National registry for patients with inflammatory rheumatic diseases (IRD) infected with SARS-CoV-2 in Germany (ReCoVery): a valuable mean to gain rapid and reliable knowledge of the clinical course of SARS-CoV-2 infections in patients with IRD

Objectives: Patients with inflammatory rheumatic diseases (IRD) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be at risk to develop a severe course of COVID-19. The influence of immunomodulating drugs on the course of COVID-19 is unknown. To gather knowledge about SARS-CoV-2 infections in patients with IRD, we established a registry shortly after the beginning of the pandemic in Germany. Methods Using an online questionnaire (www.COVID19-rheuma.de.), a nationwide database was launched on 30 March 2020, with appropriate ethical and data protection approval to collect data of patients with IRD infected with SARS-CoV-2. In this registry, key clinical and epidemiological parameters-for example, diagnosis of IRD, antirheumatic therapies, comorbidities and course of the infection-are documented. Results Until 25 April 2020, data from 104 patients with IRD infected with SARS-CoV-2 were reported (40 males;63 females;1 diverse). Most of them (45%) were diagnosed with rheumatoid arthritis, 59% had one or more comorbidities and 42% were treated with biological disease-modifying antirheumatic drugs. Hospitalisation was reported in 32% of the patients. Two-thirds of the patients already recovered. Unfortunately, 6 patients had a fatal course. Conclusions: In a short time, a national registry for SARS-CoV2-infected patients with IRD was established. Within 4 weeks, 104 cases were documented. The registry enables to generate data rapidly in this emerging situation and to gain a better understanding of the course of SARS-CoV2-infection in patients with IRD, with a distinct focus on their immunomodulatory therapies. This knowledge is valuable for timely information of physicians and patients with IRD, and shall also serve for the development of guidance for the management of patients with IRD during this pandemic

a European registries collaborative project

Funding: Individual registries had entered into agreements with pharmaceutical companies (AbbVie, BMS, Hospira, MSD, Pfizer, Roche, UCB, Samsung and Eli Lilly). The pharmaceutical companies funding these registers were, however, not involved in the planning of the project, the statistical analyses, the interpretation of the results or the decision to publish.BACKGROUND: Lymphomas comprise a heterogeneous group of malignant diseases with highly variable prognosis. Rheumatoid arthritis (RA) is associated with a twofold increased risk of both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). It is unknown whether treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) affect the risk of specific lymphoma subtypes. METHODS: Patients never exposed to (bionaïve) or ever treated with bDMARDs from 12 European biologic registers were followed prospectively for the occurrence of first ever histologically confirmed lymphoma. Patients were considered exposed to a bDMARD after having received the first dose. Lymphomas were attributed to the most recently received bDMARD. RESULTS: Among 124 997 patients (mean age 59 years; 73.7% female), 533 lymphomas were reported. Of these, 9.5% were HL, 83.8% B-cell NHL and 6.8% T-cell NHL. No cases of hepatosplenic T-cell lymphoma were observed. Diffuse large B-cell lymphoma (DLBCL) was the most frequent B-cell NHL subtype (55.8% of all B-cell NHLs). The subtype distributions were similar between bionaïve patients and those treated with tumour necrosis factor inhibitors (TNFi). For other bDMARDs, the numbers of cases were too small to draw any conclusions. Patients with RA developed more DLBCLs and less chronic lymphocytic leukaemia compared with the general population. CONCLUSION: This large collaborative analysis of European registries has successfully collated subtype information on 533 lymphomas. While the subtype distribution differs between RA and the general population, there was no evidence of any modification of the distribution of lymphoma subtypes in patients with RA treated with TNFi compared with bionaïve patients. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.publishersversionpublishe

