[The German COVID-19 rheumatism register]. / Das deutsche COVID-19-Rheumaregister.

At the beginning of the coronavirus disease 2019 (COVID-19) pandemic in December 2019 there was no available evidence regarding the management of immunosuppressive or immunomodulatory treatment and the potential outcomes of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections in inflammatory rheumatic diseases (IRD). As a result, the Justus Liebig University of Giessen, Germany, in collaboration with the German Society for Rheumatology, established the German COVID-19 register ( www.covid19-rheuma.de ). The COVID-19 register enabled for the first time a systematic documentation and evaluation of viral infections in patients with IRD. The data collection started as early as March 2020. Currently, the register is one of the largest global registers in the field of COVID-19 and IRD. As of 18 December 2023 the register has recorded more than 7100 cases. The first scientific findings on SARS-CoV­2 infections in IRD patients were generated from the register in 2020, showing an association between disease activity of IRD, certain comorbidities, such as cardiovascular diseases and treatment with rituximab, with an unfavorable course. The contents and construction of the database of the register were designed at the conception to allow collaboration and data exchange with other national and international registers (e.g., EULAR COVID-19 register, COVID-19 global rheumatology alliance and the Lean European open survey on SARS-CoV­2 infected patients). In addition, other registers and surveys were initiated. A vaccination register documents the tolerability and possible adverse reactions to COVID-19 vaccination in IRD patients. The data resulted in numerous publications and formed the basis for national and international recommendations for action in the care and vaccination of IRD patients during the COVID-19 pandemic. In summary, the German COVID-19 register has made a significant contribution to the understanding of the course of COVID-19 in IRD patients and has facilitated international collaboration for a better understanding of COVID-19 and IRD.

Systematic review to estimate the prevalence of inflammatory rheumatic diseases in Germany.

OBJECTIVE: This study aimed to update the prevalence estimates of inflammatory rheumatic diseases (IRD) in Germany. METHODS: A systematic literature search in PubMed and Web of Science (last search 08 November 2022) identified original articles (regional and nationwide surveys and claims data analyses for arthritides, connective tissue diseases, and vasculitides) on prevalences for the period 2014-2022. Data sources, collection period, case definition, and risk of bias are reported. Prevalences were estimated from available national data, with consideration of international data. RESULTS: Screening by two authors yielded 263 hits, of which 18 claims data analyses and 2 surveys met the inclusion criteria. Prevalences ranged from 0.42 to 1.85% (rheumatoid arthritis), 0.32-0.5% (ankylosing spondylitis), 0.11-0.32% (psoriatic arthritis), 0.037-0.14% (systemic lupus erythematosus), 0.07-0.77% (Sjögren's disease/sicca syndrome), 0.14-0.15% (polymyalgia rheumatica, ≥ 40 years), 0.04-0.05% (giant cell arteritis, ≥ 50 years), and 0.015-0.026% (ANCA-associated vasculitis). The risk of bias was moderate in 13 and high in 7 studies. Based on the results, we estimate the prevalence of IRD in Germany to be 2.2-3.0%, which corresponds to approximately 1.5-2.1 million affected individuals. The prevalence of juvenile idiopathic arthritis was reported to be around 0.10% (0.07-0.10%) of 0-18-year-olds, corresponding to about 14,000 children and adolescents in Germany. CONCLUSION: This systematic review shows an increase in the prevalence of IRD in Germany, which is almost exclusively based on claims data analyses. In the absence of multistage population studies, the available data are, overall, uncertain sources for prevalence estimates, with a moderate to high risk of bias.

[Systematic review to estimate the prevalence of inflammatory rheumatic diseases in Germany. German version]. / Systematisches Review zur Schätzung der Prävalenz entzündlich rheumatischer Erkrankungen in Deutschland.

