Publications by authors named "Alexander Pfeil"

106 Publications

German Society of Rheumatology recommendations for management of glucocorticoid-induced osteoporosis.

Z Rheumatol 2021 Oct 27. Epub 2021 Oct 27.

Rheumatologisches Praxiszentrum München, Munich, Germany.

Background: Glucocorticoids are of substantial therapeutic importance in the treatment of inflammatory diseases, but are also associated with bone mineral density loss, osteoporosis, and fractures, especially with long-term use.

Objective: To develop recommendations for the management of glucocorticoid-induced osteoporosis (GIOP) in adult patients on long-term glucocorticoid (GC) treatment.

Methods: A systematic literature search (SLR) was conducted to synthesize the evidence for GIOP prevention and treatment options. Recommendations were developed based on SLR/level of evidence and by previously defined questions and in a structured group consensus process.

Results: Recommendations include supplementation with calcium and vitamin D under long-term GC therapy in adults. If specific osteologic treatment is indicated, we recommend bisphosphonates or denosumab as first-line treatment. If fracture risk is high, we recommend teriparatide as primary specific osteologic treatment. Denosumab should be used in cases of severe renal insufficiency, and specific osteologic treatment should not be given in pregnancy. For patients who have not reached the treatment goal, a switch to another class of specific osteologic drugs should be performed. We recommend re-evaluation after a treatment duration of 3-5 years or after termination of long-term GC treatment.

Conclusion: This work aims to provide evidence-based and consensus-based recommendations for the best possible management of GIOP in Germany and to support treatment decisions.
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http://dx.doi.org/10.1007/s00393-021-01025-zDOI Listing
October 2021

TNFi is associated with positive outcome, but JAKi and rituximab are associated with negative outcome of SARS-CoV-2 infection in patients with RMD.

RMD Open 2021 10;7(3)

Rheumatology and Clinical Immunology, Giessen University, Bad Nauheim, Germany.

Introduction: Several risk factors for severe COVID-19 specific for patients with inflammatory rheumatic and musculoskeletal diseases (RMDs) have been identified so far. Evidence regarding the influence of different RMD treatments on outcomes of SARS-CoV-2 infection is still poor.

Methods: Data from the German COVID-19-RMD registry collected between 30 March 2020 and 9 April 2021 were analysed. Ordinal outcome of COVID-19 severity was defined: (1) not hospitalised, (2) hospitalised/not invasively ventilated and (3) invasively ventilated/deceased. Independent associations between demographic and disease features and outcome of COVID-19 were estimated by multivariable ordinal logistic regression using proportional odds model.

Results: 2274 patients were included. 83 (3.6%) patients died. Age, male sex, cardiovascular disease, hypertension, chronic lung diseases and chronic kidney disease were independently associated with worse outcome of SARS-CoV-2 infection. Compared with rheumatoid arthritis, patients with psoriatic arthritis showed a better outcome. Disease activity and glucocorticoids were associated with worse outcome. Compared with methotrexate (MTX), TNF inhibitors (TNFi) showed a significant association with better outcome of SARS-CoV-2 infection (OR 0.6, 95% CI0.4 to 0.9). Immunosuppressants (mycophenolate mofetil, azathioprine, cyclophosphamide and ciclosporin) (OR 2.2, 95% CI 1.3 to 3.9), Janus kinase inhibitor (JAKi) (OR 1.8, 95% CI 1.1 to 2.7) and rituximab (OR 5.4, 95% CI 3.3 to 8.8) were independently associated with worse outcome.

Conclusion: General risk factors for severity of COVID-19 play a similar role in patients with RMDs as in the normal population. Influence of disease activity on COVID-19 outcome is of great importance as patients with high disease activity-even without glucocorticoids-have a worse outcome. Patients on TNFi show a better outcome of SARS-CoV-2 infection than patients on MTX. Immunosuppressants, rituximab and JAKi are associated with more severe course.
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http://dx.doi.org/10.1136/rmdopen-2021-001896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529615PMC
October 2021

Ultrashort echo time MRI of the lung in children and adolescents: comparison with non-enhanced computed tomography and standard post-contrast T1w MRI sequences.

Eur Radiol 2021 Oct 20. Epub 2021 Oct 20.

Department of Paediatric Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany.

Objectives: To compare the diagnostic value of ultrashort echo time (UTE) magnetic resonance imaging (MRI) for the lung versus the gold standard computed tomography (CT) and two T1-weighted MRI sequences in children.

