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.

Trends in health care of patients with vasculitides, including giant cell arteritis, Takayasu arteritis, ANCA-associated vasculitis and Behçet's disease: cross-sectional data of the German National Database 2007-2021.

The aim of this study is to present the current care situation of patients with giant cell arteritis (GCA), Takayasu arteritis (TAK), ANCA-associated vasculitis (AAV) and Behçet's disease (BD). Trends over the last 15 years will reflect improvements and remaining deficits in the management of vasculitides. Consecutive cross-sectional data from patients with vasculitides from the German National Database (NDB) of the Collaborative Arthritis Centres between 2007 and 2021 were included. Medication, physician- and patient-reported outcomes on disease activity and disease burden, inpatient stays and occupational participation are compared for different vasculitis entities and over time. Employment rates were compared to German population rates. Between 502 and 854 vasculitis patients were annually documented. GCA and AAV were the most common vasculitides. Median disease duration ranged from 2 to 16 years. Over the years, glucocorticoids decreased in proportion and dose, most markedly in GCA and TAK, while biologic therapies increased up to 27%. Physicians rated disease activity as low for the vast majority of patients, while patients-reported moderate outcomes in many dimensions. PROs remained largely unchanged. The proportion of employed patients (< 65 years) increased from 47 to 57%. In recent years, biologics are increasingly used in patients with vasculitides, while glucocorticoids decreased significantly. PRO's have not improved. Work participation increased but remains lower than that in the German population.

Beneficial effects associated to a healthy lifestyle in systemic lupus erythematosus: A cross-sectional study.

OBJECTIVE: To assess whether a healthy lifestyle is associated to beneficial effects on various systemic lupus erythematosus (SLE) health domains. METHODS: In a cross-sectional study, Mediterranean Diet Adherence Score (MEDAS), physical activity energy expenditure (PAEE), and smoking status were assessed by questionnaires, along with clinical parameters and various health domains including Systemic Lupus Disease Activity Score (SLEDAI), Depression Scale (CES-D), Fatigue Severity (FSS), functional status (FFbH), physical and mental quality of life (PCS, MCS). Lifestyle choices were assessed with respect to health domains by linear regression modeling. Additionally, SLE patients with a healthy lifestyle (MEDAS ≥ 4, ≥ 1 h sport per week, no smoking) were compared to those without by Wilcoxon's signed-rank test. RESULTS: 49 of 145 SLE patients (44.3 ± 31.7 years, 87.6% female) followed a healthy lifestyle and showed a higher physical quality of life (ß = 4.5 (95%-CI 1.5-7.9) p = 0.01), lower depression (ß = -5.0 (-8.2 to -0.2) p = 0.02) and lower fatigue (ß = -0.8 (-1.5 to -0.2) p = 0.01) independently of SLE disease activity. Furthermore, dsDNA-antibodies were lower (146 ± 540 vs 266 ± 146 U/mL, p = 0.049). In a more detailed analysis, physical activity had the highest impact on the various health domains when compared to smoking or diet adherence, which was consistent even after adjusting for multiple potential confounders. Each 1,000 kcal of weekly PAEE was associated to a 1.8 (0.9-2.6) point increase in the PCS (p = 0.0001), a 0.2 (0.03-0.4) point decrease in the CES-D (p = 0.01) and a 2.8 (1.2-4.4) point increase in the FFbH (p = 0.0006). CONCLUSION: A healthy lifestyle, especially physical activity is associated with beneficial effects including quality of life, depression and fatigue in SLE.

[Evidence of positive care effects by digital health apps-methodological challenges and approaches]. / Nachweis positiver Versorgungseffekte von digitalen Gesundheitsanwendungen ­ methodische Herausforderungen und Lösungsansätze.

