[Clinical courses and costs for hospitalizations of potentially immunocompromised COVID-19 patients in Germany]. / Klinische Verläufe und Kosten für Hospitalisierungen von COVID-19-Patienten mit potenziell eingeschränktem Immunsystem in Deutschland.

BACKGROUND: Patients at increased risk of inadequate immune response to COVID-19 vaccinations due to their underlying disease or therapy are potentially vulnerable to severe COVID-19 courses. The aim is to assess the population size, clinical courses and hospitalization costs of these patients in Germany. METHODS: This retrospective cohort study is based on extrapolations of a representative sample of statutory health insurance (SHI) claims data from 2020. Clinical COVID-19 courses, hospitalization costs and durations are compared between the insured group at increased risk for inadequate immune response to COVID-19 vaccinations (risk group) and the insured group without this risk. RESULTS: There are approximately 1.82 million SHI-insured individuals in the risk group, of whom an estimated 240 000 insured individuals do not develop a humoral immune response after 3 COVID-19 vaccinations. The risk group shows higher proportions with COVID-19 (relative risk [RR] 1.21; 95 % confidence interval [95 % CI] 1.20-1.23), hospitalizations for COVID-19 (RR 3.40; 95 % CI 3.33-3.48), hospitalizations for COVID-19 with intensive care treatment (RR 1.36; 95 % CI 1.30-1.42), and mortality (RR 5.14; 95 % CI 4.97-5.33) compared with the group without risk. In addition, hospitalizations in the risk group are on average 18 % longer (15.36 days vs. 13.00 days) and 19 % more expensive (12 371 € vs. 10 410 €). Expected hospitalization costs in the risk group are four times greater than in the group without risk (4115 € vs. 1017 €). CONCLUSIONS: The risk group is vulnerable to COVID-19 and requires additional resources in the German hospital sector. This results in a need for further protective measures. Further studies are needed to evaluate the impact of different viral variants, active and passive immunizations, and therapies on clinical COVID-19 courses and their costs.

The Impact of Systemic Lupus Erythematosus Flares on Clinical and Economic Outcomes: The CHAMOMILE Claims Database Study in Germany.

INTRODUCTION: CHAMOMILE (CHaracteristics and impact of flares on clinicAl and econoMic OutcoMes In patients with systemic Lupus Erythematosus [SLE]) examined how flares in the year of SLE diagnosis impact future disease activity and damage, productivity, healthcare resource utilization (HCRU), and costs in patients with SLE in Germany. METHODS: CHAMOMILE was a retrospective cohort study of adults with an SLE diagnosis in the German Sickness Fund Database from 1 July 2010 to 31 December 2013. Patients were classified according to their greatest flare severity during the baseline year (none, mild, or moderate/severe). The number and severity of flares were assessed annually over 5-8.5 follow-up years, along with SLE organ/system damage, treatments, work disability, and HCRU metrics. RESULTS: Of 2088 patients (84.6% female; mean age [standard deviation] 51.4 [16.1] years; mean follow-up 6.8 [2.1] years), 34.3% (n = 716) were flare-free, 29.8% (n = 622) had mild flares, and 35.9% (n = 750) had moderate/severe flares at baseline. Baseline flare severity was related to future flares: rates during follow-up were higher in patients with moderate/severe baseline flares compared with those with mild or no baseline flares (89.6 vs 78.5 and 44.2 flares/100 patient years, respectively). Overall, 80.2% (n = 1675) of patients received glucocorticoids at least once during baseline and follow-up. Patients' HCRU was generally greatest in their baseline year. Costs were highest in patients with moderate/severe baseline flares. CONCLUSION: Baseline flare severity provided insight into a patient's disease course and the clinical and economic burden of SLE over time, highlighting the ramifications of uncontrolled disease for patients with SLE.

Real-World Burden of Immunosuppressant-Treated Lupus Nephritis: A German Claims Database Analysis.

