Publications by authors named "Jan Leipe"

43 Publications

Immune checkpoint inhibitor-associated sarcoidosis: A usually benign disease that does not require immunotherapy discontinuation.

Eur J Cancer 2021 Aug 25. Epub 2021 Aug 25.

AP-HP.Université Paris-Saclay, Hôpital Bicêtre, Department of Internal Medicine and Clinical Immunology, Le Kremlin Bicêtre, France; Université Paris-Saclay; INSERM; CEA, Centre Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, IBFJ, Le Kremlin-Bicêtre, France. Electronic address:

Objective: To analyse the clinical patterns of sarcoidosis triggered by immune checkpoint inhibitors (ICIs) in patients with cancer.

Patients And Methods: The ImmunoCancer International Registry is a big data-sharing multidisciplinary network from 18 countries dedicated to evaluating the clinical research of immune-related adverse events related to cancer immunotherapies.

Results: We identified 32 patients with biopsy-proven sarcoidosis. Underlying cancer included mainly melanoma (n = 24). Cancer immunotherapy consisted of monotherapy in 19 cases (anti-PD-1 in 18 and ipilimumab in 1) or combined ipilimumab + nivolumab in 13. The time median interval between initiation of ICI and sarcoidosis diagnosis was 3 months (range, 2-29 months). The use of combined ICI was associated with a shorter delay in developing sarcoidosis symptoms. The disease was symptomatic in 19 (59%) cases with mostly cutaneous, respiratory and general symptoms. The organs involved included mainly the mediastinal lymph nodes (n = 32), the lungs (n = 11), the skin (n = 10) and the eyes (n = 5). Pulmonary computed tomography studies showed bilateral hilar lymphadenopathy in all cases. There was no severe manifestation. Specific systemic therapy was required in only 12 patients (37%): oral glucocorticoids in 9, and hydroxychloroquine in 3. ICIs were held in 25 patients (78%) and definitively discontinued in 18 (56%) patients. Seven patients continued ICI treatment with a second flare in one case. In six additional patients, an ICI was reintroduced with no harm, and sarcoidosis relapsed in one of them.

Conclusion: Our study shows that ICI-related sarcoidosis seems to have a specific profile, possibly more benign than that of idiopathic sarcoidosis, and does not necessarily imply ICI discontinuation.
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http://dx.doi.org/10.1016/j.ejca.2021.05.041DOI Listing
August 2021

Patient and Graft Survival After Dual Kidney Transplantation With Marginal Donors in Comparison to Matched Control Groups.

Transplant Proc 2021 Aug 21. Epub 2021 Aug 21.

Vth Department of Medicine, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany; Transplant Center Mannheim, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany; European Center of Angioscience Ecas, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany; Mannheim Institute for Innate Immunoscience, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany. Electronic address:

Background: Postmortal organ donor rates remain low in Germany, whereas donor age has been increasing considerably in the last decades. As a consequence of low donation rates older and more marginal donor kidneys are accepted for transplantation. However, procured kidneys from very old a/o marginal donors may be considered as not suitable for transplantation as a single organ and subsequently be discarded. However, dual transplantation of both kidneys from such donors may provide an opportunity to nevertheless use these organs for renal transplantation, thereby providing the twofold nephron mass as a single kidney transplantation.

Methods: We compared in this retrospective analysis the outcome of 10 recipients of a dual kidney transplantation (DKT) with 40 matched recipients of a single kidney transplantation (SKT). Recipients were matched for donor and recipient age (ie, a maximum age difference of ±10 years in a ratio of 1:4 for DKT vs SKT recipients). In addition, a second SKT control group of 10 SKT recipients being transplanted immediately before each DKT recipient with a kidney from a donor aged ≥65 years was used for comparison. All renal transplant recipients were observed for up to 3 years or until July 31, 2020.

Results: Mean donor and recipient age was 77.2 ± 4.6/75.1 ± 6.6/82.1 ± 7.9 and 66.4 ± 5.8/66.1 ± 6.0/64.8 ± 8.4 for SKT group 1/SKT group 2/DKT, respectively. Procurement serum creatinine concentrations were significantly higher in the DKT group in comparison to the SKT control group 1 (P = .019) as was the rate of transplant artery atherosclerosis (P = .021). Furthermore, Kidney Donor Profile Index, and Kidney Donor Risk Index were significantly higher (P = .0138/P = .064, and P < .001/P = .038) in the DKT group than in SKT group 1 and 2. Rates of acute rejection and delayed graft function were not significantly different between groups, though biopsy-proven acute rejection was numerically higher in the SKT groups. Patient survival and overall and death-censored graft survival rates were also not significantly different between groups, although they tended to be higher after DKT.

Conclusions: DKT provides an opportunity to successfully use postmortal kidneys even from donors aged >80 years and a Kidney Donor Profile Index ≥95% for renal transplantation. DKT may thereby increase the available pool of donors to better serve patients with end-stage renal disease on the waiting list.
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http://dx.doi.org/10.1016/j.transproceed.2021.07.016DOI Listing
August 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

Updated recommendations of the German Society for Rheumatology for the care of patients with inflammatory rheumatic diseases in times of SARS-CoV-2-methodology, key messages and justifying information.

