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Objective To investigate whether methotrexate (MTX) use is associated with bone mineral density (BMD) in patients with polymyalgia rheumatica (PMR) and various forms of vasculitis. Methods Rh-GIOP is a cohort study designed to evaluate bone health in patients with inflammatory rheumatic diseases. This cross-sectional analysis assessed the baseline visits of all patients with PMR or any kind of vasculitis. Following univariable analysis, multivariable linear regression analysis was performed. The lowest T-score of either the lumbar spine or the femur was chosen as the dependent variable to examine the relationship between MTX use and BMD. These analyses were adjusted for a variety of potential confounders, including age, sex, and glucocorticoid (GC) intake. Results Of 198 patients with PMR or vasculitis, 10 patients were excluded for very high GC dose (n = 6) or short disease duration (n = 4). The remaining 188 patients had the following diseases: PMR 37.2%, giant cell arteritis 25.0%, granulomatosis with polyangiitis 16.5%, followed by rarer diseases. The mean age was 68.0 ± 11.1 years, mean disease duration was 5.58 ± 6.39 years, and 19.7% had osteoporosis by dual x-ray absorptiometry (T-score ≤ −2.5). 23.4% were taking MTX at baseline with a mean dose of 13.2 mg/week (median: 15 mg/week). 38.6% of those used a subcutaneous preparation. MTX users had similar BMD compared to non-users (minimum T-scores −1.70 (± 0.86) versus −1.75 (± 0.91), respectively; p = 0.75). There was no statistically significant dose–response relationship: neither current nor cumulative dose were associated with BMD in unadjusted or adjusted models (current dose: slope −0.02; −0.14 to 0.09; p = 0.69; cumulative dose: slope −0.12; −0.28 to 0.05; p = 0.15). Conclusion In the Rh-GIOP cohort, MTX is used in about a quarter of patients with PMR or vasculitis. It is not associated with BMD levels.

Getting access to specialists for autoinflammatory diseases (AID) can be challenging. Therefore, an increasing number of patients and healthcare professionals are seeking information on AID via the Internet, using the video platform YouTube, for example. However, the quality of such videos has not yet been evaluated. A YouTube search was conducted to assess videos about AID to evaluate the quality and usefulness from both the patient’s and healthcare professional´s perspectives. Video duration, number of views, likes, dislikes, comments, and uploading source on various AID were extracted. Video quality was evaluated by the modified global quality scale (GQS). The reliability was assessed by the modified five-point DISCERN score. In total, 140 videos were screened of which 105 videos met the inclusion criteria for further analysis. Based on the GQS, the overall quality of videos for patients was found to be low in 64.8%, intermediate in 27.6%, and high in 7.6% of videos. The quality of videos for professionals was similar (54.3% low, 23.8% intermediate, and 21.9% of high quality). Videos were more often targeting medical professionals (65.7%) and less often patients (34.3%). This analysis demonstrates that the majority of videos regarding AIDs are of limited quality. Available videos more often address users with a professional medical background. Only a small proportion of existing videos provide understandable and useful information for AID patients. Thus, there is a strong need to develop high-quality and audience-oriented videos in the context of educational campaigns for these rare disease groups.

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.

