[Immune-mediated inflammatory diseases in Germany : A cross-sectional analysis of comorbidities and pharmacotherapy]. / Chronische Entzündungserkrankungen in Deutschland : Eine Querschnittanalyse über Begleiterkrankungen und Arzneimitteleinsatz.

BACKGROUND: Immune-mediated inflammatory diseases (IMID) can lead to a substantial disease burden for those affected, in particular by the concomitant occurrence of other IMIDs or in the presence of comorbidities. The care of patients with IMIDs is complex and involves various medical disciplines. OBJECTIVE: To describe the burden of disease and the current routine drug treatment of patients with IMID. MATERIAL AND METHODS: The retrospective cross-sectional analysis was based on statutory health insurance claims data from the InGef database. Prevalent patients with psoriasis (Pso), psoriatic arthritis (PsA), spondylarthritis (SpA), rheumatoid arthritis (RA), Crohn's disease (MC), ulcerative colitis (CU), or connective tissue disease were identified among 3,988,695 insured patients in 2018. The concomitant occurrence of different IMIDs and the extent to which patients with IMID are affected by other comorbidities compared to a reference population were investigated. The current routine drug treatment was described based on the use of predefined forms of treatment. RESULTS: In the database 188,440 patients with IMID (4.7%) were identified. Compared to the reference population the prevalence of comorbidities, such as depressive episodes and cardiovascular risk factors was higher in patients with IMID. For MC, CU, RA, and PsA disease-modifying antirheumatic drugs (DMARD) and classical systemic forms of treatment were used most commonly. In Pso, SpA, and connective tissue disease nonsteroidal anti-inflammatory drugs (NSAID) were the most frequently used treatment often in combination with other drugs. CONCLUSION: A considerable number of patients with IMIDs (16.9-27.5%) suffer from different diseases of the IMID group. They are frequently affected by accompanying illnesses and require interdisciplinary medical treatment.

Adenosine signalling in T-cell activation favours development of IL-17 positive cells with suppressive properties.

Evidence suggests that the anti-inflammatory nucleoside adenosine can shape immune responses by shifting the regulatory (Treg )/helper (Th17) T-cell balance in favour of Treg . Since this observation is based on in vivo and in vitro studies mostly confined to murine models, we comprehensively analysed effects of adenosine on human T-cells. Proliferation, phenotype and cytokine production of stimulated T-cells were assessed by flow cytometry, multiplex assay and ELISA, gene expression profiling was determined by microarray. We found that the pan-adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) skews human CD3+ T-cell responses towards non-inflammatory Th17 cells. Addition of NECA during T-cell activation increased the development of IL-17+ cells with a CD4+ RORγt+ phenotype and enhanced CD161 and CD196 surface expression. Remarkably, these Th17 cells displayed non-inflammatory cytokine and gene expression profiles including reduced Th1/Th17 transdifferentiation, a stem cell-like molecular signature and induced surface expression of the adenosine-producing ectoenzymes CD39 and CD73. Thus, T-cells cultured under Th17-inducing conditions together with NECA were capable of suppressing responder T-cells. Finally, genome-wide gene expression profiling revealed metabolic quiescence previously associated with non-pathogenic Th17 cells in response to adenosine signalling. Our data suggest that adenosine induces non-inflammatory Th17 cells in human T-cell differentiation, potentially through regulation of metabolic pathways.

Automated Machine Learning Analysis of Patients With Chronic Skin Disease Using a Medical Smartphone App: Retrospective Study.

