PROFILEMust knowCD · Treatment strategy
A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial
Noor NM, et al.
Lancet Gastroenterol Hepatol 2024 · PMID 38402895 (PubMed, opens in a new tab) · doi 10.1016/S2468-1253(24)00034-7 (full paper, opens in a new tab)
| Endpoint | Top-down | Step-up | Difference |
|---|---|---|---|
| Sustained steroid- and surgery-free remission, To week 48 (primary endpoint) | 79% (149/189) | 15% (29/190) | Absolute difference 64 percentage points (95% CI 57–72); P<0.0001 |
| Endoscopic remission, Week 48 · central or local reading | 67% (90/134) | 44% (52/119) | |
| Endoscopic remission, Week 48 · centrally read endoscopies only | 60% (55/92) | 45% (33/74) |
The endoscopic gap narrowed when only centrally read endoscopies were counted, which the authors suggest reflects confirmation bias in local reading.
Source: Noor 2024, abstract (primary endpoint) and full text (PMC11001594), Results: endoscopic remission, the first ranked secondary endpoint.
Structured abstract
BackgroundWhether newly diagnosed Crohn's disease should be treated top-down or with step-up care was debated, and a T-cell gene-expression biomarker had been proposed to pick out patients who need early intensive therapy.
MethodsMulticentre (UK), open-label, biomarker-stratified randomised controlled trial. 386 patients. Primary endpoint: Sustained steroid-free and surgery-free remission to week 48. A flare needed active symptoms (HBI ≥5) plus raised CRP or faecal calprotectin ≥200 µg/g.
ResultsPrimary result. 79% (149/189) with top-down vs 15% (29/190) with accelerated step-up; absolute difference 64 percentage points (95% CI 57–72); P<0.0001.
Take-homeIn 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.
| Patients | 386 |
|---|---|
| Population | Adults aged 16–80 with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, raised CRP and/or faecal calprotectin, and endoscopic inflammation). Median 12 days from diagnosis to enrolment; mostly inflammatory (B1) behaviour. |
| Comparison | Top-down infliximab plus immunomodulator vs accelerated step-up |
| Drugs | infliximab, azathioprine, mercaptopurine, methotrexate |
| Classes | Anti-TNF, Immunomodulator |
| Published | Noor NM, et al. Lancet Gastroenterol Hepatol 2024;9:415–27. |
Key points
- Top-down: infliximab 5 mg/kg plus azathioprine, low-dose mercaptopurine with allopurinol, or methotrexate. Step-up: a steroid course for each flare, with an immunomodulator added at the first flare and infliximab added at a further flare. Randomisation was stratified by the PredictSURE-IBD T-cell biomarker.
- No biomarker–treatment interaction (absolute difference 1 percentage point, 95% CI −15 to 15; P=0.944): the biomarker had no clinical utility.
- Endoscopic remission (no ulcers) at week 48: 67% (90/134) top-down vs 44% (52/119) step-up, a 23-point difference that shrank to 15 points when only centrally read endoscopies were counted.
- Fewer adverse events (168 vs 315) and serious adverse events (15 vs 42) with top-down; abdominal surgery for complications 1 vs 10; serious infections 3 vs 8 (no significant difference).
- 5-year follow-up (2026): Crohn's-related abdominal surgery in 6 vs 26 patients; time to surgery shorter with step-up (adjusted HR 5.23, 95% CI 1.99–13.76; P=0.0008) (PMID 42721994).
- 5-year follow-up: Crohn's-related admission 11% vs 21% and progression to stricturing or penetrating disease 7% vs 17% (top-down vs step-up), with no difference in serious infections or malignancy.
Limitations
- Open-label, with a primary outcome that partly depends on symptoms and on the need for steroids, which the step-up arm received by design.
- Infliximab-based combination only; whether other advanced therapies give the same benefit as first-line treatment is unknown.
- Mostly inflammatory (B1) disease in the UK NHS; the 5-year data are observational follow-up after protocol treatment ended at week 48.
- The comparator was accelerated step-up, which escalated faster than much real-world care.
Commentary
PROFILE is the strongest randomised evidence for top-down treatment in Crohn’s disease. The biomarker it was designed to test failed, but the treatment-strategy comparison was striking: only 15% of the step-up arm stayed in sustained steroid-free remission for the year, and 85% needed escalation to an immunomodulator.
The 5-year follow-up (PMID 42721994) adds that early infliximab plus immunomodulator was associated with fewer surgeries, fewer admissions and less progression to complications, suggesting a disease-modifying effect.
How to use it in Canada: PROFILE supports offering an anti-TNF with an immunomodulator early, rather than waiting for steroid failure, in patients with objectively active, newly diagnosed disease. Public drug-plan criteria may still require documented failure of conventional therapy, so be ready to document objective inflammation when applying.
Journal club
Design
Multicentre (UK), open-label, biomarker-stratified randomised controlled trial. 386 patients.
Primary result. 79% (149/189) with top-down vs 15% (29/190) with accelerated step-up; absolute difference 64 percentage points (95% CI 57–72); P<0.0001.
Validity and applicability
- Open-label, with a primary outcome that partly depends on symptoms and on the need for steroids, which the step-up arm received by design.
- Infliximab-based combination only; whether other advanced therapies give the same benefit as first-line treatment is unknown.
- Mostly inflammatory (B1) disease in the UK NHS; the 5-year data are observational follow-up after protocol treatment ended at week 48.
- The comparator was accelerated step-up, which escalated faster than much real-world care.
Where it sits now
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.
- STRIDENT (2022): Symptomatic Crohn's strictures with active inflammation often respond to adalimumab; intensifying therapy did not significantly improve symptoms; secondary results on treatment failure and MRI stricture appearance favoured it but are hypothesis-generating.
- CALM (2017): Escalating therapy on biomarkers plus symptoms, rather than symptoms alone, gives more mucosal healing in early Crohn's disease.
- REACT (2015): Early combined immunosuppression did not improve 1-year symptom remission but lowered 2-year surgery, admissions and complications, supporting early effective therapy.
Questions for discussion
- The step-up arm received steroids by design, and the primary endpoint counted steroid use. How much does that favour top-down?
- The endoscopic difference shrank with central reading. What does that tell you about outcome assessment in open-label trials?
- Would you apply PROFILE to a newly diagnosed patient with mild disease, or with stricturing disease?