ObjectivesThe aim of this study was to assess the safety and efficacy of long-term low-dose glucocorticoids (GCs) in RA.MethodsA protocolised systematic review and meta-analysis (PROSPERO No. CRD42021252528) of double-blind, placebo-controlled randomised trials (RCTs) comparing a low dose of GCs (≤ 7.5mg/day prednisone) to placebo over at least 2 years was performed. The primary outcome investigated was adverse events (AEs). We performed random-effects meta-analyses and used the Cochrane RoB tool and GRADE to assess risk of bias and quality of evidence (QoE).ResultsSix trials with 1078 participants were included. There was no evidence of an increased risk of AEs (incidence rate ratio 1.08; 95% CI 0.86, 1.34; P = 0.52); however, the QoE was low. The risks of death, serious AEs, withdrawals due to AEs, and AEs of special interest did not differ from placebo (very low to moderate QoE). Infections occurred more frequently with GCs (risk ratio 1.4; 1.19–1.65; moderate QoE). Concerning benefit, we found moderate to high quality evidence of improvement in disease activity (DAS28: −0.23; −0.43 to −0.03), function (HAQ −0.09; −0.18 to 0.00), and Larsen scores (–4.61; −7.52 to −1.69). In other efficacy outcomes, including Sharp van der Heijde scores, there was no evidence of benefits with GCs.ConclusionThere is very low to moderate QoE for no harm with long-term low dose GCs in RA, except for an increased risk of infections in GC users. The benefit-risk ratio might be reasonable forusing low-dose long-term GCs considering the moderate to high quality evidence for disease-modifying properties.

Purpose Calcium and vitamin D co-supplementation is common and widely used, but randomized, controlled trials (RCTs) have yielded inconclusive results concerning its impact on the serum lipid profile. Methods A comprehensive literature search of Medline, Web of Science, Scopus, Embase, Cochrane Central Register of Controlled Trials, and clinical trial registry databases was conducted to identify placebo-controlled RCTs that were published through September 2020 and that evaluated the impact of calcium and vitamin D co-supplementation on total cholesterol (TC), triglycerides (TGs), low- and very-low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol (HDL-C). Standardized mean differences (SMDs) were pooled using random-effects meta-analysis models. Findings Thirteen studies in a total of 2304 participants met the inclusion criteria. Calcium and vitamin D co-supplementation was associated with significant reductions in both TC (SMD, −0.81; 95% CI, −1.35 to –0.27; I2 = 94.6%) and TGs (SMD, –0.50; 95% CI, –0.91 to –0.08; I2 = 91.5%), and with a significant increase in HDL-C (SMD, 1.22; 95% CI, 0.60 to 1.83; I2 = 95.4%). However, calcium and vitamin D co-supplementation were not found to be associated with significantly decreased low-density lipoprotein cholesterol (SMD, –0.39; 95% CI, –0.78 to 0.01; I2 = 90.1%) or very-low-density lipoprotein cholesterol (SMD, –0.01; 95% CI, –0.70 to 0.69; I2 = 82.3%). Implications The findings from the present systematic review and meta-analysis suggest that calcium and vitamin D co-supplementation has a beneficial effect on TC, TG, and HDL-C. Larger-scale, well-designed RCTs are needed to clarify the effect of calcium and vitamin D co-supplementation on all lipid-profile components.

Background: GCs remain regularly used drugs to treat rheumatoid arthritis (RA). While weight gain and hypertension are known to be common adverse events of the treatment with higher GC dosages, the effects of low dose (i.e. ≤ 7.5mg/day) treatment over longer periods of time (i.e. ≥ 24 months) as seen in RA have not been fully elucidated yet. While some observational studies have been conducted, these studies are likely subject to confounding by indication – i.e., patients with high disease activity usually receive higher doses of GCs, making it impossible to discriminate between the effects of the drug and the disease. Objective: To conduct a pooled analysis of five long-term randomized controlled trials (RCTs) in RA which compared low dose GCs to placebo or no GC in a double-blind fashion in order to evaluate the effects on weight and blood pressure after two years. Methods: We will include the following RCTs, all of which had a duration of two years: The Glucocorticoid Low Dose Outcome in Rheumatoid Arthritis Trial (GLORIA trial, Boers et al.), Arthritis and Rheumatism Council Low-Dose Glucocorticoid Trial (ARC trial, Kirwan et al.), the Intramuscular Methylprednisolone Study (Choy et al), the Low Dose Prednisone Trial (LDPT trial, Wassenberg et al.), and the BARFOT Trial (Svensson et al.). The primary analyses will be based on analysis of covariance (ANCOVA) models containing the terms, treatment, baseline value of the outcome, and trial ID, and will assess the effect of low dose GCs on two major out comes: change in weight from baseline until two years (kg) and change in mean arterial pressure (MAP; in mmHg; same time frame). If there is a significant difference between GC and control groups in MAP, we will perform a sensitivity analysis to investigate the components (i.e., systolic blood pressure and diastolic blood pressure). In further analyses, other covariates will be investigated, e.g., GC dosage, form of application (oral vs. subcutaneous), age, sex, and disease activity. Sensitivity analyses will also be conducted to underpin the findings.