Rheumatology (Oxford) 2021 05;60(5):2128-2133

Clinic for Rheumatology and Clinical Immunology, Kliniken Essen-Mitte, Essen, Germany.

A few days after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was declared a pandemic, the German Society for Rheumatology (DGRh) compiled the first group of recommendations for the care of patients with inflammatory rheumatic diseases in light of SARS-CoV-2/coronavirus disease 2019 (COVID-19). These first recommendations were based on an expert consensus and were largely non-evidence-based. Now that the first scientific data from registries, cross-sectional studies, case reports and case series are available, the DGRh has developed a timely update. This update is based on a literature search of publications available through 15 June 2020 and addresses preventive measures (such as hygiene measures or vaccinations) and the use of immunomodulatory/immunosuppressive drugs. Driven by the commitment to let patients benefit from these new evidence-based recommendations as quickly as possible, the DGRh published the update in German on its homepage and in the Zeitschrift für Rheumatologie immediately after completion. Here we report the key recommendations to make them available to the international community, provide the scientific methodology used to develop the recommendations, give additional thoughts and advice for the management of patients with rheumatic diseases during the COVID-19 pandemic and discuss our recommendations in the context of other international recommendations.
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http://dx.doi.org/10.1093/rheumatology/keab072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928544PMC
May 2021

Immune Status and Mortality in Smokers, Ex-smokers, and Never-Smokers: The Ludwigshafen Risk and Cardiovascular Health Study.

Nicotine Tob Res 2021 06;23(7):1191-1198

Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Introduction: Elevated leukocyte counts are associated with cardiovascular disease. Smoking induces inflammation and alters levels of leukocyte subtypes.

Aims And Methods: Our aim was to investigate the effect of smoking on circulating immune cells and their association with mortality. Lymphocyte subtypes were identified by flow cytometry of fluorescent-labeled cells. We analyzed the association of leukocytes with mortality using Cox regression and assessed their effect on risk prediction based on principle components (PCs) using area under the receiver operating characteristic curve and net-reclassification in 2173 participants from the Ludwigshafen Risk and Cardiovascular Health Study, a prospective case-control study in patients who underwent coronary angiography.

Results: The numbers of T cells, monocytes, and neutrophils were higher and natural killer cells were lower in smokers compared with never-smokers. In never-smokers, lymphocyte counts were inversely associated with mortality while a positive association was observed for neutrophils. The neutrophil-to-lymphocyte ratio (NLR) had the strongest association in never-smokers with a hazard ratio (95% confidence interval) of 1.43 (1.26-1.61). No associations were found in smokers. Adding the first five PCs or the NLR to a risk prediction model based on conventional risk factors did not improve risk prediction in smokers, but significantly increased the area under the curve from 0.777 to 0.801 and 0.791, respectively, in never-smokers.

Conclusions: Lymphocyte counts were inversely associated with mortality in never-smokers but not in active smokers. Markers of innate immunity, namely total neutrophils and CD11b+/CD18+ and CD31+/CD40- granulocytes, were directly associated with mortality. Adding markers of immune function like PCs or the NLR to basic risk models improved risk prediction in never-smokers only.

Implications: Total leukocyte counts were higher in active smokers as compared to never-smokers due to elevated counts of neutrophils and monocytes but declined in ex-smokers with increasing time since quitting. In the never-smokers but not in smokers, lymphocyte counts were inversely associated with mortality while there was a direct association with neutrophils, even after adjustment for conventional cardiovascular risk factors. Adding markers of immune function to basic risk models improved risk prediction in never-smokers only. Our data indicate that smoking status has an important impact on the ability of leukocyte counts to predict long-term cardiovascular outcomes.
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http://dx.doi.org/10.1093/ntr/ntab011DOI Listing
June 2021

The effect of hydroxychloroquine on platelet activation in model experiments.

J Thromb Thrombolysis 2021 Jan 2. Epub 2021 Jan 2.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Hydroxychloroquine (HCQ) is an antimalarial agent with pleiotropic effects and now represents a cornerstone in the management of patients with autoimmune conditions. While clinical series suggest anti-thrombotic properties, the way in which HCQ exerts this effect remains to be fully explained. Following a 24-h incubation of human umbilical vein endothelial cells (HUVEC) and human umbilical arterial endothelial cells (HUAEC) with HCQ (concentration 500, 1000 and 2000 ng/ml), these cells were then stimulated for an hour with tumor necrosis factor alpha (TNF-α) and were subsequently incubated in direct contact with thrombin-activated platelets. The expression of CD40L on platelets was measured by flow cytometry. The expression of CD40L on platelets significantly increased after direct incubation with 1000 ng/ml and 2000 ng/ml concentrations of HCQ. In contrast, after pre-incubation of HUAECs with 1000 ng/ml HCQ and following stimulation with platelets the expression of CD40L was significantly reduced also after stimulation with thrombin and TNF-α activated platelets. It was shown that the expression of CD40L on the platelets was not significantly reduced by different HCQ concentrations after contact with HCQ pre-incubated HUVECs. HCQ reduces the stimulatory effect of thrombin and TNF-α on platelet activation in the presence of endothelial cells. Our experiments suggest that HCQ pre-incubated HUAEC cells result in a reduced platelets activation measured by means of CD40L expression. Further, our results show that direct HCQ incubation of platelets (without the presence of EC) increased the expression of CD40L suggesting that the observed effect of HCQ on platelet activation may be EC mediated.
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http://dx.doi.org/10.1007/s11239-020-02325-yDOI Listing
January 2021

Long, relapsing, and atypical symptomatic course of COVID-19 in a B-cell-depleted patient after rituximab.