Since 2020, digital health applications (DiGA) can be prescribed at the expense of the German statutory health insurance (SHI) system after undergoing an approval procedure by the Federal Institute for Drugs and Medical Devices (BfArM). DiGA can be approved provisionally for 1 year (with the option of extension) or permanently. The latter is dependent on scientific evidence of a positive effect on care, which can be a medical benefit or a patient-relevant structural and procedural improvement in care. However, it is apparent that the investigation of DiGA in scientific studies is challenging, as they are often complex interventions whose success also includes user and prescriber factors. In addition, health services research data underpinning the benefits of DiGA are lacking to date. In the current article, methodological considerations for DiGA research are presented, and a selection of internal medicine DiGAs is used to critically discuss current research practice.

[Functional vascular acrosyndromes]. / Funktionelle akrale Durchblutungsstörungen.

Vascular acrosyndromes are characterized by sparse, uniform clinical manifestations and a variety of possible pathomechanisms. The present article focuses on the functional entities. Raynaud phenomenon is based on cold- or stress-induced vasospasms of acral arteries. It is defined by the color changes of the skin, in the typical case white-blue-red (tricolore). The long fingers are most commonly affected. The etiology is unknown, and the pathophysiology is poorly understood. A distinction is made between primary and a secondary Raynaud phenomenon. The most important underlying diseases include collagenosis, primarily systemic sclerosis, and malignancies; furthermore, medications and drugs may promote vasospasm. Treatment is aimed at preventing or breaking the vasospasm, but has been only partially effective in doing so. Acrocyanosis is a vasospastic dystonic acral disorder that results in permanent reddish-livid discoloration, especially of the hands and feet. Secondary forms occur in collagenosis, malignancies, and myelodysplastic syndromes. The etiology and pathophysiology are virtually unknown. Targeted pharmacological intervention is not possible. Unlike all other vascular acrosyndromes, erythromelalgia is characterized by hyperemia. The primary form is a genetic sodium channelopathy, while secondary forms include malignancies, connective tissue diseases, and myelodysplastic syndromes. The symptoms are often distressing and disabling. Therapy requires a multimodal approach that includes both nonpharmacological and pharmacological strategies. Close interdisciplinary collaboration is essential for the management of this disease.

[Practical use of digital health applications (DiGA) in internal medicine]. / Praktische Anwendung digitaler Gesundheitsanwendungen (DiGA) in der Inneren Medizin.

Since 2020 physicians can prescribe digital health applications (DiGA), also colloquially known as apps on prescription, which are reimbursed by the statutory health insurance when they are approved by the Federal Institute for Drugs and Medical Devices (BfArM) and are included in the DiGA Ordinance. Currently, there is one approved DiGA (indication obesity) for internal medicine. There are many questions on the practical use of the DiGA, ranging from the prescription, the effectiveness, the complexities and reimbursement as well as the liability risks. The DiGA are innovative new means, which maybe support internal medicine physicians in the diagnostics and treatment in the future. The benefits in this field of indications are limited by unclarified issues, especially on the prescription practice and the currently low number of DiGA available in internal medicine.

Musculoskeletal ultrasound as a screening-tool for rheumatoid arthritis: results of the "Rheuma-Truck" screening and awareness initiative

