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ObjectivesInflammatory rheumatic and musculoskeletal diseases (iRMDs) are associated with increased systemic bone loss that is mediated by chronic inflammation, treatment with glucocorticoids (GCs) and other factors. Our objective was to analyse the impact of variables that influence osteoporosis (OP) in patients with iRMD treated with GC.MethodsRh-GIOP (acronyme) is a prospective observational cohort study investigating bone health in consecutive patients with iRMD and current or prior GC treatment. We present an analysis of the patients’ baseline data here. Bone mineral density (BMD) measured by dual X-ray absorptiometry was the primary outcome. Multivariable linear regression models were performed to identify variables associated with BMD.ResultsData from 1066 patients with iRMD were analysed. GC doses of 7.5 mg/day showed a negative association with BMD overall, but this effect seemed to be specific only to patients with moderate or high disease activity (Disease Activity Score 28–C reactive protein >3.2).ConclusionsGCs of ≤5 mg/day did not seem to be associated with a reduction of BMD in patients with iRMD and current or prior exposure to GC. This is most likely due to the dampening of inflammation by GC, which exerts a mitigating effect on the risk of OP. In RA, current GC doses of >7.5 mg/day were negatively associated with BMD, but only in patients with moderate to high disease activity.Trial registration numberNCT02719314.

The mechanisms of mast cell (MC) degranulation and MC-driven skin symptoms are well-described. In contrast, data about the role of mitochondrial respiration for immune functions of human skin MCs are lacking. Oxygen consumption rate (OCR) in primary human skin MCs during IgE-mediated activation in the absence of glucose was examined using a metabolic flux analyzer. Effects of the inhibition of mitochondrial complex I (by rotenone A) and III (by myxothiazol) on degranulation and cytokine secretion (IL-4, IL-5, IL-6, IL-13, TNF-α, and GM-CSF) were explored by the β-hexosaminidase release assay and multiplex ELISA. IgE-mediated activation rapidly increased the mitochondrial OCR and extracellular acidification; the contribution of non-mitochondrial oxygen consumption remained unchanged at lower levels. Both myxothiazol and rotenone A reduced OCR, the mitochondrial parameters, and extracellular acidification; however, myxothiazol did not affect degranulation and cytokine secretion. In contrast, degranulation and the secretion of IL-6, IL-13, TNF-α, and GM-CSF were reduced by rotenone A, whereas the secretion of IL-4 and IL-5 was not significantly affected. The inhibitors did not affect cell viability. Our results highlight the important role played by mitochondrial respiration in primary human skin MCs and allow for a conclusion on a hierarchy of their effector functions. Drugs targeting specific pathways in mitochondria may provide future options to control MC-driven skin symptoms.

Background In chronic spontaneous urticaria (CSU), the guidelines recommend very limited diagnostic procedures during the routine workup, although additional investigations might be indicated in some patients with CSU. For physicians treating patients with CSU, it is often difficult to decide which diagnostic tests are useful. Objective To provide recommendations on what diagnostic tests should be performed on which patients with CSU. Methods We performed an extensive literature search on the respective topics and identified relevant questions that should prompt diagnostic procedures based on the published evidence and expert consensus among all authors. Results We provide questions, diagnostic testing, where appropriate, and recommendation that should be included when assessing the history of a patient with CSU, to explore and rule out differential diagnoses, to assess patients for underlying causes and modifying conditions, to explore patients for comorbid diseases and consequences of having CSU, and to assess patients for CSU components that can help to predict their disease course and response to treatment. Conclusions Here, we provide physicians treating patients with CSU with information about which clues should lead to which tests and why.

Objective: The elderly, a population defined by an age of ≥65 years, are underrepresented in rheumatology trials, possibly due to investigators’ concerns of increased premature discontinuations in higher age groups. The present study was undertaken to evaluate whether the proportion of included elderly individuals (PE) is independently associated with participant retention in rheumatology trials. Methods: Medline was searched for randomized controlled trials (RCTs) in rheumatoid arthritis (RA) and osteoarthritis (OA) of any intervention (years 2016 and 2017). PE was either extracted from the research manuscript or estimated from an assumed (truncated) normal distribution. We used mixed-effects meta-regression models including several covariates to assess whether there is an independent association between PE and participant retention. Using sensitivity analyses, we evaluated whether associations were connected to attrition due to lack of efficacy (LoE) or adverse events (AE). Results: In total, 243 RCTs comprising >48,000 participants were included. Pooled participant retention was 88%. PE was not associated with retention in the unadjusted (P = 0.97) or adjusted (all: P ≥ 0.14) models. Of all covariates, only study duration and type of intervention were associated with retention (both: P < 0.001). Post hoc analyses allowing for interaction revealed a small but statistically significant positive association between PE and retention in pharmacologic interventions and a negative association in physical/physiotherapeutic interventions (overall P for interaction = 0.05). No associations were found for PE and attrition due to LoE or AE. Conclusion: Participant retention in RA and OA trials is high and not associated with PE. These findings should motivate investigators to include more elderly participants in rheumatology trials.

Idiopathic mast cell activation syndrome (MCAS) is characterized by three diagnostic criteria: (1) episodic mast cell (MC)-driven signs/symptoms of at least two organ systems in the absence of clonal MC expansion and definite triggers, (2) episodic increase in tryptase, and (3) response to MC-targeted treatment. Many patients believe they have MCAS, but how often this is the case remains unknown.We prospectively investigated patients with suspected MCAS (n = 100) for the diagnostic criteria including baseline tryptase, KIT D816V mutation, and patient-reported outcome measures (PROMs) over the course of 12 weeks. Comorbid depression and anxiety were explored with the Hospital Anxiety and Depression Scale (HADS).In 53% of our patients (80% females), suspicion of MCAS was based on self-evaluation. In total, patients reported 87 different symptoms, mostly fatigue (n = 57), musculoskeletal pain/weakness (n = 49), and abdominal pain (n = 43), with overall high disease activity and impact. Two of 79 patients had increased tryptase (by20% +2 ng/ml) following an episode. Only 5%, with any of the PROMs used, showed complete response to MC-targeted treatment. Depression and anxiety disorders were frequent comorbidities (n = 23 each), and 65 patients had pathological HADS values, which were linked to high disease impact and poor symptom control.Mast cell activation syndrome was confirmed in only 2% of patients, which implies that it is not MC activation that drives signs and symptoms in most patients with suspected MCAS. There is a high need for comprehensive research efforts aimed at the identification of the true underlying pathomechanism(s) in patients with suspected MCAS.

