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

Neil Chanchlani; Simeng Lin; Marcus K. Auth; Chai Leng Lee; Helena Robbins; Shi Looi; Senthil V. Murugesan; Tom Riley; Cathryn Preston; Sophie Stephenson; Wendy Cardozo; Sunil A. Sonwalkar; Mohammed Allah-Ditta; Lynne Mansfield; Dharmaraj Durai; Mark Baker; Ian London; Emily London; Sanjay Gupta; Alex Di Mambro; Aisling Murphy; Edward Gaynor; Kelsey D. J. Jones; Andrew Claridge; Shaji Sebastian; Sankaranarayanan Ramachandran; Christian P. Selinger; Simon P. Borg-Bartolo; Paul Knight; Michael B. Sprakes; Julie Burton; Patricia Kane; Stephanie Lupton; Aimee Fletcher; Daniel R. Gaya; Roghan Colbert; John Paul Seenan; Jonathan MacDonald; Lucy Lynch; Iain McLachlan; Stephanie Shields; Richard Hansen; Lisa Gervais; Mwansa Jere; Muhammad Akhtar; Karen Black; Paul Henderson; Richard K. Russell; Charlie W. Lees; Lauranne A. A. P. Derikx; Melanie Lockett; Frederica Betteridge; Aminda De Silva; Arif Hussenbux; John Beckly; Oliver Bendall; James W. Hart; Amanda Thomas; Ben Hamilton; Claire Gordon; Desmond Chee; Timothy J. McDonald; Rachel Nice; Marian Parkinson; Helen Gardner-Thorpe; Jeff R. Butterworth; Asima Javed; Sarah Al-Shakhshir; Rekha Yadagiri; Sebrene Maher; Richard C. G. Pollok; Tze Ng; Priscilla Appiahene; Fiona Donovan; James Lok; Rajiv Chandy; Reema Jagdish; Daniyal Baig; Zahid Mahmood; Liane Marsh; Allison Moss; Amin Abdulgader; Angus Kitchin; Gareth J. Walker; Becky George; Yuen-Hui Lim; James Gulliver; Stuart Bloom; Holly Theaker; Sean Carlson; J. R. Fraser Cummings; Robert Livingstone; Amanda Beale; Josiah O. Carter; Andrew Bell; Archibald Coulter; Jonathon Snook; Helen Stone; Nicholas A. Kennedy; James R. Goodhand; Tariq Ahmad


Aliment Pharmacol Ther. 2022;56(8):1250-1263. 

In This Article

Abstract and Introduction


Background: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD).

Aim: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence

Methods: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab.

Results: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27–3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46–4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38–2.17, p < 0.001) and 1.99 (95%CI 1.34–2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39–4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure.

Conclusion: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.


The anti-TNF monoclonal antibodies infliximab and adalimumab have transformed the management of immune-mediated inflammatory diseases (IMIDs), including inflammatory bowel disease (IBD).[1]

Regrettably, however, anti-TNF treatment failure is common. Obesity, cigarette smoking, higher baseline markers of disease activity, anti-TNF monotherapy and the development of anti-drug antibodies are associated with low drug levels and anti-TNF treatment failure.[2] Loss of response is frequently associated with low anti-TNF drug levels and the formation of anti-drug antibodies, which can be predicted by the carriage of the HLA-DQA1*05 haplotype,[3,4] and mitigated by concomitant immunomodulator use.[2]

Whilst it is generally accepted that there is a diminishing return from second- and subsequent anti-TNF therapies,[5,6] well-designed and adequately powered sequencing studies are scarce.[7,8] Most have been small and limited to the immunogenicity of second-line adalimumab because historically infliximab has been used first. Estimates range from 28 to 40%[7,9–12] and 39 to 70%[7,12,13] for the risk of immunogenicity to second-line adalimumab and infliximab, respectively. Few studies have addressed whether the development of antibodies to the first anti-TNF drug is associated with immunogenicity[8,10–15] and treatment failure to a second.

The aim of the IMplications for Sequencing of biologic therapy and choice of second Anti-TNF in patients with IBD (IMSAT) study was to evaluate the relationship between immunogenicity to the first anti-TNF therapy and immunogenicity and drug persistence to second anti-TNF therapy. We hypothesized that immunogenicity to the first anti-TNF would be associated with immunogenicity to the second anti-TNF, irrespective of drug sequence.