Methods: Twenty-three patients with proven oncologic disease (14 male, 9 female; mean age 9.0 + / - 5.4 years) received 35 low-dose CT and MRI examinations of the lung. The MRI protocol (1.5-T) included the following post-contrast sequences: two-dimensional (2D) incoherent gradient echo (GRE; acquisition with breath-hold), 3D volume interpolated GRE (breath-hold), and 3D high-resolution radial UTE sequences (performed during free-breathing). Images were evaluated by considering image quality as well as distinct diagnosis of pulmonary nodules and parenchymal areal opacities with consideration of sizes and characterisations.

Results: The UTE technique showed significantly higher overall image quality, better sharpness, and fewer artefacts than both other sequences. On CT, 110 pulmonary nodules with a mean diameter of 4.9 + / - 2.9 mm were detected. UTE imaging resulted in a significantly higher detection rate compared to both other sequences (p < 0.01): 76.4% (84 of 110 nodules) for UTE versus 60.9% (67 of 110) for incoherent GRE and 62.7% (69 of 110) for volume interpolated GRE sequences. The detection of parenchymal areal opacities by the UTE technique was also significantly higher with a rate of 93.3% (42 of 45 opacities) versus 77.8% (35 of 45) for 2D GRE and 80.0% (36 of 45) for 3D GRE sequences (p < 0.05).

Conclusion: The UTE technique for lung MRI is favourable in children with generally high diagnostic performance compared to standard T1-weighted sequences as well as CT. Key Points • Due to the possible acquisition during free-breathing of the patients, the UTE MRI sequence for the lung is favourable in children. • The UTE technique reaches higher overall image quality, better sharpness, and lower artefacts, but not higher contrast compared to standard post-contrast T1-weighted sequences. • In comparison to the gold standard chest CT, the detection rate of small pulmonary nodules small nodules ≤ 4 mm and subtle parenchymal areal opacities is higher with the UTE imaging than standard T1-weighted sequences.
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http://dx.doi.org/10.1007/s00330-021-08236-7DOI Listing
October 2021

A review of JAK-STAT signalling in the pathogenesis of spondyloarthritis and the role of JAK inhibition.

Rheumatology (Oxford) 2021 Oct 20. Epub 2021 Oct 20.

Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, Portland, OR, USA.

Spondyloarthritis (SpA) comprises a group of chronic inflammatory diseases with overlapping clinical, genetic and pathophysiological features including back pain, peripheral arthritis, psoriasis, enthesitis, and dactylitis. Several cytokines are involved in the pathogenesis of SpA, variously contributing to each clinical manifestation. Many SpA-associated cytokines, including interleukin (IL)-23, IL-17, IL-6, type I/II interferon, and tumour necrosis factor signal directly or indirectly via the Janus kinase (JAK)-signal transducer and activator of transcription pathway. JAK signalling also regulates development and maturation of cells of the innate and adaptive immune systems. Accordingly, disruption of this signalling pathway by small molecule oral JAK inhibitors can inhibit signalling implicated in SpA pathogenesis. Herein we discuss the role of JAK signalling in the pathogenesis of SpA and summarise the safety and efficacy of JAK inhibition via reference to relevant SpA clinical trials.
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http://dx.doi.org/10.1093/rheumatology/keab740DOI Listing
October 2021

Association Between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death Among Patients With Immune-Mediated Inflammatory Disease and COVID-19.

JAMA Netw Open 2021 10 1;4(10):e2129639. Epub 2021 Oct 1.

Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco.

Importance: Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood.

Objective: To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19-associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs.

Design, Setting, And Participants: This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included.

Exposures: Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy.

Main Outcomes And Measures: The main outcome was COVID-19-associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations.

Results: A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P = .006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P = .001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P < .001), and Jak inhibitor monotherapy (OR, 1.82; 95% CI, 1.21-2.73; P = .004) but not among those who received a TNF inhibitor in combination with methotrexate therapy (OR, 1.18; 95% CI, 0.85-1.63; P = .33). Similar findings were obtained in analyses that accounted for potential reporting bias and sensitivity analyses that excluded patients with a COVID-19 diagnosis based on symptoms alone.

Conclusions And Relevance: In this cohort study, TNF inhibitor monotherapy was associated with a lower risk of adverse COVID-19 outcomes compared with other commonly prescribed immunomodulatory treatment regimens among individuals with IMIDs.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.29639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524310PMC
October 2021

Model curriculum of the German society for Rheumatology for advanced training in the discipline internal medicine and rheumatology. English version.

Z Rheumatol 2021 Oct 4. Epub 2021 Oct 4.

Department of Gastroenterology, Infectiology and Rheumatology (including Nutrition Medicine) , Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

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http://dx.doi.org/10.1007/s00393-021-01080-6DOI Listing
October 2021

Calcium pyrophosphate crystal deposition in Gitelman syndrome: which joint is affected?