Zusammenfassung Ziel der Studie Analyse der Entwicklung der Ergebnisse des Zweiten (klinisch-schriftlichen, „M2“) und Dritten (klinisch-mündlichen; „M3“) Abschnitts der Ärztlichen Prüfung in Deutschland. Methodik Es wurden öffentlich verfügbare Daten des Zweiten und Dritten Abschnitts der Ärztlichen Prüfung analysiert (Jahre 2014–2020). Meta-Regressions-Modelle (mixed-effects) schätzten Zusammenhänge zwischen Prüfungsergebnissen und dem Zeitpunkt der Prüfung ein. Ergebnisse Im untersuchten Zeitraum nahmen insgesamt 63 811 bzw. 32 852 Teilnehmer an den untersuchten M2- bzw. M3-Prüfungen teil. Der Prozentsatz durchschnittlich richtig beantworteter Fragen aller M2-Examina lag bei 77,7% (Minimum: 73%; Maximum: 82,7%). Es zeigte sich über die Zeit eine große Variation in den Ergebnissen: Der Anteil von Teilnehmern mit „sehr gutem“ Ergebnis variierte zwischen 0,1% (Frühjahr 2020) und 17% (Herbst 2015) und der Anteil von Teilnehmern mit „gutem“ Ergebnis zwischen 21% (Frühjahr 2020) und 52% (Herbst 2015). Insgesamt zeigte sich bei Analyse der M2-Examina ein negativer Trend. Über die Zeit sanken bspw. der Prozentsatz richtig beantworteter Fragen (Steigung β=-0,82%; p < 0,01) und der Anteil von Teilnehmern mit „sehr gutem“ (β=-1,17; p=0,04) und „gutem“ (β=-2,58; p=0,02) Ergebnis. In den Modellen konnte mit dem Zeitpunkt der Prüfung zwischen 20 und 34% der Heterogenität zwischen den Prüfungen erklärt werden. In den M3-Examina zeigte sich nur eine sehr geringe Variation über die Zeit, außerdem waren keine Trends zu erkennen (p=0,08–0,60). Schlussfolgerung Die Ergebnisse der M2-Examina variierten über die letzten Jahre stark, außerdem zeigte sich ein deutlicher Trend hin zu durchschnittlich schlechteren Ergebnissen. Die Ergebnisse der M3-Examina blieben hingegen bei geringer Variation auf konstantem Niveau. Mögliche Ursachen dieser Entwicklungen – etwa schlechter werdende schriftliche Fähigkeiten der Studierenden oder ein höherer Anforderungsgrad in den M2-Examina – sollten untersucht werden. Die große Variation der durchschnittlichen Ergebnisse stellt die Reliabilität und Vergleichbarkeit der M2-Examina in Frage.

