To Örebro University

BACKGROUND: Earlier studies, mainly prior to the widespread use of advanced therapy and implementation of guidelines for thromboprophylaxis indicate a doubled risk of venous thromboembolism (VTE) in patients with inflammatory bowel disease (IBD).

METHODS: Using Swedish healthcare registers, we identified a population-based cohort of patients with incident IBD 2007-2021. Patients were matched by age, sex, calendar year of birth and place of residence with up to 10 reference individuals. The primary outcome was VTE, i.e., pulmonary embolism (PE) and deep vein thrombosis (DVT). Incidence rates (IRs) per 1000 person-years, cumulative incidence and hazard ratios (HRs) were calculated for IBD overall and according to clinical characteristics. The temporal trend of the incidence of VTE by calendar year was presented.

RESULTS: We followed 55,252 IBD patients and 536,067 reference individuals, for a median of 6.5 years. The incidence of VTE in IBD was 5.03 vs. 2.35 per 1000 person-years among reference individuals, corresponding to a doubled risk of VTE (HR = 2.12; 95% confidence interval [CI] 2.02-2.23). Particularly high risks were seen in the first year of follow-up, and among patients with extensive ulcerative colitis (UC), primary sclerosing cholangitis (PSC), extraintestinal manifestations, perianal disease and hospitalization at diagnosis. The occurrence of VTE in IBD did not decrease across calendar years.

CONCLUSIONS: IBD remains linked to an elevated risk of VTE, particularly with disease characteristics associated with a higher inflammatory burden and higher age. Our findings underscore the importance of continuous vigilance and individual assessment of VTE risk in patients with IBD.

OBJECTIVES: Inflammatory bowel disease (IBD) is a chronic disorder linked to cardiovascular disease (CVD). However, the impact of histologic and clinical activity on this association remains unclear.

METHODS: We conducted a nationwide cohort study in Sweden involving 59,168 IBD patients diagnosed in 1969-2017 with histologic evaluation and 91,800 patients diagnosed in 1969-2020 with assessment of clinical activity in 2006-2021. The primary outcome was incident major adverse cardiovascular events (MACE), a composite outcome encompassing ischemic heart disease, stroke, and heart failure. Cox proportional hazards model estimated adjusted hazard ratios (aHRs) of MACE and its subcomponents.

RESULTS: We found an increased MACE risk following histologic inflammation (n = 868, incidence rate [IR]: 86.3/10,000 person-years) compared to remission (n = 558, IR = 71.3) (aHR = 1.16 [1.04-1.30]). This excess risk was evident in Crohn's disease (aHR = 1.30 [1.03-1.64]) and ulcerative colitis (aHR = 1.13 [1.01-1.27]). Histologic inflammation was associated with an increased risk of ischemic heart disease, myocardial infarction, ischemic stroke, and heart failure, but not with hemorrhagic stroke. Compared to clinically quiescent IBD, active IBD was associated with an increased MACE risk (IR: 131.4 vs. 93.7; aHR = 1.54 [1.46-1.63]) and all MACE subcomponents. In patients with clinically quiescent IBD, histologic inflammation remained linked to myocardial infarction (aHR = 1.29 [1.06-1.58]) and heart failure (aHR = 1.19 [1.00-1.43]).

CONCLUSION: Both histologic and clinical activities of IBD were associated with an increased MACE risk, suggesting that improved disease control may reduce MACE risk in IBD.

BACKGROUND: Cancer incidence data including absolute risk differences are needed for clinical risk communication to patients receiving modern-day treatments for ulcerative colitis (UC).

METHODS: We linked nationwide Swedish health registers and assessed incident cancers in patients with UC in 2007-2022. We computed age-stratified incidence rates (IRs), IR differences and hazard ratios (HRs) in a naïve cohort with no immunomodulatory treatment, and in cohorts treated with thiopurine or targeted therapies. General population comparator subjects were matched (by age, sex, calendar year, and area of residence) to each treatment cohort. We used a once-exposed - always exposed design.

