Substance and claimed effects

"Top-down" therapy for inflammatory bowel disease (IBD) is the strategy of initiating a biologic agent — typically an anti-tumor-necrosis-factor (anti-TNF) monoclonal antibody such as infliximab or adalimumab, often combined with an immunomodulator (azathioprine or methotrexate) — at or shortly after diagnosis in patients with moderate-to-severe Crohn's disease (CD) or ulcerative colitis (UC). It is the explicit alternative to the historical "step-up" approach, which begins with 5-aminosalicylates and/or systemic corticosteroids, escalates to immunomodulator monotherapy if disease persists, and reserves biologics for refractory or complicated cases. Newer agents now used in the top-down position include the IL-23 inhibitors risankizumab, mirikizumab and guselkumab; the IL-12/23 inhibitor ustekinumab; the gut-selective integrin inhibitor vedolizumab; and the oral JAK inhibitors upadacitinib and tofacitinib. The claimed consequences cluster around four endpoints: higher rates of sustained steroid-free clinical remission; higher rates of endoscopic mucosal healing; lower cumulative steroid exposure and its iatrogenic harms; and reduction of long-term complications — bowel-wall damage, strictures, fistulas, hospitalizations and surgery. Secondary felt-experience consequences follow from disease control: resolution of fatigue, normalization of bowel function, reduction of pain, return of weight and appetite, and partial reversal of the depression and anxiety that co-vary with active inflammation.

Evidence by addressing question

Mechanism

The biological argument has two layers. The first is the pharmacology of the agents themselves: infliximab is a chimeric IgG1 monoclonal antibody that binds both soluble and membrane-bound TNF-α, neutralizing its signalling, inducing apoptosis of inflammatory T cells and monocytes, downregulating downstream cytokine cascades (IFN-γ, IL-6), inducing FOXP3+ regulatory T cells, normalizing endothelial function and restoring matrix metalloproteinase / TIMP balance to permit mucosal repair Hanauer et al. 2002. The second is the "window of opportunity" hypothesis. Cross-sectional natural-history data show that approximately 20% of patients with Crohn's disease develop penetrating or stricturing complications within 90 days of diagnosis, rising to ~50% by 20 years post-diagnosis. The hypothesis is that the disease passes through a predominantly inflammatory phase early on, before fibrostenotic remodelling, fistulization and surgery have produced irreversible bowel damage; anti-inflammatory pharmacology is therefore mechanistically positioned to alter disease trajectory only if delivered before that remodelling is established. Once a stricture has fibrosed or a fistula has tracked, no biologic reverses the damage; the same drug delivered three years later acts on a different tissue substrate.

Evidence

The randomised-trial evidence base is large and unusually consistent across two decades.

D'Haens 2008 (Lancet). The original "top-down vs step-up" trial randomised 133 newly diagnosed, immunomodulator- and biologic-naïve CD patients to either early combined infliximab + azathioprine or conventional step-up (corticosteroid induction, with azathioprine added only on flare). At week 52, 60% of the top-down group were in steroid-free remission without surgery or resection vs 36% of the step-up arm; at 2 years the advantage persisted, with significantly higher mucosal healing on endoscopy in the top-down group D'Haens et al. 2008. The trial was open-label and modest in size, but it established the conceptual frame.

SONIC 2010 (NEJM). 508 immunomodulator- and biologic-naïve adults with moderate-to-severe CD were randomised to infliximab monotherapy, azathioprine monotherapy, or infliximab + azathioprine. At week 26, steroid-free remission was achieved by 56.8% on combination, 44.4% on infliximab, and 30.0% on azathioprine; mucosal healing rates followed the same hierarchy. Combination therapy also halved the rate of anti-drug antibody formation against infliximab (≈4% vs ≈13%), explaining part of its durability advantage Colombel et al. 2010.

REACT 2015 (Lancet). A pragmatic cluster-randomised trial across 41 community gastroenterology practices in Belgium and Canada. Practices were randomised to an early combined immunosuppression (ECI) algorithm — accelerated to anti-TNF + immunomodulator on any failure of steroid induction — or to conventional care. At 2 years, the ECI arm showed a significantly lower composite rate of surgery, hospitalization, and serious disease-related complications, although the primary endpoint of clinical remission at one year did not differ between arms Khanna et al. 2015.