Semin Arthritis Rheum 2020 10 30;50(5):1087-1088. Epub 2020 Jun 30.

Department of Medicine II, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.semarthrit.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833880PMC
October 2020

High rates of therapeutic changes in patients with psoriatic arthritis receiving treatment with disease-modifying antirheumatic drugs: A cross-sectional study.

Mod Rheumatol 2021 Aug 26:1-9. Epub 2021 Aug 26.

Division of Rheumatology, Department of Medicine V, University Hospital, Mannheim, Germany.

Objectives: To characterize treatment patterns for patients with psoriatic arthritis (PsA) currently receiving any disease-modifying antirheumatic drug (DMARD).

Methods: The trategy for soriatic rthritis n ermany (SPAIG) study was a retrospective observational study conducted from May to November 2017 at 46 rheumatology centers. Current and previous treatment data were collected at a single visit from adult patients with PsA and psoriasis who received DMARD treatment for ≥6 of the previous 12 months. The primary outcome was the proportion of patients receiving a biologic DMARD (bDMARD). Multinomial logistic regression analysis was used to evaluate associations between current characteristics and initial choice of therapy.

Results: Mean age of the 316 patients was 55.1 years and mean PsA disease duration was 9.9 years. PsA activity was generally comparable across treatment groups. In this cohort, 57.3% of patients were currently treated with bDMARDs, 37.7% with conventional synthetic DMARDs, and 4.4% with targeted synthetic DMARDs. Almost half (48.4%) of patients reported DMARD modifications in the previous 12 months. Specific comorbidities and patient/disease characteristics were associated with initial therapy.

Conclusion: DMARD treatment of PsA is frequently modified, suggesting the need for more effective therapies and assessment tools.
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http://dx.doi.org/10.1080/14397595.2020.1816597DOI Listing
August 2021

[Recommendations of the German Society for Rheumatology for management of patients with inflammatory rheumatic diseases in the context of the SARS-CoV-2/COVID-19 pandemic - Update July 2020].

Z Rheumatol 2020 Sep;79(7):679-685

Deutsche Gesellschaft für Rheumatologie e. V., Berlin, Deutschland.

A few days after the SARS-CoV-2 infection was declared a pandemic, the German Society for Rheumatology (DGRh) compiled first recommendations for the care of patients with inflammatory rheumatic diseases (IRD). These first recommendations were based on an expert consensus and were largely non-evidence-based. Now that the first scientific data from registers, cross-sectional studies, case reports and case series are available, the present update is intended to update the previous recommendations and to add new findings. The current recommendations are based on a literature search of publications available up to 15 June 2020 and address preventive measures (such as hygiene measures or vaccinations) and the use of immunomodulatory/immunosuppressive drugs. An important goal of the current recommendations is also to prevent harm to patients with IRD through unjustified restriction of care. The DGRh will continue to update its recommendations in the case of new aspects and will publish them as well as further information on the COVID-19 pandemic on its homepage ( www.dgrh.de ) in an ongoing process.
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http://dx.doi.org/10.1007/s00393-020-00851-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403789PMC
September 2020

Mentoring for postdoctoral researchers in rheumatology: the Emerging EULAR Network (EMEUNET) post-doc mentoring programme.

RMD Open 2020 02 3;6(1). Epub 2020 Feb 3.

Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.

Objective: This study aims to (1) assess the perceived need for a postdoctoral (post-doc) mentoring programme in rheumatology, (2) describe the characteristics and organisational aspects of a pilot mentoring programme implemented by the EMerging European League Against Rheumatism NETwork (EMEUNET) and (3) report mentors' and mentees' evaluation of the pilot programme.

Methods: An online survey was conducted among young researchers in rheumatology to evaluate the need and preferred characteristics of a post-doc mentoring initiative. Informed by the survey, a pilot programme was designed and launched. The pilot programme was evaluated with 3-month, 6-moth and 12-month surveys and interviews with mentees and a 12-month survey among mentors, after completion.

Results: From 275 responses (43 countries, 86% from Europe) collected, analyses were restricted to the target population (total population=158; post-docs (n=103 (65%)) and PhD students (n=55 (35%))). There was a clear need (99% positive responses) for a post-doc mentoring programme. Discussions about current and new projects, and how to lead projects were ranked as priorities in post-doc mentoring. The most desired mentor attribute was generosity and interest in helping (86%), followed by research experience (68%) and having a well-established network (66%). The pilot programme included four mentees (through competitive application) allocated to three mentors. Evaluation surveys and interviews revealed that the programme organisation and content were well appreciated by mentees and mentors.

Conclusions: The EMEUNET post-doc mentoring programme addresses unmet need for mentoring, is viable and appreciated by mentors and mentees. The programme structure and content are transferable to other fields where there is need for academic career mentoring.
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http://dx.doi.org/10.1136/rmdopen-2019-001139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999692PMC
February 2020

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.

