Y-ECCO Literature Review: Gregory Sebepos-Rogers
Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial
Roblin X, Williet N, Boschetti G, Phelip JM, Del Tedesco E, Berger AE, Vedrines P, Duru G, Peyrin-Biroulet L, Nancey S, Flourie B, Paul S.
Gut. 2020 Jan 24. doi: 10.1136/gutjnl-2019-319758. [Epub ahead of print]
© Gregory Sebepos-Rogers
Anti-tumour necrosis factor-α (anti-TNF) has historically been the mainstay of biologic therapy in Inflammatory Bowel Disease (IBD). However, of those who initially respond to anti-TNF, almost 50% will suffer secondary loss of response (SLR) over subsequent years [1,2]. This SLR is primarily predicated on suboptimal anti-TNF trough levels, with or without detectable anti-drug antibodies (ADAs) . Furthermore the prospective, observational study by Kennedy et al. demonstrated that suboptimal anti-TNF trough levels at week 14 predicted ADAs, low trough levels and worse clinical outcomes . This risk was mitigated for both infliximab and adalimumab by the use of immunomodulators such as azathioprine. This corroborates the retrospective data from other cohorts showing how the addition of an immunomodulator can restore clinical response and favourable pharmacokinetics [5–7]. Remission rates when switching to a second anti-TNF have been shown to be lower when the reason to withdraw the first anti-TNF is SLR as compared to intolerance (45% vs 61%) . In the event that SLR to anti-TNF is due to immunogenicity, a switch to another anti-TNF is associated with a risk of ADA to this new therapy [9,10]. A number of patients will also be on anti-TNF monotherapy at the time of switching having de-escalated from previous combination therapy. We know that open-ended prescription of anti-TNF with azathioprine is not without additional risk, notably infection and lymphoma . Furthermore, de-escalation to anti-TNF monotherapy after a period of combination therapy has been shown in most studies not to impact on relapse rates (49% monotherapy versus 48% combination therapy) . It is in precisely this important group of patients that Roblin et al. sought to compare the use of azathioprine in combination with a second anti-TNF versus this second anti-TNF as monotherapy. Over a follow-up period of 2 years, the rates of clinical and immunogenic failure, and of adverse events, were compared.
The study was a randomised, open-labelled, prospective trial conducted in two university IBD centres. Patients included were on anti-TNF monotherapy (>6 months) at optimised dose (>4 months) and had experienced clinical failure (Harvey-Bradshaw index ≥5 associated with faecal calprotectin levels >250 µg/g for CD and a Mayo score >5 with an endoscopic subscore >1 for UC) and immunogenic failure. Immunogenic failure was defined as undetectable trough levels of drug with high ADAs (≥20 ng/mL) on two occurrences within one week. For the intervention combination therapy arm, full dose of azathioprine was prescribed without optimisation of drug levels (e.g. using thiopurine metabolite monitoring). The primary outcome was clinical and immunogenic failure (same definitions as above) observed after induction at week 14 up to 2 years of follow-up. The single patient lost to follow-up for combination therapy was defined as clinical failure whereas the four lost to follow-up for monotherapy were not considered as clinical failure.
Ninety patients were randomised equally between monotherapy and combination therapy. Groups were comparable, with two-thirds having received previous immunosuppressors and the titre of anti-drug antibody to either prior anti-TNF being similar. Rates of clinical failure were significantly higher with monotherapy [log-rank test p<0.001 (HR 6.29; 95% CI 2.98–13.26)] and this was irrespective of the anti-TNF chosen for either monotherapy or combination therapy. The percentage of patients without clinical failure over the follow-up period in the combination therapy and monotherapy groups were, respectively, 80% vs 64% at 1 year (p=0.2), 77% versus 38% at 18 months (p=0.01) and 77% versus 22% at 2 years (p<0.001). Importantly in the multivariate analysis, the titres of ADAs to the first anti-TNF (≥or< 100 ng/mL), as well as other variables such as C-reactive protein levels, disease phenotype, type of anti-TNF and prior immunomodulator use, were not associated significantly with clinical failure. For immunogenic failure, the development of undetectable drug levels and ADAs was significantly higher with monotherapy [log-rank test p <0.001 (HR 8.05; 95% CI 3.91–16.58)], again irrespective of the anti-TNF chosen. As for clinical failure, a profound divergence of immunogenicity was seen between patients receiving combination therapy versus monotherapy. For those patients in clinical failure at 18 and 24 months, 80% and 87% respectively had also developed immunogenic failure. The authors helpfully applied these results using a drug-sensitive assay, in which both drug and ADAs can be measured, to a drug-tolerant assay, in which primarily only ADAs can be measured. Here they showed their findings of clinical and immunogenic failure were valid under either assay. There was no significant difference between groups for side effects (43 in total) but two patients in each group reported serious adverse events necessitating therapy cessation, including breast cancer on monotherapy and thymoma on combination therapy.