BACKGROUND: Rapid digitalization in health care has led to the adoption of digital technologies; however, limited trust in internet-based health decisions and the need for technical personnel hinder the use of smartphones and machine learning applications. To address this, automated machine learning (AutoML) is a promising tool that can empower health care professionals to enhance the effectiveness of mobile health apps. OBJECTIVE: We used AutoML to analyze data from clinical studies involving patients with chronic hand and/or foot eczema or psoriasis vulgaris who used a smartphone monitoring app. The analysis focused on itching, pain, Dermatology Life Quality Index (DLQI) development, and app use. METHODS: After extensive data set preparation, which consisted of combining 3 primary data sets by extracting common features and by computing new features, a new pseudonymized secondary data set with a total of 368 patients was created. Next, multiple machine learning classification models were built during AutoML processing, with the most accurate models ultimately selected for further data set analysis. RESULTS: Itching development for 6 months was accurately modeled using the light gradient boosted trees classifier model (log loss: 0.9302 for validation, 1.0193 for cross-validation, and 0.9167 for holdout). Pain development for 6 months was assessed using the random forest classifier model (log loss: 1.1799 for validation, 1.1561 for cross-validation, and 1.0976 for holdout). Then, the random forest classifier model (log loss: 1.3670 for validation, 1.4354 for cross-validation, and 1.3974 for holdout) was used again to estimate the DLQI development for 6 months. Finally, app use was analyzed using an elastic net blender model (area under the curve: 0.6567 for validation, 0.6207 for cross-validation, and 0.7232 for holdout). Influential feature correlations were identified, including BMI, age, disease activity, DLQI, and Hospital Anxiety and Depression Scale-Anxiety scores at follow-up. App use increased with BMI >35, was less common in patients aged >47 years and those aged 23 to 31 years, and was more common in those with higher disease activity. A Hospital Anxiety and Depression Scale-Anxiety score >8 had a slightly positive effect on app use. CONCLUSIONS: This study provides valuable insights into the relationship between data characteristics and targeted outcomes in patients with chronic eczema or psoriasis, highlighting the potential of smartphone and AutoML techniques in improving chronic disease management and patient care.

Lipopolysaccharide Tolerance in Human Primary Monocytes and Polarized Macrophages.

Innate immune memory allows macrophages to adequately respond to pathogens to which they have been pre-exposed. To what extent different pattern recognition receptors, cytokines and resolution signals influence innate immune memory needs further elucidation. The present study assessed whether lipopolysaccharide (LPS) tolerance in monocytes and macrophages is affected by these factors. Human CD14+ cells were isolated from peripheral blood, stimulated by LPS and re-stimulated after 3 days of resting. Hereafter, immune-responsive gene 1 (IRG-1), heme oxygenase 1 (HO-1), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) expression were assessed. Our study revealed the following findings: (1) While pre-stimulation with the Toll-like receptor 4 ligand LPS inhibits the induction of IRG-1, TNF-α and IL-6 expression, pre-stimulation with TLR 1/2 ligands only affects cytokine production but not IRG-1 expression upon subsequent TLR4 engagement. (2) Prior TNF-α stimulation does not affect LPS tolerance but rather increases LPS-mediated cytokine expression. (3) Dimethyl itaconate (DMI) inhibits the expression of IRG-1 in a dose-dependent manner but does not affect TNF-α or IL-6 expression. (4) Docosahexaenoic acid (DHA) partly inhibits IRG-1 expression in monocytes but not in M(IFNγ) and M(IL-4) polarized macrophages. LPS tolerance is not affected in these cells by DHA. The data presented in this study partly corroborate and extend previous findings on innate immune memory and warrant further studies on LPS tolerance to gain a better understanding of innate immune memory at the molecular level.

Perioperative management of patients with inflammatory rheumatic diseases : Updated recommendations of the German Society for Rheumatology.

BACKGROUND: Prior to surgical interventions physicians and patients with inflammatory rheumatic diseases remain concerned about interrupting or continuing anti-inflammatory medication. For this reason, the German Society for Rheumatology has updated its recommendations from 2014. METHODS: After a systematic literature search including publications up to 31 August 2021, the recommendations on the use of of glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics (bDMARDs) were revised and recommendations on newer drugs and targeted synthetic (ts)DMARDs were added. RESULTS: The glucocorticoid dose should be reduced to as low as possible 2-3 months before elective surgery (in any case <10 mg/day) but should be kept stable 1-2 weeks before and on the day of surgery. In many cases csDMARDs can be continued, exceptions being a reduction of high methotrexate doses to ≤15 mg/week and wash-out of leflunomide if there is a high risk of infection. Azathioprine, mycophenolate and ciclosporin should be paused 1-2 days prior to surgery. Under bDMARDs surgery can be scheduled for the end of each treatment interval. For major interventions Janus kinase (JAK) inhibitors should be paused for 3-4 days. Apremilast can be continued. If interruption is necessary, treatment should be restarted as soon as possible for all substances, depending on wound healing. CONCLUSION: Whether bDMARDs increase the perioperative risk of infection and the benefits and risks of discontinuation remain unclear based on the currently available evidence. To minimize the risk of a disease relapse under longer treatment pauses, in the updated recommendations the perioperative interruption of bDMARDs was reduced from at least two half-lives to one treatment interval.

[Epidemiological data and medical care situation of patients with chronic inflammatory diseases in Germany : Real-world evidence on prevalence, disease combinations, care]. / Epidemiologische Daten und medizinische Versorgungssituation von Patienten mit chronischen Entzündungserkrankungen in Deutschland : Real-World-Evidenz zu Prävalenz, Erkrankungskombinationen, Versorgung.

