Context Pheochromocytoma and sympathetic paraganglioma (PPGL) are rare catecholamine-secreting tumors but recent studies suggest increasing incidence. Traditionally, PPGL are described to present with paroxysmal symptoms and hypertension, but existing data on clinical presentation of PPGL come from referral centers. Objective We aimed to describe time trends in clinical presentation and incidence of PPGL in a population-based study. Methods We conducted a nationwide retrospective cohort study of a previously validated cohort of 567 patients diagnosed with PPGL in Denmark 1977-2015. We collected clinical data from medical records of a geographic subcohort of 192 patients. We calculated age-standardized incidence rates (SIRs) and prevalence for the nationwide cohort and descriptive statistics on presentation for the subset with clinical data. Results SIRs increased from 1.4 (95% CI 0.2-2.5) per million person-years in 1977 to 6.6 (95% CI 4.4-8.7) per million person-years in 2015, corresponding to a 4.8-fold increase. The increase was mainly due to incidentally found tumors that were less than 4 cm and diagnosed in patients older than 50 years with no or limited paroxysmal symptoms of catecholamine excess. On December 31, 2015, prevalence of PPGL was 64.4 (CI 95% 57.7-71.2) per million inhabitants. Of 192 patients with clinical data, 171 (89.1%) had unilateral pheochromocytoma, while unilateral paraganglioma (n = 13, 6.8%) and multifocal PPGL (n = 8, 4.2%) were rare. Conclusion Incidence of PPGL has increased 4.8-fold from 1977 to 2015 due to a “new” group of older patients presenting with smaller incidentally found PPGL tumors and few or no paroxysmal symptoms.

BackgroundPheochromocytoma and catecholamine-secreting paraganglioma (PPGL) are rare but potentially life-threatening tumors. We aimed to validate diagnosis codes for PPGL in the Danish National Patient Registry, the Danish National Pathology Registry, and the Danish Registry of Causes of Death and to create a national cohort of incident PPGL patients by linking these three registries.Patients and methodsWe obtained data from the three abovementioned registries for all individuals registered with pheochromocytoma or catecholamine hypersecretion in Denmark during 1977–2016 (average population 5.30 million). We then reviewed health records for all individuals living in the North Denmark Region and Central Denmark Region (average population 1.75 million) to validate the diagnosis of PPGL. We tested a number of algorithms for accurately identifying true cases of PPGL to maximize positive predictive values (PPVs) and completeness. The best algorithm was subsequently validated in an external sample.ResultsWe identified 2626 individuals with a PPGL diagnosis code in Denmark, including 787 (30.0%) in the North Denmark Region and Central Denmark Region. In this subsample, we retrieved the health records of 771/787 (98.0%) individuals and confirmed 198 incident PPGL patients (25.3%). The PPV of PPGL diagnosis codes was 21.7% in the Danish National Patient Registry, 50.0% in the Danish Registry of Causes of Death, and 79.5% in the Danish National Pathology Registry. By combining patterns of registrations in the three registries, we could increase the PPV to 93.1% (95% confidence interval [CI]: 88.5–96.3) and completeness to 88.9% (95% CI: 83.7–92.9), thus creating a national PPGL cohort of 588 patients. PPV for the optimal algorithm was 95.3% (95% CI: 88.5–98.7) in the external validation sample.ConclusionDiagnosis codes for pheochromocytoma had low PPV in several individual health registries. However, with a combination of registries we were able to identify a near-complete national cohort of PPGL patients in Denmark, as a valuable source for epidemiological research.