INTRODUCTION: This retrospective cohort study (GSK213737) aimed to characterize treatment patterns, healthcare resource utilization (HCRU), and costs in patients with lupus nephritis (LN) initiating immunosuppressant therapy in clinical practice in Germany, to better understand the full picture of the real-world burden of LN. METHODS: Adult patients with LN who initiated mycophenolate mofetil (MMF), intravenous cyclophosphamide (CYC), azathioprine (AZA), tacrolimus, cyclosporin A, or rituximab therapy in 2011-2017 (index therapy) were identified from the Betriebskrankenkassen German Sickness Fund database. Treatment patterns, including immunosuppressant discontinuations, and therapy switches, were assessed (maximum follow-up 4 years). Corticosteroid use, HCRU, and total economic costs were also evaluated. HCRU and costs were compared with matched controls (individuals without systemic lupus erythematosus [SLE]/LN matched by age, sex, and baseline Charlson Comorbidity Index). RESULTS: Among 334 patients with LN, the median (interquartile range) duration of index immunosuppressant therapy use was 380.5 (126, 1064) days. Of those patients with 4 years complete enrollment, 70.8% had ≥ 1 discontinuation and 28.8% switched therapy. While most patients (71.2%) received only one immunosuppressant, gaps in treatment were common. After 1 year of follow-up, 41.6% of patients had a prednisone-equivalent corticosteroid dose of ≥ 7.5 mg/day. Patients with LN had greater HCRU use for most categories assessed and increased mean total costs per person-year versus controls (€15,115.99 versus €4,081.88 in the first year of follow-up). CONCLUSIONS: This real-world analysis demonstrated the considerable burden of immunosuppressant-treated LN in Germany, with a high rate of discontinuations, frequent use of high-dose corticosteroids, and substantial HCRU/costs.

Impact of COPD on mortality: An 8-year observational retrospective healthcare claims database cohort study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality. Here we present a large observational study on the association of COPD and exacerbations with mortality (AvoidEx Mortality). METHODS: A real-world, observational cohort study with longitudinal analyses of German healthcare claims data in patients ≥40 years of age with a COPD diagnosis from 2011 to 2018 (n = 250,723) was conducted. Patients entered the cohort (index date) upon the first COPD diagnosis. To assess the impact of COPD on all-cause death, a propensity score-matched control group of non-COPD patients was constructed. The number and severity of exacerbations during a 12-month pre-index period were used to form subgroups. For each exacerbation subgroup the exacerbations during 12 months prior to death were analysed. RESULTS: COPD increases the all-cause mortality risk by almost 60% (HR 1.57 (95% CI 1.55-1.59)) in comparison to matched non-COPD controls, when controlling for other baseline covariates. The cumulative risk of death after 8 years was highest in patients with a history of more than one moderate or severe exacerbation. Among all deceased COPD patients, 17.2% had experienced a severe, and 34.8% a moderate exacerbation, within 3 months preceding death. Despite increasing exacerbation rates towards death, more than the half of patients were not receiving any recommended pharmacological COPD therapy in the year before death. CONCLUSION: Our study illustrates the impact of COPD on mortality risk and highlights the need for consequent COPD management comprising exacerbation assessment and treatment.

Comorbidities, healthcare resource utilization & treatment pattern among patients with prurigo nodularis, compared to a benchmark in Germany: A real-world evidence claims data study.

BACKGROUND: Prurigo nodularis (PN) is a rare chronic inflammatory skin disease with a high disease burden, but data on clinical and economic burden are still scarce. OBJECTIVE: To describe the real-world epidemiologic, clinical and therapeutic characteristics and related economic burden of patients with PN compared to a benchmark population in Germany. METHODS: This retrospective study was based on an excerpt of German Statutory Health Insurance data of patients with an initial PN diagnosis between 2012 and 2016. PN cohort contained no record of PN in eight quarters before the index quarter and was followed up for eight quarters (unless deceased). Benchmark cohort without PN was calculated using direct standardization and 1:1 matching to PN cohort. RESULTS: Out of 4,536,002 insured patients, 2309 incident patients with PN were identified and matched to the benchmark cohort out of 3,018,382 patients without PN. Patients were mostly between 45 and 80 years when diagnosed with PN. Higher comorbidity rates were reported for PN than benchmark, with a rising disease burden at follow-up. Most patients with PN (91.3%) were diagnosed outpatient and had >50% more outpatient visits than the benchmark cohort. Hospitalization rates were higher in PN (53.9%) versus benchmark (35.1%), yielding twice longer mean hospital stays for PN (12 days) compared to benchmark (6 days) (p < 0.001). The most common initial therapy for patients with PN was topical corticosteroids (47.6%); ≥10% of patients were treated with antidepressants, antihistamines or systemic corticosteroids. Therapy rates were higher for PN compared to benchmark (p < 0.001). Mean initial costs were twofold higher in PN versus benchmark for outpatient, inpatient and drugs. During follow-up, an increase of >70% in mean PN costs compared to benchmark was identified for outpatient, inpatient and concomitant treatments (p < 0.001). CONCLUSION: This study highlights the significantly higher clinical and economic burden incurred by PN compared to benchmark patients in Germany, reflecting the unmet medical need for PN.