OBJECTIVE: To update the estimated prevalence of inflammatory rheumatic diseases (IRD) in Germany. METHODS: A systematic literature search in PubMed and Web of Science (last search 8 November 2022) identified original articles (regional and nationwide surveys and routine data analyses for arthritides, connective tissue diseases, and vasculitides) on the prevalence for the period 2014-2022. Data sources, collection period, case definition, and risk of bias are reported. The prevalences were estimated from available national data, with consideration of international data. RESULTS: Screening by 2 authors yielded 263 hits, of which 18 routine data analyses and 2 surveys met the inclusion criteria. Prevalence data ranged from 0.42% to 1.85% (rheumatoid arthritis), 0.32-0.5% (ankylosing spondylitis), 0.11-0.32% (psoriatic arthritis), 0.037-0.14% (systemic lupus erythematosus), 0.07-0.77% (Sjoegren's disease/sicca syndrome), 0.14-0.15% (polymyalgia rheumatica, ≥ 40 years), 0.04-0.05% (giant cell arteritis, ≥ 50 years), and 0.015-0.026% (ANCA-associated vasculitis). The risk of bias was moderate in 13 and high in 7 studies. Based on the results, we estimate the prevalence of IRD in Germany to be 2.2-3.0%, which corresponds to approximately 1.5-2.1 million affected individuals. Prevalence data of juvenile idiopathic arthritis was reported to be around 0.10% (0.07-0.10%) of patients 0-18 years old, corresponding to about 14,000 children and adolescents in Germany. CONCLUSION: This systematic review shows an increase in the prevalence of IRD in Germany, which is almost exclusively based on routine data analyses. In the absence of multistage population studies, the available data are overall uncertain sources for prevalence estimates at moderate to high risk of bias.

[With RheMIT rheumatology centers can participate in the German national database-Expansion of the long-term rheumatological documentation]. / Mit RheMIT können Rheumazentren an der bundesweiten Kerndokumentation teilnehmen ­ Erweiterung der rheumatologischen Langzeitdokumentation.

The national database (NDB) of the German regional collaborative rheumatology centers was switched to the RheMIT documentation software last year. Rheumatology centers that already use RheMIT for care contracts or other research projects can therefore use the software to also participate in the NDB. Experiences from a hospital, a medical care center and a specialist practice show how the changeover to RheMIT from an existing documentation system or a new participation in the NDB with RheMIT can be implemented. The NDB team at the German Rheumatism Research Center in Berlin (DRFZ) welcomes new participating rheumatology centers.

[German registry www.Covid19-Rheuma.de : Status report after 1 year of the pandemic]. / Deutsches Register www.Covid19-Rheuma.de : Statusbericht nach 1 Jahr der Pandemie.

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.

Rheumatoid arthritis treatment in patients with a history of cancer.

PURPOSE OF REVIEW: What is the best treatment option in patients with active rheumatoid arthritis who have a history of malignant disease? Rheumatologists are increasingly faced with this question in their daily practice. As uncontrolled high disease activity is an important risk factor for further comorbidities and shortened life expectancy, the treatment has to be effective, without bearing a higher risk for cancer recurrence. What data is available today to guide treatment decisions and how robust is its evidence? RECENT FINDINGS: As patients with prior cancer are usually not included in randomized controlled trials, all data we have to elucidate this topic stems from observational cohort studies, mainly biologics registers established in several European countries. The registries investigated the risk of recurrence of cancer mainly by comparing treatments with csDMARDs and TNF inhibitors. Few results are available so far for the treatment with rituximab. However, because of their observational design, the data can only reflect current clinical practice. Because of the lack of evidence, questions such as: are biologics soon after cancer diagnosis safe, remain. SUMMARY: There is still insufficient data for patients with a very recent history of cancer. However, in patients with cancer being in longer remission, observational data suggest no increased risk of overall cancer recurrence when they are treated either with TNF inhibitors or rituximab.

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.

