The Natural History of Crohn’s Disease Leading to Intestinal Failure: A Longitudinal Cohort Study from 1973 to 2018

The Natural History of Crohn’s Disease Leading to Intestinal Failure: A Longitudinal Cohort Study from 1973 to 2018 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Natural History of Crohn’s Disease Leading to Intestinal Failure: A Longitudinal Cohort Study from 1973 to 2018 Tian Hong Wu, Christopher Filtenborg Brandt, Thomas Scheike, Johan Burisch, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4779921/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Jul, 2024 Read the published version in Journal of Crohn's and Colitis → Version 1 posted You are reading this latest preprint version Abstract Background and Aims: The natural history of Crohn’s disease leading to intestinal failure is not well characterised. This study aims to describe the clinical course of Crohn’s disease preceding intestinal failure, and compare disease activity and burden between Crohn’s disease patients with and without intestinal failure. Methods: Patients with Crohn’s disease complicated by intestinal failure from Rigshospitalet, Copenhagen (n=182) and a nationwide Danish Crohn’s disease cohort without intestinal failure (n=22,845) were included. Using nationwide medical and social registries in Denmark, disease activity was determined from hospitalisations, surgeries and outpatient medications, and disease burden was determined from employment and mortality data. Results: The 10-year cumulative incidence of intestinal failure following Crohn’s disease diagnosis declined from 2.7% prior to 1980 to 0.2% after 2000. Compared to Crohn’s disease patients without intestinal failure, those with intestinal failure experienced significantly longer duration of severe disease (50 vs. 19 years per 100 patient-years, p<0.01), secondary to greater corticosteroid use (71% vs. 60%, p =0.02), inpatient contacts (98% vs. 55%, p <0.01), and abdominal surgeries (99% vs. 48%, p <0.01). However, exposure to biologics was not different between the two groups (20.4% vs. 21%, p=0.95), and duration on biologics was shorter in Crohn’s disease patients with intestinal failure(2,068 vs. 4,126 days per 100 patient-years, p =0.02). Standard mortality ratio in Crohn’s disease patients with intestinal failurewas 3.66 [97.5% CI 2.79,4.72]. Conclusion: Patients with Crohn’s disease complicated by intestinal failure experienced a more persistently severe preceding course of Crohn’s disease, but were not more likely to be treated with biological therapy. Gastroenterology & Hepatology Crohn’s disease Intestinal failure natural history Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Intestinal failure (IF), defined as the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, 1 is a rare but severe end-organ sequelae of Crohn’s disease (CD). 2–4 While IF affects at most 80 people per million, 5 30–46% of IF is caused by CD, 6–12 and significant resources and expertise are required to manage IF patients with home parenteral support (HPS). 13–15 Previous studies reported long-term cumulative incidences of IF from CD from 3.4–18.4%, 16–18 indicating a non-negligible risk. The mechanisms of developing IF from CD (CDIF) were heterogenous. Repeated bowel resections, complicated surgery with intra-abdominal sepsis, enterocutaneous fistulae and extensive mucosal disease have all been reported to cause CDIF. 19,20 However, with the advent of biologics and small molecules to improve disease control, 21 the need for surgery appears to have decreased, 22 yet IF continues to occur in CD patients. 9 The full clinical characteristics and treatment history of CD preceding IF is vital for developing risk prognostication and preventative strategies for this complication, but they are lacking due to small patient numbers and a paucity of longitudinal, inception cohort data. In addition, and despite advances in the management of CD, the effect of therapeutic advances on the risk of developing IF from CD is unknown. Therefore, the aim of this study was to describe the natural history from the onset of CD to the development of IF. Specifically, we sought to: 1) Describe the incidence of IF from CD in relation to different treatment eras; 2) Compare CD-specific disease activity and burden between CDIF patients and CD patients who did not develop IF; 3) Analyse overall and cause-specific mortality in CDIF patients compared with CD patients. Methods Study Setting and Population The Department of Intestinal Failure and Liver Diseases at Rigshospitalet is the largest intestinal failure and rehabilitation service in Denmark. It managed all adult IF patients in Denmark prior to 1990 and since then has served approximately one-third to one-half of the Danish population for IF referrals. Consecutive CDIF patients managed at this centre from 1973 to 2018 were included in this study. Patients were defined as having CDIF if they required HPS at least once per week, and had CD as the underlying cause of IF. Additionally, a nationwide CD cohort from 1978 to 2018 was identified from the Danish National Patient Registry (NPR) 23 using a validated algorithm. 24 Patients with a possible diagnosis of IF were excluded from the CD cohort (Supplementary Fig. 1). Data Extraction Data was extracted from Danish population-based healthcare 25 and social registries using the patients’ unique, pseudo-anonymised civil-registration number. Specifically, all episodes of hospitalisations and surgeries from 1977, outpatient visits and treatments from 1995, dispensed outpatient medicines from 1995 and causes of death since 1970 were available and classified according to the Danish Health Care Classification System (Sundhedsvæsenets klassifikationssystem, SKS). 26 The employment status of patients over the age of 18 were available from 1977. A list of SKS codes used for data extraction and classification is available in Supplementary Methods. IF-specific data was prospectively collected on CDIF patients in the Copenhagen Intestinal Failure Database (CFID). 27 Clinical Activity Assessment Patients were followed from the date of first CD diagnosis, until IF, death, or 31st December 2018, whichever occurred first. Onset of IF was defined as the date of initiating HPS. Trends over time were summarised by decades of the follow-up period: pre-1980, 1981–1990, 1991–2000, 2001–2010, and after 2010. Medication use was defined in accordance with Danish prescribing conventions (Supplementary Methods). Systemic corticosteroids referred to oral prednisolone, where a tapering course was defined as a dispensed dose of at least 2,275 mg, as described elsewhere. 28 Azathioprine, mercaptopurine and methotrexate were included as immunomodulators. Infliximab, adalimumab, certolizumab, golimumab, eternacept, vedolizumab and ustekinumab were included as biologics. Assessment of biologics use was made after year 2000, when infliximab was approved for the treatment of CD in Denmark. A course of biologics was defined as treatment with the same biologic without a prolonged (> 6 months) break. Admissions and non-admitted emergency department presentations were included as inpatient contacts, and categorised as IBD or non-IBD depending on the discharge diagnosis (Supplementary Methods). Planned attendances for biologics and surgical procedures were excluded, as they have been accounted for elsewhere. In CDIF patients, the admission immediately prior to the commencement of HPS was considered the index IF admission. CD-related abdominal surgeries were defined as surgical procedures on the gastrointestinal tract or abdominal cavity that were likely due to CD or CD-related complications, and further classified into bowel resections and other procedures (Supplementary Methods). Multiple procedures on the same day were counted as one surgery. Complicated surgery was defined as multiple procedures on the same day, a post-operative stay longer than the 90th percentile, or a further surgery within 30 days. The overall CD activity was defined as “severe”, where there was at least one unplanned IBD inpatient contact, CD-related abdominal surgery, or course of systemic corticosteroids in a given follow-up year. 28 Chronic CD activity was calculated for the duration of follow-up, up to 10 years after CD diagnosis, and classified as: 1) Mild, where CD was severely active for 10% or less of the follow-up years; 2) Intermittently severe, where CD was severely active for 10%-50% of the follow-up years; 3) Chronically severe, where CD was severely active for more than 50% of the follow-up years. Disease Burden and Outcome Assessment The employment activity rate 29 , defined as the number of eligible-working-years that a person was working, was determined for all patients between 18 and 65 years old. Patients who were previously working and became unemployed or received sickness benefits for more than six months, or who retired before 65 years of age, were classed as “stopped working”. All-cause mortality and cause-specific mortality were analysed separately in CDIF and CD patients and compared with the general population of Denmark. Cause of death was grouped into 50 causes, from which population-level reference data are available 29 . These were further combined into nine anatomical- and mechanism-based categories (Supplementary Methods). Statistical Analysis Absolute numbers and proportions were compared using a Chi-squared test. Incidence rates of events were expressed as the number of events in 100 patient-years and compared using Poisson regression. Time-to-event analyses were made using cumulative incidence functions. Mortality rates were expressed as the number of deaths in 10,000 patient-years. Expected mortality was calculated using age-sex-year-matched population mortality, and the standard mortality ratio (SMR) was obtained as the ratio between the observed and expected mortality. A direct mortality comparison between CD and CDIF patients was made using a multivariant proportional hazard model with delayed entry to account for CDIF patients having survived until IF onset. A p < 0.05 was considered statistically significant. Statistical analyses were performed using R version 4.3.1 (R Core Team 2023). Ethical Considerations This study was approved by the Danish Data Protection Agency (jr.nr P-2021-461 & 2007-58-0015-30-0854). Ethical approval for registry-based studies was not required by Danish legislation. Results Baseline Characteristics In total, 182 CDIF patients and 22,845 CD patients were followed for 2,283 and 293,537 patient-years, respectively. At CD diagnosis, CDIF patients had a lower median age than CD patients (24, IQR 17.2–34.8 vs 35, IQR 23–55). A greater proportion of CDIF patients (n = 130, 71.5%) were diagnosed with CD before 1991, compared to CD patients (n = 3,770, 16%, p < 0.01), and a greater proportion CDIF patients (n = 156, 93%) had no comorbidities, compared to CD patients (n = 18,173, 80%, p < 0.01). Cumulative Incidence and Lead Time of Developing IF from CD New CDIF patients increased every decade until 2010, after which the number plateaued. Despite this, the 10-year cumulative incidence of developing IF in newly diagnosed CD patients decreased from 2.7% prior to 1980 to 0.2% after 2000 ( p < 0.01) (Fig. 1 ), as the number of newly diagnosed CD patients significantly increased in every decade (Table 1 ). The cumulative incidence of developing IF was higher in CD patients with younger onset compared to those with mature-age onset, with a 10-year cumulative incidence of developing IF of 0.7%, 0.5% and 0.2% for CD patients with Montreal classifications A1, A2 and A3, respectively ( p < 0.01). The median duration of CD until IF onset (lead time) in CDIF patients was 14.5 years (IQR 8–24). Lead time increased in every decade, from a median of seven years before 1980 to 25.5 years after 2010 (Fig. 2 ). CD-related Medication Use In total, 113 (62%) CDIF and 21,857 (96%) CD patients had all or part of their follow-up after 1995, when data on dispensed outpatient medicines was available. Compared with CD patients, a greater proportion of CDIF patients received corticosteroids (71% vs. 60%, p = 0.02) and immunomodulators (59% vs. 49%, p = 0.03). The proportion of patients exposed to biologics was not different between the two groups (20% vs. 21%, p = 0.95). Twenty-three percent of CDIF and 30% of CD patients received none of the above medications during follow-up ( p = 0.12). In patients who received medications, the cumulative time on biological therapy was shorter among CDIF patients than CD patients (2,068 vs. 4,126 days per 100 patient-years, p = 0.02). In addition, the time from CD diagnosis to first exposure to a biologic was significantly longer in CDIF patients, at 15.4 years (SD 9.2), than in CD patients, at 5.6 years (SD 7.4), due to a higher proportion of CDIF patients whose CD onset preceded the availability of biological therapy. In patients who received medications, no significant difference was observed between CDIF and CD patients in the mean yearly dose of corticosteroids, the number of years where at least one tapering course of corticosteroids was received, the number