Introduction

Thiopurine therapy is a cornerstone in the treatment of patients with inflammatory bowel disease (IBD).

Aims & Methods

We aimed to assess the effect of thiopurines on the risk of cancer in IBD according to drug exposure and age. Danish national registers were used to identify incident IBD patients, exposure to drugs and status of cancers, in 1996-2018. Cox regressions were used to i) compare IBD to non-IBD reference individuals, ii) analyse IBD according to drug exposure status, and iii) assess patients’ cumulative drug exposure and the association to first reported cancer, excluding non-melanoma skin cancer.

Results

In total, 43,419 IBD patients were followed for a median of 8.2 years (IQR:3.7-14.2) after IBD diagnosis. Cancer was reported in 3,128 (7.2%) IBD patients. Both monotherapy and combination therapy were associated with developing cancer (aHR:1.36 (95%CI:1.17-1.58) and (aHR:2.48 (95%CI:1.64-3.76), respectively) compared to unexposed IBD patients. Among the elderly (>65 years), the risk was especially high in those receiving combination therapy. In patients who discontinued thiopurines, the aHR returned to the level of unexposed patients (aHR:0.89 (95%CI:0.78-1.01)). The aHR was positively associated with cumulative thiopurine exposure and in patients with more than five years of exposure, reaching aHR of 1.36 (95%CI:1.14-1.61).

Conclusion

Thiopurines were associated with increased risk of cancer, especially when used in combination therapy in the elderly. The risk increased by 36% when patients were exposed to thiopurines for more than five years. Reassuringly, the risk returned to baseline after discontinuation of thiopurines. This study suggests avoiding combination therapy in the elderly and not treating patients with thiopurines for longer than five years, regardless of age.

Disclosure

This study was funded by an unrestricted grant from Aage og Johanne Louis-Hansens Fond.

Introduction

Prior studies suggest an increased risk of non-alcoholic fatty liver disease (NAFLD) in patients (pts) with inflammatory bowel disease (IBD). There is no data available on the risk of cirrhosis in IBD. Our aim was to investigate the risk of cirrhosis (compensated or decompensated) in IBD pts compared to a matched non-IBD population in a population-based cohort.

Aims & Methods

A registry-based cohort study was conducted in the Danish health registries (including the pathology register) using data, between (and including) 1998 and 2018. Incident IBD was identified using ICD-8/10 codes for Crohn’s disease (CD) or ulcerative colitis (UC), with two IBD registrations up to two years apart, living in Denmark for at least one year prior to their first IBD registration and without a diagnosis of cirrhosis prior to their IBD registrations. Those with IBD were matched 1:10 to non-IBD persons on the basis of sex, age, calendar year, and the municipality of residence. Persons were followed from index date (IBD diagnosis date/matching date) until a diagnosis of cirrhosis (study outcome), death, emigration, or end of follow-up, whichever came first. The diagnosis of cirrhosis, including both compensated and decompensated cirrhosis, and the underlying etiology, were recorded by ICD-8/10 and SNOMED codes. Kaplan-Meier approach was used to calculate the cumulative incidence of cirrhosis and Cox proportional regression analysis to calculate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for cirrhosis among pts with IBD, compared to the non-IBD population.

Results

In a study population of 495,220 persons, a total of 2,741 cirrhosis cases were identified (median [IQR] time in years between index date and diagnosis of cirrhosis: 6.3 [3.0-10.7]), with a higher proportion of cases among pts with IBD (N = 45,020) compared to non-IBD persons (0.9% vs. 0.5%, respectively). After adjusting for sex, age, and index year, pts with IBD had a higher risk of cirrhosis, compared to non-IBD persons (adjusted HR (95% CI): 1.84 [1.65 – 2.04]). Cirrhosis was diagnosed on the basis of liver biopsy and/or imaging (ultrasound, CT or MRI) in 77.3% of IBD pts vs. 69.3% of non-IBD persons. The leading etiology of cirrhosis was NAFLD (51.6%) followed by alcohol (39.0%). The risk of cirrhosis among IBD pts (compared to non-IBD persons) was more pronounced among younger persons (adjusted HR (95% CI): 3.08 [2.45-3.87] among ≤ 40 years of age; 1.63 [1.45-1.84] among > 40 years of age, p-value <0.001) and CD pts (adjusted HR (95% CI): 2.20 [1.80-2.67] among CD; 1.72 [1.52-1.95]; among UC, p-value 0.0402). The risk was also consistent across the year of cohort entry (IBD diagnosis year/index year): 1998-2001 (794 events, 1.37 [1.07-1.66]), 2002-2005 (776 events, 1.98 [1.63-2.40]), 2006-2009 (612 events, 1.94 [1.56-2.41]), 2010-2013 (378 events, 2.01 [1.53-2.64]), 2014-2018 (181 events, 2.89 [2.03-4.10]).