Real-world effectiveness of osteoporosis treatments in Germany.

This observational study assessed the impact on the fracture incidence of osteoporosis medications in postmenopausal women in Germany. Continued treatment with osteoporosis medications was associated with reductions of fracture rates in a real-world setting. PURPOSE: The efficacy of osteoporosis medications has been demonstrated in clinical trials, but a lack of evidence exists of their real-world effectiveness. This real-world study assessed the treatment patterns and impact on the fracture incidence of osteoporosis medications in postmenopausal women in Germany. METHODS: This cohort study used data from the WIG2 benchmark database, a German anonymised healthcare claims database. All women ≥ 50 years of age with ≥ 1 prescription for osteoporosis medication between 1 January 2013 and 31 December 2017 were included. The primary outcome was treatment effectiveness, evaluated as the change in fracture incidence after initiating treatment. Fracture types included all fractures, clinical vertebral, hip and wrist/forearm. Fracture incidence was assessed during the early-treatment period (0-3 months) and the on-treatment period (4-12, 13-24, 25-36 and 37-48 months). RESULTS: Baseline covariates and treatment patterns were determined for 41,861 patients. The median duration of therapy was longer with denosumab (587 days) than with intravenous ibandronate (451 days), intravenous zoledronate (389 days) or oral bisphosphonates (258 days). The baseline incidence rate of all fractures was higher in patients receiving denosumab than in those receiving other treatments (87.6, 78.2, 56.6 and 66.0 per 1000 person-years for denosumab, oral bisphosphonates, intravenous ibandronate and intravenous zoledronate, respectively). Rates of all fractures declined with continued denosumab (by 38%, 50%, 56% and 67% at 12, 24, 36 and 48 months, respectively) and oral bisphosphonates (by 39%, 44%, 49% and 42%, respectively) treatment. CONCLUSION: Continued treatment with osteoporosis medications was associated with reductions of fracture rates in a real-world setting.

COPD Exacerbation History and Impact on Future Exacerbations - 8-Year Retrospective Observational Database Cohort Study from Germany.

Background: Recent studies evaluating the predictive value of different variables on future exacerbations suggest exacerbation history as the strongest predictor. We examined the effect of exacerbation history on subsequent events in a large sample population with over 250,000 COPD patients using up to 8 years of longitudinal healthcare data from Germany. Methods: Patients 40 years or older with any COPD diagnosis in primary or secondary care were included from 2011 to 2017 (index period) from healthcare insurance claims (Germany; WIG2 research database), with 12 months before index date as baseline and at least 12-month follow-up. Exacerbations during baseline were defined as moderate (treatment with oral corticosteroids or antibiotics, J01AA, J01CA) or severe (emergency visit or hospitalization). Results: Patients without (category A), with one moderate (category B), or with either one severe or several baseline exacerbations (category C) experienced an average of 0.9 (CI 0.9-0.9), 1.9 (CI 1.9-1.9), and 6.3 (CI 6.1-6.3) exacerbations during the first 3 years of follow-up, respectively. By 8 years, 87.0% (CI 86.6-87.4), 70.5% (CI 69.9-71.0) and 49.1% (CI 48.9-49.3) of category C, B and A patients had experienced a subsequent exacerbation. Conclusion: Baseline exacerbations increased the likelihood of, and reduced time to subsequent exacerbations. Even patients without baseline exacerbations experienced exacerbations within three years, emphasizing the importance of adequate treatment in patients with less severe disease presentation as well.

The Burden of Systemic Lupus Erythematosus in Germany: Incidence, Prevalence, and Healthcare Resource Utilization.