ObjectiveTo evaluate SIGLEC1 expression on monocytes by flow cytometry as a type I interferon biomarker in idiopathic inflammatory myopathies (IIM).MethodsWe performed a retrospective analysis of adult and pediatric patients with the diagnosis of IIM. SIGLEC1 expression was assessed by flow cytometry and was compared with Physician Global Assessment (PGA) or Childhood Myositis Assessment Scale (CMAS) disease activity scores. Mann Whitney-U test and receiver operating characteristic (ROC) curves were used for cross-sectional data analysis (n=96), two-level mixed-effects linear regression model for longitudinal analyses (n=26, 110 visits). Response to treatment was analyzed in 14 patients within 12 months, using Wilcoxon test. SIGLEC1 was compared to ISG15/MxA status by immunohistochemical staining of muscle biopsies (n=17).Results96 patients with adult (a) and juvenile (j) dermatomyositis (DM, n=38), antisynthetase syndrome (AS, n=19), immune-mediated necrotizing myopathy (IMNM, n=8), inclusion body myositis (IBM, n=9), and overlap myositis (n=22) were included. SIGLEC1 distinguished significantly between active and inactive disease with an area under the curve (AUC) of 0.92 (95% CI: 0.83–1) in DM and correlated with disease activity longitudinally (aDM: standardized beta=0.54, pConclusionSIGLEC1 is a candidate biomarker to assess type I interferon activity in IIM and proved useful for monitoring disease activity and response to treatment in juvenile and adult DM.Key messagesWhat is already known about this subject?There is an unmet need for routine clinical biomarkers to assess type I interferon activity in rheumatic musculoskeletal diseasesSIGLEC1 is part of the type I interferon signature and transcripts were found to be upregulated in various autoimmune diseases such as systemic lupus erythematosus (SLE), Sjoegren syndrome and dermatomyositis.SIGLEC1 is expressed on the surface of monocytes and thus is easily assessable by flow cytometry, which enables straightforward monitoring of type I interferon activityWhat does this study add?An activation of the type I interferon system in IIM can be identified by flow cytometry analysing SIGLEC1 expression. SIGLEC1 correlated to disease activity and improvement under therapy in juvenile and adult dermatomyositis.How might this impact on clinical practice or future developments?SIGLEC1 expression is a suitable biomarker for monitoring type I interferon activation in rheumatic musculoskeletal diseases, which has clinical implications for patient stratification and treatment decision making especially in the context of interferon inhibitory therapies.

ObjectiveTo evaluate sialic acid binding Ig-like lectin 1 (SIGLEC1) expression on monocytes by flow cytometry as a type I interferon biomarker in idiopathic inflammatory myopathies (IIM).MethodsWe performed a retrospective analysis of adult and paediatric patients with the diagnosis of IIM. SIGLEC1 expression was assessed by flow cytometry and was compared with Physician Global Assessment or Childhood Myositis Assessment Scale disease activity scores. Mann Whitney U test and receiver operating characteristic curves were used for cross-sectional data analysis (n=96), two-level mixed-effects linear regression model for longitudinal analyses (n=26, 110 visits). Response to treatment was analysed in 14 patients within 12 months, using Wilcoxon test. SIGLEC1 was compared with interferon-stimulated gene 15/MxA status by immunohistochemical staining of muscle biopsies (n=17).Results96 patients with adult (a) and juvenile (j) dermatomyositis (DM, n=38), antisynthetase syndrome (AS, n=19), immune-mediated necrotising myopathy (IMNM, n=8), inclusion body myositis (IBM, n=9) and overlap myositis (n=22) were included. SIGLEC1 distinguished significantly between active and inactive disease with an area under the curve of 0.92 (95% CI 0.83 to 1) in DM and correlated with disease activity longitudinally (aDM: standardised beta=0.54, pConclusionSIGLEC1 is a candidate biomarker to assess type I interferon activity in IIM and proved useful for monitoring disease activity and response to treatment in juvenile and adult DM.

OBJECTIVES: To evaluate whether elderly people and women are adequately represented in randomized controlled trials (RCT) in rheumatoid arthritis (RA) and osteoarthritis (OA).METHODS: Four systematic searches in MEDLINE yielded RCT in RA and OA on any intervention published in 2016 and 2017 and population-based studies (PBS) in RA and OA published between 2013 and 2017. Random effects meta-analyses estimated the pooled proportion of elderly people (defined as being ≥ 65 years old), the mean age, its standard deviation (SD), and the proportion of women stratified by disease (RA and OA) and study type (RCT and PBS). Stratified estimates were subsequently compared.RESULTS: 265 RCT comprising 51,240 participants and 53 PBS comprising 523,630 participants were included. In both RA and OA, RCT included lower proportions of elderly people than PBS: RA -0.18 (95% confidence interval -0.22 to -0.13); OA -0.20 (-0.30 to -0.09); had lower mean ages: RA -5.2 years (-6.8 to -3.5); OA -4.7 years (-7.5 to -2.0); and smaller SD: RA -1.9 years (-2.6 to -1.3); OA -2.7 years (-4.2 to -1.2); (all comparisons: p ≤ 0.001). Proportions of women were comparable in RCT compared to PBS in both RA and OA.CONCLUSIONS: While women are adequately represented in RA and OA trials, the elderly are underrepresented, probably limiting applicability of current evidence to this growing subgroup. It is urgent to improve the inclusion of elderly people in clinical trials and study age as a determinant for outcome.

ZusammenfassungDie meisten Leitlinien zu chronischer Urtikaria empfehlen derzeit eine Prophylaxe bzw. Therapie mit nicht sedierenden Antihistaminika. Es spricht jedoch nur etwa die Hälfte der Patienten darauf an. Die Therapie der Urtikaria mit autologem Vollblut oder Serum wird in den Leitlinien als „alternative Behandlungsoption“ gelistet. Sie eignet sich in erster Linie zur Therapie der chronischen spontanen Urtikaria, Studien deuten darauf hin, dass Patienten mit autoimmuner Komponente am ehesten profitieren.Die aktuelle Datenlage zeigt, dass die Eigenbluttherapie bei Urtikaria nach wie vor ihren Stellenwert hat. Unklar ist aktuell aber, wie sich die verschiedenen angewendeten Protokolle bezüglich Wirksamkeit und der Wirkmechanismen unterscheiden.