Authors:
Alexander Pfeil

Rheumatology (Oxford) 2021 Sep 23. Epub 2021 Sep 23.

Department of Internal Medicine III, Jena University Hospital-Friedrich Schiller University Jena, Jena, Germany.

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http://dx.doi.org/10.1093/rheumatology/keab705DOI Listing
September 2021

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

Rheumatol Int 2021 Nov 8;41(11):1949-1956. Epub 2021 Sep 8.

Department of Rheumatology and Clinical Immunology, Kliniken Essen-Mitte, Essen, 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.
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http://dx.doi.org/10.1007/s00296-021-04986-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425463PMC
November 2021

[German Society of Rheumatology Recommendations for the management of glucocorticoid-induced Osteoporosis. German version].

Z Rheumatol 2021 Sep 6;80(7):670-687. Epub 2021 Aug 6.

Rheumatologisches Praxiszentrum München, München, Deutschland.

Background: Glucocorticoids are of substantial therapeutic importance in the treatment of inflammatory diseases, but are also associated with bone mineral density loss, osteoporosis, and fractures, especially with long-term use.

Objective: To develop recommendations for the management of glucocorticoid-induced osteoporosis (GIOP) in adult patients on long-term glucocorticoid (GC) treatment.

Methods: A systematic literature search (SLR) was conducted to synthesize the evidence for GIOP prevention and treatment options. Recommendations were developed based on SLR/level of evidence and by previously defined questions and in a structured group consensus process.

Results: Recommendations include supplementation with calcium and vitamin D under long-term GC therapy in adults. If specific osteologic treatment is indicated, we recommend bisphosphonates or denosumab as first-line treatment. If fracture risk is high, we recommend teriparatide as primary specific osteologic treatment. Denosumab should be used in cases of severe renal insufficiency, and specific osteologic treatment should not be given in pregnancy. For patients who have not reached the treatment goal, a switch to another class of specific osteologic drugs should be performed. We recommend re-evaluation after a treatment duration of 3-5 years or after termination of long-term GC treatment.

Conclusion: This work aims to provide evidence-based and consensus-based recommendations for the best possible management of GIOP in Germany and to support treatment decisions.
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http://dx.doi.org/10.1007/s00393-021-01028-wDOI Listing
September 2021

[Model curriculum of the German Society for Rheumatology for advanced training in the discipline internal medicine and rheumatology].

Z Rheumatol 2021 Sep 23;80(7):688-691. Epub 2021 Jul 23.

Abteilung für Rheumatologie, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Campus Benjamin Franklin, Charité Universitätsmedizin, Berlin, Deutschland.

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http://dx.doi.org/10.1007/s00393-021-01053-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423688PMC
September 2021

Virtual teaching for medical students during SARS-CoV-2 pandemic.

Clin Exp Rheumatol 2021 Nov-Dec;39(6):1447-1448. Epub 2021 Jul 7.

Department of Internal Medicine 3, Rheumatology and Immunology, and German Center Immune Therapy, University Hospital Erlangen, Germany.

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July 2021

[German registry www.Covid19-Rheuma.de : Status report after 1 year of the pandemic].

Z Rheumatol 2021 Sep 1;80(7):641-646. Epub 2021 Jul 1.

Klinik für Rheumatologie & Klinische Immunologie, Kliniken Essen-Mitte, Essen, Deutschland.

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.
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http://dx.doi.org/10.1007/s00393-021-01034-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246125PMC
September 2021

Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction.

Nutrients 2021 May 13;13(5). Epub 2021 May 13.

Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA.

Background: Triple-negative breast cancers (TNBCs), accounting for approximately 15% of breast cancers, lack targeted therapy. A hallmark of cancer is metabolic reprogramming, with one-carbon metabolism essential to many processes altered in tumor cells, including nucleotide biosynthesis and antioxidant defenses. We reported that folate deficiency via folic acid (FA) withdrawal in several TNBC cell lines results in heterogenous effects on cell growth, metabolic reprogramming, and mitochondrial impairment. To elucidate underlying drivers of TNBC sensitivity to folate stress, we characterized in vivo and in vitro responses to FA restriction in two TNBC models differing in metastatic potential and innate mitochondrial dysfunction.

Methods: Metastatic MDA-MB-231 cells (high mitochondrial dysfunction) and nonmetastatic M-Wnt cells (low mitochondrial dysfunction) were orthotopically injected into mice fed diets with either 2 ppm FA (control), 0 ppm FA, or 12 ppm FA (supplementation; in MDA-MB-231 only). Tumor growth, metabolomics, and metabolic gene expression were assessed. MDA-MB-231 and M-Wnt cells were also grown in media with 0 or 2.2 µM FA; metabolic alterations were assessed by extracellular flux analysis, flow cytometry, and qPCR.