of years where any immunomodulator was received, or the number of courses of biologics received (Table 2 ). All CDIF patients and 99.5% CD patients received an anti-TNF agent as the first-line biologic. Eighty-three percent of CDIF patients and 94% CD patients stayed in the same class of biologic during follow-up. While 30% of CDIF and 31% of CD patients continued their first biologic beyond three months, CDIF patients were less likely to continue their first biologic for more than a year, at 17% compared to 39% for CD patients ( p = 0.06). Unplanned Inpatient Contacts Hospitalisation data were available in 168 (92%) CDIF patients and 22,845 (100%) CD patients, who were followed from 1977 to 2018. We identified 8,269 episodes and 171,159 episodes of unplanned inpatient contacts in CDIF and CD patients, respectively, corresponding to 47.3 episodes and 7.94 episodes per patient. Among CDIF and CD patients, 49% and 25% of inpatient contacts were IBD-related ( p < 0.01), respectively, and 92% and 70% of these inpatient contacts were admissions ( p < 0.01). Compared with CD patients, a higher proportion of CDIF patients had at least one episode of IBD-related inpatient contact (98% vs. 55%, p < 0.01) during follow-up. CDIF patients had a higher rate of IBD-related inpatient contact (93 vs. 15 episodes per 100 patient-years, p < 0.01), a greater number of follow-up years with at least one IBD-related inpatient contact (93 vs. 15 years per 100 patient-years, p < 0.01), and a higher rate of all unplanned inpatient contacts (150 vs. 58 episodes per 100 patient-years, p < 0.01). CDIF patients and CD patients showed a downward trend for IBD-related inpatient contacts over time, from 169 episodes and 80 episodes per 100 patient-years before 1980, to 72 episodes and seven episodes per 100 patient-years after 2010, respectively (Fig. 3 ). IBD-related inpatient contacts declined faster among CD patients than CDIF patients, such that CDIF patients were 2.12 times more likely to have an inpatient contact prior to 1980, and 9.68 times more likely than CD patients after 2010. On the other hand, non-IBD-related inpatient contacts increased over time among CDIF patients, from 43 episodes to 127 episodes per 100 patient-years, but remained stable among CD patients. This increase was driven by CD-related complications and a reduction of intestinal function in the late stages of CD prior to onset of IF. A pattern of “decompensation” was observed in CDIF patients one year prior to IF onset, with an increase in both IBD- and non-IBD-related inpatient contacts (Supplementary Results). A review of the discharge codes of non-IBD-related inpatient contacts within a year of IF onset showed that 32.7% of these contacts were due to “volume and electrolyte disturbances” or “malnutrition”, and a further 26.8% were due to complications or symptoms that were likely related to IBD or IBD surgery (Supplementary Results). CD-related Abdominal Surgeries From 1977 to 2018, we identified 1,234 CD-related abdominal surgical procedures in 168 CDIF patients and 33,475 procedures in 22,845 CD patients. Of these procedures, 529 (42.9%) in CDIF and 13,308 (39.8%) in CD were resections. Compared to CD patients, a significantly higher proportion of CDIF patients underwent at least one CD-related abdominal surgery (99% vs. 48%, p < 0.01), resection (95% vs. 37%, p < 0.01), or colectomy (84% vs. 33%, p < 0.01) during follow-up. The rate of CD-related abdominal surgeries and bowel resections was higher in CDIF patients (33 and 23 per 100 patient-years, respectively) than in CD patients (8 and 5 per 100 patient-years, respectively, p < 0.01). In patients who underwent surgery, a higher proportion of CDIF patients received corticosteroids (30% vs. 11%, p < 0.01) and vedolizumab (7% vs. 0.3%, p < 0.01) 30 days before surgery, but not anti-TNF agents (2% vs. 6%, p = 0.47). In addition, a higher proportion of CDIF patients had complicated surgeries, characterised as multiple procedures on the same day (91% vs. 44%, p < 0.01), post-operative stays longer than the 90th percentile (21 days) (48% vs. 22%, p < 0.01), or reoperation within 30 days (34% vs. 16%, p < 0.01) (Table 2 ). CDIF patients underwent a mean of 2.8 (SD 2.1) complicated surgeries during follow-up, compared with 0.5 (SD 1.1) for CD patients. The rate of surgery over time in CDIF patients followed a different trend to CD patients (Fig. 3 ). In CDIF patients, CD-related abdominal surgeries initially decreased from 33 before 1980 to 17 surgeries per 100 patient-years in the 2000s, but subsequently increased to 30 surgeries per 100 patient-years after 2010. In CD patients, a consistent decline of CD-related abdominal surgeries was seen, from 17 surgeries per 100 patient-years before 1980 to four surgeries per 100 patient-years after 2010. These distinct trends were observed for both bowel resections and other abdominal surgeries. Two factors contributed to the diverging trends between CDIF and CD patients. First, the median time-to-first-surgery increased from 2.86 (95% CI 2.27, 4.11) to 16.22 (14.94, 17.51) years in CD patients ( p < 0.001) but did not significantly change in CDIF patients ( p = 0.22). Second, there was a significant decrease in CD patients undergoing any bowel surgery during the follow-up period, from 75–14%, but there was no comparable decrease among CDIF patients. Overall CD Activity Ninety-two percent of CDIF (n = 155/168) and 62% of CD (n = 14,285/22,845) patients had severe CD activity in the year of CD diagnosis. During follow-up, the proportion experiencing severe activity decreased in both CDIF and CD patients, to 43% (n = 40/94) and 14% (n = 1,620/11,775) after 10 years, and 30% (n = 15/50) and 11% (n = 604/5,431) after 20 years, respectively (Fig. 4 ). Overall, CDIF and CD patients had 50 and 19 years with severe CD activity per 100 patient-years, respectively (Table 2 ). For the first 10 years after CD diagnosis, 61% of CDIF patients (n = 103/168) had chronically severe disease and 6% (n = 10/168) had mild disease. In contrast, 15% of CD patients (n = 3,331/22,845) had chronically severe disease and 43% (n = 9,837/22,845) had mild disease ( p < 0.01). Notably, on average, CDIF patients who were diagnosed with CD after 2000 experienced severe activity in eight out of the first 10 years, whereas patients with an earlier diagnosis experienced severe activity in six out of the first 10 years. We observed no difference in disease activity patterns between CDIF patients who initiated, and those who did not initiate, biological therapy (Supplementary Results). Working Capacity During the follow-up period, 105 (66%) working-age CDIF patients had stopped work at least once, compared with 10,897 (58%) CD patients ( p = 0.04). The employment activity rate was 60 per 100 eligible-working-years in CDIF patients, and 70 per 100 eligible-working-years in CD patients ( p < 0.01). Mortality Seventy-seven (44%) CDIF and 5,182 (22.5%) CD patients died between 1973 and 2018. Compared with the age-, sex- and year-matched general population in Denmark, CDIF patients had a SMR of 3.66 (97.5% CI 2.79,4.72), while CD patients had a SMR of 1.66 (97.5% CI 1.61, 1.72). In both CDIF and CD patients, the excess mortality was higher in females, with a SMR of 4.71 (97.5% CI 3.32, 6.48) and 1.74 (97.5% CI 1.66, 1.81), respectively, and in patients with a young age of CD onset, who had a SMR of 7.66 (97.5% CI 1.68, 21.59) and 2.61 (97.5% CI 1.76, 3.71), respectively (Table 4). Diseases of the digestive tract were attributed as the underlying cause of death in 51.9% of CDIF and 17.6% of CD patients. Excess deaths were observed in gastrointestinal cancers and haematological malignancies in CD, but not CDIF, patients (Supplementary Results). When mortality was directly compared between CDIF and CD patients, the unadjusted all-cause mortality rate was 11.5%, 25% and 42.6% in CDIF patients at 10, 20 and 30 years after CD onset, and 15.2%, 27.1% and 39.3% in CD patients at 10, 20 and 30 years after CD onset, respectively ( p = 0.94). However, after adjusting for age, sex, baseline comorbidities and CDIF patients surviving until IF onset, CDIF patients had hazard ratio of 3.42 (95% CI 2.55,4.59, p < 0.01) for mortality compared with CD patients (Supplementary Results). Discussion This is the first study to comprehensively describe the natural history and burden of Crohn’s disease among a subset of Crohn’s patients who subsequently developed IF. This study demonstrates a steady decline in the risk of developing IF among newly diagnosed CD patients in every decade of the study period. The 10-year risk of developing IF was 12.7 times lower in 2000 than in 1980. Other Danish cohort studies have shown greater remission rates of CD diagnosed after 1995 28 compared to those diagnosed before 1987. 30 As such, the decline in IF risk likely reflects the better prognosis of CD due to improved disease control over time. However, due to a steep rise in the background prevalence of CD in Denmark, 25,31 the number of CD patients developing IF increased each decade until 2000, after which it plateaued to an average of five cases per year in our centre. Based on the catchment population, we estimate that between 2000 and 2018 the population incidence of CDIF in eastern Denmark was 1.73-2.59 per million inhabitants per year. A French multi-centre study 2 also estimated a stable, albeit lower, population incidence of 0.4 per million per year for CDIF between 1986 and 2006. Denmark has the highest case-finding rate of IF in the world due to universal access to specialist IF centres, proactive referral practices, and high awareness. 5 The large differences in incidence of CDIF are probably due to a combination of variations in background prevalence of CD and referral practices for IF. Our study sheds light on the mechanisms behind the development of IF from CD. We observed substantially greater and more sustained disease activity in CDIF patients according to healthcare utilisation patterns, with a 5.4-fold higher rate of IBD-related inpatient contacts and a three-fold higher rate of CD-related abdominal surgeries. For the first 10 years after a CD diagnosis, 61% of CDIF patients had chronically severe active CD, whereas other studies have shown that severe disease characterizes less than 20% of the CD population, and continuously active CD between 6-19% in prevalent CD patients. 28,32,33 In addition, an increase in non-IBD-related inpatient contacts was observed, especially in the year just before IF onset, akin to a pattern of “decompensation”, where patients present frequently with complications or non-specific symptoms related to CD or intestinal insufficiency. 1 CDIF patients were more likely to receive pre-operative corticosteroids, a known risk factor for post-operative complications, 34,35 and undergo complicated surgeries, which encompass both complex surgical procedures and a complicated post-operative course. A large case series from the United Kingdom showed that post-operative abdominal septic complications caused IF in 51% of CDIF patients. 36 Our study suggests that ongoing severe CD activity and pre-operative “decompensation” likely contribute to these complications. In addition, although the rate of surgery consistently declined over a 40-year period in CD patients, this trend was not found in CDIF patients, which suggests that CDIF patients represent a subset of CD patients more refractory to new medical management. To summarise, the majority of CDIF patients in our study experienced severe and refractory disease, persisting for long periods of time, with or without surgical complications, that led to IF. An unexpected finding from our study was the similar proportions of biologics used to treat CDIF and CD patients. Of the CDIF patients who were followed up in the biological era, 79% were never initiated on these treatments, despite their apparent disease activity. The reason for not trialling biologics was unclear, but we postulate that a perceived futility and concern for infective complications in the setting of intestinal fistulae or impending surgeries may have impacted clinicians’ and/or patients’ willingness to initiate a new therapy, especially when biologics were still novel. Only a few studies have reported on the use of biologics in CDIF patients before the onset of IF, with wide-ranging rates from 4% to 80%, 10,37 and one study found non-use of anti-TNF was associated with developing IF. 18 Limited efficacy of biologics in preventing surgery has been found in CDIF patients after IF onset. 38 Our results also suggest a lower efficacy of biologics in CDIF patients before IF onset, with less treatment persistence beyond 12 months in biologics-treated patients, although this difference was not statistically significant (likely due to low patient numbers). The effect of biologics on the development of IF in high-risk CD patients remains unclear. We have demonstrated significantly higher mortality in CDIF patients compared with both the general population and CD patients. While CD patients have a moderate increase in SMR of 1.66, consistent with previous studies, 39,40 CDIF patients showed a large increase in SMR of 3.66 compared with the age-, sex- and year-matched Danish population. This result confirms our group’s previous findings in IBD-Short bowel syndrome patients. 