Population-based real-world registry study to evaluate clinical outcomes of chronic graft-versus-host disease.

INTRODUCTION: Chronic graft-versus-host disease (cGVHD) is a serious immune-mediated complication after allogeneic haematopoietic stem cell transplantation (HSCT), but in patients with malignancy, cGVHD development is associated with superior survival. Lack of reliable biomarkers and clinical underreporting means there is insufficient understanding of cGVHD clinical outcomes and balance between cGVHD treatment and maintaining beneficial graft-versus-tumour effects. METHODS: We performed a Swedish population-wide registry study following patients who underwent allogeneic HSCT 2006-2015. cGVHD status was retrospectively classified using a real-world method based on the timing and extent of systemic immunosuppressive treatment. RESULTS: cGVHD incidence among patients surviving ≥6 months post-HSCT (n = 1246) was 71.9%, significantly higher than previously reported. 5-year overall survival in patients surviving ≥6 months post-HSCT was 67.7%, 63.3%, and 65.3%, in non-, mild, and moderate-severe cGVHD, respectively. Non-cGVHD patients had a mortality risk almost five-fold higher compared to moderate-severe cGVHD patients 12-months post-HSCT. Moderate-severe cGVHD patients had greater healthcare utilization compared with mild and non cGVHD patients. CONCLUSION: cGVHD incidence was high among HSCT survivors. Non-cGVHD patients had higher mortality during the first 6 months of follow-up; however, moderate-severe cGVHD patients had more comorbidities and healthcare utilization. This study highlights the urgent need for new treatments and real-time methods to monitor effective immunosuppression after HSCT.

Modelling multiple time-scales with flexible parametric survival models.

BACKGROUND: There are situations when we need to model multiple time-scales in survival analysis. A usual approach in this setting would involve fitting Cox or Poisson models to a time-split dataset. However, this leads to large datasets and can be computationally intensive when model fitting, especially if interest lies in displaying how the estimated hazard rate or survival change along multiple time-scales continuously. METHODS: We propose to use flexible parametric survival models on the log hazard scale as an alternative method when modelling data with multiple time-scales. By choosing one of the time-scales as reference, and rewriting other time-scales as a function of this reference time-scale, users can avoid time-splitting of the data. RESULT: Through case-studies we demonstrate the usefulness of this method and provide examples of graphical representations of estimated hazard rates and survival proportions. The model gives nearly identical results to using a Poisson model, without requiring time-splitting. CONCLUSION: Flexible parametric survival models are a powerful tool for modelling multiple time-scales. This method does not require splitting the data into small time-intervals, and therefore saves time, helps avoid technological limitations and reduces room for error.

Antibiotic Therapy and Risk of Early-Onset Colorectal Cancer: A National Case-Control Study.

INTRODUCTION: Antibiotic use has emerged as a risk factor for colorectal neoplasia and is hypothesized as a contributor to the rising incidence of colorectal cancer under age 50 years or early-onset colorectal cancer (EOCRC). However, the impact of antibiotic use and risk of EOCRC is unknown. METHODS: We conducted a population-based case-control study of CRC among individuals aged ≥18 years in the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) cohort (2006-2016). The primary outcome was EOCRC. A secondary outcome was CRC at any age. Incident CRC was pathologically confirmed, and for each, up to 5 population-based controls were matched on age, sex, county of residence, and calendar year. We assessed prescriptions until 6 months before CRC diagnosis. Conditional logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: We identified 54,804 cases of CRC (2,557 EOCRCs) and 261,089 controls. Compared with none, previous antibiotic use was not associated with EOCRC risk after adjustment for potential confounders (aOR 1.06, 95% CI: 0.96, 1.17) with similarly null findings when stratified by anatomic tumor site. In contrast, previous antibiotic use was weakly associated with elevated risk for CRC at any age (aOR 1.05, 95% CI: 1.02, 1.07). A potential but modest link between broad-spectrum antibiotic use and EOCRC was observed (aOR 1.13, 95% CI: 1.02, 1.26). DISCUSSION: We found no conclusive evidence that antibiotics are associated with EOCRC risk. Although antibiotic use was weakly associated with risk of CRC at any age, the magnitude of association was modest, and the study period was relatively short.

Healthcare resource utilisation and sickness absence in newly diagnosed multiple myeloma patients who did not undergo autologous stem cell transplantation: Trends in Sweden with the changing treatment landscape.

