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Objective. To evaluate the long-term safety profile of anakinra in patients with systemic juvenile idiopathic arthritis (sJIA). Methods. Data from patients with sJIA enrolled in the Pharmachild registry (ClinicalTrials.gov: NCT03932344) prior to September 30, 2018, and treated with anakinra were analyzed. The study endpoints were the occurrence of non-serious adverse events (SAEs) of at least moderate severity and SAEs, including macrophage activation syndrome (MAS), and the duration of anakinra treatment with reasons for discontinuation. All endpoints were analyzed overall by 6-month time windows, and in different treatment sets represented by those patients treated continuously with anakinra for at least 12, 18, and 24 months (set-12, -18, and -24, respectively). Results. Three hundred six patients were enrolled. Of these patients, 46%, 34%, and 28% had been treated for at least 12, 18, and 24 months, respectively. Two hundred and one AEs, mostly represented by infections, were reported for 509.3 patient-years (PY) with an overall incidence rate (IR) of 39.5 per 100 PY. Among 56 SAEs (IR 11.0/100 PY), 23.2% were infections and 19.6% MAS episodes. The IR of AEs was higher during the first 6 months of anakinra treatment, followed by decreasing IRs in the long-term treatment sets. Treatment discontinuation occurred in 76% of patients, most frequently in the first 6 months, because of inefficacy (43%), remission (31%), or AEs/intolerance (15%). No deaths or malignancies occurred during anakinra treatment. Conclusion. The results of the present study confirm the long-term safety profile of anakinra in patients with sJIA and demonstrate an overall decreasing incidence of AEs over time.

Chronic inflammation is one of the underlying risks associated with thyroid cancer. We ascertained the association between commonly measured serum biomarkers of inflammation and the risk of thyroid cancer in Swedish Apolipoprotein-related MORtality RISk (AMORIS) study. 226,212 subjects had baseline measurements of C-reactive protein, albumin and haptoglobin. Leukocytes were measured in a subgroup of 63,845 subjects. Associations between quartiles and dichotomized values of inflammatory markers and risk of thyroid cancer were analysed using multivariate Cox proportional hazard models. 202 individuals were diagnosed with thyroid cancer during a mean follow-up of 19.6 years. There was a positive association between lower albumin levels and risk of developing thyroid cancer [Hazard Ratio for albumin ≤ 40 g/L: 1.50 (95% Confidence Interval = 1.04-2.16)]. When stratified by a metabolic score, we observed similar association for albumin with higher HR among those with metabolic score ≥ 1, as compared to those with metabolic score of 0 [HR 1.98 (95% CI = 1.11-3.54) vs 1.17 (95% CI = 0.72-1.89)] (P = 0.19). Apart from albumin, none of the serum markers of inflammation studied showed a link with the risk of developing thyroid cancer-suggesting that the role of inflammation may be more complicated and requires assessment of more specialised measurements of inflammation.

Background: The long-term trajectories of lipid and glucose levels in subjects who experience a major cardiovascular (CV) event at a young age has not been well studied. Our objective was to investigate lipid, lipoprotein, apolipoprotein (apo), and glucose levels in individuals experiencing a CV event before 50 years of age. Methods and findings: A first CV event [non-fatal myocardial infarction (MI), coronary revascularisation, or CV related death] before age 50 was recorded in 2,939 (cumulative incidence 1.2% in males and 0.3% in females) of 361,353 individuals included in the prospective Swedish AMORIS (Apolipoprotein-related MOrtality RISk) study with health examinations 1985-1996 and follow-up through 2011. In a nested case-control analysis, cases with a CV event were matched to randomly selected controls. Population risk factor trajectories were calculated up to 20 years prior to an event. Total cholesterol (TC), triglyceride (TG), and glucose levels were higher in cases than in controls as early as 20 years prior to the event with differences increasing over time. Low density lipoprotein, apoB, and the apoB/apoA-1 ratio were higher and increased over time, while HDL and apoA-1 were lower in cases compared to controls. The odds ratio was 2.5 (95% confidence interval 1.6-3.7) for TC >= 5 mmol/L and TG >= 1.7 mmol/L in cases versus controls. The adjusted population-attributable fractions including lipids, glucose, diabetes, smoking, hypertension, and obesity indicated that about 50% of CV events before age 50 may be associated with elevated lipid and glucose levels. Conclusions: Elevated TC, TG, LDL, apoB, and glucose levels and high apoB/apo A-1 ratio documented two decades before a CV event in subjects younger than 50 years may account for about half of CV events before age 50, which calls for early recognition and possibly treatment of modifiable CV risk factors in young individuals.