4 When directly comparing CDIF to CD patients, the presence of IF was associated with a 2.42-fold higher hazard rate of dying after adjusting for demographic and clinical variables. Cause-specific mortality analysis showed excess deaths attributed to solid organ and haematological neoplasms among CD patients, consistent with other studies demonstrating an increased risk of cancer. 40,41 However, we did not find increased cancer-related deaths among CDIF patients, despite more exposure to thiopurines, suggesting that malignancy-related premature death was a competing event to developing IF. Finally, although high death rates were observed in CDIF patients, this should be interpreted within the context that untreated IF was universally fatal, and mortality in CDIF patients appeared lower than in patients with other end-stage organ failures, such as those with renal failure. 42,43 The main strength of this study was its design. An inception cohort study from disease onset is the gold-standard in describing the natural history of a disease and provides the highest quality of observational evidence. We ensured comprehensive data capture from multiple population-based registries to investigate patient characteristics, treatment histories and outcomes that occurred across all healthcare institutions in Denmark, with minimal loss to follow-up. However, our study does have some limitations. CDIF patients came from a single centre for the management of IF, although prior to developing IF they were managed in diverse healthcare settings. This limitation was mitigated by high uniformity in characteristics and treatment of Danish CD patients across geographical regions, 44 which maintained the validity of comparing CDIF patients to the nationwide CD cohort. Nevertheless, the granularity of registry data meant that it was not possible to directly phenotype CD in this study. We infer that at least 80% of CDIF patients had colonic involvement, in addition to small bowel disease, with an 80% colectomy rate, and we postulate that the majority of CDIF patients had an obstructing/penetrating phenotype of CD at the time of IF, leading to SBS, fistula/obstruction, or a combined pathology as the cause of their IF. Ileocolonic disease and an obstructing/penetrating phenotype in CDIF patients was much higher than in previously published Danish CD cohorts. 45 Finally, we did not have data on smoking, clinical indices of disease severity or biomarkers. In conclusion, our study has demonstrated a reduction in the incidence of CDIF in newly diagnosed CD patients, but a steady population incidence of CDIF. Therefore, IF remains a rare but important complication of CD. Many of our CDIF patients were diagnosed with CD in the pre-biological era, and experienced a high disease burden over a long disease course. Those who were diagnosed more recently appeared to have even greater disease activity, but over a shorter period; however, they were not more likely to receive biologics. Our findings highlight the need for further characterisation of CDIF patients to elucidate modifiable risk factors. In addition, close clinical follow-up and medical optimisation for severe and chronically active CD patients should be prioritised to prevent complications and IF. Declarations Funding: This work was supported by Novo Nordisk Foundation grant number 0059377 to J.B. Acknowledgement: We thank Mads Damsgaard Wewer for his guidance on the registries and Kristian Asp Fuglsang for his guidance in standardised mortality ratio calculations. References Pironi L, Cuerda C, Jeppesen PB, et al. ESPEN guideline on chronic intestinal failure in adults – Update 2023. Clinical Nutrition . 2023;42(10):1940-2021. doi:10.1016/j.clnu.2023.07.019 Elriz K, Palascak-Juif V, Joly F, et al. 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Journal of Parenteral and Enteral Nutrition . 2017;41(4):566-574. doi:10.1177/0148607115612040 Kurin M, Anderson A, Ramos Rivers C, et al. Clinical Characteristics of Inflammatory Bowel Disease Patients Requiring Long-Term Parenteral Support in the Present Era of Highly Effective Biologic Therapy. JPEN J Parenter Enteral Nutr . 2021;45(5):1100-1107. doi:10.1002/jpen.1988 Dibb M, Soop M, Teubner A, et al. Survival and nutritional dependence on home parenteral nutrition: Three decades of experience from a single referral centre. Clinical Nutrition . 2017;36(2):570-576. doi:10.1016/J.CLNU.2016.01.028 Jeppesen PB, Staun M, Mortensen PB, Bekker Jeppesen P, Staun M, Brøbech Mortensen P. Adult patients receiving home parenteral nutrition in Denmark from 1991 to 1996: who will benefit from intestinal transplantation? Scand J Gastroenterol . 1998;33(8):839-846. doi:10.1080/00365529850171503 Matarese LE, Jeppesen PB, O’Keefe SJD. Short bowel syndrome in adults: the need for an interdisciplinary approach and coordinated care. JPEN J Parenter Enteral Nutr . 2014;38(1 Suppl):60S-64S. doi:10.1177/0148607113518946 Howard L. Home Parenteral Nutrition: Survival, Cost, and Quality of Life. Published online 2006. doi:10.1053/j.gastro.2005.09.065 Fuglsang KA, Brandt CF, Scheike T, Jeppesen PB. Hospitalizations in Patients With Nonmalignant Short-Bowel Syndrome Receiving Home Parenteral Support. Nutrition in Clinical Practice . 2020;35(5):894-902. doi:10.1002/ncp.10471 Harper PH, Fazio VW, Lavery IC, et al. The long-term outcome in Crohn’s disease. Dis Colon Rectum . 1987;30(3):174-179. doi:10.1007/BF02554332 Watanabe K, Sasaki I, Fukushima K, et al. Long-term incidence and characteristics of intestinal failure in Crohn’s disease: a multicenter study. J Gastroenterol . 2014;49(2):231-238. doi:10.1007/s00535-013-0797-y Watanabe Y, Miyoshi N, Fujino S, et al. Cumulative Inflammation Could Be a Risk Factor for Intestinal Failure in Crohn’s Disease. Dig Dis Sci . 2019;64:2280-2285. doi:10.1007/s10620-019-05553-2 Agwunobi AO, Carlson GL, Anderson ID, Irving MH, Scott NA. Mechanisms of intestinal failure in Crohn’s disease. Dis Colon Rectum . 2001;44(12):1834-1837. doi:10.1007/BF02234463 Soop M, Khan H, Nixon E, et al. Causes and prognosis of intestinal failure in crohn’s disease: An 18-year experience from a national centre. J Crohns Colitis . 2020;14(11):1558-1564. doi:10.1093/ecco-jcc/jjaa060 Gordon M, Sinopoulou V, Akobeng AK, Sarian A, Moran GW. Infliximab for maintenance of medically-induced remission in Crohn’s disease. Cochrane Database Syst Rev . 2024;2(2):CD012609. doi:10.1002/14651858.CD012609.pub2 Law CCY, Tkachuk B, Lieto S, et al. Early Biologic Treatment Decreases Risk of Surgery in Crohn’s Disease but not in Ulcerative Colitis: Systematic Review and Meta-Analysis. Inflamm Bowel Dis . 2023;Jul 28: izad149. doi:10.1093/ibd/izad149 Schmidt M, Schmidt SAJ, Sandegaard JL, Ehrenstein V, Pedersen L, Sørensen HT. The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol . 2015;7:449. doi:10.2147/CLEP.S91125 Lo B, Vind I, Vester-Andersen MK, Burisch J. Validation of ulcerative colitis and Crohn’s disease and their phenotypes in the Danish National Patient Registry using a population-based cohort. Scand J Gastroenterol . 2020;55(10):1171-1175. doi:10.1080/00365521.2020.1807598 Dorn-Rasmussen M, Lo B, Zhao M, et al. The Incidence and Prevalence of Paediatric- and Adult-Onset Inflammatory Bowel Disease in Denmark during a 37-Year Period: A Nationwide Cohort Study (1980-2017). J Crohns Colitis . 2023;17(2):259-268. doi:10.1093/ecco-jcc/jjac138 Danish Health Data Authority. Classifications (SKS). Published 2023. Accessed May 1, 2023. https://sundhedsdatastyrelsen.dk/da/rammer-og-retningslinjer/om-klassifikationer/sks-klassifikationer/hovedgrupper-sks Brandt CF, Hvistendahl M, Naimi RM, et al. Home Parenteral Nutrition in Adult Patients With Chronic Intestinal Failure: The Evolution Over 4 Decades in a Tertiary Referral Center. JPEN J Parenter Enteral Nutr . 2017;41(7):1178-1187. doi:10.1177/0148607116655449 Wewer MD, Langholz E, Munkholm P, Bendtsen F, Benedict Seidelin J, Burisch J. Disease Activity Patterns of Inflammatory Bowel Disease-A Danish Nationwide Cohort Study 1995-2018. J Crohns Colitis . 2023;17(3):329-337. doi:10.1093/ecco-jcc/jjac140 Danmarks Statistik. StatBank. Accessed June 1, 2023. https://www.statistikbanken.dk/statbank5a/default.asp?w=1920 Munkholm P, Langholz E, Davidsen M, Binder V. Disease activity courses in a regional cohort of Crohn’s disease patients. Scand J Gastroenterol . 1995;30(7):699-706. doi:10.3109/00365529509096316 Agrawal M, Christensen HS, Bøgsted M, Colombel JF, Jess T, Allin KH. The Rising Burden of Inflammatory Bowel Disease in Denmark Over Two Decades: A Nationwide Cohort Study. Gastroenterology . 2022;163(6):1547-1554.e5. doi:10.1053/j.gastro.2022.07.062 Solberg IC, Vatn MH, Høie O, et al. Clinical course in Crohn’s disease: results of a Norwegian population-based ten-year follow-up study. Clin Gastroenterol Hepatol . 2007;5(12):1430-1438. doi:10.1016/j.cgh.2007.09.002 Wintjens D, Bergey F, Saccenti E, et al. Disease Activity Patterns of Crohn’s Disease in the First Ten Years After Diagnosis in the Population-based IBD South Limburg Cohort. J Crohns Colitis . 2021;15(3):391-400. doi:10.1093/ecco-jcc/jjaa173 Subramanian V, Saxena S, Kang JY, Pollok RCG. Preoperative steroid use and risk of postoperative complications in patients with inflammatory bowel disease undergoing abdominal surgery. American Journal of Gastroenterology . 2008;103(9):2373-2381. doi:10.1111/j.1572-0241.2008.01942.x Aberra FN, Lewis JD, Hass D, Rombeau JL, Osborne B, Lichtenstein GR. Corticosteroids and immunomodulators: Postoperative infectious complication risk in inflammatory bowel disease patients. Gastroenterology . 2003;125(2):320-327. doi:10.1016/S0016-5085(03)00883-7 Soop M, Khan H, Nixon E, et al. Causes and prognosis of intestinal failure in crohn’s disease: An 18-year experience from a national centre. J Crohns Colitis . 2020;14(11):1558-1564. doi:10.1093/ecco-jcc/jjaa060 Uchino M, Ikeuchi H, Bando T, et al. Risk factors for short bowel syndrome in patients with Crohn’s disease. Surg Today . 2012;42(5):447-452. doi:10.1007/s00595-011-0098-0 Limketkai BN, Parian AM, Chen PH, Colombel JF. Treatment With Biologic Agents Has Not Reduced Surgeries Among Patients With Crohn’s Disease With Short Bowel Syndrome. Clinical Gastroenterology and Hepatology . 2017;15(12):1908-1914.e2. doi:10.1016/j.cgh.2017.06.040 Jess T, Winther KV, Munkholm P, Langholz E, Binder V. Mortality and causes of death in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark. Gastroenterology . 2002;122(7):1808-1814. doi:10.1053/gast.2002.33632 Burisch J, Lophaven S, Langholz E, Munkholm P. The clinical course of Crohn’s disease in a Danish population-based inception cohort with more than 50 years of follow-up, 1962-2017. Aliment Pharmacol Ther . 2022;55(1):73-82. doi:10.1111/apt.16615 Jess T, Horváth-Puhó E, Fallingborg J, Rasmussen HH, Jacobsen BA. Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: A Danish population-based cohort study. American Journal of Gastroenterology . 2013;108(12):1869-1876. doi:10.1038/ajg.2013.249 De Jager DJ, Grootendorst DC, Jager KJ, et al. Cardiovascular and Noncardiovascular Mortality Among Patients Starting Dialysis. JAMA . 2009;302(16):1782-1789. doi:10.1001/JAMA.2009.1488 Villar E, Remontet L, Labeeuw M, Ecochard R. Effect of age, gender, and diabetes on excess death in end-stage renal failure. J Am Soc Nephrol . 2007;18(7):2125-2134. doi:10.1681/ASN.2006091048 Zhao M, Sall Jensen M, Knudsen T, et al. Trends in the use of biologicals and their treatment outcomes among patients with inflammatory bowel diseases - a Danish nationwide cohort study. Aliment Pharmacol Ther . 2022;55(5):541-557. doi:10.1111/apt.16723 Lo B, Vester-Andersen MK, Vind I, et al. Changes in Disease Behaviour and Location in Patients With Crohn’s Disease After Seven Years of Follow-Up: A Danish Population-based Inception Cohort. J Crohns Colitis . 