Elderly onset age is associated with low efficacy of first anti-tumor necrosis factor treatment in patients with inflammatory bowel disease

The outcomes of patients with elderly onset (EO) inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) remains uncertain. The present study evaluated the efficacy and safety of anti-TNF treatment for bio-naïve EO-IBD. Elderly patients were defined as those 60 years and older, and further divided into those with EO (Elderly-EO) and those with non-elderly onset (Elderly-NEO). A total of 432 bio-naïve patients were enrolled in this multicenter observational study, comprising 55 with Elderly-EO (12.7%), 25 with Elderly-NEO (5.8%), and 352 under age 60 (Non-elderly, 81.5%). After 52 weeks of anti-TNF treatment, clinical and steroid-free remission rates were significantly lower in Elderly-EO than in Non-elderly (37.7% and 60.8%; P = 0.001, and 35.9% and 57.8%; P = 0.003, respectively), and comparable between Elderly-NEO and Non-elderly. Multivariate analysis revealed that elderly onset was a significant factor for both clinical remission (OR, 0.49, 95% CI 0.25–0.96) and steroid-free remission (OR, 0.51, 95% CI 0.26–0.99) after 52 weeks of anti-TNF treatment. The rate of cumulative severe adverse events was significantly higher in Elderly-EO than in Non-elderly (P = 0.007), and comparable between Elderly-NEO and Non-elderly. In conclusion, anti-TNF treatment for bio-naïve EO-IBD may be less effective and raise safety concerns.


Results
Patient characteristics. Among the 605 patients with IBD enrolled, 444 bio-naïve patients with IBD who underwent anti-TNF treatment were included in the study. Patients who underwent a total colectomy and/or colostomy before treatment were excluded from the analysis, and 432 bio-naïve patients with IBD were included in the analyses. Of the 432 bio-naïve patients included in the analysis, 217 (50.2%) had UC and 215 (49.8%) had CD; 55 (12.7%) patients were classified as Elderly-EO, 25 (5.8%) patients were classified as Elderly-NEO, and 352 (81.5%) were classified as Non-elderly. Baseline characteristics and concomitant drugs at the start of anti-TNF treatment are shown in Table 1. The proportion of patients with UC was significantly higher in the Elderly-NEO (68.0%) and Elderly-EO (80.0%) groups than in the Non-elderly group (44.3%, P = 0.021 or P < 0.001, respectively). Although disease duration was significantly longer in the Elderly-NEO group (15 years [95% ) than in the Non-elderly group (2 years [95% CI 0-9], P < 0.001), there was no significant difference between the Elderly-EO (1 year [95% CI 0-3]) and Non-elderly groups (P = 0.048). Regarding concomitant drugs, although the proportion of patients with concomitant corticosteroid and immunomodulators did not differ between the Elderly-NEO (32.0% and 40.0%) and Non-elderly groups (31.8% and 22.7%; P = 0.985 and P = 0.050, respectively), the proportions were higher in the Elderly-EO group (61.8% and 40.0%) than in the Non-elderly group (P < 0.001 and P = 0.006, respectively).

Characteristics and concomitant drugs associated with the long-term efficacy of anti-TNF treatment for Elderly-EO patients.
We next explored the conditions in which anti-TNF treatment was more effective for Elderly-EO. Of 55 elderly-EO patients, clinical symptoms of 2 patients at 52 weeks after anti-TNF treatment could not be collected from medical records in our hospitals because those were transferred to the other hospitals until 52 weeks after anti-TNF treatment. In 53 Elderly-EO patients, we evaluated the characteristics or concomitant drugs associated with clinical remission or steroid-free remission after 52 weeks of anti-TNF treatment (   Table 3).

Safety of anti-TNF treatment for Elderly-EO patients.
We further investigated the safety of anti-TNF treatment for IBD patients by evaluating the cumulative discontinuation rate and SAE rate of anti-TNF treatment. Although the cumulative discontinuation rate and SAE rate of anti-TNF treatment did not differ significantly between the Elderly-NEO and Non-elderly groups (P = 0.329 and P = 0.949, respectively), these were significantly higher in the Elderly-EO group than in the Non-elderly group (P < 0.001 and P = 0.007, Fig. 2a,b), In addition, we investigated the details of the SAEs by evaluating the incidence rate of individual SAEs normalized to 1000 py ( Table 4). The incidence rates of infection (18/1000 py), cardiovascular event (9/1000 py), malignancy (18/1000 py), and death (27/1000 py) were higher in the Elderly-EO than in the Non-elderly groups (3/1000 py,  Lupus-like syndrome www.nature.com/scientificreports/ 2/1000 py, 2/1000 py and 2/1000 py, respectively; Table 4). None of these factors, however, was significantly different between the Elderly-NEO and Non-elderly groups.