Ann Rheum Dis 2021 01 23;80(1):36-48. Epub 2020 Apr 23.

Rheumatology, University Hospital of Bordeaux, Bordeaux, France.

Background: Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management.

Methods: First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed.

Results: The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies.

Conclusion: These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.
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http://dx.doi.org/10.1136/annrheumdis-2020-217139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788064PMC
January 2021

How We Manage Bone Marrow Edema-An Interdisciplinary Approach.

J Clin Med 2020 Feb 18;9(2). Epub 2020 Feb 18.

Comprehensive Osteology Center Munich, University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany.

Bone marrow edema (BME) is a descriptive term for a common finding in magnetic resonance imaging (MRI). Although pain is the major symptom, BME differs in terms of its causal mechanisms, underlying disease, as well as treatment and prognosis. This complexity together with the lack of evidence-based guidelines, frequently makes the identification of underlying conditions and its management a major challenge. Unnecessary multiple consultations and delays in diagnosis as well as therapy indicate a need for interdisciplinary clinical recommendations. Therefore, an interdisciplinary task force was set up within our large osteology center consisting of specialists from internal medicine, endocrinology/diabetology, hematology/oncology, orthopedics, pediatrics, physical medicine, radiology, rheumatology, and trauma surgery to develop a consenus paper. After review of literature, review of practical experiences (expert opinion), and determination of consensus findings, an overview and an algorithm were developed with concise summaries of relevant aspects of the respective underlying disease including diagnostic measures, clinical features, differential diagnosis and treatment of BME. Together, our single-center consensus review on the management of BME may help improve the quality of care for these patients.
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http://dx.doi.org/10.3390/jcm9020551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074543PMC
February 2020

Altered T cell plasticity favours Th17 cells in early arthritis.

Rheumatology (Oxford) 2020 10;59(10):2754-2763

Division of Rheumatology and Clinical Immunology, Medizinische Klinik and Poliklinik IV, University of Munich, Munich, Germany.

Objectives: The predominance of differentiated Th17 cells has been implied as a key driver of autoimmune arthritis, including early RA. Because accumulating evidence suggests that Th cell differentiation is a plastic process, we investigated plasticity and underlying molecular mechanisms to address the shift towards the Th17 phenotype in early RA.

Methods: A cohort of 61 patients with early, active, untreated RA and 45 age- and sex-matched healthy controls were studied. Viable in vitro- and in vivo-generated Th1, Th2 and Th17 cells were FACS-sorted and transdifferentiated under Th1-, Th2- or Th17-inducing conditions. The cytokine Th profile of the transdifferentiated cells was assessed by flow cytometry. Th cell-associated cytokine and transcription factor gene loci were analysed by chromatin immunoprecipitation assay and their expression by quantitative real-time PCR.

Results: In vitro-generated Th cells showed substantial plasticity, which was similar between RA and healthy controls, whereas in vivo-derived Th1 and Th2 cells from RA patients demonstrated an enhanced plasticity towards IL-17-expressing phenotypes compared with healthy controls. Further, in vivo-generated Th17 cells from RA patients showed a resistance to transdifferentiate into Th1 or Th2 cells. The serum/glucocorticoid-regulated kinase 1-forkhead box protein O1-IL-23 receptor (SGK1-FOXO1-IL-23R) axis together with increased RORC expression was associated with the predominant Th17 phenotype in early RA.

Conclusions: Our data indicate that in vivo-originated Th subsets are prone to Th17 cell transdifferentiation in early RA, while Th17 cells are resistant to changes in their phenotype. Together, the data imply that an altered plasticity contributes to the Th17 shift in early RA.
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http://dx.doi.org/10.1093/rheumatology/kez660DOI Listing
October 2020

Management of rheumatic complications of ICI therapy: a rheumatology viewpoint.

Rheumatology (Oxford) 2019 12;58(Suppl 7):vii49-vii58

Department of Rheumatology, Université Paris-Sud, AP-HP, Hôpitaux Universitaires Paris-Sud, Centre for Immunology of Viral Infections and Autoimmune Diseases, INSERM UMR1184, Le Kremlin Bicêtre, France.

Since immune checkpoint inhibitors became the standard of care for an increasing number of indications, more patients have been exposed to these drugs and physicians are more challenged with the management of a unique spectrum of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors. Those irAEs of autoimmune or autoinflammatory origin, or both, can involve any organ or tissue, but most commonly affect the dermatological, gastrointestinal and endocrine systems. Rheumatic/systemic irAEs seem to be less frequent (although underreporting in clinical trials is probable), but information on their management is highly relevant given that they can persist longer than other irAEs. Their management consists of anti-inflammatory treatment including glucocorticoids, synthetic and biologic immunomodulatory/immunosuppressive drugs, symptomatic therapies as well as holding or, rarely, discontinuation of immune checkpoint inhibitors. Here, we summarize the management of rheumatic/systemic irAEs based on data from clinical trials but mainly from published case reports and series, contextualize them and propose perspectives for their treatment.
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http://dx.doi.org/10.1093/rheumatology/kez360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900914PMC
December 2019

Influence of smoking and smoking cessation on biomarkers of endothelial function and their association with mortality.