BACKGROUND: Chronic inflammatory diseases (immune-mediated inflammatory diseases, IMID) can overlap or occur simultaneously due to clinical similarities. The resulting utilization of heathcare structures has not yet been investigated across disciplines but is of potential importance for optimizing the treatment of patients with IMID. AIM OF THE WORK: Analysis of epidemiological data including utilization of care services in patients with selected IMIDs: psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA), ankylosing spondylitis, ulcerative colitis, Crohn's disease and connective tissue disease. MATERIAL AND METHODS: In a retrospective cross-sectional analysis based on health insurances accounting data with a sample of approximately 4 million insured persons, the prevalence of the abovementioned IMID and the frequency of IMID combinations were analyzed based on documented diagnoses (ICD-10 GM). The frequency of hospitalizations and utilization of outpatient physician contacts was recorded in predefined specialist disciplines (general medicine, dermatology, gastroenterology, rheumatology) and compared with an age-adjusted and gender-adjusted reference population. RESULTS: A total of 188,440 patients had at least 1 of the IMID diagnoses analyzed (4.7%), with an age peak of 61-70 years. The highest prevalence was observed for psoriasis (1.85%), followed by rheumatoid arthritis (1.38%). Combinations with at least one other IMID were relatively common (29%), with this being most common in patients with psoriatic arthritis (82.9%, of which 68.2% had psoriasis), followed by ankylosing spondylitis (27.5%) and Crohn's disease (21.6%). Compared to the reference population, patients with IMID were hospitalized more often and more frequently utilized the outpatient disciplines. DISCUSSION: The study results describe that IMIDs occur in combination and that the patients make comparatively more use of care structures of different disciplines. A multidisciplinary approach could increase the efficiency of care; an evaluation is still pending.

Efficacy and safety of a mobile app intervention in patients with inflammatory arthritis: a prospective pilot study.

EULAR highlighted the essential role of digital health in increasing self-management and improving clinical outcomes in patients with arthritis. The objective of this study was to evaluate the efficacy and safety of the digital health application (DHA) in patients with inflammatory arthritis. We assessed demographic parameters, treatment regimen, disease activity, and other patient-reported outcomes at baseline and after 4 weeks of DHA use added to standard care treatment. Of 17 patients, who completed the study, 7 (41.2%) patients were male, ranging from 19 to 63 (40.5 ± 12.2) years. No significant change in antirheumatic treatment was observed during the study. Statistically significant improvements (p < 0.05) were noted for health-related quality of life (increase in Physical Component Summary of Short Form-36 (SF-36) by 23.6%) and disease activity (decrease of Clinical Disease Activity Index and Simple Disease Activity Index by 38.4% and 39.9%, respectively). Clinically significant improvement was demonstrated for SF-36 Total Score (+ 14.4%), disease activity (Rheumatoid Arthritis Disease Activity Index- 5 to 15.9%), and depression (Patient Health Questionnaire- 9 to 13.5%). None of the efficacy parameters showed negative trends. No adverse events were reported throughout the study. The usability level was high i.e., the mean mHealth Application Usability Questionnaire Score of 5.96 (max.: 7.0) demonstrated a high level of application usability. This suggests that using a personalized disease management program based on DHA significantly improves several measures of patient-reported outcomes and disease activity in patients with inflammatory arthritis in a timely manner. These findings highlight the potential of complementary digital therapy in patients with inflammatory arthritis.

Comparison of physician and artificial intelligence-based symptom checker diagnostic accuracy.

Symptom checkers are increasingly used to assess new symptoms and navigate the health care system. The aim of this study was to compare the accuracy of an artificial intelligence (AI)-based symptom checker (Ada) and physicians regarding the presence/absence of an inflammatory rheumatic disease (IRD). In this survey study, German-speaking physicians with prior rheumatology working experience were asked to determine IRD presence/absence and suggest diagnoses for 20 different real-world patient vignettes, which included only basic health and symptom-related medical history. IRD detection rate and suggested diagnoses of participants and Ada were compared to the gold standard, the final rheumatologists' diagnosis, reported on the discharge summary report. A total of 132 vignettes were completed by 33 physicians (mean rheumatology working experience 8.8 (SD 7.1) years). Ada's diagnostic accuracy (IRD) was significantly higher compared to physicians (70 vs 54%, p = 0.002) according to top diagnosis. Ada listed the correct diagnosis more often compared to physicians (54 vs 32%, p < 0.001) as top diagnosis as well as among the top 3 diagnoses (59 vs 42%, p < 0.001). Work experience was not related to suggesting the correct diagnosis or IRD status. Confined to basic health and symptom-related medical history, the diagnostic accuracy of physicians was lower compared to an AI-based symptom checker. These results highlight the potential of using symptom checkers early during the patient journey and importance of access to complete and sufficient patient information to establish a correct diagnosis.