2018;12(3):265-272. doi:10.1093/ecco-jcc/jjx138 Tables Table 1. Demographic Characteristics of CDIF Patients Compared with a Background CD Population Variable CDIF (n=175) CD (n=22,845) p -value Median years of follow-up [IQR] 14.5 [8, 24] 10.4 [4.3, 19.5] 0.39 Gender Female 101 (55.5) 12,834 (56.2) Male 81 (44.5) 10,011 (43.8) 0.78 Median age at CD diagnosis [IQR] 24 [17.2, 34.8] 35 [23, 55] <0.01 Age group at CD diagnosis 0-16 years 39 (21.4) 2,119 (9.3) 17-40 years 111 (61.0) 10,896 (47.7) 41+ years 32 (17.6) 9,830 (43.0) <0.01 Comorbidity at CD diagnosis* None 156 (93.1) 18,173 (79.5) Mild 11 (6.3) 3,848 (16.8) Moderate 1 (0.6) 608 (2.7) Severe 0 (0.0) 216 (0.9) <0.01 Decade of CD diagnosis pre-1980 74 (40.7) 933 (4.1) 1980+ 56 (30.8) 2,837 (12.4) 1990+ 36 (19.8) 4,939 (21.6) 2000+ 13 (7.1) 6,488 (28.4) 2010+ 3 (1.6) 7,648 (33.5) <0.01 Residential region in Denmark Capital 95 (54.3) 6,938 (30.4) Zealand 48 (27.4) 3,302 (14.5) Southern Danmark 17 (9.7) 4,908 (21.5) North Jutland 7 (4.0) 2,446 (10.7) Mid Jutland 8 (4.6) 5,245 (23.0) Other 0 (0.0) 6 (0.0) <0.01 Median age at IF onset [IQR] 43.5 [33.0, 56.8] Decade of IF onset pre-1980 17 (9.3) 1981-1990 35 (19.2) 1991-2000 29 (15.9) 2001-2010 51 (28.0) 2011+ 50 (27.5) Median lead time in years [IQR] 14.5 [8, 24] Pathology at IF onset Short Bowel Syndrome 91 (50.0) Abdominal Fistula +/- Abscess 14 (7.7) Mucosal Disease 26 (14.3) Intestinal Obstruction 6 (3.3) Dysmotility 2 (1.1) Combined Pathology 43 (23.6) * Comorbidity is based on Charlson Comorbidity Index (CCI): None = CCI 0, Mild = CCI 1-2, Moderate = CCI 3-4, Severe = CCI 5+ Table 2. CD-related Disease Burden in CDIF Patients Compared to CD Patients Variable CDIF (n=168) CD (n=22,845) p -value Outpatient Medication Use* Number of patients who received any steroids (%) 80 (70.8) 13,064 (59.8) 0.02 Number of patients who received any immunomodulators (%) 67 (59.3) 10,643 (48.7) 0.03 Number of patients who received any biologics (%) 23 (20.4) 4,593 (21.0) 0.96 Cumulative dose (grams) of steroids in steroid-treated patients/100 patient-years (97.5% CI) 584.2 (469.9, 726.2) 514.2 (502.5, 526.1) 0.25 Years on immunomodulators in immunomodulator-treated patients/100 patient-years (97.5% CI) 34.5 (27.4, 43.4) 41.4 (40.7, 42.1) 0.11 Years on biologics in biologic-treated patients/100 patient-years (97.5% CI) 5.7 (3.21, 10.0) 11.3 (10.9, 11.7) 0.02 Courses of steroids in steroid-treated patients/100 patient-years (97.5% CI) 11.8 (9.0, 15.4) 9.3 (9.1, 9.6) 0.09 Courses of biologics in biologic-treated patients/100 patient-years (97.5% CI) 16.8 (8.9, 31.6) 15.8 (15.4, 16.2) 0.85 Number of biologic-treated patients who persisted >1 year on a single course (%) 4 (17.4) 1675 (36.5) 0.06 Unplanned Inpatient Contacts Number of patients who had any unplanned IBD inpatient contacts (%) 165 (98.2) 12607 (55.2) <0.01 Rate of unplanned IBD inpatient contacts/100 patient-years (97.5% CI) 92.8 (80.2, 107.4) 14.5 (14.4, 15.0) <0.01 Rate of all unplanned inpatient contacts/100 patient-years (97.5% CI) 150.7 (133.5, 170.0) 58.3 (57.4, 59.2) <0.01 CD-related Abdominal Surgeries Number of patients who had any surgery (%) 166 (98.8) 10,877 (47.6) <0.01 Number of patients who had any bowel resection (%) 160 (95.2) 8,550 (37.4) <0.01 Number of patients who had a colectomy (%) 141 (83.9) 7,563 (33.1) <0.01 Number of patients who had endoscopic dilatation (%) 8 (4.8) 527 (2.3) 0.06 Number of patients who had any complicated surgery (%) 156 (92.9) 5952 (26.1) <0.01 Corticosteroids within 30 days of surgery 17 (29.8) 800 (10.6) <0.01 Biologics within 30 days of surgery 3 (6.7) 392 (6.1) 1.00 Rate of all CD-related abdominal surgeries/100 patient-years (97.5% CI) 33.2 (29.6, 37.2) 8.4 (8.2, 8.6) <0.01 Rate of bowel resections/100 patient-years (97.5% CI) 23.1 (20.2, 26.5) 4.5 (4.4, 4.6) <0.01 Overall CD Activity For the first 10 years after onset of CD Mild 10 (6.0) 9,837 (43.1) Intermittently severe 55 (32.7) 9,677 (42.4) Chronically severe 103 (61.3) 3,331 (14.6) <0.01 Number of severely active years/100 patient-years (97.5% CI) 49.6 (45.7, 53.8) 18.8 (18.5, 19.1) 6 months (%) 105 (66.0) 10,897 (57.8) 0.04 Number of years not working /100 eligible-working-years (97.5% CI) 43.1 (36.5, 50.9) 30.1 (29.5, 30.7) <0.01 *Medication data was available from 1995-2018 in n=113 CDIF patients and n=21,857 CD patients Additional Declarations The authors declare potential competing interests as follows: J. Burisch reports grants and personal fees from AbbVie, grants and personal fees from Janssen-Cilag, personal fees from Celgene, grants and personal fees from MSD, personal fees from Pfizer, grants and personal fees from Takeda, grants and personal fees from Tillots Pharma, personal fees from Samsung Bioepis, grants and personal fees from Bristol Myers Squibb, grants from Novo Nordisk, personal fees from Pharmacosmos, personal fees from Ferring, and personal fees from Galapagos, outside the submitted work. Supplementary Files SupplementaryMethods.docx Supplementary Methods SupplementaryResults080224.docx Supplementary Results GraphicalAbstract.png Graphical Abstract Cite Share Download PDF Status: Published Journal Publication published 23 Jul, 2024 Read the published version in Journal of Crohn's and Colitis → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Rigshospitalet","correspondingAuthor":false,"prefix":"","firstName":"Palle","middleName":"Bekker","lastName":"Jeppesen","suffix":""}],"badges":[],"createdAt":"2024-07-22 07:26:50","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-4779921/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4779921/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1093/ecco-jcc/jjae114","type":"published","date":"2024-07-23T13:13:57+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60910751,"identity":"716fdc6a-e84d-423b-b357-f8d1991d55d7","added_by":"auto","created_at":"2024-07-23 12:52:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":58835,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCumulative Incidence of IF from CD Declines Over Time and with Increasing Age of CD Onset\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4779921/v1/243acf11cf3f6d2b3f55f3c2.png"},{"id":60912103,"identity":"f640382d-c295-4e47-b4b8-f254ccd66e84","added_by":"auto","created_at":"2024-07-23 13:00:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52927,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLead Time from CD to IF Increases Over Time\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4779921/v1/634b59f49d1975cfbe6ca178.png"},{"id":60912104,"identity":"3bdc49c2-315f-442b-b4cd-aa5a8da947cf","added_by":"auto","created_at":"2024-07-23 13:00:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":80698,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDiverging Trends in Inpatient Contact and Surgery Rates Over Time between CDIF and CD Patients\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4779921/v1/d8952974409d1f454189b88b.png"},{"id":60910753,"identity":"24a4b820-243e-40a0-9028-a4228271a429","added_by":"auto","created_at":"2024-07-23 12:52:10","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":28249,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSustained Severe Disease Activity Since CD Onset in CDIF Patients Compared to CD Patients\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4779921/v1/3fa8a09f538c7c7454f67de2.png"},{"id":60913567,"identity":"79b5d7ee-65df-49b2-837e-32ae5bca3a3d","added_by":"auto","created_at":"2024-07-23 13:14:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1046422,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4779921/v1/87f85cfa-c6d8-41c3-b36e-9322c07d6817.pdf"},{"id":60910749,"identity":"7b7f9158-ccb7-4240-aab8-68bff67ef074","added_by":"auto","created_at":"2024-07-23 12:52:10","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":36411,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Methods\u003c/p\u003e","description":"","filename":"SupplementaryMethods.docx","url":"https://assets-eu.researchsquare.com/files/rs-4779921/v1/c7cea107519768274f8ddb13.docx"},{"id":60910757,"identity":"449cbd8d-a848-473b-bee5-a995d98ca776","added_by":"auto","created_at":"2024-07-23 12:52:11","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":70223,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Results\u003c/p\u003e","description":"","filename":"SupplementaryResults080224.docx","url":"https://assets-eu.researchsquare.com/files/rs-4779921/v1/9ccacd363fd4f1c7a4634851.docx"},{"id":60910752,"identity":"e5a4912e-e0e2-4912-ba29-c90f61e6c466","added_by":"auto","created_at":"2024-07-23 12:52:10","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":145923,"visible":true,"origin":"","legend":"\u003cp\u003eGraphical Abstract\u003c/p\u003e","description":"","filename":"GraphicalAbstract.png","url":"https://assets-eu.researchsquare.com/files/rs-4779921/v1/147a5f2454237bb87ed52940.png"}],"financialInterests":"The authors declare potential competing interests as follows: J. Burisch reports grants and personal fees from AbbVie, grants and personal fees from Janssen-Cilag, personal fees from Celgene, grants and personal fees from MSD, personal fees from Pfizer, grants and personal fees from Takeda, grants and personal fees from Tillots Pharma, personal fees from Samsung Bioepis, grants and personal fees from Bristol Myers Squibb, grants from Novo Nordisk, personal fees from Pharmacosmos, personal fees from Ferring, and personal fees from Galapagos, outside the submitted work.","formattedTitle":"\u003cp\u003eThe Natural History of Crohn’s Disease Leading to Intestinal Failure: A Longitudinal Cohort Study from 1973 to 2018\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIntestinal failure (IF), defined as the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, \u003csup\u003e1\u003c/sup\u003e is a rare but severe end-organ sequelae of Crohn\u0026rsquo;s disease (CD). \u003csup\u003e2\u0026ndash;4\u003c/sup\u003e While IF affects at most 80 people per million, \u003csup\u003e5\u003c/sup\u003e 30\u0026ndash;46% of IF is caused by CD, \u003csup\u003e6\u0026ndash;12\u003c/sup\u003e and significant resources and expertise are required to manage IF patients with home parenteral support (HPS). \u003csup\u003e13\u0026ndash;15\u003c/sup\u003e Previous studies reported long-term cumulative incidences of IF from CD from 3.4\u0026ndash;18.4%, \u003csup\u003e16\u0026ndash;18\u003c/sup\u003e indicating a non-negligible risk.\u003c/p\u003e \u003cp\u003eThe mechanisms of developing IF from CD (CDIF) were heterogenous. Repeated bowel resections, complicated surgery with intra-abdominal sepsis, enterocutaneous fistulae and extensive mucosal disease have all been reported to cause CDIF.\u003csup\u003e19,20\u003c/sup\u003e However, with the advent of biologics and small molecules to improve disease control,\u003csup\u003e21\u003c/sup\u003e the need for surgery appears to have decreased,\u003csup\u003e22\u003c/sup\u003e yet IF continues to occur in CD patients.\u003csup\u003e9\u003c/sup\u003e The full clinical characteristics and treatment history of CD preceding IF is vital for developing risk prognostication and preventative strategies for this complication, but they are lacking due to small patient numbers and a paucity of longitudinal, inception cohort data. In addition, and despite advances in the management of CD, the effect of therapeutic advances on the risk of developing IF from CD is unknown.\u003c/p\u003e \u003cp\u003eTherefore, the aim of this study was to describe the natural history from the onset of CD to the development of IF. Specifically, we sought to: 1) Describe the incidence of IF from CD in relation to different treatment eras; 2) Compare CD-specific disease activity and burden between CDIF patients and CD patients who did not develop IF; 3) Analyse overall and cause-specific mortality in CDIF patients compared with CD patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Setting and Population\u003c/h2\u003e \u003cp\u003eThe Department of Intestinal Failure and Liver Diseases at Rigshospitalet is the largest intestinal failure and rehabilitation service in Denmark. It managed all adult IF patients in Denmark prior to 1990 and since then has served approximately one-third to one-half of the Danish population for IF referrals. Consecutive CDIF patients managed at this centre from 1973 to 2018 were included in this study. Patients were defined as having CDIF if they required HPS at least once per week, and had CD as the underlying cause of IF. Additionally, a nationwide CD cohort from 1978 to 2018 was identified from the Danish National Patient Registry (NPR) \u003csup\u003e23\u003c/sup\u003e using a validated algorithm. \u003csup\u003e24\u003c/sup\u003e Patients with a possible diagnosis of IF were excluded from the CD cohort (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData Extraction\u003c/h2\u003e \u003cp\u003eData was extracted from Danish population-based healthcare \u003csup\u003e25\u003c/sup\u003e and social registries using the patients\u0026rsquo; unique, pseudo-anonymised civil-registration number. Specifically, all episodes of hospitalisations and surgeries from 1977, outpatient visits and treatments from 1995, dispensed outpatient medicines from 1995 and causes of death since 1970 were available and classified according to the Danish Health Care Classification System (Sundhedsv\u0026aelig;senets klassifikationssystem, SKS). \u003csup\u003e26\u003c/sup\u003e The employment status of patients over the age of 18 were available from 1977. A list of SKS codes used for data extraction and classification is available in Supplementary Methods. IF-specific data was prospectively collected on CDIF patients in the Copenhagen Intestinal Failure Database (CFID). \u003csup\u003e27\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eClinical Activity Assessment\u003c/h2\u003e \u003cp\u003ePatients were followed from the date of first CD diagnosis, until IF, death, or 31st December 2018, whichever occurred first. Onset of IF was defined as the date of initiating HPS. Trends over time were summarised by decades of the follow-up period: pre-1980, 1981\u0026ndash;1990, 1991\u0026ndash;2000, 2001\u0026ndash;2010, and after 2010.