Atherosclerosis 2020 01 15;292:52-59. Epub 2019 Nov 15.

Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; European Center for Angioscience ECAS, Medical Faculty Mannheim of the University Heidelberg, Mannheim, Germany.

Background And Aims: Endothelial dysfunction precedes atherosclerosis and smoking is a well-known risk factor for the development of endothelial dysfunction. The aim of our study was to analyse the effect of smoking on circulating markers of endothelial function and to investigate whether such effects have an influence on the potential use of these markers to estimate cardiovascular risk.

Methods: Stratified for smoking, levels of sE-/sP-/sL-selectin, von Willebrand (vWF), sICAM-1 and sVCAM-1, their association with mortality using Cox regression, and their accuracy of risk prediction using area-under-the-ROC-curve and net-reclassification-index were analysed in 1926 participants from the Ludwigshafen Risk and Cardiovascular Health (LURIC) - a prospective case-control study in patients who underwent coronary angiography with a median mortality follow-up of 10.6 years.

Results: In smokers, higher concentrations of sICAM-1, sE-selectin sP-selectin, but lower concentrations of sL-selectin and sVCAM-1, were detected compared to never-smokers. A direct association with mortality was found for levels of sICAM-1, sVCAM-1 and vWF regardless of smoking. Low sL-selectin levels were inversely associated with mortality in heavy and light smokers, with hazard ratios of 0.72 and 0.67 per 1-SD increase, adjusted for cardiovascular risk factors. Adding sL-selectin to a model based on traditional risk factors significantly improved AUC from 0.725 to 0.752 (p = 0.034) with an NRI of 43% (16.9%-62.3%).

Conclusions: Smoking alters the concentration of circulating markers of endothelial function. sL-selectin is decreased in smokers, inversely associated with risk, and could be a useful marker to improve risk prediction.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.11.017DOI Listing
January 2020

Increased plasticity of non-classic Th1 cells toward the Th17 phenotype.

Mod Rheumatol 2020 Sep 17;30(5):930-936. Epub 2019 Oct 17.

Division of Rheumatology and Clinical Immunology, Medizinische Klinik and Poliklinik IV, University of Munich, Munich, Germany.

To analyze occurrence and plasticity of two recently described distinct subtypes of Th1 cells named classic (CD161-/CCR6-) and non-classic (CD161+/CCR6+) Th1 cells in early rheumatoid arthritis (RA) patients and healthy controls (HCs). Frequencies of -generated Th1 cell populations were assessed after cytokine secretion assay for IFNγ/IL-17 and surface staining for CD161/CCR6. Viable Th1 cells (IFNγ+IL-17-) were sorted into classic Th1 (CD161-CCR6-) and non-classic Th1 (CD161+CCR6+) cells, trans-differentiated under different Th cell-inducing conditions, and assessed for plastic changes by analyzing the Th cell-associated cytokine and transcription factor profiles. frequencies of classic (CD161-CCR6-) and non-classic (CD161+CCR6+) Th1 cells as well as related Th1 cell subpopulations CD161+CCR6- and CD161-/CCR6+ did not differ significantly between RA and HCs. However, trans-differentiation of non-classic (CD161+CCR6+) and CD161-/CCR6+ Th1 cells resulted in a substantial shift toward Th17 and Th1/Th17 phenotypes, particularly under Th17-inducing conditions. In contrast, classic (CD161-/CCR6-) and CD161+CCR6- Th1 cells showed higher plasticity towards IL-4-producing cells, most of them shifting to a Th1/Th2 phenotype. Whereas non-classic (CD161+/CCR6+) and CD161-CCR6+ Th1 cells demonstrated an increased plasticity towards IL-17- phenotypes, classic Th1 and CD161+CCR6- Th1 cells showed more plasticity towards IL-4-producing phenotypes.
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http://dx.doi.org/10.1080/14397595.2019.1667473DOI Listing
September 2020

How I treat cancer: treatment of rheumatological side effects of immunotherapy.

ESMO Open 2019 17;4(Suppl 4):e000529. Epub 2019 Jul 17.

Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1136/esmoopen-2019-000529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677979PMC
July 2019

Long- and short-term association of low-grade systemic inflammation with cardiovascular mortality in the LURIC study.

Clin Res Cardiol 2020 Mar 1;109(3):358-373. Epub 2019 Jul 1.

Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6/VI 21, 8010, Graz, Austria.

Background: The present study aimed to evaluate biomarkers representing low-grade systemic inflammation and their association with cardiovascular mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

Methods: The included 3134 consecutive patients underwent coronary angiography between June 1997 and May 2001 with a median follow-up of 9.9 years. Plasma levels of IL-6, and acute-phase reactants serum amyloid A (SAA) and C-reactive protein (CRP) were measured. SAA and IL-6 polymorphisms were genotyped.