Clinical health services research in breast cancer

Ein Ziel der klinischen Versorgungsforschung ist es, die Versorgungsrealität abzubilden und zu analysieren. In dieser kumulativen Habilitationsschrift werden sechs Arbeiten vorgestellt, die mit unterschiedlichen Methoden der Versorgungsforschung klinisch relevante Fragestellung der Therapie des Mammakarzinoms behandeln. Das metastasierte Mammakarzinom zeichnet sich durch einen extrem heterogenen Verlauf aus. Wir haben deshalb zunächst das Ziel gehabt, eine prognostische Einschätzung der Patienten zu dem Zeitpunkt der Sicherung einer Fernmetastasierung mit möglichst einfachen Faktoren zu ermöglichen. In der ersten Arbeit wurde hierzu mithilfe einer Cox- Regressionsanalyse ein Score entwickelt, mit dem die Patienten drei Risikogruppen zugeteilt werden können. Dieser sogenannte B2-Score ermöglicht eine sehr gute Diskriminierung der Patienten bzgl. ihrer Prognose. Als signifikante Faktoren wurden das metastasenfreie Intervall (MFI), die Lokalisation der Metastasen sowie der Hormonrezeptorstatus ermittelt. Die zweite Arbeit stellt ein erstes Anwendungsbeispiel unseres B2-Scores dar. Es wurde der umstrittenen Frage nachgegangen, ob das Gesamtüberleben der Patientinnen mit MBC sich im Verlauf der letzten Jahrzehnte verändert hat. Hier zeigt sich, dass das Gesamtüberleben ab Metastasierung in den Zeitkohorten 1980-94, 1995-99 und 2000-2009 unverändert blieb. Allerdings veränderte sich in den Kohorten die Risikostruktur der Patientinnen signifikant mit einer Zunahme der prognostisch negativen Faktoren in den jüngeren Zeitkohorten. Eine mögliche Erklärung hierfür könnte die effektivere adjuvante Behandlung sein, die quasi eine Negativ-Selektion der Patienten bewirkt, die trotz der konsequenten adjuvanten Therapie eine Metastasierung entwickeln. Wir schlussfolgern daraus, dass die gleichbleibende Prognose bei höherem Risiko als ein indirektes Zeichen einer Verbesserung der Therapie des MBC gewertet werden kann. Es ist weiterhin eine kontroverse Frage, für welche Patientin mit Hormonrezeptor positivem Mammakarzinom eine Chemotherapie zusätzlich zur endokrinen Therapie in der adjuvanten Situation notwendig ist und bei wem eine alleinige ET ausreichend ist. In der dritten Arbeit wurde deshalb der Einfluss der Höhe des ER auf das RFS und die Wirksamkeit einer adjuvanten Hormontherapie an einem Brustkrebsregister mit 3971 Patientinnen mit primärem Mammakarzinom untersucht. Wie zu erwarten, zeigte sich ein signifikanter Einfluss auf das rezidiv-freie Überleben mit der günstigsten Prognose für die ER hoch-exprimierenden und der schlechtesten Prognose für die ER-negativen Tumoren. In der Gruppe der ER-hoch exprimierenden Tumoren zeigte sich zudem kein Zusatznutzen für die Chemo-ET-Kombination im Vergleich zur alleinigen ET. Durch eine quantitative Betrachtung der Hormonrezeptoren im Gegensatz zur (üblichen) rein dichotomen Darstellung (positiv vs. negativ) konnte ein weiterer Hinweis für die Therapieentscheidung gewonnen werden. In der vierten und fünften hier vorgestellten Publikation werden seltene aber klinisch meist dramatisch verlaufende Metastasierungsformen des Mammakarzinoms analysiert. Die Evidenzlage solch seltener Verlaufsformen ist naturgemäß schlecht, klinische Studien sind meist nicht durchführbar, deshalb bilden Kasuistiken und Fallsammlungen häufig die einzige Evidenzquelle. Bei der Mammakarzinom-induzierten thrombotischen Mikroangiopathie handelt es sich um ein Syndrom, welches durch eine Thrombozytopenie in Kombination mit einer mikroangiopathischen hämolytischen Anämie gekennzeichnet ist. Unsere Fallserie zeigt weitere Hinweise auf eine Assoziation mit einer Knochenmarkkarzinose sowie auf die Wirksamkeit und Durchführbarkeit einer fraktionierten Polychemotherapie. Die Analyse der Patientinnen mit Meningeosis carcinomatosa verstärkte die Hinweise, dass eine systemische Therapie in dieser Situation indiziert ist. In der letzten der hier eingeschlossenen eigenen Arbeiten, werden internationale LL zur Behandlung des Mammakarzinoms, die eine hohe methodische Qualität aufweisen, miteinander hinsichtlich der Therapieempfehlungen der adjuvanten Situation verglichen. Es zeigten sich nur geringe Unterschiede zwischen den LL: Dies liegt unseres Erachtens v.a. daran, dass die LL sich auf die gleichen – meist internationalen – Therapiestudien beziehen. Zudem fielen gegenseitige LL-Zitate in den einzelnen LL auf. Eine kritische Hinterfragung der gängigen Praxis der Generierung von LL auf nationaler Ebene sollte deshalb erfolgen. Da die LL-Erstellung eine sehr zeit- und kostenintensive Aufgabe darstellt, sollte eine verstärkte internationale Kooperation (z. B. auf europäischer Ebene) erwogen werden.One of the main goals of clinical health services research is to analyze real world data in order to improve daily clinical care. Six different publications on breast cancer are included in this thesis. Metastatic breast cancer is extremely heterogeneous. In the first publication we developed a clinical score to judge the prognosis of patients at the onset of metastatic disease. We then showed an usage example of our risk score. The subject of the next publication is the influence of the quantity of hormone receptor expression on recurrence free survival in early breast cancer. We also analyzed very rare complications in breast cancer. In the last publication we compared different international clinical practice guidelines of breast cancer in regard of their treatment recommendations

