Editorial: safety and efficacy of infliximab and corticosteroids in checkpoint inhibitor‐induced colitis—authors' reply

We thank Dr. Hanauer and colleagues for their interesting and important editorial comment on our study.1,2 In patients with multiple morbidities, death can have many concurrent reasons. Therefore, it is important to optimise all treatment components of the disease course. We chose to focus on steroid exposure and infliximab use, as we observed that they differed considerably from patient to patient. Further, as mentioned by Hanauer et al, corticosteroid dosing in oncology is considerably higher than the standard dose for hospitalised patients with severe ulcerative colitis. We calculated that, on average, patients with immunemediated enterocolitis (IMC) received 2.5fold more steroids than patients with severe ulcerative colitis following standard care with 3 days of IV methylprednisolone followed by an 8week tapering course of oral prednisolone (3978 vs. 1560 mg). As suggested by Hanauer et al, it would have been desirable to investigate the effect of cumulative corticosteroid exposure on overall survival and on cancer response to check point inhibitor treatment. However, due to the induction of an immortal time bias by cumulative drug exposure measures in the mortality analysis, our statistical advisor advised against the analysis. Patients who died early would not have had time to be exposed to the same amount of corticosteroid and infliximab as patients who lived longer. This may result in an overestimated survival among patients treated with high doses of corticosteroids or high number of infliximab infusions, called immortal time bias.3 This is the disadvantage of a retrospective study and, like Hanauer et al, we emphasise the need for randomised trials. Many trials have been listed on clini caltr ials.gov, including NCT04797325 from our own group, which is currently recruiting and addressing the possibility of corticosteroidsparing regimens in IMC management. We agree that the Cox regression mortality analysis is missing information regarding disease severity and that adding the Mayo endoscopic score (MES) would give more detailed information, and help clarify if IMC severity influences mortality. Interestingly, the updated analysis showed that an MES score of 1 compared to 0 leads to a decrease in hazard ratio, whereas there is no difference between MES 0 and more severe endoscopic findings (Table 1). In addition, there is a marked increase in the hazard ratio and mortality significance level in patients tapering from high prednisolone doses (HR 1.95 (1.20– 3.16), p = 0.007). If confirmed elsewhere, this may lead to a change in standard of care, with more progressive treatment towards biologics and less dependency on corticosteroids. Regarding venous thromboembolism (VTE) and mortality side effects of corticosteroids, safety data from two large populationbased studies in nonmalignant conditions demonstrated that overall corticosteroid use was associated with increased mortality and increased risk of VTE compared to matched controls.4,5 The risk of VTE seems to be most prominent within the first 30 days of corticosteroid treatment,6 consistent with our observations.