Results: During a median observation time of 9.9 years, 949 deaths (30.3%) occurred, of these 597 (19.2%) died from cardiovascular causes. High plasma levels of IL-6, CRP and SAA were associated with unstable CAD, as well as established risk factors including type 2 diabetes mellitus, smoking, low glomerular filtration rate, low TGs and low HDL-C. After adjusting for established cardiovascular risk markers and the other two inflammatory markers, SAA was found to be an independent risk factor for cardiovascular mortality after a short-term follow-up (6 months-1 year) with a HR per SD of 1.41. IL-6 was identified as an independent risk factor for long-term follow-up (3, 5, and 9.9 years) with HRs per SD of 1.21, 1.22 and 1.18. CRP lost significance after adjustment. Although 6 out of 27 SAA SNPs were significantly associated with SAA plasma concentrations, the genetic risk score was not associated with cardiovascular mortality.

Conclusions: The present findings from the large, prospective LURIC cohort underline the importance of inflammation in CAD and the prognostic relevance of inflammatory biomarkers that independently predict cardiovascular mortality.
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http://dx.doi.org/10.1007/s00392-019-01516-9DOI Listing
March 2020

Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management.

ESMO Open 2019 23;4(3):e000491. Epub 2019 May 23.

Department of Dermatology, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany.

The inhibition of the mitogen-activated protein kinases signalling pathway through combined use of BRAF and MEK inhibitors (BRAFi+MEKi) represents an established therapeutic option in patients with -mutated, advanced melanoma. These efficient therapies are well tolerated with mostly moderate and reversible side effects and a discontinuation rate due to adverse events of 11.5%-15.7%. Median duration of therapy ranges between 8.8 and 11.7 months. Based on data from confirmatory trials, safety profiles of three BRAFi+MEKi combinations were reviewed, that is, dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib. Many adverse events are class effects, such as cutaneous, gastrointestinal, ocular, cardiac and musculoskeletal events; some adverse events are substance associated. Fever (dabrafenib) and photosensitivity (vemurafenib) are the most common and clinically prominent examples. Other adverse events are less frequent and the association to one substance is less strong such as anaemia, facial paresis (encorafenib), neutropenia (dabrafenib), skin rash, QTc prolongation and increased liver function tests (vemurafenib). This narrative review provides recommendations for monitoring, adverse event evaluation and management focusing on the clinically relevant side effects of the three regimens.
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http://dx.doi.org/10.1136/esmoopen-2019-000491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555610PMC
May 2019

[Management of adverse events in immune oncology - Practical aspects of immune-related adverse events during immune oncological treatment].

Dtsch Med Wochenschr 2019 03 30;144(5):346-353. Epub 2019 Jan 30.

The immune oncological treatment approach uses immune checkpoint inhibitors to prevent tumor cells from shutting down the immune system, and thus from escaping immune response. Following the clinical success of immune checkpoint inhibitors, the number of approved immune oncological therapies continues to increase. Response rates and overall survival with anti-PD-1/PD-L1 and CTLA-4 blockade could be further improved by combining both treatment approaches. However, checkpoint inhibition is associated with a unique spectrum of side effects termed immune-related adverse events. These typically occur 3 to 6 months after treatment start and resolve with adequate management procedures if detected early on. Therefore, profound patient education, sensitizing and monitoring are mandatory. We describe in this article selected frequent and rare adverse events that are clinically relevant. Furthermore, using case reports, interdisciplinary experts share their practice-based experience in the management of frequent pneumonic, endocrine, and gastro-intestinal immune-related adverse events.
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http://dx.doi.org/10.1055/a-0739-8194DOI Listing
March 2019

Characteristics and treatment of new-onset arthritis after checkpoint inhibitor therapy.

RMD Open 2018 17;4(2):e000714. Epub 2018 Aug 17.

Division of Rheumatology and Clinical Immunology, Department of Internal Medicine IV, Ludwig-Maximilians-University Munich, Munich, Germany.

Immune checkpoint inhibitors (ICIs) may cause immune-related adverse events (IRAEs). Characterisation and data on treatment of musculoskeletal IRAEs are scarce. In this cohort study, patients receiving ICI therapy who experienced arthralgia were evaluated for the presence of synovitis. Data on demographics, ICI regime, time of onset, imaging and response to therapy of synovitis were prospectively collected. Arthritis was demonstrated in 14 of 16 patients of whom 7 showed monarthritis, 5 had oligoarthritis and 2 had polyarthritis. Patients with ICI-induced arthritis were predominantly male (57%) and seronegative (69%). Regarding the detection of synovitis in staging imaging, moderate sensitivity for contrast-enhanced CT with PET-CT as reference was observed. Disease burden at baseline was high and was significantly reduced after anti-inflammatory treatment. Nine patients were treated with systemic and eight patients with intra-articular glucocorticoids. Six patients who flared on glucocorticoid treatment on tapering were given methotrexate resulting in long-term remission. Patients with synovitis were more likely to have good tumour response. Patients with ICI-induced arthritis were predominantly male and seronegative showing different patterns of arthritis with high disease burden. Good efficacy and safety was observed for methotrexate, particularly for ICI-induced polyarthritis.
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http://dx.doi.org/10.1136/rmdopen-2018-000714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109812PMC
August 2018

Relapses in three patients with Takayasu arteritis under tocilizumab treatment detected by contrast enhanced ultrasound.

Vasa 2018 Feb 22;47(2):149-152. Epub 2017 Dec 22.