ObjectiveTo investigate the success rate of glucocorticoid (GC) discontinuation during follow-up in observational cohorts and clinical trials using temporary GC as part of initial therapy (‘bridging’) in newly diagnosed patients with rheumatoid arthritis (RA).MethodsSystematic literature searches were conducted to identify observational cohorts and clinical trials including patients with RA treated with initial GC bridging therapy, defined as discontinuation of GC within 1 year. Patient percentages still using GC were considered the reverse of successful discontinuation. Random effects meta-analyses were performed stratified by time point.ResultsThe scoping literature search for observational cohort studies could not identify studies answering the research question. The literature search for clinical trials identified 7160 abstracts, resulting in 10 included studies, with varying type and dose of GC and varying tapering schedules, of which 4 reported sufficient data on GC discontinuation or use after the bridging phase. The pooled proportion of patients who were still or again using GC was 22% (95% CI 8% to 37%, based on four trials) at 12 months and 10% at 24 months (95% CI −1 to 22, based on two trials). Heterogeneity was substantial (I²≥65%).ConclusionThe success rate of GC discontinuation after bridging as part of initial treatment of RA has been described in a limited number of studies. Reports on observational cohorts did not answer the research question. In clinical trials, protocolised discontinuation was mostly successful, although 22% of the patients who started GC bridging therapy still or again used GC at 12 months, and 10% at 24 months.

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.

Background: Glucocorticoids (GCs) can cause osteoporosis (OP). Prior observational research on bone density and the effects of GCs in polymyalgia rheumatica (PMR) and vasculitides is scarce and inconclusive. Methods: Rh-GIOP is a prospective cohort study of bone health in patients with inflammatory rheumatic diseases. In this cross-sectional baseline analysis, we focused on patients with PMR and different forms of vasculitides. Multivariable linear regression was used to model the effect of current and cumulative GC intake on the minimum T-score at any site (mTs; at either lumbar spine or hip), with comprehensive adjustment for confounders. In separate models, GCs were modelled both as continuous and categorical predictors. Sensitivity analyses, stratifying by measurement site and disease, were conducted. Results: A total of 198 patients, with a mean age of 67.7 ± 11.4 years and a mean disease duration of 5.3 ± 6.3 years, were included. Most patients suffered from PMR (36%), giant cell arteritis (26%) or granulomatosis with polyangiitis (17%). Women comprised 66.7% of the patients, and 87.4% were currently taking GCs. The mean CRP was 13.2 ± 26.1 mg/L. OP diagnosed by dual energy X-ray absorptiometry (DXA) (T-score ≤ −2.5) was present in 19.7% of the patients. While 88% were taking vitamin D supplements, calcium supplementation (4%) and treatment with anti-resorptive agents (17%) were relatively infrequent. Only 7% had a vitamin D deficit. Neither current (β(continuous model) = −0.01, 97.5% CI –0.02 to 0.01; p(all models) ≥ 0.49) nor cumulative (β(continuous model) = 0.01, 97.5% CI −0.04 to 0.07; p(all models) ≥ 0.35) GC doses were associated with mTs in any model. CRP was not associated with mTs in any model (p(all models) ≥ 0.56), and no interaction between CRP and GC intake was observed (p for interaction(all models) ≥ 0.32). Across all analyses, lower body mass index (p(all models) ≤ 0.01), history of vertebral fractures (p(all models) ≤ 0.02) and proton-pump inhibitor intake (p(all models) ≤ 0.04) were associated with bone loss. Sensitivity analyses with femoral neck and lumbar spine T-scores as dependent variables led to similar results as the analysis that excluded patients with PMR. Conclusions: In this cohort of PMR and vasculitides, we found a similar prevalence of OP by DXA to the overall elderly German population. Vitamin D supplementation was very common, and vitamin D insufficiency was less frequent than expected in Germans. There was no association between current or cumulative GC intake, CRP and impaired bone density. Proton-pump inhibitors seem to be a major, but somewhat neglected, risk factor for OP and should be given more attention. Our findings require confirmation from longitudinal analyses of the Rh-GIOP and other cohorts.

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.

Glucocorticoids (GCs) remain regularly used drugs in patients with chronic inflammatory rheumatic diseases. As long-term intake at high dosages is associated with harm, it is generally advised that GCs be tapered and stopped. However, most recommendations concerning tapering have been eminence- or consensus-based. In this narrative review, we present novel data from recent studies (SEMIRA, CORTICOLUP, and GiACTA) shedding light from different angles on the effects of tapering GCs in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and giant cell arteritis (GCA). In RA and SLE, our main findings comprise that (a) the majority of RA and SLE patients can successfully taper their GC, but that (b) tapering increases the risk of flare. In GCA, tocilizumab was shown to be a potent GC-sparing agent. Finally, we also present exemplary tapering schemes for RA, SLE, and GCA, although different tapering regimens have not yet been sufficiently compared in randomized trials.

