SONICMust knowCD · Treatment strategy
Infliximab, azathioprine, or combination therapy for Crohn's disease
Colombel JF, et al.
N Engl J Med 2010 · PMID 20393175 (PubMed, opens in a new tab) · doi 10.1056/NEJMoa0904492 (full paper, opens in a new tab)
| Endpoint | Combination | Infliximab | Azathioprine | Difference |
|---|---|---|---|---|
| Corticosteroid-free remission, Week 26 (primary endpoint) | 56.8% (96/169) | 44.4% (75/169) | 30.0% (51/170) | Combination vs infliximab P=0.02; vs azathioprine P<0.001. Infliximab vs azathioprine P=0.006 |
| Mucosal healing, Week 26 · patients with endoscopy data | 43.9% (47/107) | 30.1% (28/93) | 16.5% (18/109) | Combination vs infliximab P=0.06; vs azathioprine P<0.001. Infliximab vs azathioprine P=0.02 |
Infliximab alone beat azathioprine alone, and the combination beat both for steroid-free remission; for mucosal healing, combination vs infliximab alone was not significant (P=0.06).
Source: Colombel 2010, abstract.
Structured abstract
BackgroundInfliximab and azathioprine were both used in Crohn's disease, but how they compared with each other, and whether giving them together was better than either alone, was unknown.
MethodsRandomized, double-blind trial with placebo infusions and placebo capsules; treatment to week 30 with a blinded extension to week 50. 508 patients. Primary endpoint: Corticosteroid-free clinical remission at week 26.
ResultsPrimary result. 56.8% (96/169) with combination vs 44.4% (75/169) with infliximab alone (P=0.02) vs 30.0% (51/170) with azathioprine alone (P<0.001 vs combination; P=0.006 for infliximab vs azathioprine).
Take-homeIn thiopurine- and biologic-naive Crohn's disease, infliximab plus azathioprine beats either drug alone for steroid-free remission and mucosal healing.
| Patients | 508 |
|---|---|
| Population | Adults with moderate-to-severe Crohn's disease (CDAI 220–450 per the trial registration) who had never received a thiopurine or a biologic; corticosteroid-dependent, being considered for another steroid course, or failing 5-ASA or budesonide. |
| Comparison | Infliximab 5 mg/kg (weeks 0, 2, 6, then every 8 weeks) plus azathioprine 2.5 mg/kg/day vs infliximab alone vs azathioprine alone |
| Drugs | infliximab, azathioprine |
| Classes | Anti-TNF, Thiopurine |
| Published | Colombel JF, et al. N Engl J Med 2010;362:1383–95. |
Key points
- Mucosal healing at week 26: 43.9% (47/107) combination vs 30.1% (28/93) infliximab (P=0.06) vs 16.5% (18/109) azathioprine (P<0.001 vs combination; P=0.02 vs infliximab).
- Similar numerical trends were seen at week 50.
- Serious infections: 3.9% combination, 4.9% infliximab alone, 5.6% azathioprine alone.
- Patients were naive to both drug classes and had relatively early disease, which is where the case for combination therapy is strongest.
Limitations
- Mucosal healing was assessed only in the subset with endoscopic data (denominators 107, 93 and 109).
- Azathioprine was started at the same time as infliximab; its slow onset disadvantages the azathioprine-alone arm at week 26.
- Too small and too short to define rare long-term risks of combination therapy such as lymphoma.
- Infliximab only; the result does not automatically transfer to other biologics.
Commentary
SONIC set the standard of starting infliximab together with a thiopurine in patients new to both drugs. Part of the benefit is thought to come from higher infliximab exposure and less immunogenicity, which is why proactive drug monitoring or methotrexate co-therapy are used when a thiopurine is not suitable.
Later trials have not shown the same clinical advantage with other biologics. In DIAMOND (adalimumab with or without azathioprine, open-label, 176 patients), week 26 clinical remission was 71.8% with monotherapy vs 68.1% with combination therapy (P=0.63), although endoscopic improvement was higher with combination therapy (84.2% vs 63.8%, P=0.019) (PMID 27566367). In SEAVUE, ustekinumab and adalimumab were both highly effective as monotherapy.
In practice, weigh the benefit against the risks of thiopurines, especially in young men (hepatosplenic T-cell lymphoma) and older adults (infection, lymphoma, skin cancer). SPARE informs how to de-escalate later.
Journal club
Design
Randomized, double-blind trial with placebo infusions and placebo capsules; treatment to week 30 with a blinded extension to week 50. 508 patients.
Primary result. 56.8% (96/169) with combination vs 44.4% (75/169) with infliximab alone (P=0.02) vs 30.0% (51/170) with azathioprine alone (P<0.001 vs combination; P=0.006 for infliximab vs azathioprine).
Validity and applicability
- Mucosal healing was assessed only in the subset with endoscopic data (denominators 107, 93 and 109).
- Azathioprine was started at the same time as infliximab; its slow onset disadvantages the azathioprine-alone arm at week 26.
- Too small and too short to define rare long-term risks of combination therapy such as lymphoma.
- Infliximab only; the result does not automatically transfer to other biologics.
Where it sits now
In thiopurine- and biologic-naive Crohn's disease, infliximab plus azathioprine beats either drug alone for steroid-free remission and mucosal healing.
- SEAVUE (2022): In biologic-naive moderate-to-severe Crohn's disease, ustekinumab was not superior to adalimumab monotherapy at 1 year and both worked well, so choose by patient factors, safety and preference.
- SPARE (2023): If you de-escalate combination therapy in stable Crohn's disease, stop the immunosuppressant, not infliximab; relapse is much less likely.
- PROFILE (2024): In newly diagnosed active Crohn's disease, starting infliximab plus an immunomodulator straight away gives far better 1-year and 5-year outcomes than step-up care.
- STARDUST (2022): With ustekinumab, an endoscopy-driven treat-to-target algorithm did not improve 48-week endoscopic response over clinically driven care; treat-to-target only helps if escalation has something to add.
Questions for discussion
- Is the benefit of adding azathioprine mainly extra immunosuppression or higher infliximab levels? How would you test that, and would methotrexate do as well?
- Patients were naive to both drugs and early in their disease. How far would you extrapolate the result to someone who has already failed a thiopurine?
- How would you weigh the gain from combination therapy against lymphoma and infection risk in a young man?