Background older people remain underrepresented in clinical trials, and evidence generated in younger populations cannot always be generalized to older patients. Objective to identify key barriers and to discuss solutions to specific issues affecting recruitment and retention of older participants in clinical trials based on experience gained from six current European randomised controlled trials (RCTs) focusing on older people. Methods a multidisciplinary group of experts including representatives of the six RCTs held two networking conferences and compiled lists of potential barriers and solutions. Every item was subsequently allocated points by each study team according to how important it was perceived to be for their RCTs. Results the six RCTs enrolled 7,612 older patients. Key barriers to recruitment were impaired health status, comorbidities and diverse health beliefs including priorities within different cultural systems. All trials had to increase the number of recruitment sites. Other measures felt to be effective included the provision of extra time, communication training for the study staff and a re-design of patient information. Key barriers for retention included the presence of severe comorbidities and the occurrence of adverse events. Long study duration, frequent study visits and difficulties accessing the study site were also mentioned. Solutions felt to be effective included spending more time maintaining close contact with the participants, appropriate measures to show appreciation and reimbursement of travel arrangements. Conclusion recruitment and retention of older patients in trials requires special recognition and a targeted approach. Our results provide scientifically-based practical recommendations for optimizing future studies in this population.

Background Lanadelumab has been available in Germany for the prophylactic treatment of hereditary angioedema since February 2019. Objective To investigate real-life treatment outcome of lanadelumab and gain practical experience in adapting the therapy to individual patients. Methods The study included 34 patients. In 24 patients with hereditary angioedema and 4 patients with angioedema due to acquired C1-inhibitor deficiency, the previous treatment was switched to lanadelumab. In 6 patients with hereditary angioedema, lanadelumab from the open-label Hereditary Angioedema Long-term Prophylaxis study was continued in regular care. During the transition, patients were monitored using the angioedema control test and the angioedema quality of life questionnaire. At the time at which patients became symptom-free, the dosage interval was increased gradually (+3 days). Results On average, the angioedema control test values improved from 7.5 (poorly controlled disease) to 14.9 (well-controlled disease), and all patients showed adequate disease control. All treated patients, except 1 outlier, scored angioedema quality of life questionnaire values representing only a slight reduction in quality of life (mean, 14 points). At the time point of data collection, 9 patients used an average fixed injection interval of 30 days. Twenty-two patients were symptom-free from the beginning of the treatment phase and intended to extend their injection interval from 30 to 32.5 days (median). We recommended reducing the initial dosing interval from 24 to 21 days (median) to 3 patients because of intermediately occurring symptoms. Conclusions Gradual extension of injection intervals of lanadelumab presented in this study can minimize the burden of therapy without losing efficacy.

This document summarizes the aims of GA2 LEN/HAEi Angioedema Centers of Reference and Excellence (ACAREs) and elaborates the requirements that ACAREs must fulfill to become certified. It also provides (see Appendix S1) background information on GA2LEN and HAEi, including HAEi member organizations and regional patient advocates, on why we need an Angioedema Center of Reference and Excellence (ACARE) program and network, and on the accreditation and certification process, governance and funding, and on the interaction with other GA2LEN networks of centers of reference and excellence. The protocols, aims, requirements, and provisions related to becoming a certified CARE are based on (a) the experience of the GA2LEN UCARE network and (b) input from angioedema patients, general practitioners, and angioedema specialists.

Die differenzialdiagnostische Einordung von Angioodemen kann im klinischen Alltag eine Herausforderung darstellen. Ziel ist es, eine Ubersicht uber die aktuelle Klassifikation von Angioodemen zu geben und deren zugrunde liegende Pathophysiologie zu erlautern. Es erfolgte die Auswertung aktueller Leitlinien und Forschungsarbeiten zur Pathophysiologie und Klassifikation von Angioodemen. Angioodeme werden grundlegend in Mastzellmediator-induziert und Bradykinin-vermittelt unterschieden. Akute Angioodeme durch allergische Reaktionen oder im Rahmen einer akuten Urtikaria bzw. rezidivierende Angioodeme bei Patienten mit chronischer Urtikaria sind klassische Beispiele fur Mastzellmediator-induzierte Angioodeme. Zu den Bradykinin-vermittelten Angioodemformen gehoren das hereditare Angioodem und das ACE(„angiotensin-converting enzyme“)-Hemmer-induzierte Angioodem. Bradykinin-vermittelte Angioodeme kommen deutlich seltener vor als Mastzellmediator-induzierte Angioodeme und verlaufen of schwerer. Die Basis zur klinischen Unterscheidung beider Formen von Angioodemen ist die gezielte Anamneseerhebung und laborchemische Diagnostik. In den meisten Fallen lassen sich Angioodeme in Zusammenschau von Klinik und Diagnostik als Mastzellmediator-induziert oder Bradykinin-vermittelt unterscheiden. In sehr seltenen Fallen bleiben die Ursache und die verantwortlichen Mediatoren unklar.

BACKGROUND: Autoimmune processes are considered to play a major role in the pathogenesis of chronic spontaneous urticaria (CSU). Very recently, interleukin 24 (IL-24) has been identified as an immunoglobulin E (IgE) autoantigen in CSU. Some studies revealed that notably autologous serum skin test (ASST)-positive CSU patients may benefit from autohemotherapy; however, the mechanisms of action remain unknown. We aimed to investigate the immunological effects of autologous serum injections in ASST-positive CSU patients.METHODS: Sixty-six ASST-positive CSU patients were treated with weekly intramuscular autologous serum injections for 8 weeks and followed up for 12 weeks. Urticaria activity score (UAS7) and Dermatology Life Quality Index (DLQI) were assessed. The ASST was done at baseline, week 9 and week 21. Serum samples (baseline, weeks 9, 13 and/or 21) were analysed for the levels of IgE-anti-IL-24 and immunoglobulin G (IgG)-anti-IL-24 via ELISA and their ability to release histamine in basophils [basophil histamine release assay (BHRA)].RESULTS: Autologous serum therapy resulted in a substantial improvement in disease activity and quality of life after 8 and 20 weeks. Twenty-eight percent and 34% of patients turned ASST-negative in weeks 9 and 21, respectively, but there was no link between their response to treatment and changes of ASST results. Also, no significant or relevant changes in BHRA were observed. In contrast, autologous serum therapy significantly decreased IgE-anti-IL-24 serum levels, but not IgG-anti-IL-24 serum levels, in responders but not in non-responders.CONCLUSIONS: Our findings suggest that the immunological effects of autologous serum therapy include a reduction in IgE-anti-IL24 autoantibodies, which may contribute to the pathogenesis of CSU.