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.

Trend analysis of the results of the second clinical (written, "M2") and third clinical (oral, "M3") part of the German medical licensing examination.Publicly available data were analyzed (2014-2020) using meta-regression models (mixed-effects) for evaluation of correlations between results and the time point of the examinations.A total of 63,811 and 32,852 students participated in the M2 and M3 examinations, respectively. The average percentage of correctly answered questions across all M2 examinations was 77.7% (minimum: 73%; maximum: 82.7%). Generally, there was great variation: The percentage of participants with "very good" results varied between 0.1% (spring 2020) and 17% (fall 2015) as did the percentage of participants with "good" results (between 21% (spring 2020) and 52% (fall 2015)). Analysis of M2 examinations showed an overall negative trend. Over time, for example, the percentage of correctly answered questions (slope β=-0.82%; p0.01) and the percentage of participants with "very good" (β=-1.17; p=0.04) and "good" (β=-2.58; p=0.02) results decreased significantly. The time point of the examinations explained between 20 and 34% of heterogeneity between examination results. With regard to the M3 examinations, there was only little variation over time, and no negative trends were observed (p=0.08-0.60).Results of the M2 examinations varied greatly over the last years, and there was a significant negative trend. In contrast, results of the M3 examinations remained constant with little variation. Possible explanations such as worsening written skills or higher requirements in the M2 examinations need to be investigated. The observed great variation of average results questions the reliability and comparability of the M2 examinations in Germany.Analyse der Entwicklung der Ergebnisse des Zweiten (klinisch-schriftlichen, „M2“) und Dritten (klinisch-mündlichen; „M3“) Abschnitts der Ärztlichen Prüfung in Deutschland.Es wurden öffentlich verfügbare Daten des Zweiten und Dritten Abschnitts der Ärztlichen Prüfung analysiert (Jahre 2014–2020). Meta-Regressions-Modelle (mixed-effects) schätzten Zusammenhänge zwischen Prüfungsergebnissen und dem Zeitpunkt der Prüfung ein.Im untersuchten Zeitraum nahmen insgesamt 63 811 bzw. 32 852 Teilnehmer an den untersuchten M2- bzw. M3-Prüfungen teil. Der Prozentsatz durchschnittlich richtig beantworteter Fragen aller M2-Examina lag bei 77,7% (Minimum: 73%; Maximum: 82,7%). Es zeigte sich über die Zeit eine große Variation in den Ergebnissen: Der Anteil von Teilnehmern mit „sehr gutem“ Ergebnis variierte zwischen 0,1% (Frühjahr 2020) und 17% (Herbst 2015) und der Anteil von Teilnehmern mit „gutem“ Ergebnis zwischen 21% (Frühjahr 2020) und 52% (Herbst 2015). Insgesamt zeigte sich bei Analyse der M2-Examina ein negativer Trend. Über die Zeit sanken bspw. der Prozentsatz richtig beantworteter Fragen (Steigung β=-0,82%; p0,01) und der Anteil von Teilnehmern mit „sehr gutem“ (β=-1,17; p=0,04) und „gutem“ (β=-2,58; p=0,02) Ergebnis. In den Modellen konnte mit dem Zeitpunkt der Prüfung zwischen 20 und 34% der Heterogenität zwischen den Prüfungen erklärt werden. In den M3-Examina zeigte sich nur eine sehr geringe Variation über die Zeit, außerdem waren keine Trends zu erkennen (p=0,08–0,60).Die Ergebnisse der M2-Examina variierten über die letzten Jahre stark, außerdem zeigte sich ein deutlicher Trend hin zu durchschnittlich schlechteren Ergebnissen. Die Ergebnisse der M3-Examina blieben hingegen bei geringer Variation auf konstantem Niveau. Mögliche Ursachen dieser Entwicklungen – etwa schlechter werdende schriftliche Fähigkeiten der Studierenden oder ein höherer Anforderungsgrad in den M2-Examina – sollten untersucht werden. Die große Variation der durchschnittlichen Ergebnisse stellt die Reliabilität und Vergleichbarkeit der M2-Examina in Frage.