Results: Relative to control, dietary FA restriction decreased MDA-MB-231 tumor weight and volume, while FA supplementation minimally increased MDA-MB-231 tumor weight. Metabolic studies in vivo and in vitro using MDA-MB-231 cells showed FA restriction remodeled one-carbon metabolism, nucleotide biosynthesis, and glucose metabolism. In contrast to findings in the MDA-MB-231 model, FA restriction in the M-Wnt model, relative to control, led to accelerated tumor growth, minimal metabolic changes, and modest mitochondrial dysfunction. Increased mitochondrial dysfunction in M-Wnt cells, induced via chloramphenicol, significantly enhanced responsiveness to the cytotoxic effects of FA restriction.

Conclusions: Given the lack of targeted treatment options for TNBC, uncovering metabolic vulnerabilities that can be exploited as therapeutic targets is an important goal. Our findings suggest that a major driver of TNBC sensitivity to folate restriction is a high innate level of mitochondrial dysfunction, which can increase dependence on one-carbon metabolism. Thus, folate deprivation or antifolate therapy for TNBCs with metabolic inflexibility due to their elevated levels of mitochondrial dysfunction may represent a novel precision-medicine strategy.
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http://dx.doi.org/10.3390/nu13051637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152779PMC
May 2021

A Virtual Reality-Based App to Educate Health Care Professionals and Medical Students About Inflammatory Arthritis: Feasibility Study.

JMIR Serious Games 2021 May 11;9(2):e23835. Epub 2021 May 11.

Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany.

Background: Inflammatory arthritides (IA) such as rheumatoid arthritis or psoriatic arthritis are disorders that can be difficult to comprehend for health professionals and students in terms of the heterogeneity of clinical symptoms and pathologies. New didactic approaches using innovative technologies such as virtual reality (VR) apps could be helpful to demonstrate disease manifestations as well as joint pathologies in a more comprehensive manner. However, the potential of using a VR education concept in IA has not yet been evaluated.

Objective: We evaluated the feasibility of a VR app to educate health care professionals and medical students about IA.

Methods: We developed a VR app using data from IA patients as well as 2D and 3D-visualized pathological joints from X-ray and computed tomography-generated images. This VR app (Rheumality) allows the user to interact with representative arthritic joint and bone pathologies of patients with IA. In a consensus meeting, an online questionnaire was designed to collect basic demographic data (age, sex); profession of the participants; and their feedback on the general impression, knowledge gain, and potential areas of application of the VR app. The VR app was subsequently tested and evaluated by health care professionals (physicians, researchers, and other professionals) and medical students at predefined events (two annual rheumatology conferences and academic teaching seminars at two sites in Germany). To explore associations between categorical variables, the χ or Fisher test was used as appropriate. Two-sided P values ≤.05 were regarded as significant.

Results: A total of 125 individuals participated in this study. Among them, 56% of the participants identified as female, 43% identified as male, and 1% identified as nonbinary; 59% of the participants were 18-30 years of age, 18% were 31-40 years old, 10% were 41-50 years old, 8% were 51-60 years old, and 5% were 61-70 years old. The participants (N=125) rated the VR app as excellent, with a mean rating of 9.0 (SD 1.2) out of 10, and many participants would recommend use of the app, with a mean recommendation score of 3.2 (SD 1.1) out of 4. A large majority (120/125, 96.0%) stated that the presentation of pathological bone formation improves understanding of the disease. We did not find any association between participant characteristics and evaluation of the VR experience or recommendation scores.

Conclusions: The data show that IA-targeting innovative teaching approaches based on VR technology are feasible.
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http://dx.doi.org/10.2196/23835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150404PMC
May 2021

Do patients with rheumatoid arthritis show a different course of COVID-19 compared to patients with spondyloarthritis?

Clin Exp Rheumatol 2021 May-Jun;39(3):639-647. Epub 2021 Mar 30.

Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus Liebig University Giessen, Bad Nauheim, Germany.

Objectives: Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are the most common inflammatory rheumatic diseases (IRD). The aim of this study was to elucidate differences in the outcome of SARS-CoV-2 infection in RA- and SpA-patients.

Methods: Data from the German COVID-19 registry for IRD patients from 30th March to 16th November 2020 were analysed. 208 RA and SpA patients were included in the study, matched for gender and age.

