Incidence and Prevalence of Fibrous Dysplasia/McCune-Albright Syndrome: A Nationwide Registry-Based Study in Denmark.

CONTEXT: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare genetic disorder. Incidence and prevalence are not well-studied. Epidemiological research is complicated by the rarity of FD/MAS, absence of registries, heterogeneous presentation, and possibly asymptomatic phenotype. FD/MAS may present with FGF23-mediated hypophosphatemia, of which the epidemiology is also unclear. OBJECTIVE: Evaluate incidence and prevalence of FD/MAS and FD/MAS-related hypophosphatemia. METHODS: This cohort study based on the nationwide Danish National Patient Registry from 1995-2018, included patients identified by ICD-10 codes M85.0 (monostotic FD [MFD]) and Q78.1 (polyostotic FD [PFD]/MAS). Incidence rates and prevalence were calculated and stratified by sex, age, calendar period, and diagnosis code. Cases were screened for FD-associated hypophosphatemia by diagnosis code E.83 (disorder of mineral metabolism) and dispatched vitamin D analogues. RESULTS: A total of 408 patients were identified, 269 with MFD (66%), 139 with PFD/MAS (34%), comparable between sexes. Incidence of FD/MAS demonstrated increasing secular trend with a rate of 3.6 per 1 000 000 person-years (95% CI: 2.9, 4.5) in 2015-2018. Incidence peaked between age 11 and 20. Prevalence of FD/MAS increased over time to 61.0 (95% CI: 54.6, 67.4) per 1 000 000 persons in 2018. The incidence rate of MFD was 1.5-fold that of PFD/MAS in the first decade, rising to 2.5-fold in the last decade. No FD/MAS cases were registered with diagnosis code or treatment for hypophosphatemia. CONCLUSION: FD/MAS is rare, diagnosis peaks during adolescence without sex predominance, and MFD is most prevalent. Hypophosphatemia may be underdiagnosed and undertreated, or it may be underregistered, comparing this study to literature.

Sarcoidosis rates in BCG-vaccinated and unvaccinated young adults: A natural experiment using Danish registers.

OBJECTIVES: Sarcoidosis may have an infectious trigger, including Mycobacterium spp. The Bacille Calmette-Guérin (BCG) vaccine provides partial protection against tuberculosis and induces trained immunity. We examined the incidence rate (IR) of sarcoidosis in Danish individuals born during high BCG vaccine uptake (born before 1976) compared with individuals born during low BCG vaccine uptake (born in or after 1976). METHODS: We performed a quasi-randomized registry-based incidence study using data from the Danish Civil Registration System and the Danish National Patient Registry between 1995 and 2016. We included individuals aged 25-35 years old and born between 1970 and 1981. Using Poisson regression models, we calculated the incidence rate ratio (IRR) of sarcoidosis in individuals born during low BCG vaccine uptake versus high BCG vaccine uptake, adjusting for age and calendar year (separately for men and women). RESULTS: The IR of sarcoidosis was increased for individuals born during low BCG vaccine uptake compared with individuals born during high BCG vaccine uptake, which was largely attributed to men. The IRR of sarcoidosis for men born during low BCG vaccine uptake versus high BCG vaccine uptake was 1.22 (95% confidence interval [CI] 1.02-1.45). In women, the IRR was 1.08 (95% CI 0.88-1.31). CONCLUSION: In this quasi-experimental study that minimizes confounding, the time period with high BCG vaccine uptake was associated with a lower incidence rate of sarcoidosis in men, with a similar effect seen in women that did not reach significance. Our findings support a potential protective effect of BCG vaccination against the development of sarcoidosis. Future interventional studies for high-risk individuals could be considered.

Registry-based cohort study of alpha-1 antitrypsin deficiency prevalence, incidence and mortality in Denmark 2000-2018.

OBJECTIVE: To estimate the prevalence of diagnosed alpha-1 antitrypsin deficiency (dAATD) in Denmark as of 31 December 2018, and dAATD incidence and mortality from 1 January 2000 to 31 December 2018. STUDY DESIGN AND SETTING: We used the Danish National Patient Registry to identify patients with dAATD based on the International Classification of Diseases, 10th Revision (ICD-10) code E88.0A and the Danish Civil Registration System (CRS) for population counts and vital status. We estimated dAATD prevalence, incidence and mortality. We compared mortality among patients with dAATD and an age-matched and sex-matched cohort extracted from the Danish CRS. We conducted a sensitivity analysis to examine whether coding changes during 2000-2018, from a general to a more specific ICD-10 code for AATD, and left truncation affected results appreciably. RESULTS: The prevalence of dAATD was 12.9 (95% CI 11.9 to 13.8) per 100 000 persons. The age distribution was bimodal, with peaks at ages ≤12 and ≥45 years. The incidence rate per 100 000 person-years was 0.90 (95% CI 0.85 to 0.96), again with a bimodal age distribution. Mortality was higher for patients with dAATD than for the general population (mortality rate ratio (mRR) 4.7, 95% CI 4.1 to 5.3), especially for children (mRR 33.8, 95% CI 6.8 to 167.4). The sensitivity analysis indicated that dAATD prevalence might have been as high as 19.7 per 100 000 persons due to less specific ICD-10 coding for AATD early in the study period or 21.4 per 100 000 persons correcting for left truncation. CONCLUSION: Diagnosed AATD was associated with increased mortality, especially for children. The finding for children was based on few deaths and had very wide 95% CIs.