CALM 2017 (Lancet). 244 patients with active early CD were randomised to symptom-driven escalation (clinical management) versus "tight control" — escalation also triggered by elevated C-reactive protein or faecal calprotectin. Both arms used the same drug ladder (corticosteroid → adalimumab → adalimumab weekly + azathioprine). At week 48, the proportion in mucosal healing was 46% with tight control vs 30% with symptom-driven management Colombel et al. 2017. CALM is a treat-to-target trial rather than a pure top-down trial, but it established that letting symptoms alone gate biologic escalation systematically under-treats inflammation.

PROFILE 2024 (Lancet Gastroenterol Hepatol). The most recent, largest, and methodologically tightest test of the strategy. 386 newly-diagnosed CD adults across 40 UK hospitals were randomised at a median of 12 days post-diagnosis to either top-down infliximab + immunomodulator from week 0 or an accelerated step-up algorithm (steroid taper → immunomodulator at flare → infliximab at second flare). The primary endpoint, sustained steroid-free and surgery-free remission at week 48, was achieved by 79% (149/189) of the top-down group vs 15% (29/190) of the step-up group — a 64-percentage-point absolute difference (95% CI 57 to 72; p<0.0001). Adverse events were lower in the top-down arm (168 vs 315), as were serious adverse events (15 vs 42) and abdominal surgeries (1 vs 10); serious infections did not differ (3 vs 8) Noor et al. 2024. PROFILE also tested a blood T-cell transcriptional biomarker (PredictSURE-IBD) for treatment stratification — there was no biomarker–treatment interaction, meaning every subgroup benefitted from top-down. Five-year follow-up data, presented at ECCO 2026, showed no excess in serious infections (7% vs 8%) or malignancies (3% vs 2%) in the top-down arm and persistent inferiority of the step-up arm even when anti-TNF was started within six months.

Ulcerative colitis. Direct head-to-head top-down vs step-up RCTs are scarcer in UC than in CD. Infliximab efficacy in moderate-to-severe UC was established by ACT 1 and ACT 2 Rutgeerts et al. 2005. Observational cohorts and a 2024 evidence review concluded that early biologic initiation (within 36 months of diagnosis) improved clinical remission, mucosal healing and colectomy rates; population-based time-trend analyses show a 30–60% reduction in colectomy rates over the biologic era in most jurisdictions, although Israeli data dissent. Vedolizumab vs infliximab head-to-head data in UC favour vedolizumab on safety and possibly endoscopic response (78% vs 63% in a 297-patient cohort presented at AIBD 2024), without RCT confirmation.

Practice / clinical consensus

The 2024 ECCO Guidelines on Therapeutics in Crohn's Disease recommend adalimumab, infliximab, ustekinumab, certolizumab, vedolizumab, risankizumab, upadacitinib and ozanimod as induction options for moderate-to-severe CD; combination of infliximab with thiopurines is suggested over monotherapy for biologic-naïve patients, on the basis of SONIC and PROFILE ECCO 2024. The 2025 AGA Living Clinical Practice Guideline goes further, formally suggesting initial advanced therapy over step therapy involving corticosteroids in adults with moderate-to-severely active CD, and recommending the higher-efficacy agents (infliximab, adalimumab, ustekinumab, risankizumab, mirikizumab, guselkumab, vedolizumab) over the lower-efficacy ones (certolizumab pegol, upadacitinib) in the biologic-naïve setting AGA 2025. The British Society of Gastroenterology aligned in 2024. The PROFILE investigators argued in their conclusion that "top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease."

Protocol

Infliximab is dosed at 5 mg/kg by intravenous infusion at weeks 0, 2, and 6 for induction, then 5 mg/kg every 8 weeks for maintenance; dose can be escalated to 10 mg/kg or shortened to every-4-weekly intervals if therapeutic drug monitoring shows subtherapeutic troughs (typically <5 µg/mL) or loss of response. Subcutaneous infliximab (CT-P13 SC) is now approved for maintenance after IV induction, dosed at 120 mg every 2 weeks. Adalimumab induction is 160 mg sc at week 0, 80 mg at week 2, then 40 mg every 2 weeks (or 80 mg / 40 mg in lower-intensity induction). Combination with weight-based azathioprine (≈2–2.5 mg/kg/day) or methotrexate reduces anti-drug-antibody formation, especially against infliximab Colombel et al. 2010. Pre-treatment screening: chest X-ray plus interferon-γ release assay for latent tuberculosis, hepatitis B serology, hepatitis C, HIV, and consideration of varicella status and inactivated vaccinations before initiation.