Results: 104 SpA patients (40% patients with ankylosing spondylitis, 54% with psoriatic arthritis and 6% with enteropathic arthritis) were compared to 104 RA patients. For both groups, median age was 56 years. TNF-i treatment was reported in 45% of the SpA and in 19% of RA patients (p=0.001). Glucocorticoids were used in 13% of the SpA and in 40% of the RA patients (p=0.001). In both groups, the majority of the patients (97% SpA, 95% RA) recovered from COVID-19. Hospitalisation was needed in 16% of the SpA and in 30% of the RA patients (p=0.05), and oxygen treatment in 10% and 18% respectively (p=ns). Three versus six (p=ns) fatal courses were reported in the SpA versus the RA group.

Conclusions: The study revealed that the hospitalisation rate during COVID-19 infection, but not the mortality, was significantly higher in RA as compared to SpA patients. This could be explained either by different treatment strategies or by different susceptibilities of the two diseases.
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May 2021

Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension.

Int J Mol Sci 2021 Mar 27;22(7). Epub 2021 Mar 27.

Department of Internal Medicine I, Univerisity Hospital Jena, 07747 Jena, Germany.

Background And Aims: Pulmonary hypertension (PH) is a heterogeneous disorder associated with poor prognosis. For the majority of patients, only limited therapeutic options are available. Thus, there is great interest to develop novel treatment strategies focusing on pulmonary vascular and right ventricular remodeling. Interleukin 9 (IL9) is a pleiotropic cytokine with pro- and anti-inflammatory functions. The aim of this study was to evaluate the therapeutic activity of F8IL9F8 consisting of IL9 fused to the F8 antibody, specific to the alternatively-spliced EDA domain of fibronectin, which is abundantly expressed in pulmonary vasculature and right ventricular myocardium in PH.

Methods: The efficacy of F8IL9F8 in attenuating PH progression in the monocrotaline mouse model was evaluated in comparison to an endothelin receptor antagonist (ERA) or an IL9 based immunocytokine with irrelevant antibody specificity (KSFIL9KSF). Treatment effects were assessed by right heart catheterization, echocardiography as well as histological and immunohistochemical tissue analyses.

Results: Compared to controls, systolic right ventricular pressure (RVPsys) was significantly elevated and a variety of right ventricular echocardiographic parameters were significantly impaired in all MCT-induced PH groups except for the F8IL9F8 group. Both, F8IL9F8 and ERA treatments lead to a significant reduction in RVPsys and an improvement of echocardiographic parameters when compared to the MCT group not observable for the KSFIL9KSF group. Only F8IL9F8 significantly reduced lung tissue damage and displayed a significant decrease of leukocyte and macrophage accumulation in the lungs and right ventricles.

Conclusions: Our study provides first pre-clinical evidence for the use of F8IL9F8 as a new therapeutic agent for PH in terms of a disease-modifying concept addressing cardiovascular remodeling.
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http://dx.doi.org/10.3390/ijms22073460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037792PMC
March 2021

Reliability of a Risk-Factor Questionnaire for Osteoporosis: A Primary Care Survey Study with Dual Energy X-ray Absorptiometry Ground Truth.

Int J Environ Res Public Health 2021 01 28;18(3). Epub 2021 Jan 28.

Institute of Diagnostic and Interventional Radiology, Jena University Hospital-Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany.

(1) Purpose: Predisposing factors to osteoporosis (OP) as well as dual-source x-ray densitometry (DXA) steer therapeutic decisions by determining the FRAX index. This study examines the reliability of a standard risk factor questionnaire in OP-screening. (2) Methods: = 553 eligible questionnaires encompassed 24 OP-predisposing factors. Reliability was assessed using DXA as a gold standard. Multiple logistic regression and Spearman's correlations, as well as the confounding influence of age and body mass index, were analyzed in SPSS (IBM Corporation, Armonk, NY, USA). (3) Results: Our study revealed low patient self-awareness regarding OP and its risk factors. One out of every four patients reported a positive history for osteoporosis not confirmed by DXA. The extraordinarily high incidence of rheumatoid arthritis and thyroid disorders likely reflect confusion with other diseases or health anxiety. FRAX-determining risk factors such as malnutrition, liver insufficiency, prior fracture without trauma, and glucocorticoid therapy did not correlate with increased OP incidence, altogether demonstrating how inaccurate survey information could influence therapeutic decisions on osteoporosis. (4) Conclusions: Contradictive results and a low level of patient self-awareness suggest a high degree of uncertainty and low reliability of the current OP risk factor survey.
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http://dx.doi.org/10.3390/ijerph18031136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908374PMC
January 2021

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

RMD Open 2021 01;7(1)

Epidemiology Unit, German Rheumatism Research Center Berlin, Berlin, Germany

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.
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http://dx.doi.org/10.1136/rmdopen-2020-001464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823432PMC
January 2021

Impact of a Heutagogical, Multimedia-Based Teaching Concept to Promote Self-Determined, Cooperative Student Learning in Clinical Radiology.