3 Division of Rheumatology and Clinical Immunology, Medical Clinic and Policlinic IV, Hospital of the Ludwig-Maximilians-University, Munich, Germany.

Takayasu arteritis (TA) is a rare large vessel vasculitis, affecting the aorta and its major branches, typically in young women. In this case report, we present three cases of young women of Caucasian descent who experienced relapses while under treatment with the monoclonal humanized antibody to the interleukin 6 receptor, tocilizumab. Active vasculitic lesions of the supraaortic (common carotid and axillary) arteries were detected and characterized via high resolution contrast enhanced ultrasound. Based on these cases, we discuss the potential role of contrast enhanced ultrasound in the diagnosis and follow-up of TA as well as the current data on the efficacy of tocilizumab in the treatment of TA.
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http://dx.doi.org/10.1024/0301-1526/a000679DOI Listing
February 2018

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions.

Cancer Treat Rev 2017 Jun 18;57:36-49. Epub 2017 May 18.

Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Germany. Electronic address:

Background: Combined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in numerous cancer indications, with PD-1 inhibitor nivolumab plus CTLA-4 inhibitor ipilimumab in advanced melanoma as first-ever approved therapies for combined ICB. However, gains in efficacy must be balanced against a higher frequency and severity of adverse drug reactions (ADR). Because delays in diagnosis and management might result in symptom worsening and further complications, clinicians shall be well trained to identify ADR promptly and monitor patients adequately. This paper reviews safety data assessed by the European Medicines Agency for the anti-PD-1/CTLA-4 combination and provides a literature overview on published case reports for rare ADR with suspected potential underreporting. Incidences and kinetics of immune-related ADR are described. Recommendations for the evaluation and management of ADR are convened by an interdisciplinary expert panel focusing on rare but clinically important side effects arising from combined ICB. Pooled safety data from 1551 patients with advanced melanoma, treated either with 3mg/kg ipilimumab plus 1mg/kg nivolumab (N=407), or nivolumab alone (N=787), or ipilimumab alone (N=357) demonstrate that immune-related ADR occur more frequently for the combination, with a shorter time-to-onset, and tend to be more severe. The majority of events is reversible after systemic use of glucocorticoids, notably methylprednisolone or equivalents; in certain cases of long-lasting and refractory immune toxicities, non-steroidal immunosuppressants may be used, once ICB is interrupted or terminated. Combined ICB has considerable toxicities, therefore close monitoring and high experience in diagnosis and treatment of ADR is necessary.
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http://dx.doi.org/10.1016/j.ctrv.2017.05.003DOI Listing
June 2017

Erratum to: The influence of long distance running on sonographic joint and tendon pathology: results from a prospective study with marathon runners.

BMC Musculoskelet Disord 2016 09 2;17(1):381. Epub 2016 Sep 2.

Division of Rheumatology and Clinical Immunology, Medizinische Klinik und Poliklinik IV, University of Munich, Pettenkoferstr. 8a, D-80336, Munich, Germany.

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http://dx.doi.org/10.1186/s12891-016-1223-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010742PMC
September 2016

The influence of long distance running on sonographic joint and tendon pathology: results from a prospective study with marathon runners.

BMC Musculoskelet Disord 2016 07 11;17:272. Epub 2016 Jul 11.

Division of Rheumatology and Clinical Immunology, Medizinische Klinik und Poliklinik IV, University of Munich, Pettenkoferstr. 8a, D-80336, Munich, Germany.

Background: The impact of physical exercise on joints and tendons is still a matter of debate. The aim of this study was to investigate with ultrasound the acute effects of extreme physical exercise on knee and ankle joints and their surrounding structures in trained athletes.

Methods: Participants of the Munich marathon were examined by arthrosonography before and after long distance running. Ultrasound assessment included grey scale and power Doppler examination of the knee and talocrural joints with surrounding tendons. Findings consistent with joint effusion, tendon and/or entheseal pathologies were documented. In addition to the ultrasound evaluation, information on training habits and past or present arthralgia or joint swelling was gathered.

Results: One Hundred Five runners completed both the pre- and post-excercise ultrasound assessments (baseline and follow-up), resulting in the sonographic evaluation of 420 knee and talocrural joints. At baseline, 105 knee (50) and 38 talocrural joints (18.1) showed effusions, compared to 100 knee (47.6) and 33 talocrural joints (15.7 %) at follow-up. The differences were not significant (p > 0.05 each). Effusion size did not correlate with the timepoint of ultrasound assessment and was independent of covariates such as gender, age or running distance. Hypervascularity of the patellar tendon was detected in 21 cases (10.0 %) at follow-up in contrast to one at baseline (p < 0.001). This observation was more frequent in male than in female participants (p < 0.05).

Conclusions: Acute physical stress is significantly associated with hypervascularity of the patellar tendon. No significant changes of synovial effusion were detected in knee and talocrural joints.
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http://dx.doi.org/10.1186/s12891-016-1121-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940861PMC
July 2016

Methylation of an intragenic alternative promoter regulates transcription of GARP.

Biochim Biophys Acta 2016 Feb 14;1859(2):223-34. Epub 2015 Nov 14.