\u003c/p\u003e \u003cp\u003eMedication use was defined in accordance with Danish prescribing conventions (Supplementary Methods). Systemic corticosteroids referred to oral prednisolone, where a tapering course was defined as a dispensed dose of at least 2,275 mg, as described elsewhere.\u003csup\u003e28\u003c/sup\u003e Azathioprine, mercaptopurine and methotrexate were included as immunomodulators. Infliximab, adalimumab, certolizumab, golimumab, eternacept, vedolizumab and ustekinumab were included as biologics. Assessment of biologics use was made after year 2000, when infliximab was approved for the treatment of CD in Denmark. A course of biologics was defined as treatment with the same biologic without a prolonged (\u0026gt;\u0026thinsp;6 months) break.\u003c/p\u003e \u003cp\u003eAdmissions and non-admitted emergency department presentations were included as inpatient contacts, and categorised as IBD or non-IBD depending on the discharge diagnosis (Supplementary Methods). Planned attendances for biologics and surgical procedures were excluded, as they have been accounted for elsewhere. In CDIF patients, the admission immediately prior to the commencement of HPS was considered the index IF admission.\u003c/p\u003e \u003cp\u003eCD-related abdominal surgeries were defined as surgical procedures on the gastrointestinal tract or abdominal cavity that were likely due to CD or CD-related complications, and further classified into bowel resections and other procedures (Supplementary Methods). Multiple procedures on the same day were counted as one surgery. Complicated surgery was defined as multiple procedures on the same day, a post-operative stay longer than the 90th percentile, or a further surgery within 30 days.\u003c/p\u003e \u003cp\u003eThe overall CD activity was defined as \u0026ldquo;severe\u0026rdquo;, where there was at least one unplanned IBD inpatient contact, CD-related abdominal surgery, or course of systemic corticosteroids in a given follow-up year. \u003csup\u003e28\u003c/sup\u003e Chronic CD activity was calculated for the duration of follow-up, up to 10 years after CD diagnosis, and classified as: 1) Mild, where CD was severely active for 10% or less of the follow-up years; 2) Intermittently severe, where CD was severely active for 10%-50% of the follow-up years; 3) Chronically severe, where CD was severely active for more than 50% of the follow-up years.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eDisease Burden and Outcome Assessment\u003c/h2\u003e \u003cp\u003eThe employment activity rate \u003csup\u003e29\u003c/sup\u003e, defined as the number of eligible-working-years that a person was working, was determined for all patients between 18 and 65 years old. Patients who were previously working and became unemployed or received sickness benefits for more than six months, or who retired before 65 years of age, were classed as \u0026ldquo;stopped working\u0026rdquo;.\u003c/p\u003e \u003cp\u003eAll-cause mortality and cause-specific mortality were analysed separately in CDIF and CD patients and compared with the general population of Denmark. Cause of death was grouped into 50 causes, from which population-level reference data are available \u003csup\u003e29\u003c/sup\u003e. These were further combined into nine anatomical- and mechanism-based categories (Supplementary Methods).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAbsolute numbers and proportions were compared using a Chi-squared test. Incidence rates of events were expressed as the number of events in 100 patient-years and compared using Poisson regression. Time-to-event analyses were made using cumulative incidence functions. Mortality rates were expressed as the number of deaths in 10,000 patient-years. Expected mortality was calculated using age-sex-year-matched population mortality, and the standard mortality ratio (SMR) was obtained as the ratio between the observed and expected mortality. A direct mortality comparison between CD and CDIF patients was made using a multivariant proportional hazard model with delayed entry to account for CDIF patients having survived until IF onset. A \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were performed using R version 4.3.1 (R Core Team 2023).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEthical Considerations\u003c/h2\u003e \u003cp\u003eThis study was approved by the Danish Data Protection Agency (jr.nr P-2021-461 \u0026amp; 2007-58-0015-30-0854). Ethical approval for registry-based studies was not required by Danish legislation.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Characteristics\u003c/h2\u003e \u003cp\u003eIn total, 182 CDIF patients and 22,845 CD patients were followed for 2,283 and 293,537 patient-years, respectively.\u003c/p\u003e \u003cp\u003eAt CD diagnosis, CDIF patients had a lower median age than CD patients (24, IQR 17.2\u0026ndash;34.8 vs 35, IQR 23\u0026ndash;55). A greater proportion of CDIF patients (n\u0026thinsp;=\u0026thinsp;130, 71.5%) were diagnosed with CD before 1991, compared to CD patients (n\u0026thinsp;=\u0026thinsp;3,770, 16%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and a greater proportion CDIF patients (n\u0026thinsp;=\u0026thinsp;156, 93%) had no comorbidities, compared to CD patients (n\u0026thinsp;=\u0026thinsp;18,173, 80%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCumulative Incidence and Lead Time of Developing IF from CD\u003c/h2\u003e \u003cp\u003eNew CDIF patients increased every decade until 2010, after which the number plateaued. Despite this, the 10-year cumulative incidence of developing IF in newly diagnosed CD patients decreased from 2.7% prior to 1980 to 0.2% after 2000 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), as the number of newly diagnosed CD patients significantly increased in every decade (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe cumulative incidence of developing IF was higher in CD patients with younger onset compared to those with mature-age onset, with a 10-year cumulative incidence of developing IF of 0.7%, 0.5% and 0.2% for CD patients with Montreal classifications A1, A2 and A3, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003eThe median duration of CD until IF onset (lead time) in CDIF patients was 14.5 years (IQR 8\u0026ndash;24). Lead time increased in every decade, from a median of seven years before 1980 to 25.5 years after 2010 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCD-related Medication Use\u003c/h2\u003e \u003cp\u003eIn total, 113 (62%) CDIF and 21,857 (96%) CD patients had all or part of their follow-up after 1995, when data on dispensed outpatient medicines was available. Compared with CD patients, a greater proportion of CDIF patients received corticosteroids (71% vs. 60%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02) and immunomodulators (59% vs. 49%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03). The proportion of patients exposed to biologics was not different between the two groups (20% vs. 21%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.95). Twenty-three percent of CDIF and 30% of CD patients received none of the above medications during follow-up (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.12).\u003c/p\u003e \u003cp\u003eIn patients who received medications, the cumulative time on biological therapy was shorter among CDIF patients than CD patients (2,068 vs. 4,126 days per 100 patient-years, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02). In addition, the time from CD diagnosis to first exposure to a biologic was significantly longer in CDIF patients, at 15.4 years (SD 9.2), than in CD patients, at 5.6 years (SD 7.4), due to a higher proportion of CDIF patients whose CD onset preceded the availability of biological therapy.\u003c/p\u003e \u003cp\u003eIn patients who received medications, no significant difference was observed between CDIF and CD patients in the mean yearly dose of corticosteroids, the number of years where at least one tapering course of corticosteroids was received, the number of years where any immunomodulator was received, or the number of courses of biologics received (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAll CDIF patients and 99.5% CD patients received an anti-TNF agent as the first-line biologic. Eighty-three percent of CDIF patients and 94% CD patients stayed in the same class of biologic during follow-up. While 30% of CDIF and 31% of CD patients continued their first biologic beyond three months, CDIF patients were less likely to continue their first biologic for more than a year, at 17% compared to 39% for CD patients (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eUnplanned Inpatient Contacts\u003c/h2\u003e \u003cp\u003eHospitalisation data were available in 168 (92%) CDIF patients and 22,845 (100%) CD patients, who were followed from 1977 to 2018. We identified 8,269 episodes and 171,159 episodes of unplanned inpatient contacts in CDIF and CD patients, respectively, corresponding to 47.3 episodes and 7.94 episodes per patient. Among CDIF and CD patients, 49% and 25% of inpatient contacts were IBD-related (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), respectively, and 92% and 70% of these inpatient contacts were admissions (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003eCompared with CD patients, a higher proportion of CDIF patients had at least one episode of IBD-related inpatient contact (98% vs. 55%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) during follow-up. CDIF patients had a higher rate of IBD-related inpatient contact (93 vs. 15 episodes per 100 patient-years, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), a greater number of follow-up years with at least one IBD-related inpatient contact (93 vs. 15 years per 100 patient-years, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and a higher rate of all unplanned inpatient contacts (150 vs. 58 episodes per 100 patient-years, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003eCDIF patients and CD patients showed a downward trend for IBD-related inpatient contacts over time, from 169 episodes and 80 episodes per 100 patient-years before 1980, to 72 episodes and seven episodes per 100 patient-years after 2010, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). IBD-related inpatient contacts declined faster among CD patients than CDIF patients, such that CDIF patients were 2.12 times more likely to have an inpatient contact prior to 1980, and 9.68 times more likely than CD patients after 2010.\u003c/p\u003e \u003cp\u003eOn the other hand, non-IBD-related inpatient contacts increased over time among CDIF patients, from 43 episodes to 127 episodes per 100 patient-years, but remained stable among CD patients. This increase was driven by CD-related complications and a reduction of intestinal function in the late stages of CD prior to onset of IF. A pattern of \u0026ldquo;decompensation\u0026rdquo; was observed in CDIF patients one year prior to IF onset, with an increase in both IBD- and non-IBD-related inpatient contacts (Supplementary Results). A review of the discharge codes of non-IBD-related inpatient contacts within a year of IF onset showed that 32.7% of these contacts were due to \u0026ldquo;volume and electrolyte disturbances\u0026rdquo; or \u0026ldquo;malnutrition\u0026rdquo;, and a further 26.8% were due to complications or symptoms that were likely related to IBD or IBD surgery (Supplementary Results).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eCD-related Abdominal Surgeries\u003c/h2\u003e \u003cp\u003eFrom 1977 to 2018, we identified 1,234 CD-related abdominal surgical procedures in 168 CDIF patients and 33,475 procedures in 22,845 CD patients. Of these procedures, 529 (42.9%) in CDIF and 13,308 (39.8%) in CD were resections.\u003c/p\u003e \u003cp\u003eCompared to CD patients, a significantly higher proportion of CDIF patients underwent at least one CD-related abdominal surgery (99% vs. 48%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), resection (95% vs. 37%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), or colectomy (84% vs. 33%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) during follow-up. The rate of CD-related abdominal surgeries and bowel resections was higher in CDIF patients (33 and 23 per 100 patient-years, respectively) than in CD patients (8 and 5 per 100 patient-years, respectively, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003eIn patients who underwent surgery, a higher proportion of CDIF patients received corticosteroids (30% vs. 11%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and vedolizumab (7% vs. 0.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) 30 days before surgery, but not anti-TNF agents (2% vs. 6%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.47). In addition, a higher proportion of CDIF patients had complicated surgeries, characterised as multiple procedures on the same day (91% vs. 44%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), post-operative stays longer than the 90th percentile (21 days) (48% vs. 22%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), or reoperation within 30 days (34% vs. 16%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). CDIF patients underwent a mean of 2.8 (SD 2.1) complicated surgeries during follow-up, compared with 0.5 (SD 1.1) for CD patients.