Abstract Objective: To evaluate musculoskeletal ultrasound (MSUS) as a screening tool for rheumatoid arthritis (RA) and osteoarthritis (OA) patients in a rheumatology-screening program. Patients and methods: To raise awareness for rheumatic diseases, a mobile rheumatology office was deployed in different cities of Germany ("Rheuma-Truck"). Standardized questionnaire assessment, testing for rheumatoid factor and citrullinated peptide antibodies and medical student driven MSUS of the clinically dominant hand/foot including wrist, MCP-II, -III, -V, PIP-II, -III, MTP-II and -V were offered free of charge to the population. In case of suspicious results, a rheumatologist was consulted. Results: In MSUS, 192 of 560 selected volunteers (aged 18-89, mean 52.7 years; 72.9% female) had suspicious findings including synovitis or erosions primarily affecting the MTP-II (11.8%), dorsal wrist (8.9%), and MCP-II (7%). 354 of the 560 volunteers further visited a rheumatologist of whom 76 were diagnosed with RA. According to the 'US7 Score', a sum scores ≥ 5 was significantly predictive for RA (odds ratio (OR) 5.06; confidence interval (CI) 0.83-35.32). 313 volunteers displayed signs of OA including osteophytes, while MCP-II (36.2%), MCP-III (14.8%), and the wrist (10.5%) were mostly affected. Diagnosis of RA was favoured over OA if the wrist (OR 4.2; CI 1.28-13.95), MTP-II (OR 1.62; CI 1.0-2.6), and MCP-V (OR 2.0; CI 1.0-3.8) were involved. Conclusion: Medical student driven MSUS by the 'US7 Score' can facilitate diagnosis of RA in rheumatology-screening programs due to the level of the score and the affected joints. A high rate of unknown OA signs was detected by MSUS. A mobile rheumatology office displays an opportunity to screen patients for RA and OA.

Methyl donor micronutrients, CD40-ligand methylation and disease activity in systemic lupus erythematosus: A cross-sectional association study.

OBJECTIVE: Hypomethylation of CD40-ligand (CD40L) in T-cells is associated with increased disease activity in systemic lupus erythematosus (SLE). We therefore investigated possible associations of dietary methyl donors and products with CD40L methylation status in SLE. METHODS: Food frequency questionnaires were employed to calculate methyl donor micronutrients in 61 female SLE patients (age 45.7 ± 12.0 years, disease duration 16.2 ± 8.4 years) and compared to methylation levels of previously identified key DNA methylation sites (CpG17 and CpG22) within CD40L promotor of T-cells using quantitative DNA methylation analysis on the EpiTYPER mass spectrometry platform. Disease activity was assessed by SLE Disease Activity Index (SLEDAI). Linear regression modelling was used. P values were adjusted according to Benjamini & Hochberg. RESULTS: Amongst the micronutrients assessed (g per day), methionine and cysteine were associated with methylation of CpG17 (ß = 5.0 (95%CI: 0.6-9.4), p = 0.04; and ß = 2.4 (0.6-4.1), p = 0.02, respectively). Methionine, choline, and cysteine were additionally associated with the mean methylation of the entire CD40L (ß = 9.5 (1.0-18.0), p = 0.04; ß = 1.6 (0.4-3.0), p = 0.04; and ß = 4.3 (0.9-7.7), p = 0.02, respectively). Associations of the SLEDAI with hypomethylation were confirmed for CpG17 (ß=-32.6 (-60.6 to -4.6), p = 0.04) and CpG22 (ß=-38.3 (-61.2 to -15.4), p = 0.004), but not the mean methylation of CD40L. Dietary products with the highest impact on methylation included meat, ice cream, white bread, and cooked potatoes. CONCLUSIONS: Dietary methyl donors may influence DNA methylation levels and thereby disease activity in SLE.

Associations of site-specific CD4+-T-cell hypomethylation within CD40-ligand promotor and enhancer regions with disease activity of women with systemic lupus erythematosus.

OBJECTIVE: To comprehensively assess associations of site-specific CD4+-T-cell hypomethylation of the CD40-Ligand gene (CD40L) with disease activity of women with systemic lupus erythematosus (SLE). METHODS: CpG-sites within the DNA of the promotor and two enhancer regions (n = 22) of CD40L were identified and numbered consecutively. The rate of methylated DNA in isolated CD4+-T-cells of women with SLE were quantified for each methylation site by MALDI-TOF. Disease activity was assessed by SLE Disease Activity Index (SLEDAI). Associations of site-specific methylation rates with the SLEDAI scores were assessed by linear regression modelling. P values were adjusted according to Bonferroni-Holm as indicated. RESULTS: 60 female SLE patients participated in the study (age 45.7 ± 11.1 years, disease duration 17.0 ± 8.3 years). Significant associations to the SLEDAI were noted for CpG22 hypomethylation of the promotor (ß = -40.1, p = 0.017, adjusted p = 0.027), trends were noted for CpG17 hypomethylation of the promotor (ß = -30.5, p = 0.032, adjusted p = 0.6), and for CpG11 hypermethylation of the second enhancer (ß = 15.0, p = 0.046, adjusted p = 0.8). CONCLUSION: Site-specific hypomethylation of the CD40L promotor in CD4+-T-cells show associations with disease activity in female SLE patients.