Contraindications

Absolute: active untreated tuberculosis or other serious active infection; sepsis; severe heart failure (NYHA Class III/IV) for anti-TNF specifically. Strong relative: untreated latent TB (treat first), demyelinating disease (multiple sclerosis, optic neuritis) for anti-TNF, recent lymphoma (within 5 years) for anti-TNF + thiopurine combination. Pregnancy is not a contraindication — anti-TNF is generally continued through pregnancy, with infliximab and adalimumab now categorized as acceptable in most pregnancy guidelines because uncontrolled IBD carries greater foetal risk than the drug. Live vaccines should be avoided once therapy starts.

Failure modes

Primary non-response (failure to respond at all by induction-end, week 12–14) occurs in 10–40% across anti-TNF trials, varying by definition. Secondary loss of response occurs in 13–26% per year, driven mostly by anti-drug antibody formation accelerating clearance, with subtherapeutic troughs Kennedy et al. 2019. The PANTS cohort identified HLA-DQA1*05 carriage as a major immunogenicity risk factor for infliximab specifically. Mitigation: concomitant immunomodulator (reduces immunogenicity), therapeutic drug monitoring (proactive or reactive), dose escalation, switch within class (anti-TNF to anti-TNF) or out of class (anti-TNF to vedolizumab, ustekinumab, risankizumab, upadacitinib). Loss of response to a first anti-TNF predicts somewhat reduced response to a second.

Stakes

Two stake currencies: drug-side and disease-side. Drug-side: the historical step-up sequence routes virtually every moderate-to-severe IBD patient through repeated systemic corticosteroid courses. In the Olmsted County natural-history cohort, 28% of CD patients became steroid-dependent and 16% steroid-resistant within one year of starting steroids; 38% required CD-related surgery within that year Faubion et al. 2001. Cumulative steroid exposure produces weight gain (~40% of users in a 9,229-patient IBD survey), mood disturbance, insomnia, acne, moon facies, hypertension, hyperglycaemia, osteoporosis, cataracts and adrenal suppression. Corticosteroid exposure is independently associated with progression to stricturing disease (aHR ≈2.1) on multivariable analysis, while biologic exposure is not. Disease-side: untreated or under-treated moderate-to-severe Crohn's accumulates strictures, fistulas, abscesses, bowel resections and short-bowel syndrome over decades; quality-of-life decrements track tightly with active inflammation (the IBD-BOOST UK survey of >8,000 patients found pain and fatigue produced the largest QoL decrements; depression prevalence in CD is ~39% vs 11% general population; anxiety 24% vs 16%).

Payoff

The PROFILE arm achieved 79% sustained steroid-free, surgery-free remission at 48 weeks Noor et al. 2024. The felt translation: bowel-movement frequency falls from 6–10/day to 1–3/day within 2–6 weeks of the first infusion; nocturnal diarrhea and urgency typically resolve first; abdominal pain follows; fatigue lags but tracks resolution of inflammation over 2–4 months; weight returns. Mucosal healing on follow-up endoscopy at 6–12 months predicts longer relapse-free intervals and lower colectomy / resection rates. Depression and anxiety scores partially normalise with disease control. Five-year follow-up suggests durable benefit and no excess in serious infections or malignancy versus step-up Noor et al. 2024.

Practicalities (cost, access)

Originator infliximab and adalimumab list pricing was historically >$25,000–50,000 per patient-year in the United States; biosimilar entry (infliximab-dyyb 2016, infliximab-abda 2017, adalimumab biosimilars 2023) has compressed prices materially — by ~50–60% per infusion for infliximab originator from December 2017 to December 2021 — but coinsurance structures often leave US patient out-of-pocket cost >$3,000–5,000/year. In NHS / EU jurisdictions with biosimilar mandates, drug cost is no longer the binding constraint; the PROFILE cost-effectiveness analysis estimated top-down infliximab saved £1,681 per patient over five years at NHS prices (£10,059 with adalimumab), dominating step-up in 98.7% of model simulations at a £30,000/QALY threshold Lee et al. 2025. Infusion route burden: infliximab IV requires 2-hour infusions every 8 weeks at an infusion centre, plus ~1-hour observation; subcutaneous infliximab and adalimumab can be self-injected at home. Therapeutic drug monitoring requires periodic trough-level draws.