INTRODUCTION: We evaluated incidence, prevalence, costs, and healthcare utilization associated with systemic lupus erythematosus (SLE) in patients in Germany. METHODS: Adult patients with SLE were identified from the German Betriebskrankenkassen (BKK) health insurance fund database between 2009 and 2014. SLE incidence and prevalence were calculated for each year and extrapolated (age and sex adjusted) to the German population. The 2009 SLE population was followed through 2014. Healthcare utilization and costs for patients with SLE were calculated and compared with controls matched by age, sex, and baseline Charlson Comorbidity Index scores. RESULTS: This analysis included 1160 patients with SLE. Estimated SLE incidence between 2009 and 2014 ranged from 4.59 to 6.89 per 100,000 persons and prevalence ranged from 37.32 to 47.36 per 100,000. SLE incidence in Germany in 2014 was 8.82 per 100,000 persons; prevalence was 55.80 (corrected for right-censored data). At baseline, 12.8, 41.7, and 45.5% of patients were categorized as having mild, moderate, and severe SLE, respectively. Patients with SLE had greater mean (standard deviation [SD]) annual medical costs compared with matched controls 1 year after index diagnosis (€6895 [14,424] vs. €3692 [3994]; P < 0.0001) and in subsequent years. Patients with moderate or severe SLE had significantly more hospitalizations, outpatient visits, and prescription medication use compared with matched controls. Mean annual costs for 5 years ranged from €1890 to 3010, €4867 to 5876, and €8396 to 10,001 for patients with mild, moderate, and severe SLE, respectively. CONCLUSIONS: SLE incidence in Germany increased 1.4-fold over 5 years. Patients with SLE have higher healthcare costs, and costs increase with baseline severity. Early and effective treatments may delay progression and reduce the burden of SLE.

Epidemiology of Prurigo Nodularis compared with Psoriasis in Germany: A Claims Database Analysis.

Prurigo nodularis is an itchy skin disease with unknown epidemiology. This study aimed to describe the epidemiology of prurigo nodularis compared with that of psoriasis. The German sickness fund claims database, with 2,783,175 continuously insured patients, included 1,720 patients diagnosed with prurigo nodularis and 51,390 with psoriasis. Patients with prurigo nodularis were averagely 8 years older than psoriasis patients and more often were women (p < 0.001). Annual incidence was a constant 0.02% in prurigo nodularis, and decreased steadily from 0.53 to 0.42% in psoriasis; cumulative incidence was 0.1% for prurigo nodularis and 1.9% for psoriasis. Prevalence was 0.1% for prurigo nodularis and 4.7% for psoriasis, with a 1-year mortality of 5.4% for prurigo nodularis and 1.2% for psoriasis (p < 0.001). The most frequent pre-existing comorbidities in patients with prurigo nodularis were inflammatory dermatoses and depression. This epidemiological study found a low prevalence of prurigo nodularis, manifesting different demographics and comorbidities compared with psoriasis.

Using Data from a Sickness Fund Claims Database to Assess the Treatment Patterns and Healthcare Resource Utilization among Patients with Metastatic Renal Cell Carcinoma in Germany.

OBJECTIVES: To characterize real-world prescribing patterns and their clinical and healthcare resource utilization (HRU) implications in patients with metastatic renal cell carcinoma (mRCC) treated in Germany. METHODS: Eligible individuals were enrolled in the "Bundesverband der Betriebskrankenkassen" claims database and received targeted mRCC therapy between 1 January 2008 and 31 December 2016. Prescribing patterns and HRU were characterized by treatment line and summarized by descriptive statistics. Proxy progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier curves. RESULTS: 536 patients receiving mRCC treatment were included. The median treatment duration was 4.2 months (interquartile range [IQR]: 1.7-9.3) for first-line therapy and 3.8 months (IQR: 1.7-9.1) for second-line therapy. Median PFS and OS estimates were similar for the first- and second-line treatments: PFS, 7.4 versus 7.2 months; OS, 14.9 versus 13.6 months. Mean HRU costs were higher for patients receiving first-line therapy (€7,253.2) compared with those receiving second-line therapy (€6,242.9). Exploratory stratification of outcomes by centre expertise suggested a possible trend towards improved OS in the 10 most experienced centres versus all -others: first-line, 18.4 versus 13.2 months; second-line, 16.4 versus 12.4 months. CONCLUSIONS: In routine care, German clinicians make rational prescribing decisions; possible variations in outcomes between centres warrant further investigation.