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.

Thromboangiitis obliterans (Buerger's disease).

Thromboangiitis obliterans (TAO, Buerger's disease) is an inflammatory vascular disease affecting small and medium sized arteries and veins. It is characterized by segmental thrombotic occlusions by highly mononuclear cellular thrombi. Its occurrence and re-occurrence is closely related to tobacco use. Immunohistological examinations and the detections of various autoantibodies led to the new paradigm of an immunopathogenesis of TAO. Clinically it is characterized by distal ischemia syndromes in young people and high amputation rates. This article summarizes the disease characteristics, clinical features, and diagnostic and therapeutic approaches and focuses on new therapeutic options, i.e. stem cell derived therapies, immunoadsorption, and the endothelin-receptor-blocking agent bosentan.

An ask-the-expert service on a rheumatology web site: who were the users and what did they look for?

OBJECTIVE: To analyze the inquiries sent to an online ask-the-rheumatologist service in order to identify the users' needs and requirements. METHODS: The official web site of the German Competence Network Rheumatology (www.rheumanet.org) provided expert information for patients, relatives, and physicians. We analyzed the content of 1,133 inquiries posted over 5 years and the experts' answers were blinded for analyses. RESULTS: Patients (60.0%), relatives (24.3%), and physicians (15.7%) addressed the experts. Inquiries were predominantly sent by women (62.2%). Distinct rheumatic diseases were mentioned in 40.5% of the inquiries, and 16.3% reported musculoskeletal symptoms without a definite diagnosis. The number of questions ranged from 1-7 per inquiry (mean±SD 1.58±0.9). Of the inquiries, 33.2% contained personal histories, 24.9% searched for a rheumatologist nearby, and 11.6% asked for a "second opinion." The questions covered a wide range of interests, including medication (30.8%), diagnosis-related issues (15.7%), laboratory tests (6.9%), (treatment) guidelines (6.2%), sexual and reproductive health issues (4.1%), and clinical trials (3.4%). In more than 50% of the inquiries, the information requested from the experts was already at least partly published on the web site. The experts' answers covered the users' questions completely in 91.8%, partly in 6.1%, and not at all in 2.1%. CONCLUSION: A standardized medical web site providing tailored and trustworthy information for all user groups gains from an ask-the-expert service. Only such an interactive online application is able to satisfy users' actual demands: searching for specific individualized information on the internet. Therefore, an ask-the-expert service contributes to optimized patient care.

[Rationale for bone marrow examination in patients with inflammatory rheumatic diseases]. / Die Rationale für Knochenmarkuntersuchungen bei Patienten mit entzündlich-rheumatischen Erkrankungen.