Background The elderly (defined by an age of ≥65 years) are underrepresented in current rheumatoid arthritis (RA) and osteoarthritis (OA) trials.1 This is partly due to age-related exclusion criteria. Investigators might be reluctant to include more elderly people because they fear reduced trial retention. Objectives To evaluate whether the proportion of included elderly individuals (PE) is associated with trial retention in current RA and OA trials. Methods This study is registered with protocols.io (dx.doi.org/10.17504/protocols.io.uhaet2e). In our previous study,1 two systematic searches in MEDLINE had yielded randomized controlled trials (RCTs) in rheumatoid arthritis (RA) and osteoarthritis (OA) on any intervention published in 2016 and 2017. Here we included all trials reporting data on retention. We either extracted the PE from the research manuscript or estimated it from an assumed (truncated) normal distribution. We coded retention into proportional effect sizes (logit-transformed for analysis and back-transformed for reporting). Subsequently, multiple mixed effects meta-regression models with several covariates assessed whether there is an association between the PE and trial retention. Sensitivity analyses evaluated whether associations were connected to attrition due to lack of efficacy (LoE) or adverse events (AE). Results 243 RCTs comprising 48,288 participants were deemed eligible, and 227 RCTs provided complete data on overall retention and all covariates. Pooled trial retention (random effects) was 88% (95%-CI 87% to 90%; I2 = 90%). The PE was not associated with trial retention in the unadjusted (slope β = 0.0 [–0.0 to 0.0]; p = 0.97; Figure 1) or any protocolized adjusted model (p-values depending on the adjustment: 0.14 to 0.90). Of all included covariates, only study duration (longer study duration being associated with inferior retention: p Conclusion Trial retention in RA and OA trials is very high, and unaffected by the proportion of elderly. References [1] Palmowski A, Buttgereit T, Palmowski Y, et al. Applicability of trials in rheumatoid arthritis and osteoarthritis: A systematic review and meta-analysis of trial populations showing adequate proportion of women, but underrepresentation of elderly people. Semin Arthritis Rheum2018 [ePub ahead of print]. Acknowledgement This study is part of the GLORIA trial and project and has received funding from the European Union (Horizon 2020) under grant agreement number 634886. Disclosure of Interests Andriko Palmowski: None declared, Sabrina Mai Nielsen: None declared, Thomas Buttgereit: None declared, Yannick Palmowski: None declared, Maarten Boers Consultant for: Bristol-Myers Squibb, Teva, Novartis, Pfizer, GlaxoSmithKline, Robin Christensen Grant/research support from: AbbVie Inc, and the Oak Foundation, Speakers bureau: Roche, Frank Buttgereit: None declared

Background Reports on the prevalence of osteoporosis, osteoporotic fractures and risk factors for osteoporosis in patients with psoriasis (PSO) or psoriatic arthritis (PSOA) are scarce, and the published results on this are, at least in part, contradictory. [1] Despite the fact that IL-17 is involved in bone homeostasis under both physiologic and pathologic conditions, there is no detailed knowledge of the direct and indirect impact an IL-17 antagonist like secukinumab (SEC) has on bone mineral density (BMD). Objectives Rh-GIOP (ClinicalTrials.gov Identifier NCT02719314) is an ongoing prospective study monitoring glucocorticoid (GC)-induced osteoporosis of rheumatic patients, established in 2015 at the Charite University Hospital. For this analysis, clinical data and bone mineral density data measured by dual x-ray absorptiometry (DXA) of 936 patients with inflammatory rheumatic diseases provided the basis. The main objective of this cross-sectional analysis was to evaluate the prevalence of osteoporosis and the frequency of fractures in patients with PSO or PSOA. Additionally, patients treated with secukinumab were compared to those with methotrexate (MTX) with regard to BMD, fracture incidence, physical activity, and back pain Methods We analyzed the initial visit of 103 patients with PSO (n= 31, 74% female) or PSOA (n=72, 64% female). Descriptive analyses were performed, and values are displayed as means and standard deviations. For subgroup analyses non-parametric tests were used. Results The prevalence of osteoporosis in our patient group (mean age: 62±10 years; 67% female; mean disease duration: 17±13 years) was 19%. The prevalence of osteopenia was 26%, 34% (n=35) reported peripheral fragility fractures, and 11% (n=11) had vertebral fractures in history. Regular physical activity was reported by 41% (n=42), while 53% (n=55) suffered from movement restrictions. Back pain was present in 68% (n=70) of patients with a mean numeric rating scale of 5 (NRS; 0-10). SEC was used by 18% (n=19), and MTX by 42% (n=43, 25% sc, 13% oral, 4% unknown), respectively. Eight percent had a combination therapy of MTX and SEC. Twenty-seven percent used GC and/or other biologics/conventional disease modifying antirheumatic drugs (DMARDs). Mean glucocorticoid cumulative dose (GCCD) was 12.8±22.0g. Patients with SEC showed a significantly longer disease duration (median: 24 years vs. 13 years) compared to MTX, but showed no other differences in baseline-characteristics or risk factors. T-Scores of both femora were significantly higher in the MTX versus the SEC group. We could not find significant differences between these groups with regard to physical activity, back pain, movement restriction, fracture rates or GCCD. Twenty-five percent of the MTX users and 27% of the patients in the SEC group additionally had GC while; in contrast to no patient in the combination group. Conclusion The prevalence of osteoporosis in patients with PSO or PSOA was found to be as high as in the normal population. However, there was a high frequency of peripheral fragility, but not vertebral fractures. Patients with PSO or PSOA patients treated with SEC had a longer disease duration and lower hip BMD, but showed no differences in back pain, physical activity or movement restrictions compared to MTX users. Funding: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi. References [1] Frediani, B., et al., Bone mineral density in patients with psoriatic arthritis. J Rheumatol, 2001. 28(1): p.138-43. Disclosure of Interests Desiree Freier: None declared, Edgar Wiebe Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, Chugai, Hexal AG, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi., Kim Zeiner: None declared, Robert Biesen: None declared, Thomas Buttgereit: None declared, Sandra Hermann: None declared, Frank Buttgereit: None declared