RESULTS: We identified 63,925 patients with UC in partly overlapping cohorts and 593,072 comparators with a total follow-up time of 5,800,089 years (median 8.1 years).The IRs were elevated compared to the general population in naïve patients: 2.7 extra cancer cases per 1000 person years (HR:1.12, 95%CI:1.09-1.16), in thiopurine-treated patients: 3.4 extra cases (HR:1.48;1.37-1.61), TNFi-treated: 2.7 extra cases (HR:1.41;1.24-1.62), Thiopurine+TNFi-treated: 2.42 extra cases (HR:1.44;1.19-1.75), vedolizumab-treated: 2.88 extra cases (HR:1.27;0.90-1.79). The IR differences were not significantly increased in patients treated with ustekinumab 0.57 (HR:0.87;0,39-1.93) and tofacitinib -0.69 (HR:0.84;0.25-2.77). Across all treatment groups, the IR differences compared to the general population were highest in patients ≥60 years. The differences were driven by colorectal cancer, hepatobiliary cancer, lymphoma, and basal cell skin carcinoma.

CONCLUSION: Elevated cancer incidence was observed in patients with UC amounting to around 3 extra cases of cancer per 1000 years. Cancer risks varied more among groups defined by age than by treatment.

Background: Perianal diseases are more common in patients with Crohn's disease (CD) than in the general population, but data are scarce in other inflammatory bowel disease (IBD) subtypes.

Method: Using data from the Swedish National Patient Register (NPR) and SWIBREG, the national quality register for IBD, we estimated the cumulative incidence of perianal fistula/abscess and perianal diseases (fistula, abscess, stenosis, fissure or procedure code for perianal surgery) in relation to diagnosis, and the prevalence in 2023, in individuals with CD, ulcerative colitis (UC) and IBD-unclassified (IBD-U), and in a matched (age, sex, calendar year and region of residence) IBD-free cohort from the general population.

Results: We identified 38,364 patients with incident IBD 2007-2017, and 98,229 patients with prevalent IBD as of 31 December 2022. The cumulative incidence of fistula/abscess was 6.7% at diagnosis, 8.3% at 1 year and 10.4% at 5 years in CD. The corresponding percentages in UC were 0.9%, 1.3% and 2.1%, and in IBD-U 2.4%, 3.1% and 4.5%, respectively. In 2023, 12.8%, 3.1% and 4.1% of patients with prevalent CD, UC and IBD-U had a history of fistula/abscess, compared to 0.8% in the general population. The corresponding numbers for perianal diseases were 19.7%, 7.4%, 8.6% and 2.2%.

Conclusions: The cumulative incidence and prevalence of perianal diseases in Swedish patients with CD was in parity with reports from other countries, and in patients with UC and IBD-U, it was 3-4 times higher than in the population.

BACKGROUND: The Swedish National Patient Register (NPR) is an important source of data for epidemiological research. A review in 2010 described the validity of recorded diagnoses for inpatient care, but did not include specialised outpatient care.

METHOD: Using systematic searches of medical literature databases (Embase, Medline), and reports from members of the Swedish Epidemiological Association, we aimed to identify all studies validating diagnoses and procedure codes in inpatient care since 2010 and all studies validating specialised outpatient care. In addition, we summarize findings from register validation work performed by the National Board of Health and Welfare.

RESULTS: The literature search and personal reports generated 3990 non-duplicate original studies, of which 89 were deemed relevant. Compared to data in patient charts (reference), the median positive predictive value (PPV) for diagnostic codes in the NPR was 84% (interquartile range 72-93%), but with clear differences between types of diagnoses. The median PPV for surgical procedures was 97% (86-99%). The median sensitivity of diagnoses and procedures compared to other registers and cohorts was 73% (45-80%). The completeness of the register has improved over time. Missingness originates mainly from underreporting of procedures performed by private healthcare providers, and for certain variables, e.g. medication codes.

CONCLUSION: The NPR has good diagnostic accuracy for most diagnoses and very good for surgical procedures. The sensitivity is lower. Longitudinal comparisons of incidence or prevalence are affected by changes in completeness. Missingness is low, although it is higher among private healthcare providers and for specific variables such as drug administration.