Discussion
The present study evaluated the efficacy and safety of anti-TNF treatment in bio-naïve elderly patients with IBD according to age at onset (Elderly-EO and Elderly-NEO). The study was conducted in a multicenter setting including both an academic institution and 17 non-academic institutions and demonstrated, with standardized disease activity scores, the efficacy of anti-TNF treatment for bio-naïve Elderly-EO. The results clearly demonstrated that bio-naïve Elderly-EO IBD patients exhibit a decreased response to anti-TNF treatment compared with Non-elderly IBD patients, and that long-term efficacy of anti-TNF treatment for bio-naïve Elderly-EO could be expected if the IBD-type was CD, the disease duration was less than 1 year, and the patients were without concomitant corticosteroid treatment at the start of anti-TNF treatment. Furthermore, the results indicated that SAEs, including infection, cardiovascular events, malignancy, and death, were more frequent in Elderly-EO than in Elderly-NEO or Non-elderly IBD patients. A few previous studies demonstrated the efficacy and safety of initial anti-TNF treatment for elderly patients with IBD [23][24][25] . These studies showed that elderly patients with IBD had a lower long-term continuation rate of initial anti-TNF treatment due to SAEs, not to a loss of response 24,25 , and a lower short-term response rate as judged by the physicians 23,24 , not according to standardized disease activity indexes as used in the present study. Here, we first demonstrated the short-and long-term clinical or steroid-free remission rates of elderly patients with IBD using pMayo and HBI scores, which are generally used as disease activity indexes for patients with IBD. Also, by dividing patients according to their age at disease onset, we revealed that the long-term effectiveness of anti-TNF treatment was lower in bio-naïve Elderly-EO patients, and the short-and long-term effectiveness of anti-TNF treatment in Elderly-NEO patients did not differ from those in Non-elderly patients. In addition, multivariate analysis showed that elderly onset was extracted as significant factors for both clinical and steroidfree remissions, whereas IBD type and concomitant corticosteroid were extracted only for each ( Table 2). We then think that elderly onset was mainly associated with low efficacy of first anti-TNF treatment in patients with IBD rather than IBD type or concomitant corticosteroid. These data strongly suggest that anti-TNF treatment is less effective, especially for Elderly-EO patients with IBD, but further studies are required due to the small number of Elderly-NEO patients in the present study.
Patients with EO-rheumatoid arthritis (EO-RA) have higher serum interleukin-6 levels and lower serum TNFα levels than patients with NEO-RA, and high levels of TNFα are associated with higher risk of hospitalization and death [26][27][28] . Furthermore, anti-TNF treatment for EO-RA seems to be less effective than for NEO-RA 26 . Although serum and tissue drug concentrations of anti-TNF agents reflect long-term sustained clinical remission in CD 29 , anti-infliximab antibody levels are increased in elderly patients with IBD despite their immunosenescence 30 . No molecular studies to date have analyzed the effect of anti-TNF treatment in EO-IBD, and future studies to investigate the pharmacokinetics of anti-TNF treatment in EO-IBD are warranted.
By investigating the patient characteristics and concomitant drugs in Elderly-EO, we revealed that an IBDtype of CD, short disease duration, and no concomitant corticosteroid treatment are factors associated with the long-term efficacy of anti-TNF treatment for bio-naïve Elderly-EO patients. A previous report demonstrated that early corticosteroid exposure was a significant risk factor for IBD-related surgery in Elderly-EO 15 . Therefore, earlier transition to anti-TNF treatment is expected to have long-term efficacy for Elderly-EO patients with corticosteroid dependence or resistance. In addition, top-down treatment with anti-TNF agents or accelerating step up to anti-TNF treatment with determining the effect of corticosteroid with short disease duration have potential to be more effective for elderly onset patients with CD.
Some previous reports assessed the safety of anti-TNF treatment for elderly patients with IBD and demonstrated that older age was the only independent factor for SAEs, including infection, malignancy, and cardiovascular and death events [23][24][25]31 . Consistent with the previous reports, we revealed that SAEs leading to discontinuation of anti-TNF treatment were more frequent in Elderly-EO than in Non-elderly patients, and the cumulative SAE rate was significantly higher in Elderly-EO than in Non-elderly patients, especially at 2 years after the first anti-TNF treatment. In the present study, the proportion of concomitant immunomodulators in Elderly-EO was significantly higher than Non-elderly in the present study (Table 1). However, when analyzed in Elderly-EO, the proportion of SAE was unchanged between the concomitant immunomodulator group (31.8%) and the non-concomitant group (18.2%, P = 0.243). In the present study, we defined SAE as the events leading to the discontinuation of anti-TNF treatment and we didn't evaluate adverse events that could be managed without discontinuing the anti-TNF treatment. From these, in Elderly-EO, careful and close follow-up is required in Elderly-EO patients to assess SAEs with or without using concomitant immunomodulators, even if the anti-TNF treatment is effective.
The present study has several limitations. First, because this study was a retrospective study, a selection bias for patients receiving anti-TNF treatment could not be excluded, accurate information on comorbidities could not be collected, and endoscopic evaluation could not be performed at a designated time. Second, multivariate analysis for factors associated with clinical or steroid-free remission after 52 weeks of anti-TNF treatment could not be conducted due to the small number of Elderly-EO patients. A large and prospective validation study is required to confirm the results of this study. Third, fecal calprotectin levels were not measured because it had not been approved by insurance for patients with CD in Japan. Forth, we could not assess the frailty which was reported to affect disease activity, and treatment efficacy and safety in elderly patients with IBD 32,33 . To address these issues, a prospective study with comorbidities, frailty, endoscopic and fecal evaluation is needed.
In conclusion, anti-TNF treatment for bio-naïve EO-IBD may be less effective and raise safety concerns.