Previous literature indicates that pre-diagnostic diabetes and blood glucose levels are inversely related to glioma risk. To replicate these findings and determine whether they could be attributed to excess glucose consumption by the preclinical tumour, we used data from the Apolipoprotein MOrtality RISk (AMORIS) (n = 528,580) and the Metabolic syndrome and Cancer project (Me-Can) cohorts (n = 269,365). We identified individuals who were followed for a maximum of 15 years after their first blood glucose test until glioma diagnosis, death, emigration or the end of follow-up. Hazard ratios (HRs), 95% confidence intervals (CIs) and their interactions with time were estimated using Cox time-dependent regression. As expected, pre-diagnostic blood glucose levels were inversely related to glioma risk (AMORIS, P trend = 0.002; Me-Can, P trend = 0.04) and pre-diagnostic diabetes (AMORIS, HR = 0.30, 95% CI 0.17 to 0.53). During the year before diagnosis, blood glucose was inversely associated with glioma in the AMORIS (HR = 0.78, 95% CI 0.66 to 0.93) but not the Me-Can cohort (HR = 0.99, 95% CI 0.63 to 1.56). This AMORIS result is consistent with our hypothesis that excess glucose consumption by the preclinical tumour accounts for the inverse association between blood glucose and glioma. We discuss additional hypothetical mechanisms that may explain our paradoxical findings.

Purpose: To evaluate the association between commonly measured serum biomarkers of inflammation and penile and testicular cancer risk in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) study. Materials and methods: A total of 205,717 subjects had baseline measurements of C-reactive protein, albumin, and haptoglobin. The association between quartiles and dichotomised values of inflammatory markers and penile and testicular cancer risk were analysed by using multivariate Cox proportional hazard models. Results: A total of 125 men were diagnosed with testicular cancer and 50 with penile cancer during a mean follow-up of 20.3 years. No statistically significant trends were seen between serum inflammatory markers and risk of penile cancer, but higher albumin levels increased the risk of testicular cancer [HR for albumin (g/L): 1.10 (95% CI: 1.03-1.18)]. However, this trend was not observed when using medical cut-offs of albumin. Conclusions: In the present study, we did not find support for an association between commonly used markers of inflammation and risk of testicular or penile cancer. The role of inflammation may be more complicated and require assessment of more specialised measurements of inflammation in future studies.

Background: Inflammation has been linked with development of some cancers. We investigated systemic inflammation in relation to colorectal cancer incidence and subsequent survival using common serum inflammatory markers Design: A cohort of men and women aged 20 years and older in greater Stockholm area with serum C-reactive protein (CRP) and albumin measured between 1986 and 1999 were included (n-325 599). A subset of these had baseline measurements of haptoglobin and leukocytes. Multivariable Cox regression was performed to assess risk of colorectal cancer by levels of inflammatory markers, adjusting for potential confounders. Analyses were stratified by circulating glucose, total cholesterol and triglycerides. Overall and CRC-specific death following diagnosis were assessed as secondary outcomes. Results: A total of 4764 individuals were diagnosed with colorectal cancer. A positive association between haptoglobin and colorectal cancer incidence was found (hazard ratio (HR): 1.17; 95% CI: 1.06-1.28). A positive association was also observed with leukocytes (HR: 1.21; 95% CI: 1.03-1.42). No evidence of association was noted between CRP and colorectal cancer risk. Higher risks of all-cause death were seen with haptoglobin and leukocytes levels. Higher haptoglobin levels were linked with an increased risk of colorectal cancer death (HR: 1.19; 95% CI: 1.01-1.41). Conclusions: Prediagnostic systemic inflammation may impact colorectal cancer incidence and survival; therefore, prompting investigations linking inflammatory pathways preceding colorectal cancer with disease severity and progression.