Misconceptions

Three persistent ones in clinical practice. (1) "Step-up is the safer default — biologics carry too much long-term risk to start early." Meta-analyses and the PROFILE 5-year follow-up show top-down does not produce excess serious infections or malignancy compared with step-up; the latter exposes the patient to more cumulative steroids and more disease-driven harms Singh et al. 2020. The risk comparison is not "biologic vs nothing" — it is "biologic vs cumulative steroids + ongoing inflammation." (2) "Biomarkers can tell us who needs top-down." PROFILE specifically tested the leading T-cell transcriptional biomarker and found no interaction with treatment effect Noor et al. 2024; every subgroup benefits. (3) "Mild disease can step up safely." This is true and explicitly outside the top-down indication; top-down is the strategy for moderate-to-severe disease, defined endoscopically and biochemically. Mild disease (CDEIS <6, normal CRP/calprotectin) is properly managed with budesonide or mesalamine and watchful escalation.

Alternatives

Within the top-down position itself, alternatives to anti-TNF + immunomodulator have proliferated. Ustekinumab (anti-IL-12/23) and the more potent IL-23-specific agents risankizumab, mirikizumab and guselkumab match anti-TNF on efficacy in moderate-to-severe CD with cleaner safety profiles (no immunogenicity-driven loss of response problem and lower infection risk). Vedolizumab (gut-selective α4β7-integrin antagonist) is the alternative when systemic immunosuppression is undesirable — older patients, prior malignancy, demyelinating disease — and is the head-to-head winner against infliximab as first-line UC therapy in retrospective comparative data. Oral JAK inhibitors (upadacitinib, tofacitinib) offer rapid onset and oral dosing, traded against a black-box warning for cardiovascular events and malignancy in older / cardiovascular-risk patients. Outside of advanced therapy entirely, treat-to-target with biomarker monitoring (CALM-style) is the partial-credit option — letting calprotectin rather than symptoms gate escalation — and accelerated step-up (the comparator in PROFILE) is what most patients still receive in practice.

History

Infliximab received FDA approval for Crohn's disease in 1998. Step-up management was the explicit standard through the late 1990s and 2000s — historically rooted in the high cost of early biologics and conservative attitudes about systemic immunosuppression. The pivotal D'Haens 2008 trial coined the "top-down" terminology by analogy to early-aggressive rheumatoid-arthritis treatment D'Haens et al. 2008. SONIC reinforced the combination-therapy advantage Colombel et al. 2010. REACT extended the case at community-practice scale Khanna et al. 2015. CALM established treat-to-target with biomarkers Colombel et al. 2017. PROFILE in 2024 was the definitive demonstration that prompted both ECCO and AGA to lean their guidelines toward early advanced therapy in 2024–25 Noor et al. 2024, ECCO 2024, AGA 2025.

The credibility range

Optimist case

The strongest pro-position is that top-down is the rare paradigm shift backed by replication across two decades, four major randomised trials (D'Haens 2008, SONIC 2010, REACT 2015, PROFILE 2024) and consistent mechanism, with the most recent and largest trial showing a 64-percentage-point absolute benefit on the most clinically meaningful endpoint (steroid-free, surgery-free remission), with fewer adverse events, fewer serious adverse events, and fewer surgeries — and now five-year safety reassurance and dominant cost-effectiveness. The "biologics are dangerous" objection that delayed adoption is empirically refuted by the safety data. The "they're too expensive" objection is increasingly refuted by biosimilar pricing and by formal cost-effectiveness analysis. Major guideline bodies have moved; the historical reluctance was a conservatism error, costing patients years of unnecessary steroid-mediated harm and bowel damage. Top-down should be the default in moderate-to-severe disease; the burden of justification has flipped to the step-up defender.