Methods
Patients. This was a retrospective multicenter study. Patients at least 16 years of age that were diagnosed and hospitalized with IBD, including UC or CD, and started treatment with biologic agents (infliximab, adalimumab, golimumab, ustekinumab, or vedolizumab), tofacitinib, or tacrolimus from January 2010 to March 2019 due to corticosteroid dependence or resistance at 18 hospitals participating in the Osaka Gut Forum were enrolled in the study in November 2019. Of them, bio-naïve patients with IBD who underwent anti-TNF treatment were included in the analysis. Patients who had undergone a total colectomy and/or ostomy before the treatment were excluded. The study was carried out in accordance with the Declaration of Helsinki, and approved by the ethics committee of Osaka University Hospital and the other ethics committees (Supplemental Table 2). Written informed consent was waived by ethics committee of Osaka University Hospital, and the other ethics committees (Supplemental Table 2), by giving participants the opportunity to opt out.
Definition of elderly and patient grouping. According to previous reports 5-7 , we defined elderly patients as those 60 years of age or older, and EO as patients who were at least 60 years of age at the time of diagnosis. Furthermore, elderly patients with IBD were further divided into those with elderly onset (Elderly-EO) and those with non-elderly onset (Elderly-NEO).
Data collection. For  Outcomes. Efficacy of the anti-TNF treatment was assessed by the clinical remission and steroid-free remission rates at 8 weeks and 52 weeks of anti-TNF treatment. In addition, factors associated with the clinical remission and steroid-free remission rates were assessed at 8 and 52 weeks of anti-TNF treatment. Clinical remission was defined pMayo score of ≤ 2 and no individual sub-score > 1 in UC 38 , and an HBI score of ≤ 4 in CD. To evaluate safety, we calculated the cumulative SAE rate during anti-TNF treatment from the start of anti-TNF treatment to the cessation of treatment or follow-up and individual SAE rate during anti-TNF treatment as the number of SAEs divided by 1000 patient-years [(py) i.e., events per 1000 py].
Statistical analysis. Continuous variables are presented as the medians and interquartile range (IQR). Categorical valuables are presented as frequencies. Differences in the distribution of variables were evaluated using Pearson's chi square test or Fisher's exact test if the numbers were smaller than 5. We used Bonferroni's method for multiple comparisons (Elderly-EO to Non-elderly or Elderly-NEO to Non-elderly) and a significant P value was defined as P < 0.05/2 = 0.025. The odds ratio (OR) and corresponding 95% confidence interval (CI) were estimated by multivariate logistic regression analysis with the stratification variables. The cumulative incidence rate was estimated by the Kaplan-Meier method and evaluated by the log-rank test. In these evaluations, P values less than 0.05 were considered significant. Statistical analyses were performed using JMP statistical software (version 16.0.0; SAS Institute, Inc., Cary, NC, USA).
Ethnics approval and consent to participate. The study was carried out in accordance with the Declaration of Helsinki, and approved by the ethics committee of Osaka University Hospital and the other ethics committees (Supplemental Table 2). Written informed consent was waived by ethics committee of Osaka University Hospital, and the other ethics committees (Supplemental Table 2), by giving participants the opportunity to opt out.

Consent for publication.
This study contains no individual person's data in any form.

Data availability
The datasets generated and/or analyzed during the present study are available from the corresponding author upon reasonable request.