Rofo 2021 Jun 16;193(6):701-711. Epub 2020 Dec 16.

Institute for Medical Education, University Hospital of LMU Munich, Munich, Germany.

Purpose:  To date, didactic lecturing is a common method of university medical training. However, higher levels of competence to solve complex issues are hardly to be achieved with a largely passive learning style. We established and evaluated a heutagogical blended learning concept to investigate self-determined learning with a multimedia-based, interactive approach in the lecture room to teach clinical radiology.

Materials And Methods:  In the 2019/2020 winter semester, we included 266 medical students in their fourth academic year in our prospective, observational study. Students participated in a series of 11 radiological lectures given by 10 lecturers. They were requested to prepare for lectures by watching learning videos. During the lecture, students had to answer key-feature questions (KFQ) in small groups and to jointly submit their answers by means of an audience response system (ARS). After each lecture and the exam, we conducted surveys and compared results with a historical control group. A focus group interview with lecturers was performed after conclusion of the lecture series.

Results:  The students' overall impression of the "flipped classroom" concept and their examination grades were superior to historical controls (overall impression: 1.5 [95 % CI 1.4-1.6] vs. 2.7 [95 % CI 2.5-2.9] rated on a scale from 1 to 6, p < 0.001; examination grades: 1.8 [95 % CI 1.7-1.9] vs. 2.0 [95 % CI 1.9-2.0] rated on a scale from 1 to 5, p < 0.001). Most students agreed that learning videos (76.6 %), ARS (88.5 %), KFQ (76.5 %), and solution-oriented small group discussions (83.7 %) were useful. Lecturers stated an improved convergence of demands on learning and clinical competence. However, they also emphasized an increased initial effort for implementation.

Conclusion:  Students rated the overall benefit from the heutagogical "flipped classroom" concept as high. Examination grades improved. According to lecturers, the "flipped classroom" concept better matched later professional demands than traditional lectures.

Key Points:   · The benefit of the "flipped classroom" concept for radiological lectures was rated high by students.. · Most students were satisfied with the multimedia and interactive elements of lectures.. · Lecturers considered heutagogical learning demands as appropriate for later clinical requirements..

Citation Format: · Teichgräber U, Ingwersen M, Mentzel H et al. Impact of a Heutagogical, Multimedia-Based Teaching Concept to Promote Self-Determined, Cooperative Student Learning in Clinical Radiology. Fortschr Röntgenstr 2021; 193: 701 - 711.
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http://dx.doi.org/10.1055/a-1313-7924DOI Listing
June 2021

Dietary Energy Modulation and Autophagy: Exploiting Metabolic Vulnerabilities to Starve Cancer.

Front Cell Dev Biol 2020 5;8:590192. Epub 2020 Nov 5.

Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Cancer cells experience unique and dynamic shifts in their metabolic function in order to survive, proliferate, and evade growth inhibition in the resource-scarce tumor microenvironment. Therefore, identification of pharmacological agents with potential to reprogram cancer cell metabolism may improve clinical outcomes in cancer therapy. Cancer cells also often exhibit an increased dependence on the process known as autophagy, both for baseline survival and as a response to stressors such as chemotherapy or a decline in nutrient availability. There is evidence to suggest that this increased dependence on autophagy in cancer cells may be exploitable clinically by combining autophagy modulators with existing chemotherapies. In light of the increased metabolic rate in cancer cells, interest is growing in approaches aimed at "starving" cancer through dietary and pharmacologic interventions that reduce availability of nutrients and pro-growth hormonal signals known to promote cancer progression. Several dietary approaches, including chronic calorie restriction and multiple forms of fasting, have been investigated for their potential anti-cancer benefits, yielding promising results in animal models. Induction of autophagy in response to dietary energy restriction may underlie some of the observed benefit. However, while interventions based on dietary energy restriction have demonstrated safety in clinical trials, uncertainty remains regarding translation to humans as well as feasibility of achieving compliance due to the potential discomfort and weight loss that accompanies dietary restriction. Further induction of autophagy through dietary or pharmacologic metabolic reprogramming interventions may enhance the efficacy of autophagy inhibition in the context of adjuvant or neo-adjuvant chemotherapy. Nonetheless, it remains unclear whether therapeutic agents aimed at autophagy induction, autophagy inhibition, or both are a viable therapeutic strategy for improving cancer outcomes. This review discusses the literature available for the therapeutic potential of these approaches.
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http://dx.doi.org/10.3389/fcell.2020.590192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674637PMC
November 2020

Radiographic remission in rheumatoid arthritis quantified by computer-aided joint space analysis (CASJA): a post hoc analysis of the RAPID 1 trial.

Arthritis Res Ther 2020 10 6;22(1):229. Epub 2020 Oct 6.