Skeptic case

Several persistent concerns. (1) The 5-year follow-up at PROFILE shows no safety signal at five years, but anti-TNF in IBD has not been followed at population scale for the 30–50-year horizon of a 25-year-old at diagnosis; rare lymphomas (hepatosplenic T-cell lymphoma with combination thiopurine + anti-TNF), late demyelinating events, and other rare delayed harms cannot be ruled out by RCT timelines. (2) PROFILE was UK-based, single-payer, NHS biosimilar pricing — its cost-effectiveness does not translate directly to US fragmented insurance. (3) The trials enrolled moderate-to-severe disease as defined by composite indices, CRP, calprotectin and endoscopy; the criteria don't perfectly identify the patient who would never have progressed under step-up — meaning a fraction of top-down patients receive lifelong biologic for disease that would have been mild. (4) Biomarker stratification was the field's hope to solve that overtreatment problem and failed in PROFILE; no current tool reliably identifies the indolent subset. (5) Anti-TNF immunogenicity remains an issue — primary non-response 10–40%, secondary loss 13–26%/year — so "top-down" does not mean "set and forget," and the patient committing to it implicitly commits to therapeutic drug monitoring, possible switching, and sometimes failure. (6) Step-up enthusiasts argue that accelerated step-up (with calprotectin-gated escalation, as in PROFILE's comparator) would catch most cases without exposing low-risk patients to upfront biologics; PROFILE's data refute this but the philosophical objection persists.

Author's call

For moderate-to-severe IBD at diagnosis, the evidence converges on top-down as the default. Four positive trials over twenty years, the largest of them PROFILE at 386 patients with a 64-percentage-point effect size, plus five-year safety data showing no excess infection or malignancy versus step-up, plus formal cost dominance, plus aligned ECCO 2024 and AGA 2025 guidelines, places this in the rare "evidence base strong enough to inform a default" category — `evidence: 5`. Residual controversy is real but moderate (`controversy: 2`): the long-term-safety horizon is genuinely incomplete, biomarker stratification has not delivered, and a meaningful minority of patients will receive lifelong therapy for disease they might have managed lighter. These caveats do not weaken the case enough to defend step-up as the default in moderate-to-severe disease. The article will frame top-down as the strategy to advocate for at diagnosis when disease meets the moderate-to-severe threshold, will keep mild disease explicitly out of scope, and will be honest about the residual unknowns.

Stakeholder and incentive map

• Pharmaceutical industry — originator biologic manufacturers (Janssen for infliximab/Remicade and ustekinumab/Stelara; AbbVie for adalimumab/Humira and risankizumab/Skyrizi; Takeda for vedolizumab/Entyvio; Pfizer for tofacitinib; Eli Lilly for mirikizumab) have funded the trials and have direct commercial interest in early-and-broader adoption. SONIC, ACCENT, several PROFILE-related analyses had industry funding; trial conduct quality is generally high but the source matters for transparency.
• Biosimilar manufacturers — opposite incentive on price, aligned incentive on broader prescription. Their market entry has been the principal force collapsing biologic cost.
• Gastroenterology professional societies — ECCO, AGA, BSG, ACG have moved toward early advanced therapy across 2024–25; this reflects evidence but also the field's identity as "the specialty that uses biologics" relative to alternatives (surgeons, dieticians).
• Payers / insurers — historically incentivised step-up via prior-authorisation requirements and step-edit policies; under biosimilar pricing and PROFILE cost-effectiveness, the incentive is starting to flip. US fragmented insurance still creates patient-facing financial toxicity.
• Patient advocacy — Crohn's & Colitis Foundation and equivalent UK / EU bodies have advocated for earlier biologic access; aligned with top-down.
• Skeptic / counter-incentive — primary-care physicians and older gastroenterologists trained in the step-up era; alternative-medicine and diet-first communities (some of which medicalise IBD outside the inflammatory-disease frame); and a smaller heterodox subset arguing biologics are over-prescribed.

Population variability

Demographics. Peak IBD diagnosis falls in the 15–35 age band; a smaller second peak in 50s–60s. Crohn's slightly female-predominant in adults, UC slightly male-predominant; effect not large enough to gender-scope the entry.

Disease severity. Top-down applies to moderate-to-severe IBD at diagnosis — Crohn's Disease Activity Index ≥220 / Harvey-Bradshaw Index ≥7 / total Mayo score ≥6 in UC, plus objective inflammation (elevated CRP, calprotectin, endoscopic disease). Mild disease is outside scope and step-up appropriate.

Phenotype. Stricturing or penetrating Crohn's behaviour at diagnosis (B2, B3 in the Montreal classification), perianal disease, ileal location, early extensive UC, and young age at diagnosis are all independent predictors of more aggressive course and stronger top-down candidates.