INTRODUCTION: IgA nephropathy is the most common primary kidney disease in the world and has a highly variable clinical presentation. While studies have indicated a link between glomerular disease and infections, large-scale studies on IgA nephropathy are missing.

METHODS: In our study, IgA nephropathy was defined as having a kidney biopsy record 1997-2011 in Sweden. Each IgA nephropathy patient was matched with five reference individuals based on age, sex, calendar year, and county of residence. We excluded individuals with earlier organ transplants, HIV, immunodeficiency, or end-stage kidney disease. Linear and Cox regressions, adjusted for age, sex, education, and diabetes, were performed to analyze total infections and antimicrobial treatments in both patients and reference individuals. Sibling analyses were also performed.

RESULTS: The linear regression analysis revealed a significant association between IgA nephropathy and the overall frequency of infections compared to the general population (β = 0.44; 95% CI: 0.35-0.53) and siblings (β = 0.36; 95% CI: 0.23-0.49). Similarly, antimicrobial prescriptions, especially antibiotics, were more common in IgA nephropathy compared to the general population and to siblings. Cox regression showed an elevated risk of any infection (adjusted hazard ratio [aHR] = 2.00; 95% CI: 1.84-2.18) and sepsis (aHR = 3.18; 95% CI: 2.17-4.65) corresponding to one extra case of sepsis per 63 patients followed for 10 years. The strongest associations were seen for urinary tract infections; ear, nose, and throat infections; and musculoskeletal and gastrointestinal infections.

CONCLUSION: Conclusively, our study demonstrates an increased prevalence of infections and antibiotic prescriptions in IgA nephropathy patients. The increased risk of sepsis warrants clinical awareness and prevention.

OBJECTIVES: Pulmonary manifestations have been postulated in inflammatory bowel disease (IBD), but supporting data are scarce. We examined the risk of interstitial lung diseases (ILD) in IBD and its subtypes (ulcerative colitis, Crohn's disease, and IBD-unclassified).

METHODS: We conducted a nationwide cohort study of individuals diagnosed with IBD in Sweden between 1969-2019 and followed until 2021. For each patient, we identified up to 5 matched general-population comparators. Through Cox regression, we examined adjusted hazard ratios (aHR) for ILD as defined by diagnostic codes in the National Patient Register. In a secondary analysis, patients with IBD were compared with their siblings free of IBD.

RESULTS: We identified 85,705 patients with IBD and 412,677 general-population comparators. Over a median follow-up of 14 years, 438 (0.51%) patients with IBD and 1,253 (0.30%) comparators were diagnosed with ILD, corresponding to incidence rates of 34 and 20 per 100,000 person-years, respectively. Patients with IBD had a 48% greater relative risk of ILD (95% confidence interval (CI): 1.30-1.69). Stratified analyses showed increased risk in both ulcerative colitis and Crohn's disease. Patients with IBD also had a significantly greater risk of developing ILD compared with their siblings (aHR: 1.81, 95% CI: 1.43-2.27).

CONCLUSION: In this nationwide cohort study of >85,000 patients with incident IBD, we found an increased risk of ILD.

INTRODUCTION: It is uncertain whether the risk of major congenital anomalies (mCAs) is increased in children of women with inflammatory bowel disease (IBD).

METHODS: We aimed to determine the risk of mCAs in a Swedish nationwide cohort of 13,131 singleton live births from 1997 to 2020 to women with IBD and 61,909 matched children to women without IBD from the general population. We additionally examined mCAs according to periconceptional histological inflammation (vs remission: 1,124 and 646 births, respectively) or clinically active IBD (vs quiescent: 3,380 and 6,603 births, respectively). Adjusted risk ratios (aRRs) for overall and organ-specific mCAs were estimated using generalized linear models. These models adjusted for maternal sociodemographics, comorbidities, body mass index, and smoking.

