Glucocorticoid treatment in SLE is associated with infections, comorbidities and mortality-a national cohort study.

OBJECTIVES: Patients with SLE have an increased risk of comorbidities and impaired survival. We aimed to assess whether various thresholds of oral CS (OCS) can predict development of infections, comorbidities, malignancies and survival in SLE using data from national health registries in Sweden. METHODS: All incident SLE cases, age >18 years, in Sweden (n = 5309) between 2005 and 2020 and matched population controls (n = 26 545) were included and followed until 2020, a total of 257 942 patient years. Data from national registers were retrieved including information from the National Prescribed Drug Register. Risk factors were analysed using time-dependent Cox regression models. RESULTS: Compared with no OCS, >0 to <5.0 mg/day, 5.0-7.5 mg/day as well as >7.5 mg/day OCS predicted development of infections (pneumonia, influenza, herpes zoster and urinary tract infection), osteoporosis, osteonecrosis, gastroduodenal ulcers, cataracts, hypertension and mortality (all P < 0.05). OCS >0 to <5.0 mg/day was associated with lower hazard ratios for these comorbidities than higher doses of OCS. Fifteen years after diagnosis, 48% of patients were taking OCS at a median dose of 5.7 mg/day. A small reduction of OCS treatment 5 years after diagnosis in patients diagnosed with SLE 2006-10 compared with 2011-15 was observed, 49% vs 46% respectively (P = 0.039). CONCLUSION: Results highlight the potential harm associated with even low OCS dose treatment in SLE and the need to judiciously use OCS at the lowest possible dose to maximize efficacy and minimize harm.

Changes in primary care management of atrial fibrillation patients following the shift from warfarin to non-vitamin K antagonist oral anticoagulants: a Norwegian population based study.

BACKGROUND: To assess baseline characteristics, drug utilisation and healthcare use for oral anticoagulants (OACs) following the introduction of non-vitamin K antagonist oral anticoagulants among patients with atrial fibrillation in primary care in Norway. METHODS: In this retrospective longitudinal cohort study, 92,936 patients with atrial fibrillation were identified from the Norwegian Primary Care Registry between 2010 and 2018. Linking to the Norwegian Prescription Database, we identified 64,112 patients (69.0%) treated with OACs and 28,824 (31%) who were untreated. Participants were followed until 15 May 2019, death, or loss to follow-up, whichever came first. For each OAC, predictors of initiation were assessed by modelling the probability of initiating the OAC using logistic regression, and predictors of the first switch after index date were assessed using multivariable Cox proportional hazards models. The numbers of primary care visits per quarter by index OAC were plotted and analysed with negative binomial regression analyses offset for the log of days at risk. RESULTS: Patients treated with OACs were older, had more comorbidities, and higher CHA2DS2-VASc scores than untreated patients. However, the mean CHA2DS2-VASc in the non-OAC group was 1.58 for men and 3.13 for women, suggesting an indication for OAC therapy. The percentage of patients with atrial fibrillation initiating OACs increased from 59% in 2010 to 79% in 2018. Non-vitamin K antagonist oral anticoagulant use increased throughout the study period to 95% of new OAC-treated patients in 2018, and switches from warfarin to non-vitamin K antagonist oral anticoagulants were common. The persistence of OAC treatment was > 60% after four years, with greatest persistence for apixaban. Patients treated with non-vitamin K antagonist oral anticoagulants had fewer primary care visits compared with those treated with warfarin (incidence rate ratio: 0.73, 95% confidence interval 0.71 to 0.75). CONCLUSION: In this Norwegian primary care study, we found that the shift from warfarin to non-vitamin K antagonist oral anticoagulants was successful with 95% use in patients initiating OACs in 2018, and associated with fewer general practitioner visits. Persistence with OACs was high, particularly for apixaban. However, many patients eligible for treatment with OACs remained untreated.

A Novel Risk Score (P-score) Based on a Three-Gene Signature, for Estimating the Risk of Prostate Cancer-Specific Mortality.