The protective effect of tumor necrosis factor-alpha inhibitors in COVID-19 in patients with inflammatory rheumatic diseases compared to the general population-A comparison of two German registries.

Objectives: To investigate, whether inflammatory rheumatic diseases (IRD) inpatients are at higher risk to develop a severe course of SARS-CoV-2 infections compared to the general population, data from the German COVID-19 registry for IRD patients and data from the Lean European Survey on SARS-CoV-2 (LEOSS) infected patients covering inpatients from the general population with SARS-CoV-2 infections were compared. Methods: 4310 (LEOSS registry) and 1139 cases (IRD registry) were collected in general. Data were matched for age and gender. From both registries, 732 matched inpatients (LEOSS registry: n = 366 and IRD registry: n = 366) were included for analyses in total. Results: Regarding the COVID-19 associated lethality, no significant difference between both registries was observed. Age > 65°years, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, spondyloarthritis and the use of rituximab were associated with more severe courses of COVID-19. Female gender and the use of tumor necrosis factor-alpha inhibitors (TNF-I) were associated with a better outcome of COVID-19. Conclusion: Inflammatory rheumatic diseases (IRD) patients have the same risk factors for severe COVID-19 regarding comorbidities compared to the general population without any immune-mediated disease or immunomodulation. The use of rituximab was associated with an increased risk for severe COVID-19. On the other hand, the use of TNF-I was associated with less severe COVID-19 compared to the general population, which might indicate a protective effect of TNF-I against severe COVID-19 disease.

Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer.

The influence of CYP2D6 genotype on the efficacy of tamoxifen (Tam) has been extensively analyzed in early breast cancer with conflicting results. However, there is only scarce data regarding this potential influence in advanced breast cancer (ABC). We hypothesize that Tam is more effective in patients with a functional CYP2D6 allele than in patients with impaired CYP2D6 activity. ABC patients with prior or ongoing palliative Tam treatment (20 mg/d) were eligible. Genomic DNA was extracted from blood (n = 51) and formalin-fixed, paraffin-embedded tissue (n = 43). CYP2D6*2, *3, *4, *5, *6, *10, *17, *29, *41, CYP2D6 duplication and multiplication were determined in blood and CYP2D6*4 in tissue samples. Primary endpoint was progression free survival (PFS); secondary endpoints included clinical benefit (CB), and overall survival (OS). The clinical charts were retrospectively analyzed regarding survival and treatment effects. Genotyping was performed blinded and clinical data were analyzed separately. 94 patients were identified with a median age of 59 years (29-90 years). In 6 patients genotyping did not show conclusive results, therefore these patients were excluded from further analysis. Genotyping results were as follows: 1.1 % ultrarapid, 84.1 % extensive, 3.4 % intermediate, and 11.4 % poor metabolizers. Patients without any fully functional allele (IM/IM, IM/PM, PM/PM) had a significant shorter PFS and OS compared to patients with at least one functional allele (EM/EM, EM/IM, EM/PM) (PFS: p = 0.017; HR = 2.19; 95 % CI 1.15-4.18; OS: p = 0.028; HR = 2.79; 95 % CI 1.12-6.99). The CB rate was 73 % for EM-group and 38.5 % for IM + PM-group (p = 0.019). Our results show a significant influence of the CYP2D6 genotype on the efficacy of Tam in the treatment of ABC. In contrast to the adjuvant setting, the evidence in the palliative setting is congruent. CYP2D6 testing in ABC should be considered.

Depressive symptoms are associated with fatigue, poorer functional status and less engagement in sports in axSpA and PsA: an analysis from the RABBIT-SpA cohort.