Omalizumab is an effective treatment for patients with chronic spontaneous urticaria (CSU). In routine clinical practice, physicians often face complex cases of CSU and need to decide whether patients are suitable for omalizumab treatment and how to manage this therapy. Here, we provide evidence and experience-based answers to the most common and important questions on omalizumab treatment of CSU. At 4 large urticaria centers, questions on the use of omalizumab in the treatment of patients with CSU were collected and then ranked by frequency and importance and grouped into top 5 domains using an interactive consensus approach. We suggest that omalizumab can be used to treat patients with CSU with any of the 3 CSU phenotypes (wheals only, angioedema only, wheals and angioedema), with comorbid chronic inducible urticaria, with cancer, who receive other biologics or cyclosporine, or who are pregnant or want to become pregnant, or are breast-feeding. Omalizumab treatment should be started with 300 mg every 4 weeks, monitored with validated patient-reported outcome measures, and maintained, in responders, until remission of CSU. Finally, partial responders or non responders can benefit from omalizumab updosing or adding or switching to cyclosporine. We believe our suggestions on the use of omalizumab in CSU will help to inform clinical decision making. Follow-up efforts should increase, systematically review, and profile the data available and provide evidence-based recommendations on how to best use omalizumab in CSU. (C) 2019 American Academy of Allergy, Asthma & Immunology

Background:At sites of inflammation, monocytes carry out specific immunological functions while facing challenging bioenergetic restrictions.Objectives:Here, we investigated the potential of human monocytes to adapt under conditions of reduced energy supply by gradually inhibiting oxidative phosphorylation (OXPHOS) under glucose free conditions.Methods:We modelled this reduced energy supply with myxothiazol, an inhibitor of mitochondrial respiration, at 0, 2 and 4 pmol/106 cells to decrease mitochondrial ATP production for 0%, 25% and 66% under glucose free conditions. For the three energy levels, we assessed (i) phagocytosis of FITC-labelled E.coli using flow cytometry, (i) production of reactive oxygen species (ROS) through NADPH oxidase (NOX) as determined by VAS2870-sensitive OCR using a Clark-type electrode, (iii) ATP generation and steady state level using a Clark-type electrode and luminometric assessment (iv) expression of surface activation markers CD16, CD80, CD11b, HLA-DR and (v) production of the inflammatory cytokines IL-1β, IL-6 and TNF-α using flow cytometry in peripheral blood-derived human monocytes with and without LPS-stimulation.Results:As a prerequisite for our study, we demonstrate that human monocytes survived strong inhibition of mitochondrial respiration without any sign of apoptosis as determined by flow cytometry. As a result of the inhibition of OXPHOS, we demonstrate a reduction of VAS2870-sensitive OCR (ROS production through NOX), ATPase-dependent OCR and ATP steady-state levels. Focusing on immune function, we observed that phagocytosis and the production of IL-6 were the least sensitive to reduced energy supply while surface expression of CD11b, HLA-DR, production of TNF-α and IL-1β were most affected by inhibition of OXPHOS.Conclusion:Our data demonstrate an energy-dependent hierarchy of immune functions in monocytes, which may represent a potential therapeutic target in monocyte-mediated inflammatory diseases.Disclosure of Interests:None declared

Background:Idiopathic inflammatory myopathies (IIM) are autoimmune diseases that mainly affect skeletal muscle, lung, skin and joints. IIM can be separated into dermatomyositis (DM), inclusion body myositis (IBM), antisynthetase syndrome (AS) and immune-mediated necrotizing myopathy (IMNM). Type I interferons (IFN) are known to play a crucial role in the etiopathogenesis of some of these entities such as DM.[1] Sialic acid binding Ig-like lectin 1 (SIGLEC1, CD169) is part of the type I IFN signature found in SLE and DM and is expressed on the cell surface of monocytes. Thus, analysis of SIGLEC1 expression by flow cytometry enables a straightforward assessment of the type I IFN signature. Its utility has been shown for juvenile and adult SLE and other rheumatic diseases but not in IIM.[2,3] The assessment of the type I IFN system in clinical practice is an unmet need and, in this context, SIGLEC1 might be useful.Objectives:To assess SIGLEC1 expression on monocytes by flow cytometry as a type I IFN biomarker in IIMMethods:Pediatric and adult patients with a clinical diagnosis of DM, AS, IMNM and IBM and at least one measurement of SIGLEC1 who have been treated at the Department of Rheumatology, Charité - Universitätsmedizin Berlin between 2015 and 2020 were included in this retrospective study. Control groups of healthy individuals (n=19) and SLE patients (n=30) were included. Disease activity was assessed by Physician Global Assessment (PGA) and Childhood Myositis Assessment Scale (CMAS). SIGLEC1 expression on monocytes was analyzed by flow cytometry. Cross-sectional analyses (n=74) were performed using Mann Whitney-U test (MWU) and two-level mixed-effects linear regression model was used for longitudinal analyses (n=26, 110 visits). This study was approved by the local ethics committee of the Charité - Universitätsmedizin Berlin.Results:74 patients (adult/juvenile DM: n=21/n=17; AS: n=19; IMNM: n=8; IBM: n=9) were included. In cross-sectional analysis, SIGLEC1 expression was significantly upregulated in adult and juvenile DM patients with moderate to severe disease activity (PGA≥5) compared with adult/juvenile DM patients with no to moderate disease activity (PGAConclusion:SIGLEC1 is a useful biomarker to identify an activated type I IFN system in IIM. Flow cytometry is used widely in laboratory medicine, which could facilitate the implementation of SIGLEC1 into clinical routine.References:[1]Gallay L, Mouchiroud G, Chazaud B. Interferon-signature in idiopathic inflammatory myopathies: Current Opinion in Rheumatology 2019;31:634–42. doi:10.1097/BOR.0000000000000653[2]Rose T, Grutzkau A, Hirseland H, et al. IFNalpha and its response proteins, IP-10 and SIGLEC-1, are biomarkers of disease activity in systemic lupus erythematosus. Ann Rheum Dis 2013;72:1639–45. doi:10.1136/annrheumdis-2012-201586[3]Stuckrad SL von, Klotsche J, Biesen R, et al. SIGLEC1 (CD169) is a sensitive biomarker for the deterioration of the clinical course in childhood systemic lupus erythematosus. Lupus 2020;:961203320965699. doi:10.1177/0961203320965699Figure 1.SIGLEC1 expression on monocytes in IIM subgroups and control groups; in IIM subgroups, patients with low disease activity (PGADisclosure of Interests:None declared