Sarcoidosis incidence after mTOR inhibitor treatment.

OBJECTIVE: Mechanistic target of rapamycin (mTOR) inhibitors are effective in animal models of granulomatous disease, but their benefit in sarcoidosis patients is unknown. We evaluated the incidence of sarcoidosis in patients treated with mTOR inhibitors versus calcineurin inhibitors. METHODS: This was a cohort study using the Optum Clinformatics® Data Mart (CDM) Database (2003-2019), IBM® MarketScan® Research Database (2006-2016), and Danish health and administrative registries (1996-2018). Patients aged ≥18 years with ≥1 year continuous enrollment before and after kidney, liver, heart, or lung transplant treated with an mTOR inhibitor or calcineurin inhibitor were included. Patients diagnosed with sarcoidosis before, or up to 90 days after, transplant were excluded. The incidence of sarcoidosis by treatment group was calculated. RESULTS: In the Optum CDM/IBM MarketScan cohort, 1,898 patients were treated with an mTOR inhibitor (mean age 49 years; 34% female) and 9,894 patients were treated with a calcineurin inhibitor (mean age 50 years; 37% female). The mean follow-up in the mTOR inhibitor group was 1.1 years, with no incident sarcoidosis diagnosed. In the calcineurin inhibitor group, the mean follow-up was 2.2 years, with 12 incident sarcoidosis cases diagnosed. In the Danish cohort, 230 patients were treated with an mTOR inhibitor (mean age 49; 45% female), with no incident sarcoidosis diagnosed. There were 3,411 patients treated with a calcineurin inhibitor (mean age 45; 40% female), with 10 incident cases of sarcoidosis diagnosed. CONCLUSIONS: This study indicates a potential protective effect of mTOR inhibitor treatment compared with calcineurin inhibitor treatment against the development of sarcoidosis.

Healthcare resource utilization among patients with cold agglutinin disease in Denmark.

OBJECTIVES: Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia that may manifest in complement-mediated chronic hemolytic anemia, profound fatigue, and transient agglutination-mediated circulatory symptoms. This study compared the healthcare resource utilization (HRU) of patients with CAD with a matched non-CAD comparison cohort using national Danish health registry data. METHODS: All cases of CAD were identified from 1 January 1999 to 30 June 2016, in the Danish National Patient Registry using the International Classification of Diseases, Tenth Revision, discharge diagnosis codes. A subcohort of patients with primary CAD was identified based on the absence of secondary predisposing concomitant diseases. CAD cases were matched to individuals without CAD from the general population based on birth year, sex, and 19 disease categories of the Charlson Comorbidity Index. Comparative analyses assessed inpatient hospitalizations, outpatient clinic visits, emergency room visits, transfusion use, and expensive drug use between cohorts 6 months before and 12 months after the admission date of the first hospital visit with CAD diagnosis (index date). RESULTS: A total of 104 patients with CAD were matched to 1003 comparison cohort members. Throughout the 12 months after the index date, patients with CAD were more likely to have at least one inpatient hospitalization (odds ratio [OR], 3.9; 95% confidence interval [CI], 2.5-6.0), outpatient clinic visit (OR, 17.2; 95% CI, 6.8-43.1), and blood transfusion (OR, 93.0; 95% CI, 33.3-259.8) than matched comparisons. HRU was similarly higher among patients with CAD than matched comparisons during the 6 months before the index date. Findings were similar among patients with primary CAD. CONCLUSIONS: Characterization of HRU among European patients with CAD has not previously been conducted. This study shows that patients with CAD utilize significant resources in Denmark. Increased HRU uses among patients with CAD before diagnosis presents opportunities for earlier diagnosis and management.

Survival in patients diagnosed with castration-resistant prostate cancer: a population-based observational study in Sweden.