Comorbidities. Older patients (≥60), cardiovascular comorbidity, prior malignancy, demyelinating disease all shift the agent choice within the top-down position — typically toward vedolizumab or ustekinumab — rather than against the strategy itself.

Pregnancy. Anti-TNF and other biologics are continued through pregnancy in current ECCO and AGA guidance; uncontrolled IBD is a greater fetal risk than the medication.

Pediatric IBD. The strategy applies; pediatric trials (Lee 2015 single-centre, ongoing multicentre work) show similar benefit. Outside this entry's adult scope but worth flagging.

Knowledge gaps

Several remain. (1) The 30–50-year horizon of safety is not directly studied; only the 5-year PROFILE follow-up and registry / pharmacovigilance data extrapolate forward. (2) Biomarker-driven personalization failed in PROFILE; a tool to identify the indolent moderate-to-severe disease that would never have progressed under step-up has not emerged. (3) Optimal de-escalation strategy is not established — the SPARE trial (Louis et al., Lancet Gastro Hepatol 2023) showed thiopurine withdrawal is safer than infliximab withdrawal at year 2 of combination therapy, but durable monotherapy regimens and full discontinuation criteria remain under study. (4) Head-to-head comparisons between top-down agent classes (anti-TNF vs anti-IL-23 vs anti-integrin) in the newly-diagnosed top-down position are largely absent; observational and indirect-comparison data dominate. (5) UC top-down has weaker direct RCT evidence than CD — most extrapolation is from observational cohorts and the UC literature on individual biologics. (6) The optimal handling of the patient who fails first-line top-down (primary non-response or early secondary loss) is heterogeneous in practice.

Scope decisions. The brief named several consequences (mucosal healing, surgery rates, steroid exposure, long-term complications, side-effect profile). The article covers all five — mucosal healing in protocol and payoff, surgery and complications in stakes and evidence, steroid exposure throughout but principally in stakes, side-effect profile in contraindications and failure-modes. Top-down is treated as a strategy rather than a single drug; the article centres anti-TNF as the most-studied option but covers anti-IL-23, vedolizumab, and JAK inhibitors as substitutable in the same position.

Mild disease deliberately out of scope. The whole evidence base — D'Haens 2008, SONIC 2010, REACT 2015, CALM 2017, PROFILE 2024 — enrolled moderate-to-severe disease. Top-down is not recommended for mild disease and the entry says so explicitly in misconceptions. A separate entry on "managing mild IBD" would be useful eventually.

Ulcerative colitis evidence is thinner. The largest top-down RCTs were in Crohn's. UC top-down evidence comes from observational cohorts and individual-drug RCTs (ACT 1/2 for infliximab; GEMINI for vedolizumab). The article notes vedolizumab is often preferred first-line in UC. A dedicated UC top-down entry, once the ongoing pediatric and adult UC RCTs report, may be warranted.

Rating difficulties. Cadence was a hard call. The strategic decision is once at diagnosis; the medication continues indefinitely. Picked "once" because the entry's purpose is to help the reader make the one-time decision; the drug schedule itself is described under protocol. Contraindications vocabulary doesn't include "active-infection", "tuberculosis", "demyelinating-disease", or "lymphoma-history" which are the real anti-TNF contraindications; settled on cardiac-condition as the closest fit (severe heart failure being a documented anti-TNF contraindication) and covered the rest as prose in the contraindications addressing section.

Adjacent entries flagged for future work. Faecal calprotectin testing, therapeutic drug monitoring for biologics, exclusive enteral nutrition in Crohn's, smoking and IBD, iron-deficiency anaemia in IBD, and the IBD–depression / IBD–anxiety axis are all named in out-of-scope. None of these exists in the catalogue yet; once they do, this entry should link back to them.

Cost framing. The cost picture is jurisdiction-dependent in a way the catalogue doesn't normally encode. The article handles this by giving both the US picture (high but compressing, patient-assistance programmes available) and the UK / EU picture (biosimilars dominate, cost-effective or cost-saving). Reader experience differs more by country than by individual case here.

5-year PROFILE follow-up data. Cited from ECCO 2026 conference presentation (Noor et al.), which is not yet a peer-reviewed publication. Flagged in the research dossier; the article treats the safety reassurance as preliminary rather than definitive. If the formal publication appears, swap the framing accordingly.