Systemic juvenile idiopathic arthritis (SJIA) is a severe childhood-onset inflammatory disease characterized by arthritis accompanied by systemic auto-inflammation and extra-articular symptoms. While recent advances have unraveled a range of risk factors, the pathomechanisms involved in SJIA and potential prognostic markers for treatment success remain partly unknown. In this study, we included 70 active SJIA and 55 healthy control patients from the National Center for Biotechnology Information to analyze for differentially expressed genes (DEGs) using R. Functional enrichment analysis, protein-protein interaction (PPI), and gene module construction were performed for DEGs and hub gene set. We additionally examined immune system cell composition with CIBERSORT and predicted prognostic markers and potential treatment drugs for SJIA. In total, 94 upregulated and 24 downregulated DEGs were identified. Two specific modules of interest and eight hub genes (ARG1, DEFA4, HP, MMP8, MMP9, MPO, OLFM4, PGLYRP1) were screened out. Functional enrichment analysis suggested that complex neutrophil-related functions play a decisive role in the disease pathogenesis. CIBERSORT indicated neutrophils, M0 macrophages, CD8+ T cells, and na��ve B cells to be relevant drivers of disease progression. Additionally, we identified TPM2 and GZMB as potential prognostic markers for treatment response to canakinumab. Moreover, sulindac sulfide, (-)-catechin, and phenanthridinone were identified as promising treatment agents. This study provides a new insight into molecular and cellular pathogenesis of active SJIA and highlights potential targets for further research.

Background Curcumin is a biologically active phytochemical ingredient found in turmeric. It has several pharmacologic effects that might benefit patients with polycystic ovary syndrome (PCOS). Objective We hypothesized curcumin to be effective in improving blood sugar levels, insulin resistance and hyperandrogenism in individuals with PCOS. Methods In a randomized double-blind placebo-controlled trial, individuals with PCOS were treated with curcumin (500 mg three times daily) or placebo for 12 weeks. Primary outcome measures were fasting plasma glucose (FPG), fasting insulin (FI), sex hormone levels, and hirsutism (Ferriman-Gallwey [mFG] score). Secondary outcomes included anthropometric measurements. Results Of 72 randomized individuals, 67 completed the trial. The two groups were comparable at baseline. At the end of the study, FPG and Dehydroepiandrosterone levels had decreased significantly in the intervention group compared to control (difference of change (post-pre) between intervention and placebo groups: -4.11 mg/dL; 95% CI: -8.35, -0.35 mg/dL; p = 0.033 and -26.53 microg/dL; 95% CI: -47.99, -4.34 µg/dL; p = 0.035, respectively). We also observed a statistically non-significant increase (p = 0.082) in Estradiol levels in the intervention group compared to control. No serious adverse events were reported throughout the trial. Conclusions Curcumin might be a safe and useful supplement to ameliorate PCOS-associated hyperandrogenemia and hyperglycemia. However, longer trials investigating different dosages in longer durations are needed to underpin these findings.