\u003c/p\u003e \u003cp\u003eThe rate of surgery over time in CDIF patients followed a different trend to CD patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In CDIF patients, CD-related abdominal surgeries initially decreased from 33 before 1980 to 17 surgeries per 100 patient-years in the 2000s, but subsequently increased to 30 surgeries per 100 patient-years after 2010. In CD patients, a consistent decline of CD-related abdominal surgeries was seen, from 17 surgeries per 100 patient-years before 1980 to four surgeries per 100 patient-years after 2010. These distinct trends were observed for both bowel resections and other abdominal surgeries.\u003c/p\u003e \u003cp\u003eTwo factors contributed to the diverging trends between CDIF and CD patients. First, the median time-to-first-surgery increased from 2.86 (95% CI 2.27, 4.11) to 16.22 (14.94, 17.51) years in CD patients (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) but did not significantly change in CDIF patients (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.22). Second, there was a significant decrease in CD patients undergoing any bowel surgery during the follow-up period, from 75\u0026ndash;14%, but there was no comparable decrease among CDIF patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eOverall CD Activity\u003c/h2\u003e \u003cp\u003eNinety-two percent of CDIF (n\u0026thinsp;=\u0026thinsp;155/168) and 62% of CD (n\u0026thinsp;=\u0026thinsp;14,285/22,845) patients had severe CD activity in the year of CD diagnosis. During follow-up, the proportion experiencing severe activity decreased in both CDIF and CD patients, to 43% (n\u0026thinsp;=\u0026thinsp;40/94) and 14% (n\u0026thinsp;=\u0026thinsp;1,620/11,775) after 10 years, and 30% (n\u0026thinsp;=\u0026thinsp;15/50) and 11% (n\u0026thinsp;=\u0026thinsp;604/5,431) after 20 years, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOverall, CDIF and CD patients had 50 and 19 years with severe CD activity per 100 patient-years, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). For the first 10 years after CD diagnosis, 61% of CDIF patients (n\u0026thinsp;=\u0026thinsp;103/168) had chronically severe disease and 6% (n\u0026thinsp;=\u0026thinsp;10/168) had mild disease. In contrast, 15% of CD patients (n\u0026thinsp;=\u0026thinsp;3,331/22,845) had chronically severe disease and 43% (n\u0026thinsp;=\u0026thinsp;9,837/22,845) had mild disease (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Notably, on average, CDIF patients who were diagnosed with CD after 2000 experienced severe activity in eight out of the first 10 years, whereas patients with an earlier diagnosis experienced severe activity in six out of the first 10 years.\u003c/p\u003e \u003cp\u003eWe observed no difference in disease activity patterns between CDIF patients who initiated, and those who did not initiate, biological therapy (Supplementary Results).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eWorking Capacity\u003c/h2\u003e \u003cp\u003eDuring the follow-up period, 105 (66%) working-age CDIF patients had stopped work at least once, compared with 10,897 (58%) CD patients (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04). The employment activity rate was 60 per 100 eligible-working-years in CDIF patients, and 70 per 100 eligible-working-years in CD patients (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eMortality\u003c/h2\u003e \u003cp\u003eSeventy-seven (44%) CDIF and 5,182 (22.5%) CD patients died between 1973 and 2018. Compared with the age-, sex- and year-matched general population in Denmark, CDIF patients had a SMR of 3.66 (97.5% CI 2.79,4.72), while CD patients had a SMR of 1.66 (97.5% CI 1.61, 1.72). In both CDIF and CD patients, the excess mortality was higher in females, with a SMR of 4.71 (97.5% CI 3.32, 6.48) and 1.74 (97.5% CI 1.66, 1.81), respectively, and in patients with a young age of CD onset, who had a SMR of 7.66 (97.5% CI 1.68, 21.59) and 2.61 (97.5% CI 1.76, 3.71), respectively (Table\u0026nbsp;4).\u003c/p\u003e \u003cp\u003eDiseases of the digestive tract were attributed as the underlying cause of death in 51.9% of CDIF and 17.6% of CD patients. Excess deaths were observed in gastrointestinal cancers and haematological malignancies in CD, but not CDIF, patients (Supplementary Results).\u003c/p\u003e \u003cp\u003eWhen mortality was directly compared between CDIF and CD patients, the unadjusted all-cause mortality rate was 11.5%, 25% and 42.6% in CDIF patients at 10, 20 and 30 years after CD onset, and 15.2%, 27.1% and 39.3% in CD patients at 10, 20 and 30 years after CD onset, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.94). However, after adjusting for age, sex, baseline comorbidities and CDIF patients surviving until IF onset, CDIF patients had hazard ratio of 3.42 (95% CI 2.55,4.59, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) for mortality compared with CD patients (Supplementary Results).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first study to comprehensively describe the natural history and burden of Crohn’s disease among a subset of Crohn’s patients who subsequently developed IF. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study demonstrates a steady decline in the risk of developing IF among newly diagnosed CD patients in every decade of the study period. The 10-year risk of developing IF was 12.7 times lower in 2000 than in 1980. Other Danish cohort studies have shown greater remission rates of CD diagnosed after 1995 \u003csup\u003e28\u003c/sup\u003e compared to those diagnosed before 1987. \u003csup\u003e30\u003c/sup\u003e As such, the decline in IF risk likely reflects the better prognosis of CD due to improved disease control over time. However, due to a steep rise in the background prevalence of CD in Denmark, \u003csup\u003e25,31\u003c/sup\u003e the number of CD patients developing IF increased each decade until 2000, after which it plateaued to an average of five cases per year in our centre. Based on the catchment population, we estimate that between 2000 and 2018 the population incidence of CDIF in eastern Denmark was 1.73-2.59 per million inhabitants per year. A French multi-centre study \u003csup\u003e2\u003c/sup\u003e also estimated a stable, albeit lower, population incidence of 0.4 per million per year for CDIF between 1986 and 2006. Denmark has the highest case-finding rate of IF in the world due to universal access to specialist IF centres, proactive referral practices, and high awareness. \u003csup\u003e5\u003c/sup\u003e The large differences in incidence of CDIF are probably due to a combination of variations in background prevalence of CD and referral practices for IF. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study sheds light on the mechanisms behind the development of IF from CD. We observed substantially greater and more sustained disease activity in CDIF patients according to healthcare utilisation patterns, with a 5.4-fold higher rate of IBD-related inpatient contacts and a three-fold higher rate of CD-related abdominal surgeries. For the first 10 years after a CD diagnosis, 61% of CDIF patients had chronically severe active CD, whereas other studies have shown that severe disease characterizes less than 20% of the CD population, and continuously active CD between 6-19% in prevalent CD patients. \u0026nbsp;\u003csup\u003e28,32,33\u003c/sup\u003e In addition, an increase in non-IBD-related inpatient contacts was observed, especially in the year just before IF onset, akin to a pattern of “decompensation”, where patients present frequently with complications or non-specific symptoms related to CD or intestinal insufficiency. \u003csup\u003e1\u003c/sup\u003e CDIF patients were more likely to receive pre-operative corticosteroids, a known risk factor for post-operative complications, \u003csup\u003e34,35\u003c/sup\u003e and undergo complicated surgeries, which encompass both complex surgical procedures and a complicated post-operative course. A large case series from the United Kingdom showed that post-operative abdominal septic complications caused IF in 51% of CDIF patients. \u003csup\u003e36\u003c/sup\u003e Our study suggests that ongoing severe CD activity and pre-operative “decompensation” likely contribute to these complications. In addition, although the rate of surgery consistently declined over a 40-year period in CD patients, this trend was not found in CDIF patients, which suggests that CDIF patients represent a subset of CD patients more refractory to new medical management. To summarise, the majority of CDIF patients in our study experienced severe and refractory disease, persisting for long periods of time, with or without surgical complications, that led to IF. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAn unexpected finding from our study was the similar proportions of biologics used to treat CDIF and CD patients. Of the CDIF patients who were followed up in the biological era, 79% were never initiated on these treatments, despite their apparent disease activity. The reason for not trialling biologics was unclear, but we postulate that a perceived futility and concern for infective complications in the setting of intestinal fistulae or impending surgeries may have impacted clinicians’ and/or patients’ willingness to initiate a new therapy, especially when biologics were still novel. Only a few studies have reported on the use of biologics in CDIF patients before the onset of IF, with wide-ranging rates from 4% to 80%, \u003csup\u003e10,37\u003c/sup\u003e and one study found non-use of anti-TNF was associated with developing IF. \u003csup\u003e18\u003c/sup\u003e Limited\u0026nbsp;efficacy of biologics in preventing surgery has been found in CDIF patients after IF onset. \u003csup\u003e38\u003c/sup\u003e Our results also suggest a lower efficacy of biologics in CDIF patients before IF onset, with less treatment persistence beyond 12 months in biologics-treated patients, although this difference was not statistically significant (likely due to low patient numbers). The effect of biologics on the development of IF in high-risk CD patients remains unclear.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe have demonstrated significantly higher mortality in CDIF patients compared with both the general population and CD patients. While CD patients have a moderate increase in SMR of 1.66, consistent with previous studies, \u003csup\u003e39,40\u003c/sup\u003e CDIF patients showed a large increase in SMR of 3.66 compared with the age-, sex- and year-matched Danish population. This result confirms our group’s previous findings in IBD-Short bowel syndrome patients. \u003csup\u003e4\u003c/sup\u003e When directly comparing CDIF to CD patients, the presence of IF was associated with a 2.42-fold higher hazard rate of dying after adjusting for demographic and clinical variables. Cause-specific mortality analysis showed excess deaths attributed to solid organ and haematological neoplasms among CD patients, consistent with other studies demonstrating an increased risk of cancer. \u003csup\u003e40,41\u003c/sup\u003e However, we did not find increased cancer-related deaths among CDIF patients, despite more exposure to thiopurines, suggesting that malignancy-related premature death was a competing event to developing IF. Finally, although high death rates were observed in CDIF patients, this should be interpreted within the context that untreated IF was universally fatal, and mortality in CDIF patients appeared lower than in patients with other end-stage organ failures, such as those with renal failure. \u003csup\u003e42,43\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe main strength of this study was its design. An inception cohort study from disease onset is the gold-standard in describing the natural history of a disease and provides the highest quality of observational evidence. We ensured comprehensive data capture from multiple population-based registries to investigate patient characteristics, treatment histories and outcomes that occurred across all healthcare institutions in Denmark, with minimal loss to follow-up.