[Continue or interrupt? Antirheumatic treatment in elective surgery]. / Fortsetzen oder Pausieren? Die antirheumatische Therapie bei elektiven Operationen.

In patients with inflammatory rheumatic diseases, a decision is needed prior to elective surgery on whether the medicinal treatment can be continued or whether the dose needs to be changed or interrupted. The German Society for Rheumatology (DGRh) has developed updated recommendations that specify a course of action for disease-modifying antirheumatic drugs (DMARD) and glucocorticoids. The recommendations for action can be adapted to the individual situation and coordinated with the interdisciplinary treating physicians and the patient. Depending on the dose, glucocorticoids have a high risk of infection and should be set as low as possible in the preoperative period. Most of the conventional synthetic (cs)DMARDs can be continued. Under biologic (b)DMARDs treatment surgery can be scheduled for the end of each treatment interval. It is recommended that Janus kinase (JAK) inhibitors should be interrupted for 3-4 days before major interventions. Treatment should be restarted as soon as possible, depending on the wound healing.

[Perioperative management of treatment of patients with inflammatory rheumatic diseases : Updated recommendations of the German Society of Rheumatology]. / Perioperativer Umgang mit der Therapie von Patienten mit entzündlich rheumatischen Erkrankungen : Aktualisierte Empfehlungen der Deutschen Gesellschaft für Rheumatologie.

BACKGROUND: Prior to surgical interventions physicians and patients with inflammatory rheumatic diseases remain concerned about interrupting or continuing anti-inflammatory medication. For this reason, the German Society for Rheumatology has updated its recommendations from 2014. METHODS: After a systematic literature search including publications up to 31 August 2021, the recommendations on the use of of glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics (bDMARDs) were revised and recommendations on newer drugs and targeted synthetic (ts)DMARDs were added. RESULTS: The glucocorticoid dose should be reduced to as low as possible 2-3 months before elective surgery (in any case <10 mg/day) but should be kept stable 1-2 weeks before and on the day of surgery. In many cases csDMARDs can be continued, exceptions being a reduction of high methotrexate doses to ≤15 mg/week and wash-out of leflunomide if there is a high risk of infection. Azathioprine, mycophenolate and ciclosporin should be paused 1-2 days prior to surgery. Under bDMARDs surgery can be scheduled for the end of each treatment interval. For major interventions Janus kinase (JAK) inhibitors should be paused for 3-4 days. Apremilast can be continued. If interruption is necessary, treatment should be restarted as soon as possible for all substances, depending on wound healing. CONCLUSION: Whether bDMARDs increase the perioperative risk of infection and the benefits and risks of discontinuation remain unclear based on the currently available evidence. To minimize the risk of a disease relapse under longer treatment pauses, in the updated recommendations the perioperative interruption of bDMARDs was reduced from at least two half-lives to one treatment interval.

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

OBJECTIVES: To characterize treatment patterns for patients with psoriatic arthritis (PsA) currently receiving any disease-modifying antirheumatic drug (DMARD). METHODS: The Strategy for Psoriatic Arthritis In Germany (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.

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

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.

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.

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.

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

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.

The effect of hydroxychloroquine on platelet activation in model experiments.

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.

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

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.

[German Society of Rheumatology Recommendations for the management of glucocorticoid-induced Osteoporosis. German version]. / Empfehlungen der Deutschen Gesellschaft für Rheumatologie zum Management der Glukokortikoid-induzierten Osteoporose.

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.

Altered T cell plasticity favours Th17 cells in early arthritis.

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.

[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]. / Handlungsempfehlungen der Deutschen Gesellschaft für Rheumatologie e. V. für die Betreuung von Patienten mit entzündlich rheumatischen Erkrankungen im Rahmen der SARS-CoV-2/COVID-19-Pandemie ­ Update Juli 2020.

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.

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

Objectives: 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).Methods: Frequencies of in vivo-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.Results: Ex vivo 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 ex vivo 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.Conclusion: 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.