Endothelial function (EF) and arterial stiffness (AS) are predictors of cardiovascular disease. As previous research concerning the effect of coffee intake on EF and AS was controversial, we conducted a systematic review and meta-analysis to synthesize research.We performed a systematic search in PubMed, Scopus and Web of Science to find clinical trials investigating the effect of coffee intake on EF or AS up to March 2020.Random-effects models were used to estimate the pooled weighted mean difference (WMD) between intervention and control groups for randomized controlled trials (RCTs). Between study heterogeneity was estimated using Cochran's Q and theTwenty-three articles were included for qualitative and 11 articles for quantitative synthesis. Meta-analysis of 14 RCTs (nine articles) indicated a positive short-term (postprandial) effect of coffee intake on flow-mediated dilation (FMD) as a measure of EF (WMD: 1.93%[95% CI: 1.10-2.75];The results from this meta-analysis suggest a beneficial short-term effect of coffee intake on EF as measured by FMD. Base on systematic review results acute and chronic intake of coffee products may exerts an unfavorable effect on AS. While we found no such effect concerning long-term coffee intake, this latter finding must be interpreted cautiously as the number of studies were low and included studies had a considerable risk of bias.

Recent evidence indicates a beneficial effect of Melissa officinalis (MO) intake on several chronic diseases. However, the effects of MO intake have not yet been systematically reviewed. Therefore, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of MO intake and focused on several cardiometabolic outcomes. MEDLINE, Scopus, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials were searched for MO-RCTs evaluating cardiometabolic outcomes. Random-effects meta-analyses estimated the pooled standardized mean differences (SMD) between intervention and control groups. Risk of bias was assessed with the Cochrane Collaboration's tool for assessing the risk of bias in RCTs. Seven RCTs were finally deemed eligible. MO intake was associated with a reduced total cholesterol (TC) (SMD: -0.26; 95% CI: -0.52, -0.01; I2 = 13.7%; k = 6) and a reduced systolic blood pressure (SBP) (SMD: -0.56; 95% CI: -0.85, -0.27; I2 = 00.0%; k = 3). MO intake was not associated with statistically significant changes in triglycerides, low-density lipoprotein, diastolic blood pressure, high sensitivity c-reactive protein levels, fasting blood sugar, HbA1c, insulin or high-density lipoprotein levels. No serious adverse events were reported. The risk of bias was high in a considerable amount of studies. Our study suggests that MO is a safe supplement with beneficial effects on TC and SBP. However, the findings of our study must be seen in the light of major limitations such as a low number of included studies and a serious risk of bias. High-quality RCTs are needed for firm conclusions concerning the effects of MO on cardiometabolic outcomes.

Purpose While glucocorticoids (GCs) are effective in large vessel vasculitis (LVV), they may cause serious adverse events (AEs), especially if taken for longer durations and at higher doses. Unfortunately, patients suffering from LVV often need long-term treatment with GCs; therefore, toxicity needs to be expected and countered. Recent Findings GCs remain the mainstay of therapy for both giant cell arteritis and Takayasu arteritis. In order to minimize their toxicity, the following strategies should be considered: GC tapering, administration of conventional synthetic (e.g., methotrexate) or biologic (e.g., tocilizumab) GC-sparing agents, as well as monitoring, prophylaxis, and treatment of GC-related AEs. Several drugs are currently under investigation to expand the armamentarium for the treatment of LVV. Summary GC treatment in LVV is effective but associated with toxicity. Strategies to minimize this toxicity should be applied when treating patients suffering from LVV.

OBJECTIVE: To identify barriers and solutions for the recruitment and retention of older (aged ≥65 years) people in clinical trials.DESIGN: Systematic literature review.METHODS: Three databases (Medline, Embase, and CENTRAL) were searched for articles reporting on barriers or solutions regarding the recruitment or retention of older people. Only original research articles were included.RESULTS: Fifty eligible articles were identified. Exclusion criteria were the most common cause of poor recruitment of older adults (mainly age and comorbidities). Patients' families or physicians often advised against participation (22% of included studies). Lack of interest (18%) and problems with transportation (18%) were also commonly cited as challenges. Fourteen trials (28%) reported that monitoring and adapting their recruitment methods helped, along with a flexible research team (26%) and provision of transportation (24%). Retention was impaired by death (12%), illness (8%), and loss of interest (6%). Methods with a positive effect on retention included financial incentives and regular information about the progress of the study (12%), a low staff turnover (12%), flexibility in appointment making (10%), and expression of appreciation by the staff through letters, gifts, and cards to the participants (10%).CONCLUSION: We identified several barriers and have listed potential solutions that may improve recruitment and lead to fewer dropouts in trials involving older populations. Implementation of our findings may help mitigate the manifold challenges that come with running a trial with older people.