Purpose: To develop and validate a risk score (P-score) algorithm which includes previously described three-gene signature and clinicopathological parameters to predict the risk of death from prostate cancer (PCa) in a retrospective cohort. Patients and Methods: A total of 591 PCa patients diagnosed between 2003 and 2008 in Stockholm, Sweden, with a median clinical follow-up time of 7.6 years (1-11 years) were included in this study. Expression of a three-gene signature (IGFBP3, F3, VGLL3) was measured in formalin-fixed paraffin-embedded material from diagnostic core needle biopsies (CNB) of these patients. A point-based scoring system based on a Fine-Gray competing risk model was used to establish the P-score based on the three-gene signature combined with PSA value, Gleason score and tumor stage at diagnosis. The endpoint was PCa-specific mortality, while other causes of death were treated as a competing risk. Out of the 591 patients, 315 patients (estimation cohort) were selected to develop the P-score. The P-score was subsequently validated in an independent validation cohort of 276 patients. Results: The P-score was established ranging from the integers 0 to 15. Each one-unit increase was associated with a hazard ratio of 1.39 (95% confidence interval: 1.27-1.51, p < 0.001). The P-score was validated and performed better in predicting PCa-specific mortality than both D'Amico (0.76 vs 0.70) and NCCN (0.76 vs 0.71) by using the concordance index for competing risk. Similar improvement patterns are shown by time-dependent area under the curve. As demonstrated by cumulative incidence function, both P-score and gene signature stratified PCa patients into significantly different risk groups. Conclusion: We developed the P-score, a risk stratification system for newly diagnosed PCa patients by integrating a three-gene signature measured in CNB tissue. The P-score could provide valuable decision support to distinguish PCa patients with favorable and unfavorable outcomes and hence improve treatment decisions.

Plasma Thymidine Kinase Activity as a Novel Biomarker in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibitors.

Background. Immune checkpoint inhibitors (ICI) are effective in fractions of patients with disseminated melanoma. This study is the first to analyze the plasma activity of thymidine kinase (TK), an enzyme involved in DNA synthesis and repair, as a biomarker in melanoma patients. Methods. Plasma samples were collected prior to treatment start in patients with unresectable metastatic cutaneous melanoma, treated with ICI (anti-CTLA-4 and/or anti-PD-1). Plasma TK activity (TKa) levels were determined using the DiviTum TKa ELISA assay. TKa levels were correlated with patients' baseline characteristics, response rate (RR), progression-free survival (PFS), and overall survival (OS). Results. In the 90 study patients, the median TKa level was 42 Du/L (range <20-1787 Du/L). A significantly higher plasma TKa was found in patients with ECOG performance status ≥1 (p = 0.003), M1c-d disease (p = 0.015), and elevated lactate dehydrogenase levels (p < 0.001). The RR was 63.2% and 30.3% in those with low or high TKa, respectively (p = 0.022). The median PFS was 19.9 and 12.6 months in patients with low or high TKa, respectively (hazard ratio (HR) 1.83 (95% CI, 1.08-3.08), p = 0.024). The median OS was >60 months and 18.5 months in patients with low or high TKa, respectively (HR: 2.25 (95% CI, 1.25-4.05), p = 0.011. Conclusions. High pretreatment plasma TKa levels were significantly associated with worse baseline characteristics and poor response and survival in ICI-treated melanoma patients. TKa is hence a novel and interesting plasma biomarker in melanoma and should be further studied to define its role as a prognostic and predictive marker in this disease.

Effectiveness and safety of oral anticoagulants in elderly patients with atrial fibrillation.