Background:Age-related impairment of classical neutrophil functions is well described (Fortin, McDonald et al. 2008). However, experimental evidence for age-related alterations of neutrophil metabolic adaptation towards nutrient deprivation -a feature of neutrophil battlefields- remains elusive. Moreover, age-related differences in neutrophil metabolic adaptation may contribute to age-related pathologies such as atherosclerosis, cancer, and autoimmune diseases including rheumatoid arthritis.Objectives:Therefore, we hypothesized that metabolic adaptation of human neutrophils to glucose deprivation is impaired with increasing age.Methods:We isolated human peripheral CD15+ neutrophils from four healthy young donors (mean age: 23.4 ± 2.7) and four healthy donors with a mean age of 58.7 ± 2.4. First, we analyzed the survival of neutrophils either stimulated with PMA or left untreated and subsequently incubated for 0 h and 6 h under varying glucose concentrations (0, 0.5, 1, 5, and 10 mM). To address this, we used 7-AAD staining and flow cytometry. Using Seahorse™ technology, we determined basal respiration, ATP-bound respiration, and maximal and spare capacity.Results:We show that neutrophils (purity > 95%) survived for 6 hours in vitro, independent of treatment with PMA or concentrations of glucose in the culture medium. With negligible differences between the various concentrations of glucose used, the percentage of living cells after 6 h was 95% ± 2.5 without PMA and 75% ± 4.7 with PMA stimulation. No differences were uncovered in this respect between the two age groups. However, Seahorse™ technology revealed significant differences in basal, maximal, and spare respiratory capacity. Briefly, OCR (pmol/min/cell count) with respect to basal, maximal and reserve respiratory capacity was lower in the elderly donors compared to the young donors. For instance, with a concentration of 5 mM glucose, the basal respiration (OCR) was 17 ± 0.7 in elderly donors compared to 22.5 ± 1 in young donors, while the maximal respiration was 25 ± 0.8 in elderly and 41 ± 0.6 in the young donor group. Interestingly, these differences were independent of glucose concentration in the medium.Conclusion:Our data show that basal metabolic parameters differ between neutrophils from young and older donors. Further experiments are needed to understand in detail the mechanisms and effects of age-related differences in metabolism on neutrophil functions.References:[1]Fortin, C. F., P. P. McDonald, O. Lesur and T. Fülöp, Jr. (2008). “Aging and neutrophils: there is still much to do.” Rejuvenation Res11(5): 873-882.Disclosure of Interests:None declared

Background:The prevalence of osteoporosis in inflammatory rheumatic diseases such as psoriatic arthritis (PsA) has not been sufficiently clarified yet, and the data in the literature are heterogeneous. In addition, it is still unclear to what extent patients with PsA differ in terms of bone density from patients with other forms of spondyloarthritis such as ankylosing spondylitis (AS).Objectives:In an interim analysis of the Rh-GIOP Study (ClinicalTrials.gov IdentifierNCT02719314), we observed that PsA patients demonstrated more frequently normal bone density than any other patient group analyzed (suffering from e.g. rheumatoid arthritis or systemic sclerosis). The main objective of this investigation was to compare bone density data from patients with PsA and AS, as both diseases belong to the spondyloarthritis group. 1100 patients with inflammatory rheumatic diseases provided the basis of Rh-GIOP, a prospective study monitoring glucocorticoid (GC)-induced osteoporosis in patients with rheumatic diseases. Rh-GIOP was established in 2015 at the Charité University Hospital. Bone mineral density data were measured by dual x-ray absorptiometry (DXA).Methods:92 patients with PsA (65% female) were compared with 51 patients suffering from AS (35% female). Potential risk and protective factors (e.g. data on GC treatment, anti-rheumatic therapy), laboratory parameters (e.g. Vitamin D, alkaline phosphatase, calcium and inflammatory markers) and functional status (e.g. Health Assessment Questionnaire, sporting activities, back pain) were compared between these groups. Statistical analysis was performed descriptively using mean and standard deviation, t-tests for metric variables, and chi-square tests for nominal variables. Due to the heterogeneous gender distribution, an additional statistical matching was performed to compare patients matched by age and gender.Results:Patients with PsA displayed significantly higher minimal T-scores than patients with AS (p=0.003) even though patients with AS were younger and more often male (pConclusion:Our results demonstrate that patients with PsA display higher bone density compared to age and gender matched patients with ankylosing spondylitis. Possible influencing factors could be the higher frequency of csDMARD use, higher BMI or the lower frequency of back pain in PsA patients. Multivariate tests and additional biomarker investigations in larger cohorts are necessary to corroborate these findings and to identify underlying pathogenic differences which could serve for an explanation.Disclosure of Interests:Desiree Freier: None declared, Edgar Wiebe: None declared, Robert Biesen: None declared, Thomas Buttgereit: None declared, Sandra Hermann: None declared, Timo Gaber: None declared, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi.