Division of Rheumatology and Clinical Immunology, Medizinische Klinik und Poliklinik IV, University of Munich, 80336 Munich, Germany.

Alternative promoter usage has been proposed as a mechanism regulating transcriptional and translational diversity in highly elaborated systems like the immune system in humans. Here, we report that transcription of human glycoprotein A repetitions predominant (GARP) in regulatory CD4 T cells (Tregs) is tightly regulated by two alternative promoters. An intragenic promoter contains several CpGs and acts as a weak promoter that is demethylated and initiates transcription Treg-specifically. The strong up-stream promoter containing a CpG-island is, in contrast, fully demethylated throughout tissues. Transcriptional activity of the strong promoter was surprisingly down-regulated upon demethylation of the weak promoter. This demethylation-induced transcriptional attenuation regulated the magnitude of GARP expression and correlated with disease activity in rheumatoid arthritis. Treg-specific GARP transcription was initiated by synergistic interaction of forkhead box protein 3 (Foxp3) with nuclear factor of activated T cells (NFAT) and was underpinned by permissive chromatin remodeling caused by release of the H3K4 demethylase, PLU-1. Our findings describe a novel function of alternative promoters in regulating the extent of transcription. Moreover, since GARP functions as a transporter of transforming growth factor β (TGFβ), a cytokine with broad pleiotropic traits, GARP transcriptional attenuation by alternative promoters might provide a mechanism regulating peripheral TGFβ to avoid unwanted harmful effects.
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http://dx.doi.org/10.1016/j.bbagrm.2015.11.003DOI Listing
February 2016

Increased Th17 cell frequency and poor clinical outcome in rheumatoid arthritis are associated with a genetic variant in the IL4R gene, rs1805010.

Arthritis Rheumatol 2014 May;66(5):1165-75

Medizinische Klinik and Poliklinik IV, University of Munich, Munich, Germany.

Objective: The minor allele of the IL4R gene single-nucleotide polymorphism, rs1805010, confers impaired interleukin-4 (IL-4) signaling and has been associated with an aggressive destructive course of rheumatoid arthritis (RA). IL-4 inhibits the development of Th17 cells, a cell population recently identified as being prominent in RA patients and being associated with cartilage and bone destruction. The purpose of the present study was to investigate whether rs1805010 modulates Th17 cell development and, hence, subsequent clinical outcome in RA.

Methods: A total of 90 patients with early, active RA (mean ± SD Disease Activity Score in 28 joints 4.6 ± 1.1) and 39 control subjects (24 healthy subjects and 15 patients with osteoarthritis [OA]) were genotyped. Serum levels of IL-17 and IL-22 as well as frequencies of Th17 cells were analyzed by enzyme-linked immunosorbent assay and flow cytometry. Clinical and radiographic data were collected and evaluated at baseline and 1 year after disease onset.

Results: Twenty-six percent of the RA patients were homozygous for the major allele of rs1805010, 60% were heterozygous, and 14% were homozygous for the minor allele. The RA patients who were homozygous for the minor allele demonstrated significantly higher clinical activity associated with the presence of erosions after 1 year of followup as compared to the other RA patients. The inhibitory effect of IL-4 on Th17 cell development in these patients was significantly less prominent. Accordingly, the frequencies of Th17 cells and serum levels of IL-17 and IL-22 were significantly increased.

Conclusion: The data indicate that the rs1805010 minor allele contributes to increased Th17 cell frequency, enhanced clinical activity, and accelerated radiographic progression in RA by rendering CD4 T cells from RA patients insensitive to the attenuating effect of IL-4 on Th17 cell development.
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http://dx.doi.org/10.1002/art.38343DOI Listing
May 2014

Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis.

Ann Rheum Dis 2015 Jun 21;74(6):1265-74. Epub 2014 Feb 21.

Division of Rheumatology and Clinical Immunology, Medizinische Klinik und Poliklinik IV, University of Munich, Munich, Germany.

Objectives: MicroRNAs (miRNAs) have been implicated in the pathogenesis of autoimmune diseases, not least for their critical role in the regulation of regulatory T cell (Treg) function. Deregulated expression of miR-146a and miR-155 has been associated with rheumatoid arthritis (RA). We therefore investigated miR-146a and miR-155 expression in Tregs of patients with RA and their possible impact on Treg function and disease activity.

Methods: Expression of miR-146a and miR-155 was assessed in RA patients and controls. MiRNA expression was correlated with disease activity and expression of target genes. Interference with biological activity of miRNAs was evaluated in functional Treg assays.

Results: Diminished upregulation of miR-146a and miR-155 in response to T cell stimulation was found in Tregs of RA patients. Diminution of miR-146a expression was observed in particular in patients with active disease, and correlated with joint inflammation. In patients with active RA, Tregs demonstrated a pro-inflammatory phenotype characterised by inflammatory cytokine expression. This was due to an augmented expression and activation of signal transducer and activator transcription 1 (STAT1), a direct target of miR-146a.

Conclusions: Our results suggest that in RA miR-146a facilitates a pro-inflammatory phenotype of Tregs via increased STAT1 activation, and contributes thereby to RA pathogenesis.
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http://dx.doi.org/10.1136/annrheumdis-2013-204377DOI Listing
June 2015
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