\u003c/p\u003e\n\u003cp\u003eHowever, our study does have some limitations. CDIF patients came from a single centre for the management of IF, although prior to developing IF they were managed in diverse healthcare settings. This limitation was mitigated by high uniformity in characteristics and treatment of Danish CD patients across geographical regions,\u0026nbsp;\u003csup\u003e44\u003c/sup\u003e\u0026nbsp; \u0026nbsp;which maintained the validity of comparing CDIF patients to the nationwide CD cohort. Nevertheless, the granularity of registry data meant that it was not possible to directly phenotype CD in this study. We infer that at least 80% of CDIF patients had colonic involvement, in addition to small bowel disease, with an 80% colectomy rate, and we postulate that the majority of CDIF patients had an obstructing/penetrating phenotype of CD at the time of IF, leading to SBS, fistula/obstruction, or a combined pathology as the cause of their IF. Ileocolonic disease and an obstructing/penetrating phenotype in CDIF patients was much higher than in previously published Danish CD cohorts. \u003csup\u003e45\u003c/sup\u003e Finally, we did not have data on smoking, clinical indices of disease severity or biomarkers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, our study has demonstrated a reduction in the incidence of CDIF in newly diagnosed CD patients, but a steady population incidence of CDIF. Therefore, IF remains a rare but important complication of CD. Many of our CDIF patients were diagnosed with CD in the pre-biological era, and experienced a high disease burden over a long disease course. Those who were diagnosed more recently appeared to have even greater disease activity, but over a shorter period; however, they were not more likely to receive biologics. Our findings highlight the need for further characterisation of CDIF patients to elucidate modifiable risk factors. In addition, close clinical follow-up and medical optimisation for severe and chronically active CD patients should be prioritised to prevent complications and IF. \u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Novo Nordisk Foundation grant number 0059377 to J.B.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Mads Damsgaard Wewer for his guidance on the registries and Kristian Asp Fuglsang for his guidance in standardised mortality ratio calculations.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003ePironi L, Cuerda C, Jeppesen PB, et al. 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Accessed May 1, 2023. https://sundhedsdatastyrelsen.dk/da/rammer-og-retningslinjer/om-klassifikationer/sks-klassifikationer/hovedgrupper-sks\u003c/li\u003e\n \u003cli\u003eBrandt CF, Hvistendahl M, Naimi RM, et al. Home Parenteral Nutrition in Adult Patients With Chronic Intestinal Failure: The Evolution Over 4 Decades in a Tertiary Referral Center. \u003cem\u003eJPEN J Parenter Enteral Nutr\u003c/em\u003e. 2017;41(7):1178-1187. doi:10.1177/0148607116655449\u003c/li\u003e\n \u003cli\u003eWewer MD, Langholz E, Munkholm P, Bendtsen F, Benedict Seidelin J, Burisch J. Disease Activity Patterns of Inflammatory Bowel Disease-A Danish Nationwide Cohort Study 1995-2018. \u003cem\u003eJ Crohns Colitis\u003c/em\u003e. 2023;17(3):329-337. doi:10.1093/ecco-jcc/jjac140\u003c/li\u003e\n \u003cli\u003eDanmarks Statistik. StatBank. Accessed June 1, 2023. https://www.statistikbanken.dk/statbank5a/default.asp?w=1920\u003c/li\u003e\n \u003cli\u003eMunkholm P, Langholz E, Davidsen M, Binder V. Disease activity courses in a regional cohort of Crohn\u0026rsquo;s disease patients. \u003cem\u003eScand J Gastroenterol\u003c/em\u003e. 1995;30(7):699-706. doi:10.3109/00365529509096316\u003c/li\u003e\n \u003cli\u003eAgrawal M, Christensen HS, B\u0026oslash;gsted M, Colombel JF, Jess T, Allin KH. The Rising Burden of Inflammatory Bowel Disease in Denmark Over Two Decades: A Nationwide Cohort Study. \u003cem\u003eGastroenterology\u003c/em\u003e. 2022;163(6):1547-1554.e5. doi:10.1053/j.gastro.2022.07.062\u003c/li\u003e\n \u003cli\u003eSolberg IC, Vatn MH, H\u0026oslash;ie O, et al. Clinical course in Crohn\u0026rsquo;s disease: results of a Norwegian population-based ten-year follow-up study. \u003cem\u003eClin Gastroenterol Hepatol\u003c/em\u003e. 2007;5(12):1430-1438. doi:10.1016/j.cgh.2007.09.002\u003c/li\u003e\n \u003cli\u003eWintjens D, Bergey F, Saccenti E, et al. Disease Activity Patterns of Crohn\u0026rsquo;s Disease in the First Ten Years After Diagnosis in the Population-based IBD South Limburg Cohort. \u003cem\u003eJ Crohns Colitis\u003c/em\u003e. 2021;15(3):391-400. doi:10.1093/ecco-jcc/jjaa173\u003c/li\u003e\n \u003cli\u003eSubramanian V, Saxena S, Kang JY, Pollok RCG. Preoperative steroid use and risk of postoperative complications in patients with inflammatory bowel disease undergoing abdominal surgery. \u003cem\u003eAmerican Journal of Gastroenterology\u003c/em\u003e. 2008;103(9):2373-2381. doi:10.1111/j.1572-0241.2008.01942.x\u003c/li\u003e\n \u003cli\u003eAberra FN, Lewis JD, Hass D, Rombeau JL, Osborne B, Lichtenstein GR. Corticosteroids and immunomodulators: Postoperative infectious complication risk in inflammatory bowel disease patients. \u003cem\u003eGastroenterology\u003c/em\u003e. 2003;125(2):320-327. doi:10.1016/S0016-5085(03)00883-7\u003c/li\u003e\n \u003cli\u003eSoop M, Khan H, Nixon E, et al. Causes and prognosis of intestinal failure in crohn\u0026rsquo;s disease: An 18-year experience from a national centre. \u003cem\u003eJ Crohns Colitis\u003c/em\u003e. 2020;14(11):1558-1564. doi:10.1093/ecco-jcc/jjaa060\u003c/li\u003e\n \u003cli\u003eUchino M, Ikeuchi H, Bando T, et al. Risk factors for short bowel syndrome in patients with Crohn\u0026rsquo;s disease. \u003cem\u003eSurg Today\u003c/em\u003e. 2012;42(5):447-452. doi:10.1007/s00595-011-0098-0\u003c/li\u003e\n \u003cli\u003eLimketkai BN, Parian AM, Chen PH, Colombel JF. Treatment With Biologic Agents Has Not Reduced Surgeries Among Patients With Crohn\u0026rsquo;s Disease With Short Bowel Syndrome. \u003cem\u003eClinical Gastroenterology and Hepatology\u003c/em\u003e. 2017;15(12):1908-1914.e2. doi:10.1016/j.cgh.2017.06.040\u003c/li\u003e\n \u003cli\u003eJess T, Winther KV, Munkholm P, Langholz E, Binder V. Mortality and causes of death in Crohn\u0026rsquo;s disease: follow-up of a population-based cohort in Copenhagen County, Denmark. \u003cem\u003eGastroenterology\u003c/em\u003e. 2002;122(7):1808-1814. doi:10.1053/gast.2002.33632\u003c/li\u003e\n \u003cli\u003eBurisch J, Lophaven S, Langholz E, Munkholm P. The clinical course of Crohn\u0026rsquo;s disease in a Danish population-based inception cohort with more than 50 years of follow-up, 1962-2017. \u003cem\u003eAliment Pharmacol Ther\u003c/em\u003e. 2022;55(1):73-82. doi:10.1111/apt.16615\u003c/li\u003e\n \u003cli\u003eJess T, Horv\u0026aacute;th-Puh\u0026oacute; E, Fallingborg J, Rasmussen HH, Jacobsen BA. Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: A Danish population-based cohort study. \u003cem\u003eAmerican Journal of Gastroenterology\u003c/em\u003e. 2013;108(12):1869-1876. doi:10.1038/ajg.2013.249\u003c/li\u003e\n \u003cli\u003eDe Jager DJ, Grootendorst DC, Jager KJ, et al. Cardiovascular and Noncardiovascular Mortality Among Patients Starting Dialysis. \u003cem\u003eJAMA\u003c/em\u003e. 2009;302(16):1782-1789. doi:10.1001/JAMA.2009.1488\u003c/li\u003e\n \u003cli\u003eVillar E, Remontet L, Labeeuw M, Ecochard R. Effect of age, gender, and diabetes on excess death in end-stage renal failure. \u003cem\u003eJ Am Soc Nephrol\u003c/em\u003e. 2007;18(7):2125-2134. doi:10.1681/ASN.2006091048\u003c/li\u003e\n \u003cli\u003eZhao M, Sall Jensen M, Knudsen T, et al. Trends in the use of biologicals and their treatment outcomes among patients with inflammatory bowel diseases - a Danish nationwide cohort study. \u003cem\u003eAliment Pharmacol Ther\u003c/em\u003e. 2022;55(5):541-557. doi:10.1111/apt.16723\u003c/li\u003e\n \u003cli\u003eLo B, Vester-Andersen MK, Vind I, et al. Changes in Disease Behaviour and Location in Patients With Crohn\u0026rsquo;s Disease After Seven Years of Follow-Up: A Danish Population-based Inception Cohort. \u003cem\u003eJ Crohns Colitis\u003c/em\u003e. 2018;12(3):265-272. doi:10.1093/ecco-jcc/jjx138\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Demographic Characteristics of CDIF Patients Compared with a Background CD Population \u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable \u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCDIF (n=175) \u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCD (n=22,845) \u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value \u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian years of follow-up [IQR]\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e14.5 [8, 24]\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e10.4 [4.3, 19.5]\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e0.39\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender \u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e101 (55.5) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e12,834 (56.2) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eMale \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e81 (44.5) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e10,011 (43.8) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e0.78\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian age at CD diagnosis [IQR]\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e24 [17.2, 34.8] \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e35 [23, 55] \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge group at CD diagnosis\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e0-16 years \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e39 (21.4) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;2,119 (9.3) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e17-40 years \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e111 (61.0) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e10,896 (47.7) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e41+ years \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e32 (17.6) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;9,830 (43.0) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidity at CD diagnosis*\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e156 (93.1) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e18,173 (79.5) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eMild\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;11 (6.3) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;3,848 (16.8) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eModerate\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 1 (0.6) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;608 (2.7) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eSevere\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 0 (0.0) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;216 (0.9) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDecade of CD diagnosis\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003epre-1980\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e74 (40.7) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e933 (4.1) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e1980+\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e56 (30.8) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e2,837 (12.4) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e1990+\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e36 (19.8) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e4,939 (21.6) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e2000+\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e13 (7.1) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e6,488 (28.4) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e2010+\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e3 (1.6) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e7,648 (33.5) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eResidential region in Denmark\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eCapital\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e95 (54.3) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e6,938 (30.4) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eZealand\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e48 (27.4) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e3,302 (14.5) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eSouthern Danmark\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e17 (9.7) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e4,908 (21.5) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eNorth Jutland\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e7 (4.0) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e2,446 (10.7) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eMid Jutland\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e8 (4.6) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e5,245 (23.0) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eOther\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0.0) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e6 (0.0) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian age at IF onset [IQR]\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e43.5 [33.0, 56.8] \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDecade of IF onset\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003epre-1980\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e17 (9.3) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e1981-1990\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e35 (19.2) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e1991-2000\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e29 (15.9) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e2001-2010\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e51 (28.0) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e2011+\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e50 (27.5) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian lead time in years [IQR]\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e14.5 [8, 24] \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathology at IF onset\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eShort Bowel Syndrome\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e91 (50.