This is an important study that greatly assists in the clinical decision-making required at the point of anti-TNF secondary loss of response due to immunogenicity. Whilst numerous additional biologics and now oral small molecules have become available to our prescribing armamentarium, this study’s findings indicate that the use of anti-TNF as a biologic class can be extended by the addition of a thiopurine when a subsequent anti-TNF is used. Furthermore, this is in a patient cohort who have already been through dose optimisation on their first anti-TNF and still developed immunogenicity. In this study, the significance of combination therapy in avoiding clinical and immunogenic failure was apparent towards the end of the 2-year study period, which points towards the value of a longer duration of combination therapy. An important limitation is that neither the second anti-TNF nor the thiopurine was dose optimised. Although limited to retrospective data and first anti-TNF use, proactively optimised monotherapy can be as effective as combination therapy [13–15]. Studies have also indicated that lower doses of thiopurine can prevent the development of ADAs and this may be relevant in managing the risk of serious adverse events associated with combination therapy . Overall, this is a very valuable study which, in combination with proactive therapeutic drug monitoring of both the second anti-TNF and the immunomodulator, points to an important ongoing role for anti-TNFs as the options for prescribing advanced therapies in IBD rapidly expand.
- Casanova MJ, Chaparro M, Mínguez M, et al. Effectiveness and safety of the sequential use of a second and third anti-TNF agent in patients with inflammatory bowel disease: results from the Eneida Registry. Inflamm Bowel Dis. 2019;26:606–16.
- Fine S, Papamichael K, Cheifetz A. Etiology and management of lack or loss of response to anti-tumor necrosis factor therapy in patients with inflammatory bowel disease. Gastroenterol Hepatol. 2019;15:656–65.
- Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13:522–30.e2.
- 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.
- Ben-Horin S, Waterman M, Kopylov U, et al. Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11:444–7.
- Ungar B, Kopylov U, Engel T, et al. Addition of an immunomodulator can reverse antibody formation and loss of response in patients treated with adalimumab. Aliment Pharmacol Ther. 2017;45:276–82.
- Strik AS, van den Brink GR, Ponsioen C, Mathot R, Löwenberg M, D’Haens GR. Suppression of anti-drug antibodies to infliximab or adalimumab with the addition of an immunomodulator in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:1128–34.
- Gisbert JP, Marín AC, McNicholl AG, Chaparro M. Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed. Aliment Pharmacol Ther. 2015;41:613–23.
- Roblin X, Vérot C, Paul S, et al. Is the pharmacokinetic profile of a first anti-TNF predictive of the clinical outcome and pharmacokinetics of a second anti-TNF? Inflamm Bowel Dis. 2018;24:2078–85.
- Frederiksen MT, Ainsworth MA, Brynskov J, Thomsen OØ, Bendtzen K, Steenholdt C. Antibodies against infliximab are associated with de novo development of antibodies to adalimumab and therapeutic failure in infliximab-to-adalimumab switchers with IBD. Inflamm Bowel Dis. 2014;20:1714–21.
- Papamichael K, Mantzaris GJ, Peyrin-Biroulet L. A safety assessment of anti-tumor necrosis factor alpha therapy for treatment of Crohn’s disease. Expert Opin Drug Saf. 2016;15:493–501.
- Boyapati RK, Torres J, Palmela C, et al. Withdrawal of immunosuppressant or biologic therapy for patients with quiescent Crohn’s disease. Cochrane Database Syst Rev. 2018;5:CD012540.
- Lega S, Phan BL, Rosenthal CJ, et al. Proactively optimized infliximab monotherapy is as effective as combination therapy in IBD. Inflamm Bowel Dis. 2019;25:134–41.
- Drobne D, Kurent T, Golob S, et al. Optimised infliximab monotherapy is as effective as optimised combination therapy, but is associated with higher drug consumption in inflammatory bowel disease. Aliment Pharmacol Ther. 2019;49:880–9.
- Colombel JF, Adedokun OJ, Gasink C, et al. Combination therapy with infliximab and azathioprine improves infliximab pharmacokinetic features and efficacy: a post hoc analysis. Clin Gastroenterol Hepatol. 2019;17:1525–32.e1.
- Roblin X, Boschetti G, Williet N, et al. Azathioprine dose reduction in inflammatory bowel disease patients on combination therapy: an open-label, prospective and randomised clinical trial. Aliment Pharmacol Ther. 2017;46:142–9.
Greg Sebepos-Rogers is a gastroenterology trainee at University College Hospital and a PhD candidate at University College London. He is exploring the role of optineurin, an adaptor protein, in the regulation of the inflammasome and has an interest in organoid development in IBD.