OBJECTIVES: The introduction of novel drugs has significantly improved outcomes for multiple myeloma (MM) patients. This study describes survival, healthcare resource utilisation and sickness absence in association with the changing MM treatment landscape over time, focussing on patients who did not undergo autologous stem cell transplantation (ASCT). METHODS: Population-based, retrospective registry study in Sweden, where 7012 non-ASCT patients diagnosed between 2001 and 2015 were stratified into diagnosis periods 2001-2005 (n = 2053), 2006-2010 (n = 2372) and 2011-2015 (n = 2587). RESULTS: Median survival increased from 2.5 to 3.4 years from 2001-2005 to 2011-2015. During the first 3 years of follow-up, patients diagnosed during 2011-2015 spent 29% and 12% less time in health care (55 days; inpatient admissions and outpatient visits) than patients diagnosed during 2001-2005 (78 days) and 2006-2010 (63 days), respectively. This was associated with less inpatient and more outpatient healthcare usage. Average 3-year sickness absence (362 days) was 31% and 12% less than for patients diagnosed during 2001-2005 (522 days) and 2006-2010 (410 days), respectively. CONCLUSIONS: These findings of improved survival, reduced healthcare needs and greater productivity in non-ASCT MM patients with access to improved treatment practices and novel drugs provide important real-world cost-benefit insights for the continued development and introduction of treatments for MM.

Risk of infections in patients with myeloproliferative neoplasms-a population-based cohort study of 8363 patients.

Infections are a common complication in patients with many hematologic malignancies, however, whether patients with myeloproliferative neoplasms (MPN) also are at an increased risk of infections is largely unknown. To assess the risk of serious infections, we performed a large population-based matched cohort study in Sweden including 8 363 MPN patients and 32,405 controls using high-quality registers between the years 1992-2013 with follow-up until 2015. The hazard ratio (HR) of any infection was 2.0 (95% confidence interval 1.9-2.0), of bacterial infections 1.9 (1.8-2.0), and of viral infections 2.1 (1.9-2.3). One of the largest risk increases was that of sepsis, HR 2.6 (2.4-2.9). The HR of any infection was highest in primary myelofibrosis 3.7 (3.2-4.1), and significantly elevated in all MPN subtypes; 1.7 (1.6-1.8) in polycythemia vera and 1.7 (1.5-1.8) in essential thrombocythemia. There was no significant difference in risk of infections between untreated patients and patients treated with hydroxyurea or interferon-α during the years 2006-2013. These novel findings of an overall increased risk of infections in MPN patients, irrespective of common cytoreductive treatments, suggest the increased risk of infection is inherent to the MPN.

P043 Resource Utilization and Productivity Loss among Patients with Inflammatory Bowel Disease in Sweden: A Longitudinal Nationwide Population-based Study.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are the two most prevalent forms of inflammatory bowel disease (IBD) causing frequent diarrhea, rectal bleeding, fatigue, and abdominal pain. IBD may result in complications requiring hospitalizations and surgical procedure, hence IBD can negatively impact patients' quality of life, work productivity, and increase societal economic burden. Limited data exists assessing epidemiologic trends and population-level health outcomes among patients with IBD in Sweden. This study assessed the trends in annual incidence and prevalence of CD, annual inpatient and outpatient visits, employment status and sickness absence among adults with IBD in Sweden from 2001 to 2017. METHODS: Data were acquired from four nationwide registers provided by the National Board of Health and Welfare in Sweden and linked through the unique personal identity number. Individuals aged ≥18 years with ≥2 primary diagnoses of CD (ICD-10 K50) or ≥2 primary diagnoses of UC (ICD-10 K51) from 01/01/2001 to 12/30/2017 were selected. Date of the first CD or UC diagnosis was designated as index date. All individuals were followed until death, lost to follow up or end of study. RESULTS: A total of 30,895 patients with CD and 50,415 with UC were included in the analysis, respectively. The mean follow-up for patients was 10.1 (±5.33) and 10.4 (±5.21) years for CD and UC. The mean (±SD) age among CD patients was 40.4 (±18.4) years and 42.6 (±18.2) years for UC. The most frequently observed comorbid condition was noninfective enteritis and colitis for patients with CD (24.2%) and UC (15.7%). The annual incidence of CD was 10 per 100,000 person-years in 2017, while the incidence of UC was 3 per 100,000 in 2017. 40.6% of CD patients and 30.8% of UC patients had ≥ 1 inpatient admission during 1-year post-index period, of which 53.5% and 51.2% had inpatient care lasting more than 1 week. Among patients with ≥ 1 outpatient services (CD: n = 30,675; UC: n = 50,183), 41.7% and 29.2% of patients had more than 5 visits during 1-year post-index period. Among patients who were eligible for employment and disability benefit analyses who had at least 1-year follow-up (CD: n = 23,731; UC: n = 39,391), 27.9% of CD patients and 23.1% of UC patients were not in employment; among those who were in employment (CD: n = 17,039; UC: n=30,302), 30% and 24.6% reported sickness absence within the calendar year after the index date, respectively. CONCLUSION: Findings from this study of a large national cohort of patients followed for many years demonstrates the significant epidemiological, clinical, and socioeconomic impact of patients with CD and UC. Further research is needed to understand underlying factors driving inpatient admissions among patients with IBD. With an increasing annual prevalence, IBD continues to impose a substantial public health burden to patients, their families and health care services.

