Y-ECCO Literature Review: Georgina Cunningham

In this post-hoc analysis of the randomised evaluation of an algorithm for treatment of Crohn’s Disease (REACT trial), the authors investigated whether a more aggressive treatment approach with early combination therapy is effective and safe in patients over the age of 60, compared with younger patients. The original study was an open-label cluster-randomised trial that recruited patients from community practices in Belgium and Canada between 2010 and 2013 [5]. In this study, practices were randomly assigned to either early combined immunosuppression (ECI) or conventional management. Each practice could enrol up to 60 patients with Crohn’s Disease into the study. Practices that were randomised to the ECI group were guided with an algorithm depending on whether or not the patient achieved remission with corticosteroids after 4 or 12 weeks. If remission was not achieved, the patient was commenced on adalimumab in combination with either azathioprine or methotrexate. The patient was then re-evaluated every 12 weeks and treatment was escalated or modified according to the treatment algorithm. The primary outcome of the study was corticosteroid-free remission at 12 months (Harvey-Bradshaw Index ≤4), and risk of major adverse outcomes (surgery, hospitalisation or disease-related complications) at 24 months were also measured. In the original study the key findings were that there was no difference in corticosteroid-free remission between the two groups, there were higher rates of adverse outcomes in the conventional arm and there was no significant difference in drug-related adverse events between the groups.

Key findings

Of the original 1981 patients in the study, 311 were ≥60 years old; of these, 173 were randomised to ECI and 138 to conventional management. After adjusting for relevant baseline characteristics, there was no significant difference in risk of achieving corticosteroid-free remission with ECI at 24 months between the younger and older groups: RR 1.06 [0.98–1.15] vs 1.09 [0.09–1.33] (p=0.78) respectively. There was also no difference in terms of time to major adverse outcome: HR 0.71 [0.53–0.96] vs 0.69 [0.31–1.51] (p=0.92). The rates of Crohn’s Disease-related surgery, hospitalisation and serious disease-related complications were also not significantly different. As expected, mortality was higher in the older group: 4.5% vs 0.2%. The leading causes of death were cardiopulmonary disease (47%), malignancy (29%) and sepsis (12%). However, interestingly more deaths were observed in the conventional management group.

Conclusion

In this trial there was no significant difference in the outcomes between patients under and over the age of 60, and the authors concluded that ECI should be considered in elderly patients with Crohn’s Disease who have suboptimal control.

There are limitations of this study. Most importantly, it was not designed to compare the two age groups and the conclusions drawn need to be regarded with some reservation. Furthermore, the study was unblinded and the duration of follow-up was only 24 months. Changes to therapy, as dictated by the algorithm, were based on clinical assessment alone, which may have led to overtreatment in some patients given that the correlation between clinical and endoscopic activity in Crohn’s Disease is poor [6]. Conventional management is vaguely defined and may not be reflective of current real-world practices given the advent of newer biologics which may be more suitable for elderly patients, in particular the gut-specific anti-integrin therapies.

When it comes to deciding the management for an elderly patient with Crohn’s Disease, at the forefront of a physician’s mind is the risk associated with immunosuppressive medications [7]. Drug-related complications were not recorded in this study and despite mortality being lower in the ECI group, there remains a question mark as to the safety of aggressive treatment in this cohort. Of particular concern is the risk of lymphoma in patients receiving anti-TNF therapies and thiopurines [8, 9]. Reassurance regarding the risks associated with these therapies in elderly patients remains elusive.

It is important to note that the main reasons for increased hospitalisations and mortality among elderly IBD patients reported by Nguyen and colleagues [3] were cardiovascular disease and serious infections rather than IBD-related complications. It has previously been postulated that this may be due to increased corticosteroid use, and reducing corticosteroid exposure in this age group remains important. However, this study failed to show that an ECI approach reduces corticosteroid use in the older age group.

Despite providing insight into the response to treatment in elderly patients, this study fails to provide adequate reassurance that the outcomes of more aggressive treatment strategies justify increased exposure to therapies that have been proven to have increased side effects in the elderly. In the era of multiple new biologic and small molecule therapies, the optimal treatment strategy in the elderly remains to be defined.

References

1. Gisbert JP, Chaparro M. Systematic review with meta-analysis: Inflammatory bowel disease in the elderly. Aliment Pharmacol Ther. 2014;39:459–77.
2. Ananthakrishnan AN, Donaldson T, Lasch K, et al. Management of inflammatory bowel disease in the elderly patient: challenges and opportunities. Inflamm Bowel Dis. 2017;23:882–93.
3. Nguyen NH, Ohno-Machado L, Singh S, et al. Infections and cardiovascular complications are common causes for hospitalization in older patients with inflammatory bowel diseases. Inflamm Bowel Dis. 2018;24:916–23.
4. Bots S, Gecse K, Barclay M, et al. Combination immunosuppression in IBD. Inflamm Bowel Dis. 2018;24:539–45.
5. Khanna R, Bressler B, Levesque BG, et al. Early combined immunosuppression for the management of Crohn’s disease (REACT): A cluster randomised controlled trial. Lancet. 2015;386:1825–34.
6. Sandborn WJ, Feagan BG, Hanauer SB, et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn’s disease. Gastroenterology. 2002;122:512–30.
7. Cottone M, Kohn A, Daperno M, et al. Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol. 2011;9:30–5.
8. Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet. 2009;374:1617–25.
9. Brown SL, Greene MH, Gershon SK, et al. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum. 2002;46:3151–8.

Georgina Cunningham originally trained in Melbourne, Australia and is currently working as a Senior Clinical and Research Fellow in IBD at Guy’s and St. Thomas’ Hospital. Her interests include therapeutic drug monitoring for biological agents and she is currently working on a prospective study investigating the faecal loss of vedolizumab (FAVOUR).