BACKGROUND: In patients with axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA), concomitant depression might have a negative impact on the course of disease and treatment outcomes. The aims of this analysis are to determine the prevalence of depressive symptoms in axSpA and PsA patients in a real-world cohort study and to identify sociodemographic and clinical associated factors for moderate or severe depressive symptoms in both diseases. METHODS: Patients from the RABBIT-SpA cohort with an axSpA or PsA diagnosis and a valid WHO-5 Well-Being Index score at baseline were included. A descriptive analysis of baseline and outcome parameters by category of depressive symptoms was performed and factors associated with the presence of depressive symptoms (moderate or severe) were examined in a logistic regression. RESULTS: Two thousand four hundred seventy patients (1,245 axSpA; 1,225 PsA) were included in the analysis. In both diagnoses, the proportion of patients with moderate depressive symptoms was 8% and 21% with severe symptoms. Patients with moderate or severe depressive symptoms were less likely to engage in sports than those with no or mild depressive symptoms, had more comorbidities and higher scores for disease activity, functional limitations, fatigue, and pain and took more analgesics. In axSpA, patients with a higher disease activity, a greater functional impairment and more severe fatigue were more likely to experience depressive symptoms, while patients with more years in education and engaging in sports for at least 1 h/week were less likely to experience depressive symptoms. PsA patients with a greater functional impairment and more severe fatigue were more likely to experience depressive symptoms while those engaging in sports for at least 1 h/week were less likely to experience depressive symptoms. CONCLUSION: We confirmed a high prevalence of depressive symptoms in both PsA and axSpA. Factors negatively associated with the presence of depressive symptoms were fatigue, not engaging in sports, and greater functional limitations. Depressive symptoms may affect the perception of disease activity / severity by patients. Thus, depressive symptoms are an important condition in axSpA and PsA that should be considered when evaluating disease activity and treatment outcomes.

The Sensitivity to Change of the ASAS Health Index in an Observational Real-Life Cohort Study.

OBJECTIVE: The Assessment of Spondyloarthritis international Society Health Index (ASAS HI) measures global functioning and health in patients with axial spondyloarthritis (axSpA) covering domains of physical, emotional, and social functioning. The main aim of this study was to investigate the sensitivity to change of ASAS HI in comparison with established variables of disease activity, function, and mental health. METHODS: Patients with axSpA from the disease register RABBIT-SpA with follow-up time of at least 12 months and available ASAS HI questionnaires were included. Patients received questionnaires addressing disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Ankylosing Spondylitis Disease Activity Score [ASDAS]), physical function (Bath Ankylosing Spondylitis Functional Index [BASFI]), mental health (5-item World Health Organization Well-Being Index [WHO-5]), and global functioning (ASAS HI). Standardized response means (SRMs) were calculated to compare the sensitivity to change of different variables. RESULTS: Six hundred and sixty-seven patients were included, 552 treated with biologic disease-modifying antirheumatic drugs (bDMARDs) and 115 with conventional synthetic DMARDs and/or nonsteroidal antiinflammatory drugs (control group). Between baseline and month 12, the mean ASAS HI declined from 6.9 to 5.1 in the bDMARD group and from 5.9 to 5.6 in the conventionally treated group. In the bDMARD group, the SRM of ASAS HI was 0.52, compared to 0.59 for BASFI, 0.65 for WHO-5, 0.73 for BASDAI, and 0.90 for ASDAS. The following ASAS HI domains were most frequently affected: pain (78% agreed), maintaining body position (75%), and energy/drive (73%). In the patients receiving bDMARDs, there was an improvement in all items. In the control group, the largest improvement was seen in pain. CONCLUSION: As expected, ASDAS and BASDAI as disease activity scores showed high sensitivity to change, whereas changes in physical function (BASFI), mental health (WHO-5), and the broader concept of functioning and health (ASAS HI) were moderate.

5FU continuous infusion in heavily pretreated advanced breast cancer patients.