Background:Osteoporosis is a skeletal disease characterized by the loss of bone density resulting in an increased fracture risk. Female sex, advanced age, Caucasian ancestry, previous history of fractures, menopause and certain genetic factors predispose for osteoporosis. In addition, recent studies could prove that chronic inflammatory diseases such as Rheumatoid Arthritis (RA) and long-term treatment with higher doses of glucocorticoids (GCs) represent independent risk factors for the development of osteoporosis. On the other hand, the intake of vitamin D, a calcium-rich diet and physical exercise can be protective. Data describing the prevalence of osteoporosis in patients with other rheumatic diseases like psoriatic arthritis (PsA) are lacking.Objectives:We compared the prevalence of osteopenia and osteoporosis in patients with RA and PsA, respectively, based on data obtained from our ongoing prospective monocentric study Rh-GIOP investigating glucocorticoid (GC)-induced osteoporosis in patients with different rheumatic diseases (NCT02719314).Methods:Bone mineral density data measured by dual x-ray absorptiometry (DXA) in patients with PsA (n=92) were compared with data measured in 92 age- and gender-matched patients with RA. The results were analysed with respect to clinical and laboratory parameters such as data on GC treatment (frequency, duration defined as start of treatment until timepoint of measurement, actual and cumulative dose), csDMARD and bDMARD (including as well tsDMARDs) therapy, serological parameters (Vitamin D, alkaline phosphatase, calcium, inflammatory markers and rheumatoid factor) and functional status (e.g. Health Assessment Questionnaire (HAQ), sporting activities). Statistical analyses were performed descriptively using mean and standard deviation, t-tests for metric variables, and chi-square tests for nominal variables. For subgroup analyses with less than 30 patients per group, tests for non-normally distributed data were used due to the lower test power.Results:RA patients showed significantly lower means of bone density values (minimal T-score, p=0.03) than PsA patients leading to a higher frequency of osteopenic bone densities (pConclusion:The lower bone density in RA patients seems not to be fully explained by higher GCCD, disease duration or higher levels of inflammation. However, RA patients had a higher frequency of current GC intake. Additionally, differences in bone density between the two groups could be related to the higher number of bDMARD therapies in PsA patients, but further investigations like multivariate analyses with higher numbers of patients are necessary. Furthermore there is more need for research on possible molecular and genetic factors in PsA, which are protecting from low bone density.Disclosure of Interests:Desiree Freier: None declared, Edgar Wiebe: None declared, Robert Biesen: None declared, Thomas Buttgereit: None declared, Sandra Hermann: None declared, Timo Gaber: None declared, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi.

Background:Randomised controlled trials (RCTs) are considered the gold standard in clinical research. Their results, however, may not be generalizable to patients in routine care.1Together with methotrexate, glucocorticoids (GCs) constitute the mainstay of therapy for many patients with rheumatoid arthritis (RA), but it is unclear whether trial evidence is actually generalizable to real-world patients.Objectives:This review assesses to what extent RA patients participating in GC-RCTs differ from RA patients taking GCs in routine care.Methods:This study was registered with PROSPERO (CRD42019134675). MEDLINE was searched for RCTs and, as comparators, cohort studies in RA evaluating systemic GC therapy. Cohorts were not allowed to exhibit apparent selection mechanisms concerning gender or age. Random-effects meta-analyses combined descriptive baseline characteristics that may modify the benefit-risk-ratio of various RA therapeutics. Meta-analyses were stratified by study type (RCT and CS). Stratified estimates were subsequently compared.Results:55 RCTs and ten cohort studies (21,657 participants overall) were included. Twelve characteristics (related to general demographics and disease activity) were reported frequently enough to allow for comparative analysis. Compared to cohorts, RCT participants were younger (-4.7 [-7.2 to -2.1] years) and had somewhat higher erythrocyte sedimentation rates (12 [6 to 18] mm/h) (Table 1). In the other ten characteristics, estimates did not differ significantly. Numerically, cohort patients had more longstanding disease and slightly more favourable disease levels in core set variables. Comorbidities could not be assessed.Table 1.Pooled estimatesOutcomeRCTkCohortkContrast(95% CI)pGeneral demographics Age (years)54.25058.910–4.7(–7.2 to –2.1) Female (proportion)0.70520.73100.89(0.68 to 1.16)0.38 Current or previous smokers (proportion)0.5930.5121.38(0.61 to 3.14)0.44 BMI (kg/m2)25.9525.930.0(–1.9 to 1.9)0.98 Disease duration (months)56.54385.17–28.6(–85.6 to 28.4)0.33Disease activity ESR (mm/h)40.13128.2311.8(5.7 to 18.0) DAS5.3244.950.4(–0.1 to 0.9)0.12 RF+, (proportion)0.67320.6361.19(0.80 to 1.78)0.39 ACPA+, (proportion)0.6470.5631.38(0.64 to 3.00)0.41 HAQ1.3311.140.2(–0.1 to 0.5)0.15 Pain (0-10)5.2264.820.4(–0.8 to 1.6)0.52 Patient global assessment (0-10)5.2174.930.3(–0.9 to 1.5)0.58Conclusion:The results of our study suggest that evidence from RA GC-RCTs can be generalized to most patients in routine practice. We note that comorbidities – a frequent exclusion criterion for trial participation – could not be evaluated due to insufficient reporting. Our findings contrast with a similar study on RCTs investigating biologics in RA: There, trial participants were found to differ significantly in 4 out of 8 investigated baseline characteristics.2References:1]Palmowski A et al. Applicability of trials in rheumatoid arthritis and osteoarthritis: A systematic review and meta-analysis of trial populations showing adequate proportion of women, but underrepresentation of elderly people.Semin Arthritis Rheum2018 doi: 10.1016/j.semarthrit.2018.10.017 and[2]Kilcher G et al. Rheumatoid arthritis patients treated in trial and real world settings: comparison of randomized trials with registries.Rheumatology (Oxford) 2017 doi: 10.1093/rheumatology/kex394Acknowledgments:Part of the GLORIA project and trial, funded by the EU (Horizon 2020, Grant No 634886)Disclosure of Interests:Andriko Palmowski: None declared, Sabrina Mai Nielsen: None declared, Thomas Buttgereit: None declared, Yannick Palmowski: None declared, Maarten Boers: None declared, Robin Christensen: None declared, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi.

Importance Recently, we showed that the elderly are significantly underrepresented in randomized controlled trials (RCT) in rheumatoid arthritis (RA) and osteoarthritis (OA). While this phenomenon has been detected in other fields as well, efforts by various international institutions to tackle the issue were without decisive success. Researchers might be cautious about including more elderly people because they fear reduced trial retention rates. Objective To evaluate whether the proportion of included elderly individuals (defined by an age of ≥65 years) is independently associated with trials’ retention rates. Data Source MEDLINE (via PubMed). Eligibility RCT on any intervention in RA or OA published in 2016 or 2017. Outcome Retention rate. Critical Appraisal We will not address any conclusion made by included RCT. Thus, we will not perform a formal risk of bias assessment. Synthesis Methods The proportion of elderly people is either directly abstracted from the research manuscript or estimated from an assumed truncated normal distribution. Multivariable meta-regression will explore whether the proportion of included elderly people is independently associated with trials’ retention rates, even after adjusting for trial duration. The model will include as covariates – apart from the proportion of elderly people and study duration - disease, type of intervention, region, sample size at enrollment, and the proportion of women. Additional models will explore whether the proportion of included elderly people is independently associated with trial retention rates when only drop-outs due to adverse events, resp. lack of efficacy are counted.