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BackgroundSystemic lupus erythematosus (SLE) has been associated with more than 100 genetic loci. This parallels positively to the clinical diversity that is reflected by the classification of SLE.ObjectivesWe aimed to investigate associations between disease manifestations of SLE and risk gene variants relevant to Danish subjects of European ancestry.MethodsWe included 427 SLE patients of European ancestry similar to previous reports.[1] We also included 89,699 controls from the Danish Blood Donor Study Genomic Cohort. SLE risk loci in this population were identified by genome-wide association methodology and hereafter correlated to cumulative occurrence of SLE classification items.ResultsFourteen variants mapped to the following genes: NCF2, STAT4, TNPO3/TPI1P2, IRF5, and ITGAM, were significantly associated (p<5E-8) with SLE.The five lead variants were associated (p<0.05) with the following manifestations; NCF2: proteinuria and anti-phospholipid antibodies, STAT4: arthritis, serositis, neurologic disorder, lymphopenia, and anti-Smith antibodies, IRF5: seizures and proteinuria, TNPO3: proteinuria, and ITGAM: photosensitivity (Table 2).ConclusionOur findings support the future use of select, relevant genetic markers in predicting various SLE phenotypes.References[1]Leffers HCB, Troldborg A, Voss A, et al. Smoking associates with distinct clinical phenotypes in patients with systemic lupus erythematosus: a nationwide Danish cross-sectional study. Lupus Sci Med 2021;8(1).Table 1.Associations between five SLE risk loci and specific disease manifestations in 427 Danish patients with SLE*.NCF2STAT4IRF5TNPO3ITGAMrs17849502_Trs7574865_Trs4728142_Ars13239597_Ars11860650_TN (%)Malar rash233 (55%)1.28 (0.84-1.96)0.83 (0.62-1.11)1.01 (0.74-1.38)1.44 (0.97-2.12)1.14 (0.80-1.61)Discoid rash46 (11%)1.49 (0.81-2.73)0.90 (0.56-1.45)1.01 (0.62-1.66)1.16 (0.63-2.12)0.76 (0.42-1.41)Photosensitivity219 (51%)0.96 (0.63-1.46)1.09 (0.81-1.47)0.98 (0.71-1.34)0.84 (0.57-1.25)0.67 (0.47-0.97)Oral ulcers132 (31%)0.96 (0.61-1.50)0.90 (0.65-1.23)0.83 (0.60-1.16)1.30 (0.87-1.96)1.43 (0.99-2.05)Non-erosive Arthritis342 (80%)0.84 (0.52-1.37)1.49 (1.02-2.18)0.93 (0.63-1.36)1.04 (0.64-1.68)1.16 (0.74-1.80)Serositis-Pleuritis124 (29%)0.63 (0.38-1.05)1.38 (1.01-1.89)1.22 (0.87-1.72)0.85 (0.56-1.29)0.84 (0.57-1.24)-Pericarditis72 (17%)0.75 (0.41-1.40)1.35 (0.93-1.96)1.05 (0.70-1.58)1.15 (0.70-1.89)1.09 (0.70-1.72)Persistent proteinuria158 (37%)1.63 (1.07-2.49)1.08 (0.80-1.46)0.68 (0.49-0.94)1.74 (1.16-2.61)1.09 (0.76-1.57)Neurologic disorder-Seizures23 (5%)1.58 (0.75-3.35)1.49 (0.80-2.76)2.10 (1.04-4.25)0.61 (0.26-1.44)0.93 (0.42-2.06)-Psychosis8 (2%)0.76 (0.097-5.87)2.77 (0.94-8.15)0.35 (0.10-1.23)0 (0)2.96 (0.85-10.3)Haematologic disorder-Haemolytic anaemia38 (9%)0.78 (0.34-1.76)1.37 (0.85-2.22)0.75 (0.44-1.29)1.11 (0.57-2.19)1.24 (0.70-2.20)-Leukopenia130 (30%)1.04 (0.67-1.61)1.19 (0.87-1.63)1.00 (0.72-1.39)0.90 (0.60-1.37)0.94 (0.64-1.37)-Lymphopenia228 (53%)0.95 (0.63-1.44)1.35 (1.01-1.81)0.95 (0.70-1.29)1.16 (0.79-1.70)1.09 (0.77-1.54)-Thrombocytopenia102 (24%)1.42 (0.91-2.22)0.84 (0.60-1.18)0.83 (0.58-1.18)1.35 (0.86-2.11)0.91 (0.60-1.37)Immunologic disorder-anti-DNA ab.330 (77%)0.69 (0.44-1.09)1.02 (0.72-1.44)0.94 (0.65-1.35)0.97 (0.62-1.53)1.08 (0.71-1.65)-anti-Smith ab.44 (10%)1.44 (0.79-2.64)1.58 (1.00-2.49)1.23 (0.73-2.07)1.47 (0.80-2.69)1.07 (0.61-1.84)-anti-phospholipid ab.183 (43%)1.63 (1.07-2.49)1.05 (0.79-1.41)0.84 (0.61-1.14)1.14 (0.77-1.68)1.14 (0.80-1.62)* Logistic regression models for each manifestation included all five lead variants (multivariate) and were adjusted for age and sexDisclosure of InterestsHenrik Leffers: None declared, David Westergaard: None declared, Saedis Saevarsdottir: None declared, Ingileif Jonsdottir: None declared, Ole Birger Pedersen: None declared, Anne Troldborg: None declared, Anne Voss: None declared, Salome Kristensen: None declared, Jesper Lindhardsen: None declared, Prabhat Kumar: None declared, Asta Linauskas: None declared, Lars Juul: None declared, Niels Steen Krogh: None declared, Bent Deleuran: None declared, Lene Dreyer Speakers bureau: Speakers bureau: Eli Lilly, Galderma and Janssen, Grant/research support from: from BMS outside the present work, Michael Schwinn: None declared, Lise wegner Thørner: None declared, Lotte Hindhede: None declared, Christian Erikstrup: None declared, Henrik Ullum: None declared, Søren Brunak Shareholder of: SB has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, Kari Stefansson: None declared, Karina Banasik: None declared, Søren Jacobsen: None declared

Background Pheochromocytomas and catecholamine-secreting paragangliomas (PPGL) are rare catecholamine-producing tumors. Due to the rarity, limited data on prognosis exists. Here, we present national data on mortality for radically operated patients compared to the background population over a period of 40 years. Materials and methods We have previously identified a national cohort of 588 PPGL patients diagnosed in Denmark 1977-2016. After excluding 80 patients diagnosed post-mortem, we found that out of 508 patients diagnosed alive, 479 (94%) underwent radical surgery. Each operated patient was matched on birth year, age and sex with 100 random controls from the general population. PPGL patients and comparison cohort members were then followed from date of surgery (or matched index date) to date of death, emigration or 31 st of December 2016. Mortality rate-ratios (MRR) were calculated in patient-comparisons strata using Cox regression and adjusted for Charlson Comorbidity Index (CCI). CCI was determined using diagnosis codes registered before time of PPGL diagnosis (or matched index date). To identify prognostic factors, we obtained health records and analyzed clinical data in a geographic subgroup of patients (N=162). Results Operated PPGL patients had a median age of 55 years (Q1-Q3 42-65) and 56% were female. 26% of PPGL patients had a Charlson Comorbidity Index of 2 or more, compared to only 9% in the comparison cohort, with a higher proportion of patients registered with cardiovascular disease (19% vs 7%), cancer (16% vs 5%) and with diabetes (12% vs 3%). Median follow-up time for patients was 7.2 years (Q1-Q3 3.4-15.6), with 10- and 20-year survival after surgery of 78% (95% CI 73-82) and 64% (95% CI 57-69), respectively. MRR for PPGL patients was 1.8 (95% CI 1.5-2.2) compared to the comparison cohort and 1.4 (95% CI 1.2-1.7) when adjusted for CCI. In the subcohort of PPGL patients with available clinical data (N=162), we found, that patients diagnosed with PPGL due to diagnostic work-up for secondary hypertension (N=27) had the highest mortality after surgery with an adjusted MRR of 3.1 (95% CI 1.7-5.8) compared to these patients’ matched comparison cohorts. Adjusted MRR was 0.9 (95% CI 0.4-1.8, N=49) for patients evaluated for paroxysmal symptoms, 1.0 (95% CI 0.2-4.6, N=16) for patients diagnosed due to hereditary PPGL in family or after syndromic presentation, 1.3 (95% CI 0.7-2.2, N=58) for adrenal incidentalomas, and 2.2 (95% CI 0.9-4.9, N=10) in patients diagnosed due to other causes. Conclusion PPGL patients undergoing radical curative surgery have a higher mortality compared to the background population even when considering their higher comorbidity index at time of diagnosis. Especially patients diagnosed due to work-up for secondary hypertension have an increased mortality. These results indicate that radical surgery might not completely reverse the harmful effects of ...