BACKGROUND: Despite advances in the first- and secondline treatment of advanced breast cancer, optimal therapy thereafter remains controversial. Treatment of heavily pretreated patients is not standardized, often of low efficacy, and limited by comorbidity. In these patients, an effective treatment with low toxicity is needed. PATIENTS AND METHODS: We retrospectively analyzed all metastatic breast cancer patients treated with 5-fluorouracil as continuous infusion (CI-5FU) with daily doses of 150-300 mg/m(2). RESULTS: 43 patients were treated with CI-5FU until disease progression. The median number of metastatic sites was 3. Most patients were heavily pretreated with a median of 3 palliative chemotherapies (range 1-11). 42 patients were evaluable for objective response; among them 5 (12%) showed a partial response (PR) and 6 (15%) showed stable disease (SD) lasting at least 6 months, leading to a clinical benefit (CB) rate (complete response + PR + SD ≥ 6 months) of 27%. The median time to progression of patients with CB was 10 months (range 3-22). Overall survival of all patients from the start of CI-5FU was 8 months (range 1-75) and from the time of first metastases 42 months (range 9-281). Toxicity was low even in patients with hepatic insufficiency. CONCLUSION: CI-5FU showed a positive efficacy/toxicity ratio. Taking into account the high number of previous treatments, it results in a remarkable CB rate of 27%.

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.

The mTOR inhibitor everolimus in combination with carboplatin in metastatic breast cancer--a phase I trial.

AIM: Despite advances in the the first- and second-line treatment of metastatic breast cancer, there remains a large unmet need for additional treatment options. As preclinical studies have suggested that combining everolimus with carboplatin may produce higher activity than each drug by itself, we initiated a phase I study of this combination. PATIENTS AND METHODS: Patients with pre-treated metastatic breast cancer received weekly carboplatin at AUC2 and daily oral everolimus at different dose-levels (level I: 2.5 mg; II: 5 mg; III: 7.5 mg; IV: 10 mg). Three patients were assigned to dose-levels I to III, and six to dose-level IV. The primary end-point was to determine the maximum tolerated dose (MTD). RESULTS: Fifteen patients were recruited to the study. The median number of previous chemotherapies was four (range: 1-11). No dose-limiting toxicity occurred at levels I-III during the first cycle. Based on the pre-determined definition, the maximum planned dose-level IV was selected as the MTD. Patients received a median of four cycles of treatment (range 1-13). Most frequent grade 3 and 4 toxicities included leukopenia, thrombocytopenia and infection. Response rates were as follows: 21% partial response, 43% stable disease, and 36% progressive disease. CONCLUSION: Carboplatin and everolimus is a well-tolerated combination for heavily pre-treated metastatic breast cancer. Everolimus (10 mg/d) and carboplatin (AUC2 weekly) were defined as the MTD. This dose is currently being employed in an ongoing phase II trial.

Breast Cancer-Associated Thrombotic Microangiopathy.

BACKGROUND: Thrombotic microangiopathy (TMA) is defined as thrombocytopenia and microangiopathic hemolytic anemia. Cancer-associated TMA, a rare but fatal condition, seems an entity distinct from classical thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS). PATIENTS AND METHODS: All patients with breast cancer-associated TMA treated at our institution between 2003 and 2008 were analyzed retrospectively. To elucidate pathophysiological mechanisms, we measured the serum activity of the metalloprotease ADAMTS13. RESULTS: 8 patients were identified. All showed bone marrow infiltration of breast cancer as well as thrombocytopenia, schistocytes, and hemolytic anemia. ADAMTS13 activity was mildly decreased in 4/6 patients (20-108%, normal range 30-120%), but none showed severely low levels as is characteristic of classical TTP. 6 patients were treated with anthracycline-containing fractionated chemotherapy, 5/6 patients experienced partial response. Overall survival was 13 months. Fractionated chemotherapy was well tolerated. CONCLUSIONS: Cancer-associated TMA has an underlying mechanism different from classical TTP. While bone marrow infiltration might be of major relevance, ADAMTS13 deficiency seems to be an epiphenomenon. Fractionated chemotherapy resulted in higher remission rates and comparatively long survival.