Dr. Elizabeth Squirell
Landmark IBD trials · Summary of an original articleLancet Gastroenterol Hepatol 2019;4:341–53

PANTSMust knowCD · Drug monitoring

Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study

Kennedy NA, et al.

Lancet Gastroenterol Hepatol 2019 · PMID 30824404 (PubMed, opens in a new tab) · doi 10.1016/S2468-1253(19)30012-3 (full paper, opens in a new tab)

Figure 1. Multivariable predictors of anti-TNF failure: week-14 drug concentration for primary non-response and week-54 non-remission, and an immunomodulator for antidrug antibodies. Log scale; squares are estimates, lines are 95% CIs.
Data for this figure: Ratio (95% CI). Left of the null line: Lower risk. Right: Higher risk.
OutcomeEstimate (confidence interval)P
Primary non-response at week 14 · odds ratio for week-14 drug level
Infliximab (primary)0.35 (95% CI 0.20–0.62)P=0.00038
Adalimumab (primary)0.13 (95% CI 0.06–0.28)P<0.0001
Non-remission at week 54 · odds ratio for week-14 drug level
Infliximab0.29 (95% CI 0.16–0.52)P<0.0001
Adalimumab0.03 (95% CI 0.01–0.12)P<0.0001
Antidrug antibodies · hazard ratio with an immunomodulator
Infliximab0.39 (95% CI 0.32–0.46)P<0.0001
Adalimumab0.44 (95% CI 0.31–0.64)P<0.0001

Every interval sits below 1: drug exposure, and the immunomodulator that protects it, were the factors linked with success.

Source: Kennedy 2019, abstract. The abstract does not state the unit of drug concentration behind the odds ratios; ratios below 1 mean that higher week-14 concentrations went with lower odds of failure.

Structured abstract

BackgroundPrimary non-response and loss of response to anti-TNF drugs were common in Crohn's disease, but which clinical and pharmacokinetic factors drive treatment failure was unclear.

MethodsProspective, observational, multicentre cohort study (UK-wide); not randomised. 1,610 patients. Primary endpoint: Treatment failure: primary non-response at week 14, non-remission at week 54, and adverse events leading to drug withdrawal.

ResultsPrimary result. Primary non-response 23.8% (295/1241; 95% CI 21.4–26.2); non-remission at week 54 63.1% (764/1211; 60.3–65.8); adverse events stopping treatment 7.8% (126/1610; 6.6–9.2). Low week 14 drug level was the only independent predictor of primary non-response (infliximab OR 0.35, 95% CI 0.20–0.62; adalimumab OR 0.13, 0.06–0.28).

Take-homeAnti-TNF failure in Crohn's disease is common and is driven largely by low drug levels and immunogenicity; an immunomodulator reduces antibodies, and primary non-responders need a change, not more of the same.

Table 1. Trial at a glance
Patients1,610
PopulationAnti-TNF-naive patients aged 6 years or older with active luminal Crohn's disease starting infliximab (955; 753 originator, 202 biosimilar) or adalimumab (655). Followed for 12 months or until drug withdrawal.
ComparisonNo comparison arm: clinical and pharmacokinetic factors (drug levels, antidrug antibodies, immunomodulator use) were tested as predictors of treatment failure.
Drugsinfliximab, adalimumab
ClassesAnti-TNF
PublishedKennedy NA, et al. Lancet Gastroenterol Hepatol 2019;4:341–53.

Key points

  • Week 14 drug concentration also independently predicted non-remission at week 54: OR 0.29 (95% CI 0.16–0.52) for infliximab and 0.03 (0.01–0.12) for adalimumab.
  • Week 14 drug levels linked with remission at both week 14 and week 54: 7 mg/L for infliximab and 12 mg/L for adalimumab.
  • Antidrug antibodies developed in 62.8% (95% CI 59.0–66.3) on infliximab and 28.5% (24.0–32.7) on adalimumab; low week 14 levels predicted antibodies, and antibodies predicted later low levels.
  • An immunomodulator (thiopurine or methotrexate) reduced antibody formation: HR 0.39 (95% CI 0.32–0.46) for infliximab and 0.44 (0.31–0.64) for adalimumab.
  • Continuing standard dosing after primary non-response rarely worked: only 12.4% (14/113) reached remission by week 54.

Limitations

  • Observational cohort: associations, not proof that targeting the reported levels improves outcomes.
  • Remission was defined clinically and biochemically rather than endoscopically.
  • Partly industry funded (AbbVie, Merck Sharp and Dohme, Napp, Pfizer, Celltrion) alongside charity funding.

Commentary

PANTS is the largest prospective study of how anti-TNF therapy fails in Crohn’s disease. It explains why: patients who do not respond usually have low drug exposure at the end of induction, and immunogenicity is very common with infliximab monotherapy. It supports checking levels around week 14, using an immunomodulator with infliximab (as in SONIC) or monitoring levels closely when one is not used, and switching rather than persisting with a standard dose after primary non-response.

Whether adjusting doses to hit the PANTS levels improves outcomes is a question for randomised trials; see NOR-DRUM B and TAXIT.

Journal club

PopulationAnti-TNF-naive patients aged 6 years or older with active luminal Crohn's disease starting infliximab (955; 753 originator, 202 biosimilar) or adalimumab (655). Followed for 12 months or until drug withdrawal.
InterventionNo comparison arm: clinical and pharmacokinetic factors (drug levels, antidrug antibodies, immunomodulator use) were tested as predictors of treatment failure.
ComparisonNo separate comparison group (see design)
Primary outcomeTreatment failure: primary non-response at week 14, non-remission at week 54, and adverse events leading to drug withdrawal.

Design

Prospective, observational, multicentre cohort study (UK-wide); not randomised. 1,610 patients.

Primary result. Primary non-response 23.8% (295/1241; 95% CI 21.4–26.2); non-remission at week 54 63.1% (764/1211; 60.3–65.8); adverse events stopping treatment 7.8% (126/1610; 6.6–9.2). Low week 14 drug level was the only independent predictor of primary non-response (infliximab OR 0.35, 95% CI 0.20–0.62; adalimumab OR 0.13, 0.06–0.28).

Validity and applicability

  • Observational cohort: associations, not proof that targeting the reported levels improves outcomes.
  • Remission was defined clinically and biochemically rather than endoscopically.
  • Partly industry funded (AbbVie, Merck Sharp and Dohme, Napp, Pfizer, Celltrion) alongside charity funding.

Where it sits now

Anti-TNF failure in Crohn's disease is common and is driven largely by low drug levels and immunogenicity; an immunomodulator reduces antibodies, and primary non-responders need a change, not more of the same.

  • SONIC (2010): In thiopurine- and biologic-naive Crohn's disease, infliximab plus azathioprine beats either drug alone for steroid-free remission and mucosal healing.
  • NOR-DRUM B (2021): In patients on maintenance infliximab, scheduled drug-level monitoring with a dosing algorithm kept more patients in sustained disease control over a year than standard dosing without levels.
  • TAXIT (2015): A one-time optimisation to an infliximab trough of 3–7 µg/mL is worthwhile (fewer relapses, lower cost when levels are high), but repeated proactive trough-based dosing did not increase 1-year remission.

Questions for discussion

  1. PANTS is observational. Could low drug levels be a marker of more inflammatory disease rather than a cause of failure?
  2. How would you use the week-14 level targets (7 mg/L for infliximab, 12 mg/L for adalimumab), given that they come from an association study?
  3. Should every patient starting infliximab also receive an immunomodulator? How would you weigh that against its risks?
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