Kennedy NA, Heap GA, Green HD, Hamilton B, Bewshea C, Walker GJ, Thomas A, Nice R, Perry MH, Bouri S, Chanchlani N, Heerasing NM, Hendy P, Lin S, Gaya DR, Cummings JRF, Selinger CP, Lees CW, Hart AL, Parkes M, Sebastian S, Mansfield JC, Irving PM, Lindsay J, Russell RK, McDonald TJ, McGovern D, Goodhand JR, Ahmad T, UK Inflammatory Bowel Disease Pharmacogenetics Study Group*
Lancet Gastroenterol Hepatol. 2019;4:341–53
© Misha Kabir
The anti-TNF monoclonal antibodies infliximab and adalimumab have been integral to the management of Crohn’s Disease over the past two decades. However, primary non-response and secondary loss of response in the first year of treatment remain common, at 10%–40% [1–3] and 23%–46%  respectively. Immunogenicity has been implicated as an important predictive factor for anti-TNF therapy failure. However, target-to-treat drug and anti-drug antibody concentrations have not yet been validated in an adequately powered prospective study. The Personalised Anti-TNF Therapy in Crohn’s Disease Study (PANTS) aimed to investigate the factors that predict primary non-response, non-remission and adverse events with anti-TNF therapy in luminal Crohn’s Disease.
PANTS was a UK-wide, multicentre, prospective observational cohort study. Anti-TNF naive patients over the age of five years with active small intestine and/or colonic Crohn’s Disease were included. Active luminal disease was supported by a C-reactive protein (CRP) greater than 3 mg/L 90 days before the first dose of anti-TNF or faecal calprotectin more than 50 μg/g at any time between 90 days before and 28 days after the first dose. Eligible patients were recruited between March 2013 and July 2016 and commenced on infliximab (originator Remicade or biosimilar CT-P13) or adalimumab (Humira) at the discretion of the treating physician and prescribed according to the licensed dosing schedule. They were followed up for 12 months or until drug withdrawal. Treatment failure endpoints were primary non-response at week 14, non-remission at week 54 and adverse events leading to drug withdrawal.
Primary non-response was defined as (1) exit before week 14 because of treatment failure (including resectional bowel surgery) or (2) corticosteroid use at week 14 or (3) lack of CRP decrease to 3 mg/L or less or by 50% or more from baseline or (4) failure of the Harvey Bradshaw Index (HBI) score to decrease to 4 points or less or by 3 points or more from baseline or (5) in children, failure of the Short Paediatric Crohn’s Disease Activity Index (sPCDAI) to decrease to 15 points or less and by more than 12.5 points from baseline.
Non-remission at week 54 was defined as (1) CRP of more than 3 µg/L or (2) HBI score of greater than 4 points (or sPCDAI >15 points for children) or (3) ongoing steroid therapy or (4) exit due to treatment failure.
A total of 1610 patients were recruited; 753 (47%) were treated with originator infliximab, 202 (13%) with biosimilar infliximab and 655 (41%) with adalimumab. All these patients were included in the immunogenicity and safety analyses. Seven percent (n=107) were excluded from the effectiveness analyses as they had peri-anal disease only, or stomas, or their baseline CRP and calprotectin were not raised. At week 14, 1241 patients were assessable for effectiveness. Primary non-response occurred in 170/755 [21.9% (95% CI 19.1%–25.0%)] infliximab-treated patients and 125/466 [26.8% (95% CI 22.9%–31.1%)] adalimumab-treated patients. At week 54, non-remission occurred in 469/770 [60.9% (95% CI 57.4%–64.0%)] infliximab-treated patients and 295/441 [66.9% (95% CI 62.3%–71.3%)] adalimumab-treated patients. Continuing standard dosing regimens after primary non-response rarely resulted in remission at week 54 (12.4%). Adverse events leading to treatment withdrawal occurred in 84/955 infliximab-treated patients [8.8% (95% CI 7.1%–10.8%)] and 42/655 adalimumab-treated patients [6.4% (95% CI 4.7%–8.6%)].
Multivariable analysis identified that the anti-TNF concentration at week 14 was the only factor to be independently associated with primary non-response at week 14 and non-remission at week 54. The optimal drug concentration at week 14 that was associated with remission at week 54 was 7 mg/L for infliximab and 12 mg/L for adalimumab. Anti-drug antibody formation, CRP and faecal calprotectin at week 14 were independently associated with low drug concentrations at weeks 14 and 54. Concomitant immunomodulator (thiopurine or methotrexate) use at baseline was independently associated with higher week 54 drug concentrations in the infliximab-treated group [OR 1.27 (95% CI 1.02–1.59), p=0.034] but not the adalimumab-treated group. Immunomodulator use was shown to be the main protective factor against immunogenicity in both the infliximab [HR 0.39 (95% CI 0.32–0.46), p<0.0001] and the adalimumab [HR 0.44 (95% CI 0.31–0.64), p<0.0001] group. This benefit was dose dependent, without an obvious threshold effect in the infliximab group.
PANTS is the largest prospective study of anti-TNF therapy in Crohn’s Disease to date. The investigators have shown that the major modifiable factors associated with treatment failure are low drug concentrations and immunogenicity. They advocate early identification of at-risk individuals, with drug trough concentrations lower than 7 mg/L for infliximab and 12 mg/L for adalimumab, and a personalised approach to dose escalation within the induction period. However, the GETAID group proof-of-concept randomised controlled study of proactive infliximab dose escalation, based on trough drug levels in anti-TNF naive Crohn’s Disease (TAILORIX), did not show a significant benefit in maintaining corticosteroid-free remission . This study, however, only escalated drug doses to a target of 3 mg/L or more and was not statistically powered to determine superiority of therapeutic drug monitoring. Further adequately powered randomised trials are required to evaluate whether optimising drug concentration on a treat-to-target basis during induction leads to better outcomes.
Misha Kabir is a gastroenterology trainee and clinical research fellow at St Mark's Hospital, London, UK. Her research is focussed on dysplasia risk stratification and communication and management decision-making in Inflammatory Bowel Disease.