Y-ECCO Literature Review: Hiruni Jayasena

With the ever-expanding array of novel IBD therapies, the future for combination therapy with ATI and IMM remains to be clarified. Hence the authors of this article performed a systemic review with meta-analysis to examine the risk of relapse and serious adverse events in IBD patients in sustained corticosteroid-free remission for more than 6 months on combination therapy with ATI and IMM who underwent withdrawal of either ATI or IMM compared with continuation of combination therapy.

Methods and key findings

Eight randomised controlled studies (RCT) comparing IMM or ATI to combination therapy were analysed in this study. Out of the eight RCTs analysed, five included patients with Crohn’s Disease (CD), one, patients with Ulcerative Colitis (UC), and two, patients with both UC and CD.

1. IMM withdrawal vs continuation of combination treatment

On meta-analysis of five RCTs, there was no significant difference in the risk of relapse in patients who underwent IMM withdrawal (and continued ATI monotherapy) (34/202; 16.8%) versus patients who continued to receive combination therapy (30/202; 14.9%) over 1–2 years (RR of relapse 1.15; 95% CI 0.75–1.76), without any heterogeneity (I² =0%). While only limited subgroup analysis was performed, the authors did not observe a difference in estimates based on IBD phenotype (CD vs UC) nor did they identify any interaction between clinical, endoscopic or biochemical remission or duration of remission at time of randomisation and success of IMM withdrawal. There was no significant difference in the risk of serious adverse events between those who underwent IMM withdrawal (21/202; 10.4%) and those who continued combination therapy (19/206; 9.2%) (RR 1.21; 95% CI 0.68–2.17). On exploratory analysis of endoscopic outcomes, none of the RCTs identified a significant difference in endoscopic disease activity scores for patients who underwent IMM withdrawal versus those who continued combination therapy [3–7].

Interestingly in three trials, the infliximab trough concentration at the end of the trial was lower and the proportion of patients with antibodies to infliximab was higher among those who underwent IMM withdrawal versus those who continued combination therapy [3, 5, 7]. This is in contrast to one trial (DIAMOND2) that had adalimumab as the ATI, in which the mean adalimumab trough concentration (6.5±3.2 µg/ml vs 7.1±3.0 µg/ml; p=0.52) and the anti-adalimumab antibody positivity rate (10% vs 20%; p=0.44) were not significantly different in patients who underwent IMM withdrawal (and continued adalimumab monotherapy) versus those who continued combination therapy [6].

2. ATI withdrawal vs continuation of treatment

At meta-analysis of four RCTs, withdrawal of ATI (and continuation of IMM monotherapy) was associated with a 2.4-fold higher risk of relapse compared with continuation of combination therapy [63/200 (31.5%) vs 22/196 (11.2%); RR 2.35; 95% CI 1.38–4.01), with minimal heterogeneity (I²=17%) [7–10]. It was noted that in those with CD, the risk of relapse with ATI withdrawal was 35%, and in patients with UC, the risk of relapse was 36.7%. There was further downgrading of the body of evidence for ATI withdrawal due to serious risk of bias and imprecision (owing to open label trials with subjective end points/a low event rate). Hence the low certainty of evidence favours continuation of combination therapy of ATI and IMM compared with ATI withdrawal (and continuation of IMM monotherapy) in IBD patients in corticosteroid-free clinical remission for at least 6 months. Furthermore, there was no difference in the risk of serious adverse events between those who underwent ATI withdrawal (9/130; 6.9%) and those who continued combination therapy (11/130; 8.5%) (RR 0.82; 95% CI 0.36–1.88).

Conclusions

The authors note variability among the included studies relating to depth and duration of remission at the time of randomisation. Additionally, there was variability with regard to disease, treatment duration prior to randomisation and outcome definition. Furthermore, the authors mention that there was no consistency in reporting endoscopic and biochemical outcomes. Factors associated with successful de-escalation of IMM or ATI were not consistently reported, either.

Despite these limitations, several important observations were made:

1. No difference in the risk of serious adverse events was observed in patients in whom IMM or ATI were withdrawn versus patients who continued to receive combination therapy.
2. There was no difference in the risk of relapse between patients with IMM withdrawal (and continued ATI monotherapy) and those who continued combination therapy. Hence there is no direct benefit in continuing IMM compared with IMM withdrawal (and continuation of ATI monotherapy) in patients with sustained corticosteroid-free remission for more than 6 months on combination therapy. Therefore, withdrawal of IMM (with continuation of ATI) can safely be done in those patients with sustained corticosteroid-free remission for more than 6 months on combination therapy. This will significantly reduce the patient’s pill burden and remove the risk of adverse effects due to continued IMM therapy. Nevertheless, one should be mindful that withdrawal of IMM may negatively impact the pharmacokinetics of ATI, as shown with infliximab [3, 5, 7]. Hence future trials are warranted to establish the role of concomitant IMM in patients treated with non-TNF-targeting biologics.
3. Given that a greater risk of relapse was observed in the ATI withdrawal group, the decision to withdraw ATI must not be taken lightly. The decision to withdraw ATI should therefore be carefully considered in each individual patient, with appropriate counselling and discussion of relapse monitoring strategies, unlike in the case of IMM withdrawal.

References

1. Colombel JF, Sandborn WJ, Reinisch W, et al.; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010;362:1383–95.
2. Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 2014;146:392–400.e3.
3. Van Assche G, Magdelaine-Beuzelin C, D'Haens G, et al. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology. 2008;134:1861–8.
4. Kierkus J, Iwanczak B, Grzybowska-Chlebowczyk U, et al. Monotherapy with infliximab versus combination therapy in the maintenance of clinical remission in children with moderate to severe Crohn disease. J Pediatr Gastroenterol Nutr 2015;60:580–5.
5. 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.
6. Hisamatsu T, Kato S, Kunisaki R, et al.; DIAMOND2 Study Group. Withdrawal of thiopurines in Crohn’s disease treated with scheduled adalimumab maintenance: a prospective randomised clinical trial (DIAMOND2). J Gastroenterol 2019;54:860–70.
7. Louis E, Resche-Rigon M, Laharie D, et al. GETAID and the SPARE-Biocycle research group. Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn’s disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol Hepatol 2023;8:215–27.
8. Kobayashi T, Motoya S, Nakamura S, et al; HAYABUSA Study Group. Discontinuation of infliximab in patients with ulcerative colitis in remission (HAYABUSA): a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol Hepatol 2021;6:429–37.
9. Buhl S, Steenholdt C, Brynskov J, et al. the Stop Infliximab Treatment (STOP-IT) Study Group. Discontinuation of infliximab therapy in patients with Crohn’s disease. NEJM Evidence 2022;1.
10. 10. Chapparo M, Garcia Donday M, Riestra S, et al; EXIT Study group of GETECCU. Is the withdrawal of anti-tumour necrosis factor in inflammatory bowel disease patients in remission feasible without increasing the risk of relapse? Results from the randomised clinical trial of GETECCU (EXIT). J Crohns Colitis 2023;17(Suppl 1):i50–4.

Hiruni Jayasena  - Short Biography

Hiruni Jayasena is a gastroenterologist and Lecturer in Clinical Medicine from Colombo, Sri Lanka. She is currently undertaking a clinical and research fellowship in Inflammatory Bowel Disease at Guy’s & St Thomas’ NHS Trust Hospitals in London, United Kingdom. Her research interests include non-invasive diagnostics and the development of novel therapies for IBD.