Conclusion

IBD pts had a higher incident risk of cirrhosis compared to matched non-IBD persons, especially with age at IBD diagnosis ≤ 40 years and those with CD. These data point towards a need for focused screening for cirrhosis among IBD pts, especially in certain risk groups.

Introduction

Patient-reported outcomes (PROs) are pivotal in assessing treatment efficacy, delivering patient-centered care, and estimating the burden for inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD).

Aims & Methods

We aimed to investigate PROs at IBD diagnosis, including associated factors.
Since May 1^st, 2021, all adult and pediatric patients with incident IBD within a catchment area encompassing 20% of the Danish population were enrolled in the prospective population-based Copenhagen IBD Inception Cohort.¹ Upon diagnosis, all adult patients diagnosed between May 2021 and May 2023 were asked to report PROs including Short inflammatory Bowel Disease Questionnaires (SIBDQ), IBD-Disability Index (IBD-DI), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Symptoms were evaluated using Memorial Symptom Assessment Scale, IBD Symptom Inventory, and Mayo Assessment of Functional Gastrointestinal Disease. Multivariable logistical analysis adjusting for gender, age, and disease phenotype was conducted (adjusted odds ratio, aOR (95% confidence interval)).

Results

The population consisted of 203 and 116 patients with UC and CD (66% and 58% of the original cohort), respectively, who completed the PROs questionnaires within a median of 1.2 (IQR 0.3–3.0) months from diagnosis. The only baseline difference between participants and non-participants was a higher proportion of females with UC in the former group (60% vs. 44%, p<0.01).
In total, 160 (79%) and 99 (85%, p=0.18) patients with UC and CD, respectively, reported moderate to severe affection of at least one PRO, while 44% and 64% (p<0.01), respectively, reported moderate to severe affection of at least two PROs.
Specifically, a higher proportion of patients with CD reported moderately to severely impaired quality of life (QoL) (96 (82.8%)) compared to UC (141 (69.5%), p<0.01). Of those, 33 (82.5%) and 41 (56.9%), respectively, reported simultaneously moderate to severe fatigue and disability (p=0.48), while 19 (19.8%) and 27 (19.1%, p=0.90), respectively, reported moderate to severe QoL and fatigue but not disability. In addition, among 71 (35.0%) and 52 (44.8%) with UC and CD, respectively, reporting moderate to severe fatigue (p=0.08), all but three patients with UC had moderate to severe QoL, while 57.6% and 63.5%, respectively, reported moderate to severe disability. Accordingly, FACIT-F correlated strongly with SIBDQ in both UC (Pearson correlation coefficient (PCC) 0.76 (0.70-0.82) and CD (PCC 0.84 (0.78-0.89).
The most frequent symptoms of UC were bloody stool (88%), lack of energy (82%), and abdominal pain (78%), whereas those of CD were lack of energy (86%, p=0.36) and abdominal pain (84%, p=0.17). These symptoms as well as bowel urgency (46% vs. 43%, p=0.60) were equally common in UC and CD, while bloody stool was less frequent in CD (54%, p<0.01). Finally, bowel urgency was linked to moderate to severe disability in UC (aOR=4.01 (1.11;14.51)), but not QoL or fatigue, which was confirmed in sensitivity analysis of proctitis.

Conclusion

Our prospective population-based inception cohort study highlights a considerable burden of UC and CD at the time of diagnosis, with moderate to severe impairment of PROs in most patients. In addition, we observed a clustering of impaired PROs in half of the patients, underscoring the interconnectedness of PRO metrics and symptoms. These findings emphasize the importance of tight monitoring of PROs and symptoms in clinical practice, allowing timely interventions.