OBJECTIVES: To assess the risk of stroke/systemic embolism (SE) and major bleeding associated with the use of oral anticoagulants in elderly patients with atrial fibrillation (AF) in a real-world population. METHODS: We identified all anticoagulant-naive initiators of warfarin, dabigatran, rivaroxaban and apixaban for the indication AF in Norway between January 2013 and December 2017. Multivariate competing risk regression was used to calculate subhazard ratios (SHRs) describing associations between non-vitamin K antagonist oral anticoagulants (NOACs) compared with warfarin for risk of stroke/SE and major bleeding. RESULTS: Among 30 401 patients ≥75 years identified (median age 82 years, 53% women, mean CHA2DS2-VaSc score 4.5), 3857 initiated dabigatran, 6108 rivaroxaban, 13 786 apixaban and 6650 warfarin. Reduced dose was initiated in 11 559 (49%) of the NOAC-treated patients. For stroke, the SHRs for standard dose NOAC against warfarin were 0.80 (95% CI 0.57 to 1.13) for dabigatran; 1.07 (95% CI 0.89 to 1.30) for rivaroxaban and 0.95 (95% CI 0.78 to 1.15) for apixaban. For major bleeding, the SHRs against warfarin were 0.75 (95% CI 0.52 to 1.08) for dabigatran; 0.96 (95% CI 0.78 to 1.16) for rivaroxaban and 0.74 (95% CI 0.60 to 0.91) for apixaban. Comparing reduced doses of NOACs with warfarin yielded similar results. Sensitivity analyses were in accordance with the main results. CONCLUSION: In this nationwide cohort study of patients ≥75 years initiating oral anticoagulation for AF, standard and reduced dose NOACs were associated with similar risks of stroke/SE as warfarin and lower or similar risks of bleeding. The NOACs seem to be a safe option also in elderly patients.

Comparison of dabigatran, rivaroxaban, and apixaban for effectiveness and safety in atrial fibrillation: a nationwide cohort study.

AIMS: The aim of this study was to compare the risk of stroke or systemic embolism (SE) and major bleeding in patients with atrial fibrillation (AF) using dabigatran, rivaroxaban, and apixaban in routine clinical practice. METHODS AND RESULTS: Using nationwide registries in Norway from January 2013 to December 2017, we established a cohort of 52 476 new users of non-vitamin K antagonist oral anticoagulants (NOACs) with AF. Users of individual NOACs were matched 1:1 on the propensity score to create three pairwise-matched cohorts: dabigatran vs. rivaroxaban (20 504 patients), dabigatran vs. apixaban (20 826 patients), and rivaroxaban vs. apixaban (27 398 patients). Hazard ratios (HRs) for the risk of stroke or SE and major bleeding were estimated. In the propensity-matched comparisons of the risk of stroke or SE, the HRs were 0.88 [95% confidence interval (CI) 0.76-1.02] for dabigatran vs. rivaroxaban, 0.88 (95% CI 0.75-1.02) for dabigatran vs. apixaban, and 1.00 (95% CI 0.89-1.14) for apixaban vs. rivaroxaban. For the risk of major bleeding, the HRs were 0.75 (95% CI 0.64-0.88) for dabigatran vs. rivaroxaban, 1.03 (95% CI 0.85-1.24) for dabigatran vs. apixaban, and 0.79 (95% CI 0.68-0.91) for apixaban vs. rivaroxaban. CONCLUSION: In this nationwide study of patients with AF in Norway, we found no statistically significant differences in risk of stroke or SE in propensity-matched comparisons between dabigatran, rivaroxaban, and apixaban. However, dabigatran and apixaban were both associated with significantly lower risk of major bleeding compared with rivaroxaban.

Incidence, prevalence, and outcome of primary biliary cholangitis in a nationwide Swedish population-based cohort.

Available epidemiological data on primary biliary cholangitis (PBC) in Sweden originate from regional studies in the 1980s and may not reflect modern day PBC. We aimed to estimate incidence and prevalence, survival and death causes, and gender differences in PBC. We used international classification of disease (ICD) codes to identify patients with PBC in inpatient and outpatient registries 1987-2014 who were then linked to the Swedish cause of death, cancer and prescribed drug registries. Each PBC patient was matched with 10 reference individuals from the general population. In sensitivity analyses, we examined PBC patients identified through clinical patient records from Karolinska, Sahlgrenska and Örebro University Hospitals. We identified 5,350 adults with PBC. Prevalence of PBC increased steadily from 5.0 (1987) to 34.6 (2014) per 100,000 inhabitants whereas the yearly incidence rate was relatively constant with a median of 2.6 per 100,000 person-years, with a female:male gender ratio of 4:1. Compared to reference individuals, PBC individuals aged 15-39 years at diagnosis had a substantially higher risk of death (Hazard Ratio [HR] 12.7, 95% Confidence Interval [CI] 8.3-19.5) than those diagnosed between 40-59 (HR 4.1, 95% CI 3.7-4.5) and >60 (HR 3.7, 95% CI 3.5-3.9) years of age. Relative risks of mortality were highest in men. In conclusion, we found that recorded prevalence of PBC in Sweden has increased substantially during the last 30 years although incidence has been stable. Patients diagnosed in young adulthood were at a 12.7-fold increased risk of death, and male PBC patients had worse prognosis.

Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control - a randomized controlled trial.

STUDY QUESTION: Does pre-treatment with a low dose of mifepristone improve irregular vaginal bleeding patterns during the initial 3 months after LNG-IUS placement? SUMMARY ANSWER: Mifepristone treatment prior to LNG-IUS insertion results in significantly lower bleeding and spotting rates but no significant reduction post insertion. WHAT IS KNOWN ALREADY: One of the leading causes of premature discontinuation of the LNG-IUS is unscheduled bleeding in the first months following its insertion. Up to now, there has been no effective treatment to prevent this side effect which reduces continuation rates for one of the most effective contraceptives. STUDY DESIGN, SIZE, DURATION: This randomized, double blinded, controlled trial was conducted between 2009 and 2015. In total, 68 women opting for a LNG-IUS were screened for eligibility, of whom 58 were randomized at a ratio of 1:1 in blocks of 10 to pre-treatment with mifepristone or a comparator. The main outcome was the rate of bleeding and spotting days reported during the first 3 months post LNG-IUS 52 mg placement. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthy women with regular and normal menstrual cycles aged 18-43 years were enrolled at a single center in a university hospital; 29 were allocated to 2 months pre-treatment with a low dose mifepristone and 29 to the comparator prior to insertion of the LNG-IUS. Women were advised to use barrier methods during the pre-treatment period. Bleeding diaries were collected for the pre-treatment period and for the first 6 months after the LNG-IUS placement. MAIN RESULTS AND THE ROLE OF CHANCE: There were no differences in demographics or baseline characteristics between the study groups. Data for analysis of the main outcome were contributed by a per protocol population of 19 women per group. There was a significant lower bleeding and spotting rate in the mifepristone group (-17.8% points, P < 0.001) after 2 months of pretreatment but after the LNG-IUS insertion no significant difference could be seen. While no pregnancies occurred prior to LNG-IUS insertion in the mifepristone group, there were three unintended pregnancies in the comparator group which emphasizes the need for a reliable contraceptive potential in any pre-treatment regiment used in clinical practice. LIMITATIONS, REASONS FOR CAUTION: The use of mifepristone prior to the LNG-IUS insertion in this trial was used as prophylaxis against unscheduled bleeding after the placement of the device. Although this side effect constitutes a major concern in a clinical setting, only a subset of women are at risk. This is the first study using pre-treatment to attempt improved bleeding control. The differences were small and the effect was short lasting but the reduced rate of bleeding and spotting observed during the first month following LNG-IUS insertion, even though not statistically significant, indicates that this approach may be further explored. The fact that there were three pregnancies in the comparator group stresses the need for any pre-treatment to also protect against unplanned pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: Modified treatment protocols of mifepristone could be used prior to the LNG-IUS insertion to investigate possible further improvement of the outcome. The effect size of the current dose used might have been more prominent in women with LNG-IUS if the treatment also continued some weeks after the placement of the device. Although the low dose of mifepristone used in this trial is not available in Europe, other progesterone receptor modulators currently available could be investigated in larger clinical trials. To avoid unintended pregnancy in the pretreatment period, the dosage used should, ideally, also be effective for contraception and the pretreatment period should be kept as short as possible. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Swedish Research Council (2012-2844, 2017-00932), Stockholm County Council and Karolinska Institutet (ALF). Conflicts of interests for K.G.D. and H.K.K. are listed at the end of the paper. The other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: EudraCT number 2009-009014-40. Regional ethical review board at Karolinska Institutet permit 2009/144-31/4. TRIAL REGISTRATION DATE: 20 July 2009. DATE OF FIRST PATIENT'S ENROLMENT: 24 November 2009.