Early Combined Immunosuppression may be Effective and Safe in Older Patients With Crohn's Disease

Post Hoc Analysis of REACT

Siddharth Singh; Larry W. Stitt; Guangyong Zou; Reena Khanna; Parambir S. Dulai; William J. Sandborn; Brian G. Feagan; Vipul Jairath

Disclosures

Aliment Pharmacol Ther. 2019;49(9):1188-119. 

In This Article

Discussion

In this post hoc analysis of the REACT trial comparing the magnitude of benefit with an algorithmic early combined immunosuppression strategy vs conventional management, we found no difference in older vs younger patients in maintaining corticosteroid-free clinical remission and delaying risk of Crohn's disease-related surgery, hospitalisation and/or serious complications. As anticipated, a greater percentage of deaths occurred in older patients, but the percentage was not higher in patients in the early combined immunosuppression group compared to the conventional management group in the two age groups. In the absence of clinical trials specifically focusing on older patients and clear evidence-based guidance, these data provide useful information on the safety and efficacy of a strategy of algorithmic early combined immunosuppression compared to conventional management in older patients with Crohn's disease.

There are considerable challenges in the management of older patients with IBD. Besides intrinsic differences in disease phenotype and behaviour, particularly those with older disease onset, there are systematic differences in risks of disease-related and treatment-related complications, and extra-intestinal complications (eg cardiovascular disease, malignancy) between older and younger patients.[16,17] This may be attributed to immunosenescence, diminished physical reserve, multiple comorbidities and polypharmacy frequently seen in this patient population. In a nationally representative cohort study, Nguyen and colleagues observed that older patients with IBD have higher annual burden and costs associated with hospitalisation, as compared to younger patients, with higher rates of hospitalisation attributed to serious infections and cardiovascular diseases.[8] This leads to difficulty in estimating risk-benefit trade-offs of chronic immunosuppressive therapy in older patients, and has resulted in greater use of long-term corticosteroids and lower use of corticosteroid sparing therapies.[10,11] The results of this post hoc analysis challenge the notion of 'undertreating' older patients to avoid treatment complications by demonstrating that a strategy of algorithmic early combined immunosuppression may also be effective and safe in older patients with IBD, potentially decreasing corticosteroid use and risk of Crohn's disease-related complications. The benefit of a strategy of treating with TNFα-based therapy over chronic corticosteroids was also demonstrated in a retrospective matched cohort study among Medicaid and Medicare beneficiaries.[18] In their study, Lewis et al observed that TNFα antagonist-based therapy in Crohn's disease was associated with lower risk of death, major adverse cardiovascular outcomes and pathologic fractures as compared to chronic corticosteroid therapy, without any difference in the risk of serious infections. This benefit was seen in both older and younger patients.

A major concern with the use of combined immunosuppression in older adults is the risk of serious infections. However, it is important to recognise that besides advanced age and immunosuppressive therapy, most consistent disease-related factors associated with serious infections in patients with IBD include severe disease activity, exposure to corticosteroids and narcotics.[19–21] Underlying severely active disease may increase the risk of serious infections through impaired immune surveillance, increased risk of abdominal infections (eg intra-abdominal or perianal abscesses in patients with penetrating Crohn's disease) or through the need for repeated courses of corticosteroids to temporarily improve inflammation-driven symptoms. In our study, a strategy of early combined immunosuppression was not found to be differentially effective in younger than older patients with Crohn's disease in terms of decreasing risk of serious disease-related complications and hospitalisation.

There are several strengths of our study. This was a post hoc analysis of a prospective pragmatic cluster-randomised trial of community gastroenterologists, and hence the findings would be broadly applicable. With a 2-year follow-up, we were able to ascertain clinically important outcomes including the risk of disease-related complications, surgery and hospitalisation. However, there are important limitations to our analysis. First, the trial was not designed or powered to compare the effectiveness of early combined immunosuppression vs conventional management between older and younger adults and, hence, the results should be considered exploratory and interpreted with caution. Second, since this was a community practice-level pragmatic trial of treatment strategies (not of specific medications), detailed assessment and attribution of all treatment-emergent and treatment-related adverse events were not performed, possibly resulting in a low observed rate of serious drug-related complications. With a potentially lower event rate and follow-up restricted to a maximum of 24 months, treatment-related harm could not be adequately assessed in this analysis. Third, while this was one of the largest clinical trials of IBD with a 2-year follow-up, long-term comparative effectiveness and safety of these strategies remains to be seen. Fourth, our study does not adequately inform on the treatment targets—clinical remission vs endoscopic remission—in older patients. Recognising suboptimal correlation between clinical and endoscopic disease activity in patients with Crohn's disease, algorithmic treatment step-up based on clinical disease activity alone may lead to overtreatment of some patients who otherwise have no objective evidence of inflammation. The ongoing follow-up REACT-2 trial will inform the impact of treating to a target of mucosal healing. Finally, in this trial, treatment steps focused on the TNFα antagonist-based therapy. With the availability of several non-TNFα-based biologic therapies and ongoing trials of targeted small molecules with varying efficacy and safety profiles, risk-benefit trade-offs of algorithmic early treatment step-up in older patients using non-TNF therapy may be different.

In conclusion, based on a post hoc analysis of the REACT trial, we have demonstrated that, there is no evidence that a treatment strategy of early combined immunosuppression based on TNFα antagonist is any less effective in older adults than younger adults with Crohn's disease. Whilst more deaths were observed in older patients, there was a similar proportion in patients in both the early combined immunosuppression and conventional management groups. In selected older patients with suboptimal disease control, an algorithmic treatment step-up strategy may be considered to decrease treatment disutility and avoid persistence on chronic corticosteroids. Future studies focusing on older patients at higher risk of disease complications and designed to evaluate optimally tailored treatment approaches and treatment targets and to evaluate the impact of non-TNFα biologics and targeted small molecules are warranted.

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