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eAbdominal Fistula +/- Abscess\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e14 (7.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eMucosal Disease\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e26 (14.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eIntestinal Obstruction\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e6 (3.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eDysmotility\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e2 (1.1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.688442211055275%\" valign=\"top\"\u003e\n \u003cp\u003eCombined Pathology\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e43 (23.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.12562814070352%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.06030150753769%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;* Comorbidity is based on Charlson Comorbidity Index (CCI): None = CCI 0, Mild = CCI 1-2, Moderate = CCI 3-4, Severe = CCI 5+\u003c/p\u003e\n\u003cp\u003eTable 2. CD-related Disease Burden in CDIF Patients Compared to CD Patients\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"601\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCDIF (n=168)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCD (n=22,845)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutpatient Medication Use*\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients who received any steroids (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e80 (70.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e13,064 (59.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e0.02\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients who received any immunomodulators (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e67 (59.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e10,643 (48.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e0.03\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients who received any biologics (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e23 (20.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e4,593 (21.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e0.96\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eCumulative dose (grams) of steroids in steroid-treated patients/100 patient-years (97.5% CI)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e584.2 (469.9, 726.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e514.2 (502.5, 526.1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e0.25\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eYears on immunomodulators in immunomodulator-treated patients/100 patient-years (97.5% CI)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e34.5 (27.4, 43.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e41.4 (40.7, 42.1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e0.11\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eYears on biologics in biologic-treated patients/100 patient-years (97.5% CI)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e5.7 (3.21, 10.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e11.3 (10.9, 11.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e0.02\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eCourses of steroids in steroid-treated patients/100 patient-years (97.5% CI)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e11.8 (9.0, 15.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e9.3 (9.1, 9.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e0.09\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eCourses of biologics in biologic-treated patients/100 patient-years (97.5% CI)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e16.8 (8.9, 31.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e15.8 (15.4, 16.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e0.85\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of biologic-treated patients who persisted \u0026gt;1 year on a single course (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e4 (17.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e1675 (36.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e0.06\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnplanned Inpatient Contacts\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients who had any unplanned IBD inpatient contacts (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e165 (98.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e12607 (55.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eRate of unplanned IBD inpatient contacts/100 patient-years (97.5% CI)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e92.8 (80.2, 107.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e14.5 (14.4, 15.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eRate of all unplanned inpatient contacts/100 patient-years (97.5% CI)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e150.7 (133.5, 170.0) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e58.3 (57.4, 59.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCD-related Abdominal Surgeries\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients who had any surgery (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e166 (98.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e10,877 (47.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients who had any bowel resection (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e160 (95.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e8,550 (37.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients who had a colectomy (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e141 (83.9)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e7,563 (33.1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients who had endoscopic dilatation (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e8 (4.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e527 (2.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients who had any complicated surgery (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e156 (92.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e5952 (26.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eCorticosteroids within 30 days of surgery\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e17 (29.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e800 (10.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eBiologics within 30 days of surgery\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e3 (6.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e392 (6.1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e1.00\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eRate of all CD-related abdominal surgeries/100 patient-years (97.5% CI)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e33.2 (29.6, 37.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e8.4 (8.2, 8.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eRate of bowel resections/100 patient-years (97.5% CI)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e23.1 (20.2, 26.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e4.5 (4.4, 4.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall CD Activity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eFor the first 10 years after onset of CD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;10 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"bottom\"\u003e\n \u003cp\u003e9,837 (43.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eIntermittently severe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;55 (32.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"bottom\"\u003e\n \u003cp\u003e9,677 (42.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eChronically severe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e103 (61.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"bottom\"\u003e\n \u003cp\u003e3,331 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of severely active years/100 patient-years (97.5% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e49.6 (45.7, 53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e18.8 (18.5, 19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWorking capacity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients who ever stopped working for \u0026gt;6 months (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e105 (66.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e10,897 (57.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e0.04\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.91181364392679%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of years not working /100 eligible-working-years (97.5% CI)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.469217970049918%\" valign=\"top\"\u003e\n \u003cp\u003e43.1 (36.5, 50.9)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.136439267886857%\" valign=\"top\"\u003e\n \u003cp\u003e30.1 (29.5, 30.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Medication data was available from 1995-2018 in n=113 CDIF patients and n=21,857 CD patients\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"Copenhagen University Hospital - Rigshospitalet","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Crohn’s disease, Intestinal failure, natural history","lastPublishedDoi":"10.21203/rs.3.rs-4779921/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4779921/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground and Aims:\u003c/p\u003e\n\u003cp\u003eThe natural history of Crohn’s disease leading to intestinal failure is not well characterised. This study aims to describe the clinical course of Crohn’s disease preceding intestinal failure, and compare disease activity and burden between Crohn’s disease patients with and without intestinal failure.\u003c/p\u003e\n\u003cp\u003eMethods:\u003c/p\u003e\n\u003cp\u003ePatients with Crohn’s disease complicated by intestinal failure from Rigshospitalet, Copenhagen (n=182) and a nationwide Danish Crohn’s disease cohort without intestinal failure (n=22,845) were included. Using nationwide medical and social registries in Denmark, disease activity was determined from hospitalisations, surgeries and outpatient medications, and disease burden was determined from employment and mortality data.\u003c/p\u003e\n\u003cp\u003eResults:\u003c/p\u003e\n\u003cp\u003eThe 10-year cumulative incidence of intestinal failure following Crohn’s disease diagnosis declined from 2.7% prior to 1980 to 0.2% after 2000. Compared to Crohn’s disease patients without intestinal failure, those with intestinal failure experienced significantly longer duration of severe disease (50 vs. 19 years per 100 patient-years, p\u0026lt;0.01), secondary to greater corticosteroid use (71% vs. 60%, \u003cem\u003ep\u003c/em\u003e=0.02), inpatient contacts (98% vs. 55%, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.01), and abdominal surgeries (99% vs. 48%, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.01). However, exposure to biologics was not different between the two groups (20.4% vs. 21%, p=0.95), and duration on biologics was shorter in Crohn’s disease patients with intestinal failure(2,068 vs. 4,126 days per 100 patient-years, \u003cem\u003ep\u003c/em\u003e=0.02). Standard mortality ratio in Crohn’s disease patients with intestinal failurewas 3.66 [97.5% CI 2.79,4.72].\u003c/p\u003e\n\u003cp\u003eConclusion:\u003c/p\u003e\n\u003cp\u003ePatients with Crohn’s disease complicated by intestinal failure experienced a more persistently severe preceding course of Crohn’s disease, but were not more likely to be treated with biological therapy.\u003c/p\u003e","manuscriptTitle":"The Natural History of Crohn’s Disease Leading to Intestinal Failure: A Longitudinal Cohort Study from 1973 to 2018","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-23 12:52:05","doi":"10.21203/rs.3.rs-4779921/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f996813f-0b60-4533-97b3-256accdcba7b","owner":[],"postedDate":"July 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":34928469,"name":"Gastroenterology \u0026 Hepatology"}],"tags":[],"updatedAt":"2024-07-23T13:13:57+00:00","versionOfRecord":{"articleIdentity":"rs-4779921","link":"https://doi.org/10.1093/ecco-jcc/jjae114","journal":{"identity":"journal-of-crohns-and-colitis","isVorOnly":true,"title":"Journal of Crohn's and Colitis"},"publishedOn":"2024-07-23 13:13:57","publishedOnDateReadable":"July 23rd, 2024"},"versionCreatedAt":"2024-07-23 12:52:05","video":"","vorDoi":"10.1093/ecco-jcc/jjae114","vorDoiUrl":"https://doi.org/10.1093/ecco-jcc/jjae114","workflowStages":[]},"version":"v1","identity":"rs-4779921","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4779921","identity":"rs-4779921","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}