Background: This study investigated prostate cancer (PC)-specific survival and overall survival (OS) in a population-based castration-resistant PC (CRPC) cohort.Methods: Data from Stockholm Prostate-Specific Antigen (PSA) and Biopsy Register patients with increasing PSA despite gonadotropin-releasing hormone treatment or surgical castration (n = 1,712) included PSA values and biopsies from 2003 to 2015 and were linked to the National Prostate Cancer Register and Prescribed Drug Register. Kaplan-Meier method estimated PC-specific survival and OS, stratified by metastasis at PC diagnosis, and Cox regression estimated hazard ratios (HRs) for Gleason score and T-stage at PC diagnosis and for age and calendar period at CRPC onset by metastasis status at diagnosis.Results: Median OS after CRPC onset was 23.2 months (95% CI = 21.0-25.9) among patients without metastases (M0) at primary diagnosis, and 13.2 months (11.3-14.5) among patients with metastases (M1). Median PC-specific survival from CRPC onset was 30.3 (27.5-34.1) months and 13.3 (12.1-15.8) months for M0 and M1 patients, respectively. Biopsy Gleason score ≥ 8 was associated with higher all-cause mortality than ≤6 (HR = 2.07 [95% CI = 1.43-3.01]) and PC-specific mortality (2.07 [1.27-3.40]) after CRPC among patients with M0 disease. Patients developing CRPC from 2012 onward had lower all-cause mortality (HR = 0.71 [95% CI = 0.60-0.85] [M0]; 0.60 [0.47-0.77] [M1]) and PC-specific mortality (0.73 [0.57-0.94] [M0]; 0.62 [0.46-0.84] [M1]) compared with those prior to 2012.Conclusions: M1 disease at PC diagnosis was associated with worse survival after CRPC onset versus M0. Higher Gleason score at diagnosis was associated with higher mortality after CRPC onset in M0 patients at diagnosis.

Survival outcomes in myelofibrosis patients treated with ruxolitinib: A population-based cohort study in Sweden and Norway.

OBJECTIVE: To estimate survival in Swedish and Norwegian myelofibrosis (MF) patients who received ruxolitinib. METHODS: Swedish and Norwegian patients with MF diagnosis in the National Cancer Registries (Sweden: 2001-2015; Norway: 2002-2016) and ≥1 record of ruxolitinib in the Prescribed Drug Registries (2013-2017) were included. Patients were followed from ruxolitinib initiation until death or end of follow-up; those who discontinued ruxolitinib were followed from ruxolitinib discontinuation. Relative survival (RS) and excess mortality rate ratios (EMRRs) were calculated vs a matched general population. Average loss in life expectancy (LEL) was predicted using flexible parametric models. RESULTS: Among patients who initiated ruxolitinib (n = 190), 1- and 4-year RS were 0.80 (95% confidence interval [CI]: 0.74, 0.86) and 0.52 (95% CI: 0.42, 0.64), respectively, and LEL was 11 years. EMRR was greater in patients aged >70 vs <60 years (3.16; 95% CI: 1.34-7.40). Among patients who discontinued ruxolitinib (n = 71), median RS was 16.0 months (95% CI: 6.3, NE), and LEL was 12 years. After ruxolitinib treatment discontinuation, Swedish patients (n = 37) received glucocorticoids, hydroxyurea, busulfan, danazol and lenalidomide. CONCLUSION: Swedish and Norwegian MF patients who discontinued ruxolitinib had dismal survival outcomes and limited subsequent treatment options, highlighting the need for improved therapies.

Methods for time-varying exposure related problems in pharmacoepidemiology: An overview.

PURPOSE: Lack of control for time-varying exposures can lead to substantial bias in estimates of treatment effects. The aim of this study is to provide an overview and guidance on some of the available methodologies used to address problems related to time-varying exposure and confounding in pharmacoepidemiology and other observational studies. The methods are explored from a conceptual rather than an analytical perspective. METHODS: The methods described in this study have been identified exploring the literature concerning to the time-varying exposure concept and basing the search on four fundamental pharmacoepidemiological problems, construction of treatment episodes, time-varying confounders, cumulative exposure and latency, and treatment switching. RESULTS: A correct treatment episodes construction is fundamental to avoid bias in treatment effect estimates. Several methods exist to address time-varying covariates, but the complexity of the most advanced approaches-eg, marginal structural models or structural nested failure time models-and the lack of user-friendly statistical packages have prevented broader adoption of these methods. Consequently, simpler methods are most commonly used, including, for example, methods without any adjustment strategy and models with time-varying covariates. The magnitude of exposure needs to be considered and properly modelled. CONCLUSIONS: Further research on the application and implementation of the most complex methods is needed. Because different methods can lead to substantial differences in the treatment effect estimates, the application of several methods and comparison of the results is recommended. Treatment episodes estimation and exposure quantification are key parts in the estimation of treatment effects or associations of interest.