References

1. Attauabi M, Madsen GR, Bendtsen F, et al. Influence of Genetics, Immunity and the Microbiome on the Prognosis of Inflammatory Bowel Disease (IBD Prognosis Study): the protocol for a Copenhagen IBD Inception Cohort Study. BMJ Open. 2022;12(6):e055779. doi:10.1136/bmjopen-2021-055779

Disclosure

Mohamed Attauabi: None
Gorm Roager Madsen: Personal fees from Tillotts
Flemming Bendtsen: Tillotts, Ferring
Jakob Benedict Seidelin: has received research grants from Takeda, Janssen, the Danish Research Council, and the Capital Region Denmark, and is national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim.
Johan 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, personal fees from Galapagos, outside the submitted work.

Introduction

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), are associated with an increased risk of metabolic bone diseases (MBD), primarily osteopenia and osteoporosis; however, the risk at IBD diagnosis is currently unknown.

Aims & Methods

The aim of the current study was to evaluate a screening strategy for MBD in which all patients with newly diagnosed IBD are offered a Dual-energy X-ray absorptiometry (DXA) scan. Secondly, we aimed to identify risk factors for development of MBD.
All adult patients with newly diagnosed IBD within a catchment area corresponding to ~20% of the Danish population have since May 2021 been enrolled in an ongoing prospective population-based inception cohort, IBD Prognosis Study. Herein, all participants were, as part of the initial work-up, invited to a DXA scan at IBD diagnosis. A T-score< −2.5 standard deviations (SD) was diagnostic for osteoporosis, while a T-score between –1 and –2.5 defined osteopenia. Multivariate analyses adjusted findings for age, gender, and medication differences.

Results

As of April 15^th, 2023, a total of 316 newly diagnosed patients with IBD (UC: 178, CD: 117, IBD unclassified (IBDU): 21) received a DXA scan within 90 days (interquartile range (IQR) 51-139 days). Baseline characteristics of the population were similar to those previously described for newly diagnosed IBD.
In total, 48 (27.0%, females (F): 26.3%, males (M): 27.7%) and 17 (9.6%, F: 13.7%, M: 4.8%) patients with UC were found to have osteopenia and osteoporosis, respectively. The corresponding numbers for CD were 23 (19.7%, F: 15.3%, M: 24.1%) and nine (7.7%, F: 6.8%, M: 8.6%).
Subgroup analysis showed a high occurrence of osteopenia in both UC and CD regardless of age group (Table 1). Further, no difference between UC and CD was observed in terms of the risk of osteopenia (adjusted odds ratio (aOR)=1.86 (95% confidence interval (CI) 0.99-3.60) or osteoporosis (OR=1.42 (95% CI 0.53-4.08)).
Further, low albumin level (<36 g/L) was the only factor associated with the risk of osteopenia in patients with UC (aOR=2.57 (95% CI 1.05-6.53). In patients with CD, no risk factors were identified for development of osteopenia, although a trend was seen with high age (aOR=4.28 (95% CI 0.99-20.23). However, the risk of osteoporosis was independently associated with age higher than 65 years in both UC (aOR=13.4 (95% CI 3.78-51.36)) and CD (aOR=6.39 (95% CI 1.09-35.47)), while female gender was not relevant (UC: aOR=2.63 (95% CI 0.75-10.98), CD: (aOR=0.47 (95% CI 0.08-2.20)).
Finally, in both UC and CD, the risk of these MBD was not associated with IBD phenotype, medications, or patient-reported or endoscopic severity.

Table 2: Prevalence of osteopenia and osteoporosis in different age groups in patients with newly diagnoses patients with inflammatory bowel diseases

Conclusion

To our knowledge, the current study is the first evaluation of DXA scans as a screening tool for patients with newly diagnosed IBD in a population-based setting. We found a high incidence of osteopenia affecting every fourth patient at IBD diagnosis. These findings are concerning given the high risk of repeated need for systemic steroids in this patient population.