Background Reports on the prevalence of osteoporosis, osteoporotic fractures and risk factors for osteoporosis in patients with Psoriasis or Psoriasisarthritis are scarce, and the published results on this are, at least in part, contradictory. Additionally, there is no firm understanding of the impact of potential risk factors such as smoking and low Vitamin D (Vit D) levels have on the occurrence of osteoporotic fractures in this patient group. Objectives Rh-GIOP is an ongoing prospective study monitoring glucocorticoid (GC)-induced osteoporosis of rheumatic patients, established in 2015 at the Charite University Hospital. To date, the database comprises clinical data and bone mineral density data measured by dual x-ray absorptiometry (DXA) of 592 patients with inflammatory rheumatic diseases. (ClinicalTrials.gov Identifier NCT02719314) The objective of this cross-sectional analysis was to evaluate the prevalence of osteoporosis and frequency of fractures in patients with Psoriasis (PSO) or Psoriasisarthritis (PSOA). Additionally, smoking and Vit D status were investigated as possible risk factors for low BMD. Methods We evaluated the initial visit of 55 patients with PSO (80% female) or PSOA (60% female). Descriptive analyses were performed, and values are displayed as means and standard deviations. For subgroup analyses non-parametric tests were used. Results Overall mean age was 60 years (±12 years), and 69% of the patients were female. The mean disease duration was 16±13 years and patients generally showed a good functional status as quantified by the Health Assessment Questionnaire (HAQ mean: 1.0±0.8). While osteoporosis and osteopenia were present in 16% and 38%, respectively, osteoporotic fractures were found in 33% of all patients. However, the family history for osteoporosis was positive in 20% of the patients. The prevalence of osteopenia and osteoporosis was higher in PSO compared to PSOA patients (70% vs. 45%) without reaching statistical significance. 27% of all patients were treated with glucocorticoids: mean daily dose 3±8 mg, mean cumulative dose (GCCD) 10.9 g±20.3 g. No significant difference was seen comparing medians of BMD in patients with a GCCD >10 g versus a GCCD Conclusions In our patient cohort, the GCCD does not have a measurable impact on the BMD. Additionally, according to current literature the prevalence of osteoporosis seems to be in the same range as in the normal population.1 Keeping in mind the (still) small number of patients, neither smoking nor Vit D deficiency could be identified as possible risk factors for low BMD, but further investigations are necessary to corroborate these observations. Reference [1] Hadji, P., et al., The epidemiology of osteoporosis–Bone Evaluation Study (BEST): an analysis of routine health insurance data. Dtsch Arztebl Int, 2013. 110(4): p. 52–7. Disclosure of Interest D. Freier Grant/research support from:. Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, K. Zeiner Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, R. Biesen Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, E. Wiebe Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, T. Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, S. Hermann Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, F. Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche

Seventy years ago, the first administration of cortisone in a patient with RA marked a milestone in the treatment of inflammatory diseases. However, the initial enthusiasm rapidly vanished as the administration of high doses for lengthy periods revealed worrisome adverse effects. It has taken several decades to overcome the (sometimes excessive) mistrust and to achieve a more differentiated evaluation of the benefit–risk profile and the adequate usage of glucocorticoids (GCs). Today, GCs remain indispensable for the treatment of many inflammatory conditions and their usefulness in RA as a disease-modifying low-dose co-medication is widely acknowledged. Recent studies show promising results concerning both traditional GCs and new formulations. Still, decades of relatively little scientific attention have resulted in a continuing lack of detailed evidence. Hence there is an ongoing need for further research regarding mechanisms of GC actions, the further optimization of treatment parameters for traditional GCs and new formulations.

Objective To describe the perception of the current role of systemic glucocorticoids in the management of rheumatoid arthritis (RA) by examining their importance and the current level of evidence in recent guidelines, and to identify open questions to be addressed in future guidelines and research projects. Methods We conducted a systematic literature review using the databases Ovid Embase, PubMed Medline, and Cochrane Library for guidelines on the pharmacologic treatment of RA. Retrieved articles were evaluated regarding their quality using the Appraisal of Guidelines for Research and Evaluation II tool and scrutinized for all relevant information concerning the use of glucocorticoids. Results All guidelines agree that glucocorticoids, especially if given at low doses and for a short duration, are an appropriate option in the treatment of RA. However, many recommendations remain vague, as reliable and detailed evidence is scarce. Important aspects of glucocorticoid therapy are partially or completely neglected, and the existing nomenclature is not used uniformly. Quality evaluation revealed flaws in many articles, concerning not only glucocorticoid-specific recommendations but also guideline quality in general. Conclusion Current recommendations for use of glucocorticoids in the management of RA are suboptimal. More rigorous evaluation of doses, timing, and duration of their use is needed. Existing nomenclature on glucocorticoid therapy should be used uniformly.

Objective: Randomized controlled trials (RCTs) are considered the gold standard in clinical research due to credible causality. Their results, however, may not be generalizable to real-world populations. While glucocorticoids (GCs) remain a mainstay of rheumatoid arthritis (RA) treatment, it is unclear whether the results of GC-RCTs are generalizable to current real-world RA patients. Methods: MEDLINE was searched for RCTs and, as comparators, cohort studies (CSs) in RA evaluating systemic GCs. Random-effects meta-analyses were performed for descriptive baseline characteristics (including general demographics, comorbidities, and disease activity) that have been shown to be able to modify the benefit-risk-ratio of various RA therapeutics. These meta-analyses were stratified by study type (RCT and CS). Stratified estimates were subsequently compared. Further sensitivity analyses were performed stratifying by disease duration. Results: 56 RCTs (7053 participants) and 10 CSs (14,688 participants) were included. 12 characteristics were reported frequently enough to allow for comparative analysis. In 10/12 characteristics (83%), RCT estimates did not appear to differ from CS estimates. However, RCT participants were younger (-4.7 years [95% CI -7.2 to -2.1]; p < 0.001) and had higher erythrocyte sedimentation rates (11.8 mm/h [5.7 to 17.8]; p < 0.001) than CS participants. Comorbidities could not be assessed due to insufficient reporting. Conclusion: Our findings suggest that evidence from GC trials in RA is of acceptable generalizability to current real-world patients – especially compared to findings from biologic agents in RA. However, RCT participants were younger than real-world patients, potentially limiting the generalizability of trial results to elderly patients. Systematic review registration: PROSPERO (CRD42019134675)