Older age, comorbidity, glucocorticoid use and disease activity are risk factors for COVID-19 hospitalisation in patients with inflammatory rheumatic and musculoskeletal diseases

Introduction Whether patients with inflammatory rheumatic and musculoskeletal diseases (RMD) are at higher risk to develop severe courses of COVID-19 has not been fully elucidated. Aim of this analysis was to describe patients with RMD according to their COVID-19 severity and to identify risk factors for hospitalisation.Methods Patients with RMD with PCR confirmed SARS-CoV-2 infection reported to the German COVID-19 registry from 30 March to 1 November 2020 were evaluated. Multivariable logistic regression was used to estimate ORs for hospitalisation due to COVID-19.Results Data from 468 patients with RMD with SARS-CoV-2 infection were reported. Most frequent diagnosis was rheumatoid arthritis, RA (48%). 29% of the patients were hospitalised, 5.5% needed ventilation. 19 patients died. Multivariable analysis showed that age >65 years (OR 2.24; 95% CI 1.12 to 4.47), but even more>75 years (OR 3.94; 95% CI 1.86 to 8.32), cardiovascular disease (CVD; OR 3.36; 95% CI 1.5 to 7.55), interstitial lung disease/chronic obstructive pulmonary disease (ILD/COPD) (OR 2.79; 95% CI 1.2 to 6.49), chronic kidney disease (OR 2.96; 95% CI 1.16 to 7.5), moderate/high RMD disease activity (OR 1.96; 95% CI 1.02 to 3.76) and treatment with glucocorticoids (GCs) in dosages >5 mg/day (OR 3.67; 95% CI 1.49 to 9.05) were associated with higher odds of hospitalisation. Spondyloarthritis patients showed a smaller risk of hospitalisation compared with RA (OR 0.46; 95% CI 0.23 to 0.91).Conclusion Age was a major risk factor for hospitalisation as well as comorbidities such as CVD, ILD/COPD, chronic kidney disease and current or prior treatment with GCs. Moderate to high RMD disease activity was also an independent risk factor for hospitalisation, underlining the importance of continuing adequate RMD treatment during the pandemic

Implementing an automated monitoring process in a digital, longitudinal observational cohort study

Background: Clinical data collection requires correct and complete data sets in order to perform correct statistical analysis and draw valid conclusions. While in randomized clinical trials much effort concentrates on data monitoring, this is rarely the case in observational studies- due to high numbers of cases and often-restricted resources. We have developed a valid and cost-effective monitoring tool, which can substantially contribute to an increased data quality in observational research. Methods: An automated digital monitoring system for cohort studies developed by the German Rheumatism Research Centre (DRFZ) was tested within the disease register RABBIT-SpA, a longitudinal observational study including patients with axial spondyloarthritis and psoriatic arthritis. Physicians and patients complete electronic case report forms (eCRF) twice a year for up to 10 years. Automatic plausibility checks were implemented to verify all data after entry into the eCRF. To identify conflicts that cannot be found by this approach, all possible conflicts were compiled into a catalog. This “conflict catalog” was used to create queries, which are displayed as part of the eCRF. The proportion of queried eCRFs and responses were analyzed by descriptive methods. For the analysis of responses, the type of conflict was assigned to either a single conflict only (affecting individual items) or a conflict that required the entire eCRF to be queried. Results: Data from 1883 patients was analyzed. A total of n = 3145 eCRFs submitted between baseline (T0) and T3 (12 months) had conflicts (40–64%). Fifty-six to 100% of the queries regarding eCRFs that were completely missing were answered. A mean of 1.4 to 2.4 single conflicts occurred per eCRF, of which 59–69% were answered. The most common missing values were CRP, ESR, Schober’s test, data on systemic glucocorticoid therapy, and presence of enthesitis. Conclusion: Providing high data quality in large observational cohort studies is a major challenge, which requires careful monitoring. An automated monitoring process was successfully implemented and well accepted by the study centers. Two thirds of the queries were answered with new data. While conventional manual monitoring is resource-intensive and may itself create new sources of errors, automated processes are a convenient way to augment data quality