Disclosure

Mohamed Attauabi: None
Gorm Roager Madsen: None
Flemming Bendtsen: Tillotts, Ferring
Klaus Theede: Ferring, Janssen, Takeda, Pfizer and Tillotts
Jakob Benedict Seidelin: has received research grants from Takeda, Janssen, the Danish Research Council, and the Capital Region Denmark, and is national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim.
Johan 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, personal fees from Galapagos, outside the submitted work.

Introduction

There is evidence linking inflammatory bowel disease (IBD) and cardiovascular diseases. However, the roles of histologic and clinical activity of IBD in the development of arrhythmias remain unknown.

Aims & Methods

In this nationwide cohort study in Sweden, we included IBD patients with histologic data (n = 61,383; diagnosed 1969–2017; classified as histologic inflammation vs. remission based on the Swedish version of the Systematized Nomenclature of Medicine codes) and clinical activity data (n = 96,154; diagnosed 1969–2020; classified as clinically active vs. quiescent IBD based on IBD-related hospitalization, surgery, and treatment escalation) and followed them through December 31, 2021. The primary outcome was incident arrhythmias (including atrial fibrillation/flutter, bradyarrhythmias, other supraventricular arrhythmias, and ventricular arrhythmias/cardiac arrest) within 2 years after documented histologic inflammation (vs. remission) or clinically active IBD (vs. quiescent IBD). Poisson regression models estimated incidence rates (IRs) of arrhythmias, while Cox proportional hazards models estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). We adjusted for age at IBD diagnosis, sex, calendar year at index date, county of residence, educational attainment, country of birth, number of health care visits, and history of CVD-related comorbidities in the model.

Results

Histologic inflammation was associated with an increased risk of developing any arrhythmias compared to histologic remission (IR: 62.0 vs. 47.2 per 10,000 person-years; aHR = 1.35, 95%CI: 1.18–1.54), corresponding to one additional event of arrhythmia per 338 IBD patients over 2 years after histologic inflammation. We found an excess risk for atrial fibrillation/flutter (aHR = 1.38, 95%CI: 1.18–1.62) and ventricular arrhythmias/cardiac arrest (aHR = 1.73, 95%CI: 1.22–2.44), but not for bradyarrhythmias or other supraventricular arrhythmias. Compared to clinically quiescent IBD, active IBD was also related to a higher risk of arrhythmias (IR: 67.4 vs. 108.4; aHR = 1.77, 95%CI: 1.66–1.88), affecting all subtypes except bradyarrhythmias. In patients with clinically quiescent IBD, histologic inflammation was also associated with an increased risk of arrhythmias (aHR = 1.16, 95%CI: 1.00–1.36, P=0.054).

Conclusion

Histologic and clinical activity were associated with a slightly increased risk of arrhythmias in patients with IBD.

Disclosure

All authors have completed the ICMJE uniform disclosure form and declare:
OO has been PI on projects at Karolinska Institutet financed by grants from Janssen, Pfizer, AbbVie, Takeda, Galapagos/Alfasigma, Ferring, and Bristol Myer Squibb. JH served as speaker or advisory board member for AbbVie, BMS, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Index Pharma, Janssen, Medtronic, Merck, MSD, Novartis, Pfizer, Sandoz, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma, and Vifor Pharma and received grant support from Takeda, Janssen, and MSD. FE has served as an advisory board member for Boehringer Ingelheim. JFL has coordinated a study for the Swedish IBD Quality Register (SWIBREG), which received funding from Janssen Corporation. JFL has also received financial support from MSD to develop a paper reviewing national healthcare registers in China. JFL has a research collaboration on celiac disease with Takeda and has a research collaboration on fibrosis in IBD with MSD. The other authors report no disclosures relevant to the manuscript.

Introduction

The incidence of elderly onset inflammatory bowel disease (IBD) is expected to increase in partial due to an aging population [1]. In comparison to pediatric or adult IBD patients, elderly IBD patients are complex. Comorbidities, higher frailty, and polypharmacy seen in elderly IBD patients can present problems in treatment [1]. This presents new dilemmas in treating this growing patient group.

