Y-ECCO Literature Review: Konstantinos Sarras
Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the Immunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study
Chanchlani N, Lin S, Auth MK et al.
Aliment Pharmacol Ther. 2022;56:1250–63.
Anti-TNF monoclonal antibodies play an important role in the management of immune-mediated inflammatory diseases, including Inflammatory Bowel Disease . However, anti-TNF failure is common . Loss of response is usually associated with the development of anti-drug antibodies and low anti-TNF drug levels.
The aim of this study was to evaluate the relationship between immunogenicity to a patient’s first anti-TNF therapy and immunogenicity and drug persistence to the second anti-TNF therapy, irrespective of drug sequence.
The authors conducted a UK-wide, multicentre, retrospective cohort study to investigate rates of immunogenicity to second anti-TNF therapies in patients with IBD [Crohn’s Disease (CD), Ulcerative Colitis (UC) and IBD-unclassified (IBD-U)].
Data collected between May 1, 2013 and November 31, 2020 were extracted from the Academic Department of Blood Sciences at the Royal Devon and Exeter NHS Foundation Trust in the UK.
Patients previously treated with an anti-TNF drug prior to the index course with therapeutic drug measurement and those who had not been exposed to two anti-TNF drugs were excluded.
The primary outcome was immunogenicity to the second anti-TNF drug, defined at any time point as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. The secondary outcome was second anti-TNF drug persistence, defined as the length of time from initiation of second anti-TNF to discontinuation of therapy.
Treatment failure endpoints were primary non-response at week 20, loss of response after week 20 and adverse events leading to drug withdrawal.
A total of 1058 patients were included in the final analysis: 71.4%, 24.4% and 4.3% patients were diagnosed with CD, UC and IBD-U, respectively. Of these, 80.0% were treated with infliximab and then adalimumab, and 20.0% with adalimumab and then infliximab.
There was no difference in the duration of treatment with the first anti-TNF drug. However, more patients treated with infliximab as first anti-TNF were treated with a concomitant immunomodulator. Similar proportions of infliximab- and adalimumab-treated patients had their first anti-TNF dose escalated before switching drugs.
Among patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab than those who did not develop antibodies to infliximab. Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab. For each tenfold increase in antibody concentration, the odds of subsequently developing antibodies to the second anti-TNF increased by 1.73 for patients treated with infliximab first and 1.99 for patients treated with adalimumab first.
Sensitivity analyses according to drug clearance (undetectable anti-TNF drug levels, presence of antibodies) showed that patients who developed immunogenicity with undetectable drug levels to infliximab first were more than twice as likely to then develop immunogenicity with undetectable drug levels to adalimumab second, compared to those who failed to respond to infliximab first with no antibodies present. An increase in likelihood was seen in the adalimumab first group, but with less statistical significance.
At 4-year follow-up, patients treated with adalimumab as a second anti-TNF were more likely to continue the anti-TNF therapy compared to patients treated with infliximab as a second anti-TNF, as 64% and 36% of patients subsequently developed anti-drug antibodies to infliximab and adalimumab, respectively. No differences were seen in drug persistence in patients treated with adalimumab as a second anti-TNF, according to infliximab treatment failure status. Among patients treated with infliximab as a second anti-TNF, those who developed non-immunogenic–pharmacokinetic failure (defined as anti-TNF failure with low drug levels but no antibody presence) had lower drug persistence compared to all other treatment failure groups.
Drug persistence improved with the use of a concomitant immunomodulator at the time or prior to switching to the second anti-TNF, but only in patients who developed antibodies and had low/undetectable drug levels on the first anti-TNF.
The study managed to demonstrate that patients who developed antibodies to their first anti-TNF were more likely to develop antibodies to their second anti-TNF, irrespective of drug sequence. The findings support the switch to a new biologic class when drug levels are therapeutic, and within class with an immunomodulator when anti-TNF drug levels are low and associated with antibody development. However, the study did not demonstrate a clear correlation between immunogenicity and drug persistence to the second anti-TNF. As there were no data on patients who failed an anti-TNF drug but did not have therapeutic drug monitoring undertaken, this may have resulted in underestimation of the rates of immunogenicity and overestimation of drug persistence. The lack of alternative biologic treatments during the timeframe of the study probably explains why over half of patients, regardless of their immunogenicity status, were being treated with their second anti-TNF after 4 years. Moreover, the study did not take into account objective markers of disease activity and endoscopic outcomes, which could have caused the timing and rate of anti-TNF discontinuation to be subject to bias.
- Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362:1383–95.
- Kennedy NA, Heap GA, Green HD, et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 2019;4:341–53.
Konstantinos Sarras - Short Biography
Konstantinos Sarras is a Gastroenterology clinical fellow at Kings College Hospital, London, with a particular interest in Inflammatory Bowel Disease.