A survey to evaluate knowledge, perceptions and attitudes toward COVID-19 vaccinations among rheumatologists in Germany

The objective is to evaluate the attitude of rheumatologists regarding the use of COVID-19 vaccination in patients with inflammatory rheumatic diseases (IRDs). From February 2nd until March 15th, 2021, rheumatologists from Germany were asked to participate anonymously in a survey addressing their attitude with respect to COVID-19 vaccinations of IRD patients. The survey was completed by 214 participants (107 men, 103 women, 4 unspecified). More than half of the physicians (61%) were working in rheumatologic private practices and 62% had more than 20 years of experience in rheumatology. 90% reported to be at least confidential in handling issues of COVID-19 vaccination and 99% would recommend COVID-19 vaccination for IRD patients. The majority would not recommend to stop or reduce immunomodulatory drugs for vaccination except for rituximab. More than 70% would prefer vaccination with a mRNA vaccine for their IRD patients. This study shows that almost all rheumatologists in Germany support the COVID-19 vaccination for their IRD patients without reducing or terminating the actual immunomodulatory medication to potentially improve the response to the vaccine. This attitude is in accordance with the current recommendations of the German Society of Rheumatology regarding COVID-19 vaccination in IRD patients, and indicates that these have been well accepted and work in everyday clinical practice

Deutsches Register www.Covid19-Rheuma.de

The COVID-19 registry ( www.covid19-rheuma.de ) of the German Society of Rheumatology was the first registry for the acquisition and systemic evaluation of viral infections in patients with inflammatory rheumatic diseases (IRD). This has enabled rapid generation of scientific data that will help to improve the care of patients with IRD in the context of the pandemic. In addition to confirming general risk factors, such as patient age and comorbidities (e.g. cardiovascular, chronic lung and kidney diseases), the use of glucocorticoids and the disease activity of the rheumatic disease could be identified as disease-specific independent risk factors for the need of hospitalization due to COVID-19. Evaluations of the continuously growing cohort of patients with IRD and COVID-19 enable recommendations for patient care to be based on better evidence. Cooperation with international rheumatology registries (e.g. European COVID-19 registry for IRD) enables analyses of aggregated cohorts of patients with IRD and COVID-19 for international comparisons and statistically even more reliable statements

Spectrum of lymphomas across different drug treatment groups in rheumatoid arthritis : a European registries collaborative project

Background Lymphomas comprise a heterogeneous group of malignant diseases with highly variable prognosis. Rheumatoid arthritis (RA) is associated with a twofold increased risk of both Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). It is unknown whether treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) affect the risk of specific lymphoma subtypes. Methods Patients never exposed to (bionaïve) or ever treated with bDMARDs from 12 European biologic registers were followed prospectively for the occurrence of first ever histologically confirmed lymphoma. Patients were considered exposed to a bDMARD after having received the first dose. Lymphomas were attributed to the most recently received bDMARD. Results Among 124 997 patients (mean age 59 years; 73.7% female), 533 lymphomas were reported. Of these, 9.5% were HL, 83.8% B-cell NHL and 6.8% T-cell NHL. No cases of hepatosplenic T-cell lymphoma were observed. Diffuse large B-cell lymphoma (DLBCL) was the most frequent B-cell NHL subtype (55.8% of all B-cell NHLs). The subtype distributions were similar between bionaïve patients and those treated with tumour necrosis factor inhibitors (TNFi). For other bDMARDs, the numbers of cases were too small to draw any conclusions. Patients with RA developed more DLBCLs and less chronic lymphocytic leukaemia compared with the general population. Conclusion This large collaborative analysis of European registries has successfully collated subtype information on 533 lymphomas. While the subtype distribution differs between RA and the general population, there was no evidence of any modification of the distribution of lymphoma subtypes in patients with RA treated with TNFi compared with bionaïve patients