adalimumab, azathioprine, mercaptopurine, methotrexate |
| Classes | Anti-TNF, Immunomodulator |
| Published | Gisbert JP, et al. Gut 2025;74:387–96. |
Key points
- Objective activity was higher after withdrawal: calprotectin above 250 µg/g at the end of follow-up 33% (17/52) vs 13% (8/59), P=0.01; significant endoscopic lesions 19% (11/59) vs 8.5% (5/59), P=0.1.
- Baseline calprotectin above 250 µg/g was the only predictor of losing remission (HR 5.2, 95% CI 1.5–18); anti-TNF level was not.
- Serious adverse events 4% vs 7%; no change in quality of life or work productivity.
- Long-term extension (125 patients): cumulative relapse 35% (95% CI 23–48) with maintenance vs 47% (34–60) after withdrawal; P=0.3. Of 26 who restarted anti-TNF after relapse, 69% regained remission (PMID 40317957).
- Contrast with STOP-IT (115 patients with Crohn's disease in deep remission on infliximab; about half on an immunomodulator): no relapses with continued infliximab vs 23 of 56 with placebo; relapse-free survival at week 48 100% vs 51%; HR 0.080 (95% CI 0.035–0.186); P<0.001 (PMID 38319804).
Limitations
- Underpowered after recruitment shortfall (powered for an 18-point difference).
- Pooled Crohn's disease and UC, and infliximab and adalimumab; effects in each group cannot be separated.
- Highly selected patients; results do not apply to those on intensified dosing, with perianal disease or after resection.
Commentary
EXIT is the first placebo-controlled trial of anti-TNF withdrawal that kept all patients on an immunomodulator, and its result is more reassuring than earlier trials. The authors attribute the difference from SPARE, STOP-IT and HAYABUSA to the fully blinded design and to patient selection: deep remission, standard dosing, no previous surgery, and continued immunomodulator therapy in everyone.
How to use it: if a patient in sustained deep remission on combination therapy wants to stop the anti-TNF, EXIT supports an informed trial off it with the immunomodulator continued, calprotectin monitoring, and a plan to restart promptly. A raised calprotectin at baseline argues against stopping. SPARE remains the evidence that, if one drug is to be stopped, stopping the immunomodulator carries the lowest relapse risk.
Journal club
Design
Quadruple-blind, placebo-controlled, multicentre randomised trial (33 Spanish IBD units); 12 months; enrolment closed at 140 of a planned 200. 140 patients.
Primary result. 84% (59/70; 95% CI 74–92) continuing anti-TNF vs 76% (53/70; 64–85) on placebo; P=0.2 (no significant difference).
Validity and applicability
- Underpowered after recruitment shortfall (powered for an 18-point difference).
- Pooled Crohn's disease and UC, and infliximab and adalimumab; effects in each group cannot be separated.
- Highly selected patients; results do not apply to those on intensified dosing, with perianal disease or after resection.
Where it sits now
In carefully selected patients in deep remission who stay on an immunomodulator, stopping the anti-TNF did not significantly reduce 1-year sustained remission, but calprotectin rose more often; withdrawal is an option to discuss, not a default.
- SPARE (2023): If you de-escalate combination therapy in stable Crohn's disease, stop the immunosuppressant, not infliximab; relapse is much less likely.
- HAYABUSA (2021): Stopping infliximab in UC remission lowered remission at week 48 (54.3% vs 80.4% when continued), although most patients respond to retreatment; continue anti-TNF therapy unless there is a strong reason to stop.
Questions for discussion
- The trial was powered for an 18-point difference and found 8 points. Is 'no significant difference' the same as 'safe to stop'?
- Calprotectin rose after withdrawal while symptoms did not. Which would you act on, and how often would you check it?
- Every patient stayed on an immunomodulator. How would you apply EXIT to a patient on anti-TNF monotherapy?