Faculty of Medicine, Jena University Hospital - Friedrich Schiller, University Jena, Am Klinikum 1, 07747, Jena, Germany.

Background: The reduction of finger joint space width (JSW) in patients with rheumatoid arthritis (RA) is strongly associated with joint destruction. Treatment with certolizumab pegol (CZP), a PEGylated anti-TNF, has been proven to be effective in RA patients. The computer-aided joint space analysis (CAJSA) provides the semiautomated measurement of joint space width at the metacarpal-phalangeal joints (MCP) based on hand radiographs. The aim of this post hoc analysis of the RAPID 1 trial was to quantify MCP joint space distance (JSD-MCP) measured by CAJSA between baseline and week 52 in RA patients treated with certolizumab pegol (CZP) plus methotrexate (MTX) compared with MTX/placebo.

Methods: Three hundred twenty-eight patients were included in the post hoc analysis and received placebo plus MTX, CZP 200 mg plus MTX and CZP 400 mg plus MTX. All patients underwent X-rays of the hand at baseline and week 52 as well as assessment of finger joint space narrowing of the MCP using CAJSA (Version 1.3.6; Sectra; Sweden). The joint space width (JSW) was expressed as mean joint space distance of the MCP joints I to V (JSD-MCP).

Results: The MTX group showed a significant reduction of joint space of - 4.8% (JSD-MCP), whereas in patients treated with CZP 200 mg/MTX and CZP 400 mg/MTX a non-significant change (JSD-MCP + 0.6%) was observed. Over 52 weeks, participants with DAS28 remission (DAS28 ≤ 2.6) exhibited a significant joint space increase of + 3.3% (CZP 200 mg plus MTX) and + 3.9% (CZP pegol 400 mg plus MTX).

Conclusion: CZP plus MTX did not reduce JSD-MCP estimated by CAJSA compared with MTX/placebo. Furthermore, clinical remission (DAS28 ≤ 2.6) in patients treated with CZP plus MTX was associated with an increasing JSD, indicating radiographic remission in RA.
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http://dx.doi.org/10.1186/s13075-020-02322-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541323PMC
October 2020

Musculoskeletal Ultrasound Can Aid in Diagnosis and Follow-up of a Patient With Eosinophilic Fasciitis.

J Clin Rheumatol 2020 Sep 23. Epub 2020 Sep 23.

From the Department of Internal Medicine III, Jena University Hospital-Friedrich-Schiller-University Jena, Jena.

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http://dx.doi.org/10.1097/RHU.0000000000001477DOI Listing
September 2020

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.

RMD Open 2020 09;6(2)

Department of Rheumatology and Clinical Immunology, KEM Kliniken Essen-Mitte,Essen, Germany.

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.
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http://dx.doi.org/10.1136/rmdopen-2020-001332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507994PMC
September 2020

Refractory giant cell arteritis: the value of clinical symptoms and imaging.

BMJ Case Rep 2020 Sep 2;13(9). Epub 2020 Sep 2.

Clinic of Nuclear Medicine, University Hospital Jena, Jena, Germany.

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http://dx.doi.org/10.1136/bcr-2020-237623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470493PMC
September 2020

Influence of Macitentan on the Vascular Tone and Recruitment of Finger Capillaries Under Hypobaric Hypoxia in High Altitude.

High Alt Med Biol 2020 Dec 31;21(4):336-345. Epub 2020 Jul 31.

Division of Cardiology, Department of Internal Medicine I, University Hospital Jena, Jena, Germany.

Betge, Stefan, Stefan Drinda, Thomas Neumann, Laura Bäz, Alexander Pfeil, Christian Schulze, Ralf Mrowka, Christian Jung, and Marcus Franz. Influence of macitentan on the vascular tone and recruitment of finger capillaries under hypobaric hypoxia in high altitude. . 21:336-345, 2020. Acute normobaric (NH) and hypobaric hypoxia (HH) has effects on the vascular tone of larger arteries and may have effects on the microcirculation. These effects may be noninvasively detectable by automated devices. A part of these effects may be mediated by endothelin (ET) and should be influenced by macitentan (MAC), a dual endothelin receptor antagonist (ERA). We used photoplethysmographic sensors, fingertip volume sensors, nailfold capillaroscopy, and laser Doppler probes at rest and after a 5-minute forearm ischemia in healthy study subjects under NH, under HH, and under HH plus a single dose of MAC. NH at simulated 4000 m led to increased heart rates (HR) and pulse wave velocities (PWV) and reduced augmentation index (AIX). The values for the AIX showed a high SD and differed between the used devices. At simulated 5500 m, only baseline mean value (BMV; EndoPAT) showed a further change, indicating less filled capillaries of the fingertips. HH (2978 m) increased HR, blood pressure values, and PWV. Focusing on the microcirculation of the fingertips, HH reduced the BMV and the nailfold capillary density and the postischemic capillary recruitment. MAC had no effect on the BMV, but antagonized the effects of HH on the nailfold capillaries and led to a strongly increased postischemic diameter of the arterial limbs. Concordantly, the postischemic blood flow velocity increment, measured through ultrasound Doppler, was increased at ALT+MAC. The BMV may be a parameter for changes of the microcirculation of the finger tips. A single dose of MAC blocked hypoxia-induced capillary rarefaction and enhanced postischemic hyperemia of the fingertips. These results indicate the importance of ET-1 for the regulation of the microcirculation under hypoxia. The German Registry of Clinical Studies (DRKS) ID: 00005459.
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http://dx.doi.org/10.1089/ham.2019.0120DOI Listing
December 2020