Real-world study of direct medical and indirect costs and time spent in healthcare in patients with chronic graft versus host disease.

Chronic graft versus host disease (cGVHD) is a debilitating and costly complication following haemopoietic stem cell transplantation (HSCT). This study describes the economic burden associated with cGVHD. Direct costs associated with specialised healthcare utilisation (inpatient admissions and outpatient visits), as well as indirect costs associated with sickness absence-associated productivity loss were estimated in patients who underwent allogeneic HSCT in Sweden between 2006 and 2015, linking population-based health and economic registers. To capture the period of chronic GVHD, patients were included who survived > 182 days post-HSCT (start of follow-up), and cGVHD was classified based on patient treatment records to correct for any diagnosis underreporting. Patients were classified as 'non-cGVHD' if they received no immunosuppressive treatment, 'mild cGVHD' if they received only systemic corticosteroid treatment or immunosuppressive treatment, or 'moderate-severe cGVHD' if they received extracorporeal photopheresis (ECP) only, corticosteroid treatment and immunosuppressive treatment, or systemic corticosteroid treatment and ECP treatments. Patients with moderate-severe cGVHD spent more time in healthcare, had higher healthcare resource costs and higher sickness absence-related productivity loss compared to patients with non- or mild cGVHD. The cumulative total costs during the first 3 years of follow-up were EUR 14,887,599, EUR 20,544,056, and EUR 47,811,835 for non-, mild, and moderate-severe groups, respectively. The long-term costs incurred with cGVHD following HSCT continue to be very high and significantly impacted by cGVHD severity. This study adds real-world health resource and economic insight relevant for policy-makers and healthcare providers when considering the clinical challenge of balancing immunosuppression to reduce cGVHD.

Hepatitis C Virus Infection and the Temporal Trends in the Risk of Liver Cancer: A National Register-Based Cohort Study in Sweden.

BACKGROUND: In many countries, including Sweden, the birth cohorts with the highest prevalence of hepatitis C virus (HCV) infection have now reached the ages with high risk of primary liver cancer (PLC). The aims of this study were to investigate the temporal trends in PLC incidence and the relative risks of PLC among people diagnosed with HCV infection between 1990 and 2015. METHODS: The HCV cohort (n = 52,853) was compared with a matched non-HCV comparison cohort (n = 523,649). Both the national Cancer Register (CR) and Cause of Death Register (DR) were used for follow-up. The crude and age-standardized PLC incidence rates were calculated. The relative risk was estimated as standardized incidence ratios (SIR) and as HRs using stratified Cox hazards regression. RESULTS: There were 1,609 with PLC diagnosis in the HCV cohort; the annual number increased continuously with the crude incidence rate reaching 4.56 per 1,000 person-years in 2013 while remaining low and stable in the comparison cohort. In the HCV cohort, the age-standardized PLC incidence rates per 1,000 person-years remained relatively constant at 2.64 [95% confidence interval (CI), 1.54-3.75] in 2000 and 3.31 (2.51-4.12) in 2014. The highest SIR was 73 (65.9-79.5) among those infected for 35 to 40 years; and the highest HR was 65.9 (55.9-77.6) for men and 62.2 (31.9-121.1) for women. CONCLUSIONS: There was a considerable increase in PLC incidence over time and an extremely high relative risk in the population with HCV infection for more than 35 years. IMPACT: The national HCV-associated PLC incidence should be monitored in future studies to evaluate the effect of direct-acting antiviral (DAA) treatment.