SPAREMust knowCD · Positioning and de-escalation
Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial
Louis E, et al.
Lancet Gastroenterol Hepatol 2023 · PMID 36640794 (PubMed, opens in a new tab) · doi 10.1016/S2468-1253(22)00385-5 (full paper, opens in a new tab)
| Endpoint | Continue both | Stop infliximab | Stop immunosuppressant | Difference |
|---|---|---|---|---|
| Relapse by 2 years, Co-primary endpoint (primary endpoint) | 14% (n=67), 95% CI 4–23 | 36% (n=71), 95% CI 24–47 | 10% (n=69), 95% CI 2–18 | Stopping infliximab: HR 3.45 (95% CI 1.56–7.69) vs continuing both, and 4.76 (1.92–11.11) vs stopping the immunosuppressant |
Stopping the immunosuppressant kept relapse close to continuing both drugs; stopping infliximab did not.
Source: Louis 2023, abstract (207 patients in the final analysis).
Structured abstract
BackgroundConcerns about long-term combination therapy made de-escalation common, but which drug to stop in stable Crohn's disease had not been compared in a randomised trial.
MethodsMulticentre, open-label, randomised controlled trial (64 hospitals, seven countries in Europe and Australia). 211 patients. Primary endpoint: Co-primary over 2 years: relapse rate (superiority) and time in remission (non-inferiority, margin 35 days).
ResultsPrimary result. 2-year relapse: 14% (95% CI 4–23) combination, 36% (24–47) infliximab withdrawal, 10% (2–18) immunosuppressant withdrawal. HR 3.45 (95% CI 1.56–7.69; P=0.003) for infliximab withdrawal vs combination and 4.76 (1.92–11.11; P=0.0004) vs immunosuppressant withdrawal.
Take-homeIf you de-escalate combination therapy in stable Crohn's disease, stop the immunosuppressant, not infliximab; relapse is much less likely.
| Patients | 211 |
|---|---|
| Population | Adults with Crohn's disease in steroid-free clinical remission for more than 6 months on infliximab plus an immunosuppressant (thiopurine or methotrexate) for at least 8 months. 207 analysed. |
| Comparison | Continue combination therapy vs stop infliximab vs stop the immunosuppressant (1:1:1); treatment optimised or resumed at relapse |
| Drugs | infliximab, azathioprine, mercaptopurine, methotrexate |
| Classes | Anti-TNF, Immunomodulator |
| Published | Louis E, et al. Lancet Gastroenterol Hepatol 2023;8:215–27. |
Key points
- Of 23 patients who relapsed after stopping infliximab and were retreated per protocol, 22 regained remission.
- Mean time in remission over 2 years: 698 days combination, 684 days infliximab withdrawal, 706 days immunosuppressant withdrawal.
- Difference in time in remission: −14 days (95% CI −56 to 27) infliximab withdrawal vs combination; the CI crossed the −35-day margin, so non-inferiority was not shown.
- 31 serious adverse events in 20 patients, with no difference between groups; no deaths or malignancies.
Limitations
- Open-label.
- Infliximab only; findings may not apply to other biologics.
- Ulcers at baseline endoscopy were allowed (randomisation was stratified by their presence), so not all patients had mucosal healing.
Commentary
SPARE gives randomised support to a common practice: after a period of stable remission on infliximab plus a thiopurine or methotrexate, stopping the immunosuppressant keeps relapse rates similar to continuing both drugs. Stopping infliximab more than tripled the hazard of relapse compared with continuing both drugs, although most patients regained remission when infliximab was restarted.
Check infliximab trough levels before and after stopping the immunosuppressant, since the immunosuppressant may have been supporting drug levels. Withdrawing infliximab can still be discussed with low-risk patients who strongly prefer it, using the risk factors from STORI.
Later evidence: in the placebo-controlled EXIT trial (2025; 140 patients with Crohn’s disease or UC in deep remission, all continuing an immunomodulator), stopping the anti-TNF did not significantly reduce sustained clinical remission at 12 months (76% vs 84%; P=0.2), although calprotectin above 250 µg/g was more common after withdrawal (33% vs 13%; P=0.01). Stopping the immunomodulator remains the lower-risk choice, but anti-TNF withdrawal can be discussed in carefully selected patients.
Journal club
Design
Multicentre, open-label, randomised controlled trial (64 hospitals, seven countries in Europe and Australia). 211 patients.
Primary result. 2-year relapse: 14% (95% CI 4–23) combination, 36% (24–47) infliximab withdrawal, 10% (2–18) immunosuppressant withdrawal. HR 3.45 (95% CI 1.56–7.69; P=0.003) for infliximab withdrawal vs combination and 4.76 (1.92–11.11; P=0.0004) vs immunosuppressant withdrawal.
Validity and applicability
- Open-label.
- Infliximab only; findings may not apply to other biologics.
- Ulcers at baseline endoscopy were allowed (randomisation was stratified by their presence), so not all patients had mucosal healing.
Where it sits now
If you de-escalate combination therapy in stable Crohn's disease, stop the immunosuppressant, not infliximab; relapse is much less likely.
- STORI (2012): About half of patients relapse within a year of stopping infliximab from combination therapy, but most regain remission on re-treatment, and biomarkers identify a lower-risk group.
- EXIT (2025): 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.
Questions for discussion
- Why might stopping the immunosuppressant lower infliximab levels, and how would you check?
- Mean time in remission over 2 years was 698, 684 and 706 days, but non-inferiority was not shown. Does that change how you weigh the higher relapse rate after stopping infliximab?
- Which patients might still reasonably stop infliximab rather than the immunosuppressant?