How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study.

AIMS: Enrollment criteria vary substantially among cardiovascular outcome trials (CVOTs) of sodium-glucose cotransporter-2 inhibitors (SGLT-2is), which impacts the relationship between a trial population and the general type 2 diabetes (T2D) population. The aim of this study was to evaluate the representativeness of four SGLT-2i CVOTs of a general T2D population. METHODS: T2D patients from Germany, The Netherlands, Norway and Sweden were included in the study. Given the available data per country, key inclusion and exclusion criteria were defined by diagnoses, procedures and drug treatments to facilitate comparability among countries. Representativeness was determined by dividing the number of patients fulfilling the key enrolment criteria of each CVOT (CANVAS, DECLARE-TIMI 58, EMPA-REG OUTCOME, VERTIS-CV) by the total T2D population. RESULTS: In 2015, a total T2D population of 803 836 patients was identified in Germany (n = 239 485), in The Netherlands (n = 36 213), in Norway (n = 149 782) and in Sweden (n = 378 356). These populations showed a 25% to 44% cardiovascular (CV) disease baseline prevalence and high CV-preventive drug use (>80%). The general T2D population had less prevalent CV disease and patients were slightly older than those included in the CVOTs. The DECLARE-TIMI 58 trial had the highest representativeness, 59% compared to the general T2D population, and this representativeness was almost 2-, 3- and 4-fold higher compared to the CANVAS (34%), EMPA-REG OUTCOME (21%) and VERTIS-CV (17%) trials, respectively. CONCLUSIONS: In large T2D populations within Europe, consistent patterns of representativeness of CVOTs were found when applying the main enrolment criteria. The DECLARE-TMI 58 trial had the highest representativeness, indicating that it included and examined patients who are most representative of the general T2D patients in the studied countries.

Improvement of Hepatic and Extrahepatic Complications from Chronic Hepatitis C After Antiviral Treatment: A Retrospective Analysis of German Sickness Fund Data.

INTRODUCTION: German data regarding the economic burden of chronic hepatitis C (CHC) and potential benefits of CHC treatment are limited. To address this issue, we evaluated the role of treatment in mitigating the economic burden of hepatic and extrahepatic complications (EHCs) from CHC virus infection in Germany. METHODS: This retrospective, cross-sectional study used claims data from the Betriebskrankenkasse German sickness fund (2007-2014) to assess the medical costs of hepatic complications and EHCs, including conditions that are prevalent and behavioral factors associated with CHC. All-cause costs, medical costs related to hepatic and EHCs, and CHC-related and non-CHC-related pharmacy costs (adjusted to the 2016 euro rate) were calculated and compared between CHC patients' treated (n = 1714) and untreated time (n = 7124) and CHC patients that initiated treatment early (i.e., without cirrhosis; n = 1552) vs. late (i.e., with cirrhosis; n = 162). RESULTS: CHC treatment was associated with an average adjusted savings of €1885 in annual all-cause medical costs per patient, with a significant proportion attributed to EHC-related cost savings (adjusted difference, €1363; P < 0.01). Although initiating CHC treatment early was economically beneficial compared with initiating treatment late, the total cost savings were not significantly different (annual average adjusted difference, €3831; P = 0.27). However, nearly 60% of these savings were EHC related (adjusted difference, €2255; P < 0.01). CONCLUSION: CHC is associated with a significant economic burden in Germany, largely due to EHCs. Antiviral treatment may reduce the burden of CHC and result in significant cost savings, even when initiated at earlier stages of liver disease. FUNDING: AbbVie Inc.

Clinical and Economic Burden of Hepatic and Extrahepatic Complications from Chronic Hepatitis C: A Retrospective Analysis of German Sickness Fund Data.