BACKGROUND: Diabetes is associated with an increased risk of micro- and macrovascular disease and mortality. Two main methods for diagnosis and control of type 2 diabetes are the measurements of blood glucose and glycosylated hemoglobin (HbA1c). These methods have some limitations where other techniques may complement. Hence, there is a need for other methods to be scientifically investigated and documented. Fructosamine is a biochemical marker of the amount of glycated proteins in the extracellular compartment of the blood and can serve as a complement to established blood markers of glycemic exposure. This thesis aims to evaluate fructosamine in relation to serum glucose and HbA1c and as a risk factor for type 2 diabetes (T2D), coronary heart disease (CHD) and death. METHODS AND RESULTS: For all studies in this thesis, subpopulations of the AMORIS cohort (n=812,073) were used. Study I. In 871 subjects with a documented diagnosis of type 2 diabetes (T2D), the mean fasting fructosamine was 2.7 mmol/L and the mean value for fasting glucose and HbA1c respectively was 9.6 mmol/L and 7.2%. The linear correlation of fructosamine and HbA1c was high (r=0.75). Across three repeated measurements within one year, fructosamine and HbA1c followed the changes of fasting glucose over time. At a fructosamine level of 2.5 mmol/L, the sensitivity for the diagnostic criteria for diabetes was 61% and the specificity 97%. Study II. In 338,443 subjects, we observed an increased incidence of myocardial infarction or death from coronary heart disease (CHD) in subjects with higher levels of fructosamine. A fructosamine level of ≥ 2.7 mmol/L was associated with an increased hazard compared to a reference group of normoglycemic individuals (Adjusted HR=2.1 (2.0-2.2). Comparable risk increases of CHD events and all-cause mortality were seen in groups of hyperglycemia defined by HbA1c. Study III. We investigated the risk of all-cause mortality based on fasting fructosamine levels over a study

To investigate the association between serum calcium and risk of breast cancer using a large cohort and a systematic review with meta-analysis. From the Swedish Apolipoprotein Mortality Risk (AMORIS) Study we included 229,674 women who had baseline measurements of serum total calcium and albumin. Multivariable Cox regression was used to assess the association between total and albumin-corrected calcium and breast cancer risk. For the systematic review, an electronic search of MEDLINE and EMBASE databases was performed to identify other prospective cohorts assessing the relationship between serum calcium and breast cancer risk. We pooled the results of our AMORIS cohort with other eligible studies in a meta-analysis using a random effects model. I-2 test was used to assess heterogeneity. In the AMORIS study, 10,863 women were diagnosed with breast cancer (mean follow-up: 19 years). We found an inverse association between total serum calcium and breast cancer when comparing the fourth quartile to the first quartile (HR: 0.94, 95% CI: 0.88-0.99, p value for trend 0.04) and similar results using albumin-corrected calcium. In the systematic review, we identified another two prospective cohorts evaluating pre-diagnostic serum total calcium and breast cancer. Combining these studies and our findings in AMORIS in a meta-analysis showed a protective effect of serum calcium against breast cancer, with a summary RR of 0.80 (95% CI: 0.66-0.97). No substantial heterogeneity was observed. Our findings in AMORIS and the meta-analysis support an inverse association between serum calcium and breast cancer risk, which warrants mechanistic investigations.