RESULTS: There were 38.0 (n = 499) mCAs per 1,000 births to women with IBD vs 33.9 (n = 2,101) in matched comparators and a risk difference of 1 extra mCA per 246 births to women with IBD (aRR 1.11; 95% confidence interval [CI] 1.01-1.23). Risks of heart defects and mCAs of the urinary system partly drove estimates. The risk of mCAs was similar in children of women with ulcerative colitis and Crohn's disease. Periconceptional histological inflammation (vs remission) or clinically active (vs quiescent) IBD did not further influence the risk of mCA in the child (aRR 0.87 [95% CI 0.55-1.40] and aRR 1.04 [95% CI 0.85-1.27], respectively).

DISCUSSION: Children of women with IBD had a heightened susceptibility to mCAs, although absolute and relative risks were lower than previously reported. IBD activity was not linked to mCA risks, but those analyses included relatively few events.

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been linked to pancreatic diseases, but evidence from population-based studies with liver histology is lacking.

Aims and methods: In this population-based cohort including all Swedish adults (n = 8563) with biopsy-proven MASLD, we aimed to investigate incidences of pancreatic diseases compared with matched reference individuals from the general population (n = 38,858) and full siblings (n = 6696). Using Cox proportional hazard models, we calculated multivariable adjusted hazard ratios (aHRs) and confidence intervals (CIs).

Results: We documented 359 incidents of pancreatic diseases in MASLD patients and 880 events in matched reference individuals, resulting in an incidence rate difference of 1.54 (95% CI, 1.25-1.84). The relative risk of pancreatic disease was highest in the first two years after MASLD diagnosis (aHR, 2.19 [95% CI, 1.92-2.50), but remained statistically significant increased even up to ten years [aHR, 1.60 (95% CI, 1.38-1.85)]. The most common pancreatic disease in individuals with MASLD was acute non-biliary pancreatitis (1.44 vs. 0.44 events/1000 PY), followed by chronic pancreatitis (0.54 vs. 0.12/1000 PY) and pancreatic cancer (0.88 vs. 0.47/1000 PY). We documented 130 versus 344 pancreas-related deaths among individuals with MASLD and their matched comparators, yielding an absolute risk difference of 0.51/1000 PY and an aHR of 2.41 (95%CI = 1.95-2.97). The findings were consistent in sibling-controlled analyses with an aHR of 2.21 (95%CI = 1.69-2.90).

Conclusions: MASLD was associated with significantly higher rates of acute and chronic pancreatitis of predominantly non-biliary origin, as well as an increased risk of pancreatic cancer and pancreas-related mortality.

INTRODUCTION: Inflammatory diseases have been associated with increased risk of venous thromboembolism (VTE). However, data on VTE is lacking in large population-based cohorts of microscopic colitis (MC).

METHODS: This study included all Swedish adults with incident MC without prior VTE (1990-2017; n=12,489; follow-up until 2021). MC and subtypes (collagenous colitis and lymphocytic colitis) were defined from prospectively recorded colorectal histopathology reports from all 28 pathology departments in Sweden. Individuals with MC were matched for birth year, sex, calendar year and county with up to five general population reference individuals (n=55,809) without prior MC. Sensitivity analyses included full sibling comparisons and stricter definitions of VTE requiring a primary diagnosis of VTE and a prescription of anticoagulant medication. Incidence rates and multivariable-adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) for VTE events were calculated using Cox proportional hazards modelling.

RESULTS: Over a median of 10.0 years of follow-up, 755 (6.0%; 11.3/1000 person-years) incident VTE events occured in individuals with MC and 2674 (4.8%; 8.6/1000 person-years) in reference individuals. Individuals with MC had a higher overall relative risk of any VTE event compared with reference individuals (aHR=1.21, 95%CI=1.11-1.32) including higher risk of pulmonary embolism (aHR=1.23, 95%CI=1.08-1.40), deep vein thrombosis of the legs (aHR=1.16, 95%CI=1.03-1.32), and other VTE events (aHR=1.31, 95%CI=1.08-1.58). The results remained robust in sensitivity analyses.

DISCUSSION: In this population-based study, individuals with MC had a 21% higher risk of VTE compared with reference individuals, equivalent to one extra VTE event for every 37 MC individuals followed for ten years.