INTRODUCTION: German data regarding the burden of complications from chronic hepatitis C (CHC) virus infection are limited. To address this issue, this study evaluates the clinical and economic burden of hepatic and extrahepatic complications (EHCs) associated with CHC in Germany. METHODS: This retrospective, cross-sectional study used claims data from the Betriebskrankenkasse German sickness fund (2007-2014) to assess the risks and medical costs of hepatic complications and EHCs, including conditions that are prevalent and behavioral factors associated with CHC. Prevalence, incidence, and risks were calculated for 1:1 matched patients with and without CHC (n = 3994). All-cause cost, medical costs related to hepatic and EHCs, as well as CHC-related and non-CHC-related pharmacy costs (adjusted to the 2016 Euro rate), were calculated and compared between 1:5 matched patients with (n = 8425) and without CHC (n = 42,125). RESULTS: Patients with CHC had a 3-fold higher risk for any EHC (OR = 3.0; P < 0.05) and higher EHC-related medical costs (adjusted difference, €1606; P < 0.01) compared with patients without CHC. Total costs (€10,108 vs. €5430), hepatic complication-related medical costs (€1425 vs. €556), EHC-related costs (€3547 vs. €1921), CHC-related pharmacy costs (€577 vs. €116), and non-CHC-related pharmacy costs (€3719 vs. €1479) were all significantly greater for patients with CHC compared with patients without CHC. EHC-related medical costs were a major contributor to the higher all-cause medical (84.4%) and total (44.3%) cost differences between patients with CHC and the matched sample of patients without CHC. CONCLUSION: CHC is associated with substantial clinical and economic burden in Germany, largely due to hepatic complications and EHCs. FUNDING: Abbvie Inc.

Design of a new fluorescent cofactor for DNA methyltransferases and sequence-specific labeling of DNA.

Sequence-specific labeling of DNA is of immense interest for analytical and functional studies of DNA. We present a novel approach for sequence-specific labeling of DNA using a newly designed fluorescent cofactor for the DNA methyltransferase from Thermus aquaticus (M.TaqI). Naturally, M.TaqI catalyzes the nucleophilic attack of the exocyclic amino group of adenine within the double-stranded 5'-TCGA-3' DNA sequence onto the methyl group of the cofactor S-adenosyl-L-methionine (AdoMet) leading to methyl group transfer. The design of a new fluorescent cofactor for covalent labeling of DNA was based on three criteria: (1) Replacement of the methionine side chain of the natural cofactor AdoMet by an aziridinyl residue leads to M.TaqI-catalyzed nucleophilic ring opening and coupling of the whole nucleoside to DNA. (2) The adenosyl moiety is the molecular anchor for cofactor binding. (3) Attachment of a fluorophore via a flexible linker to the 8-position of the adenosyl moiety does not block cofactor binding. According to these criteria the new fluorescent cofactor 8-amino[1''-(N''-dansyl)-4''-aminobutyl]-5'-(1-aziridinyl)-5'-deoxyadenosine (3) was synthesized. 3 binds about 4-fold better than the natural cofactor AdoMet to M.TaqI and is coupled with a short duplex oligodeoxynucleotide by M.TaqI. The identity of the expected modified nucleoside was verified by electrospray ionization mass spectrometry after enzymatic fragmentation of the product duplex. In addition, the new cofactor 3 was used to sequence-specifically label plasmid DNA in a M.TaqI-catalyzed reaction.

Rapid parallel mutation scanning of gene fragments using a microelectronic protein-DNA chip format.

We have developed a method for the de novo discovery of genetic variations, including single nucleotide polymorphisms and mutations, on microelectronic chip devices. The method combines the features of electronically controlled DNA hybridisation on open-format microarrays, with mutation detection by a fluorescence-labelled mismatch- binding protein. Electronic addressing of DNA strands to distinct test sites of the chip allows parallel analysis of several individuals, as demonstrated for mutations in different exons of the p53 gene. This microelectronic chip-based mutation discovery assay may substitute for time-consuming sequencing studies and will complement existing technologies in genomic research.

Coupling of a Nucleoside with DNA by a Methyltransferase.

How to outwit a methyltransferase: Methyltransferases (Mtases) catalyze the transfer of the activated methyl group from the cofactor S-adenosyl-L-methionine (1) to acceptors R within a large variety of biomolecules. Through the use of the cofactor analogue 2 a whole nucleoside was coupled to DNA in a Mtase-catalyzed reaction.