OBJECTIVE: Inflammatory rheumatic diseases and the applied immunosuppressive treatments can lead to bone marrow depressions and promote hematologic malignancies. Our objective was to explore indications for and results of bone marrow examinations in a large cohort. METHODS: Between 1990 and 2004 146 bone marrow examinations in 3638 patients were performed due to abnormal laboratory results. Medical history, results of bone marrow examination (morphology, histology) and cytogenetic data were investigated retrospectively. RESULTS: Patients' (67.8% female) mean age at bone marrow examination was 53.5 years (SD 15.5), median disease duration 2.9 years. Indications for bone marrow examination were changes in peripheral blood counts in 81.7%. In 52 patients (35.6%) clinically relevant, partially neoplastic bone marrow changes (5 non-Hodgkin lymphoma, 9 myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) and 3 myeloproliferative neoplasias) were evident. Medication history showed intake of hydroxy-/chloroquine (13.5%), methotrexate (17.3%), cyclosporin (7.7%), sulfasalazine (7.7%), mycophenolatmofetil, gold, leflunomide (each 1.9%), azathioprine (aza, 25.0%) or cyclophosphamide (cyc, 7.7%) prior to bone marrow examination. 7 out of 9 patients, who developed MDS/AML had been treated with either azathioprine alone or additionally with cyclophosphamide (n = 3). CONCLUSION: One third of our patients showed relevant bone marrow changes that might be associated to therapy. The risk seems to be increased especially in patients with inflammatory rheumatic diseases who had received azathioprine alone or in combination with cyclophosphamide. Health care providers should bear in mind the risk of hematologic malignancies and monitor patients closely in this respect. Bone marrow examination should be performed in case of changes in peripheral blood counts; especially clinically relevant anemia, granulocytes < 2,500/microl, thrombocytes < 100,000/microl and relevant changes over time should lead to bone marrow examinations.

[RheumaCheck: development and evaluation of a German language screening instrument for rheumatic diseases]. / RheumaCheck: Entwicklung und Evaluation eines deutschsprachigen Rheuma-Screening Instruments.

OBJECTIVE: Early diagnosis of inflammatory rheumatic diseases is important for patients' prognosis and outcome. The mean time delay of 1 to 5 years in Germany between the initial symptoms and the first rheumatologist contact should be reduced. Efficiency of patient questionnaires for the identification of inflammatory rheumatic diseases has been demonstrated in other countries. The aim of our study was to develop a patient questionnaire in German identifying inflammatory rheumatic diseases with a high sensitivity and specificity as well as a high positive predictive value. PATIENTS AND METHODS: The RheumaCheck questionnaire was developed by adoption of the FDA-approved Connective Tissue Disease Screening Questionnaire. 1448 patients (195 controls, 437 patients suspicious for and 816 patients with known inflammatory rheumatic diseases) recruited by rheumatologists and general practitioners answered the questionnaire that additionally assessed comorbidities and sociodemographic data. A predictive algorithm was calculated. RESULTS: Mean age of the complete group (73.1% female) was 52.5 +/- 15.1 years. 53.1% had no comorbidity. Application of the algorithm yields a high sensitivity (77.6%) and specificity (79.9%). The area under the ROC curve was 0.85 (p < 0.0001). CONCLUSION: Being aware of a possible high rate of false true results RheumaCheck is a simple, efficient instrument easily filled out by patients. It can identify the group of patients that needs further investigation, care and assessment by a rheumatologist leading to earlier diagnosis and therapy. A web version of RheumaCheck is provided on www.rheuma-check.de .

Differential diagnosis of high serum creatine kinase levels in systemic lupus erythematosus.

We report the clinical and bioptic findings for a 57-year-old woman with severe chloroquine-induced myopathy. Since 1989, she had been suffering from systemic lupus erythematosus (SLE) with renal involvement and undergone periods of treatment with azathioprine and cyclophosphamide. Additional therapy with chloroquine (CQ) was started because of arthralgia. At the same time, slightly increased creatine kinase (CK) levels were noted. Myositis was suspected, and the patient was treated with steroids. The CK increase persisted, however, and she developed progressive muscular weakness and muscular atrophy. Routine controls revealed markedly elevated CK levels of 1,700 U/l. The neurological and electrophysiological findings were not typical of myositis. Thus, muscle biopsy of the deltoid muscle was performed in order to exclude polymyositis or toxic myopathy. As it revealed chloroquine-induced myopathy, medication was stopped. Discriminating between primary SLE-induced affection of the musculoskeletal system and drug-induced side effects is important for appropriate treatment of SLE patients.