Serum Biomarkers of Cardiovascular Remodelling Reflect Extra-Valvular Cardiac Damage in Patients with Severe Aortic Stenosis.

Int J Mol Sci 2020 Jun 11;21(11). Epub 2020 Jun 11.

Department of Internal Medicine I, University Hospital Jena, Friedrich Schiller University, 07747 Jena, Germany.

In patients with aortic stenosis (AS), a novel staging classification of extra-valvular left and right heart damage with prognostic relevance was introduced in 2017. The aim of the study was to evaluate the biomarkers of cardiovascular tissue remodelling in relation to this novel staging classification. Patients were categorized according to the novel staging classification into stages 0 to 4. The levels of matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinases 1 (TIMP-1), B and C domain containing tenascin-C (B Tn-C, C Tn-C), the ED-A and ED-B domain containing fibronectin (ED-A Fn, ED-B Fn), endothelin 1 (ET-1) and neutrophil gelatinase-associated lipocalin (NGAL) were determined in serum by ELISA. There were significantly decreased serum levels of MMP-9 and increased levels of B Tn-C and C Tn-C when comparing stages 0 and 1 with stage 2, with no further dynamics in stages 3 and 4. In contrast, for TIMP-1, C Tn-C, ED-A Fn, ET-1 and NGAL, significantly increased serum levels could be detected in stages 3 and 4 compared to both stages 0 and 1 and stage 2. ED-A Fn and ET-1 could be identified as independent predictors of the presence of stage 3 and/or 4. To the best of our knowledge, this is the first study identifying novel serum biomarkers differentially reflecting the patterns of left and right heart extra-valvular damage in patients suffering from AS. Our findings might indicate a more precise initial diagnosis and risk stratification.
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http://dx.doi.org/10.3390/ijms21114174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312014PMC
June 2020

Granulomatosis with polyangiitis mimics ST-elevation myocardial infarction.

BMJ Case Rep 2020 May 5;13(5). Epub 2020 May 5.

Department of Internal Medicine III, University Hospital Jena, Jena, Thueringen, Germany.

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http://dx.doi.org/10.1136/bcr-2020-234728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228444PMC
May 2020

Cell Intrinsic and Systemic Metabolism in Tumor Immunity and Immunotherapy.

Cancers (Basel) 2020 Apr 1;12(4). Epub 2020 Apr 1.

Department of Nutrition, University of North Carolina, Chapel Hill, NC 27516, USA.

Immune checkpoint inhibitor (ICI) therapy has shown extraordinary promise at treating cancers otherwise resistant to treatment. However, for ICI therapy to be effective, it must overcome the metabolic limitations of the tumor microenvironment. Tumor metabolism has long been understood to be highly dysregulated, with potent immunosuppressive effects. Moreover, T cell activation and longevity within the tumor microenvironment are intimately tied to T cell metabolism and are required for the long-term efficacy of ICI therapy. We discuss in this review the intersection of metabolic competition in the tumor microenvironment, T cell activation and metabolism, the roles of tumor cell metabolism in immune evasion, and the impact of host metabolism in determining immune surveillance and ICI therapy outcomes. We also discussed the effects of obesity and calorie restriction-two important systemic metabolic perturbations that impact intrinsic metabolic pathways in T cells as well as cancer cells.
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http://dx.doi.org/10.3390/cancers12040852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225951PMC
April 2020

Eyelid edema as first manifestation of anti-MDA5 positive dermatomyositis with rapidly progressive interstitial lung disease: A case report.

J Dtsch Dermatol Ges 2020 Mar 10;18(3):263-265. Epub 2020 Jan 10.

Department of Dermatology, University Hospital Jena, Jena, Germany.

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http://dx.doi.org/10.1111/ddg.14014DOI Listing
March 2020
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