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Anti-TNF mechanistic failure in Crohn's disease — ESEGH MCQ

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HardGI PharmacologyAnti-TNF mechanistic failure in Crohn's diseaseESEGH

A 41-year-old man with ileocolonic Crohn's disease has persistent diarrhoea and abdominal pain and has lost 6 kg despite adalimumab 40 mg subcutaneously every other week for 6 months, with documented good adherence. Stool culture and Clostridioides difficile testing are negative. CRP is 38 mg/L and faecal calprotectin is 1450 micrograms/g. Ileocolonoscopy and MR enterography show active ulcerating ileocolitis without fixed stricture, fistula or abscess. His pre-dose (trough) adalimumab concentration is 11.8 mg/L (local therapeutic threshold 7.5 mg/L) and anti-adalimumab antibodies are undetectable. Which management strategy is most appropriate?

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Correct answer: B — Switch to a non-TNF advanced therapy such as ustekinumab or vedolizumab

Explanation lettering: D = shown as A · C = shown as B · E = shown as C · A = shown as D · B = shown as E

The answer is C. Objectively active inflammation despite a trough adalimumab concentration well above the therapeutic threshold, with undetectable anti-drug antibodies, defines pharmacodynamic (mechanistic) failure: the disease is not TNF-driven. NICE's therapeutic drug monitoring guidance reserves dose intensification and within-class switching for inadequate drug exposure or immunogenicity, and states that when TNF-alpha inhibitors fail, switching to an agent with a different mechanism of action is logical. A adds exposure that is already ample and is unlikely to restore response. B targets the same cytokine pathway and performs poorly when trough levels are adequate. D treats immunogenicity that is demonstrably absent. E is ineffective as principal therapy in moderate-to-severe ileocolonic Crohn's disease and would leave him untreated. Infection and penetrating or obstructive complications are excluded, so an out-of-class advanced therapy (ustekinumab or vedolizumab, chosen by phenotype, safety and patient preference) is correct.

Reference: NICE. Therapeutic monitoring of TNF-alpha inhibitors in Crohn's disease (LISA-TRACKER, IDKmonitor, Promonitor ELISA kits), HTG401 (formerly DG22), section 3: Clinical need and practice. https://www.nice.org.uk/guidance/htg401/chapter/3-Clinical-need-and-practice