Aims & Methods

We aimed to determine current treatments for patients with elderly onset IBD in comparison to patients with pediatric or adult onset IBD.
Through data from the Danish Civil Registration System and the National Patient Registry, all Danish patients diagnosed with either ulcerative colitis (UC) or Crohn’s disease (CD) between 2000 to 2018 were identified. Patients were grouped based on the age of diagnosis: pediatric patients (< 18 yrs.), young adult patients (18-39 yrs.), adult patients (40-60 yrs.), and elderly patients (≥ 60 yrs.). Medical treatments were defined using relevant ATC codes, while biological treatment and surgery were defined through procedure codes. To determine relevant IBD dosages of systemic steroid, only systemic steroids taken within 28 days of an IBD related hospital contact were included. Differences in treatment between age groups were assessed using Kaplan-Meier survival plots and multivariate Cox regression analyses adjusting for sex, year of diagnosis, and Charlson Comorbidity Index.

Results

25,735 UC patients and 14,404 CD patients were diagnosed between 2000 to 2018 in Denmark. Of those patients, 5,812 (22.6%) UC patients and 2,952 (20.5%) CD patients were elderly at diagnosis.
Elderly UC and CD patients had a significantly (P < 0.05) decreased risk of treatment with 5-aminosalicylates (5-ASA), immunomodulators, and biologics in comparison to all other age groups (Table 1). Also, elderly UC and CD patients had a significantly decreased risk of being treated with systemic steroids except in comparison to adult UC patients in which elderly UC patients had a significantly increased risk. Additionally, elderly CD patients had a significantly increased risk for bowel surgery. However, the same was not true for elderly UC patients and colectomies, which had a significantly a decreased risk in comparison to young adult and pediatric patients (P < 0.05) but no significant risk in comparison to adult patients.

Conclusion

In conclusion, elderly onset IBD patients received less 5-ASA, immunomodulators, and biologics. Elderly patients also received less systemic steroids except in comparison to adult UC patients. Additionally, elderly CD patients had an increased risk for bowel surgery, while elderly UC patients had a decreased risk for colectomy in comparison to pediatric and young adult patients.

References

1. Sturm A, Maaser C, Mendall M, et al. European Crohn’s and Colitis Organisation Topical Review on IBD in the Elderly. J Crohns Colitis 2017;263-273.

Disclosure

RLMN, MDW, MM, VM and TB: no relevant disclosures.
JB: 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, personal fees from Galapagos, outside the submitted work.

Introduction

Patients with inflammatory bowel disease (IBD) have an increased risk of developing intestinal and extra-intestinal cancers. Specific therapies used to control inflammation in IBD may have a different impact on cancer risk. However, there are no long-term studies investigating cancer risk in patients with IBD.

Aims & Methods

In the present study we aimed to quantify the overall risk for of developing cancer and to identify specific risk factors for the occurrence of intestinal and extra-intestinal cancers in 560 consecutive patients with Crohn's disease (CD, N=310) or ulcerative colitis (UC, N=250) referred to our outpatient department between January 2021 and February 2022. Demographic data, smoking status, alcohol consumption, age at IBD diagnosis, disease location and course, therapies, and cancer development after IBD diagnosis were recorded. Odds ratios (OR) were estimated by logistic regression analysis. Standardized Incidence Ratios (SIRs) were estimated compared with the general population.

Results

During a median follow-up interval or time of 10 years (range 1-26 years), 6.6% of patients (37/550, female 65 %, mean age 51 years) developed cancer (SIR 1.94, 95%CI 1.4-2.6). The most common cancers were colorectal (12.3%), skin (8.2%), and breast cancer (7.2%). Female patients had an increased risk for all cancers (SIR 3.11, 95%CI 2.06-4.3), melanoma (SIR 5.6, 95%CI 1.14-16.2) and colorectal cancer (SIR 7.59, 95%CI 3-15.4). Male patients had an increased risk of lymphoma (SIR 26.15, 95%CI 3.2-95.7). Younger age at diagnosis of CD (A1 Montreal classification, OR 37.9, 95%CI 10-14), immunosuppressive monotherapy (OR 5.5, 95%CI 2.65- 11) or in combination with anti-TNFα (OR 9.9, 95%CI 3.3-29.09) were associated with an increased risk of cancer in the study population.

Conclusion

We have identified subgroups of IBD patients who would particularly benefit from screening programs. Our findings need to be validated in independent cohorts.