Importance Elderly patients are underrepresented in clinical trials. Objective To identify barriers and strategies concerning recruitment and retention of elderly patients in clinical trials. Data Source MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials (via Cochrane Library), Embase (via Ovid) Eligibility Publications stemming from original research that report on barriers of or strategies for better recruitment or retention of elderly people. Outcomes Barriers and strategies concerning recruitment and retention of elderly people in clinical trials. Critical Appraisal This study is about identifying barriers and solutions concerning recruitment and retention of elderly patients in clinical trials. Typical endpoints requiring a risk of bias appraisal such as ones that concern efficacy or safety will not be assessed, consequently, there will be no risk of bias assessments. Furthermore, a very heterogeneous set of studies will be included for which there exists no single risk of bias-assessment tool.

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:Glucocorticoids (GCs) are regularly used as a bridging therapy in early rheumatoid arthritis (eRA). As long-term treatment, especially at higher dosages, may lead to undesirable adverse events, GCs should be tapered as rapidly as clinically feasible.Objectives:To assess real-world trajectories of GC-therapy initiated in patients with eRA and in methotrexate-naïve RA patients.Methods:We conducted a scoping search in MEDLINE (via PubMed) to find articles (years 2005 – 2020) reporting on eRA (or methotrexate-naïve RA) patients from observational cohorts who start or take GCs at baseline. Articles had to describe either dosages or proportions of patients who took GCs or were able to taper GCs at two (minimum) pre-specified time points. The articles were screened by one reviewer (AP). Random-effects meta-analyses pooled results per outcome and time point if ≥3 studies were available. R software with package metafor was used for statistical analyses. A research protocol was published with protocols.io (10.17504/protocols.io.bpyfmptn).Results:Our highly specific search strategy yielded 165 results. Twelve articles on nine cohorts were finally included. Eight cohorts originated in Europe, one in Africa. At baseline, about half of the patients with eRA were prescribed GCs with a mean dosage of 8mg/d prednisone equivalent (fig 1). Over time, both the proportion taking GCs and the mean dosage declined. There was substantial heterogeneity between studies.Conclusion:Our results indicate that GCs remain regularly used drugs in eRA patients and in methotrexate-naïve patients with RA. While about 40% of patients still receive GCs after 24 months, mean dosages were tapered to “low” dosages (≤7.5mg/d prednisone equivalent)1 in all cohorts that reported respective data. Heterogeneity might be caused by country-specific differences. Unfortunately, the validity of sensitivity analyses would be poor due to the paucity of published data regarding GC dosages and proportions of patients taking GCs in observational RA cohorts. Major limitations of this scoping review are the very specific (and consequently less sensitive) search strategy and that the screening was conducted by one reviewer only.References:[1]Buttgereit F, Da Silva JAP, Boers M, et al. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann Rheum Dis 2002;61(8):718-22. doi: 10.1136/ard.61.8.718.Figure 1.Meta-analyses of proportions taking glucocorticoids and mean dosages at baseline and 24 months. GCs: Glucocorticoids; CI: Confidence interval.Disclosure of Interests:None declared

Resveratrol, a natural polyphenolic ingredient extracted from herbs, suppresses oxidative stress and inflammation. We performed a comprehensive review to find any evidence about the effects of Resveratrol on acute pancreatitis (AP). Resveratrol has been found to directly impact cytokine generation. As these factors play a crucial role in the pathophysiology of AP, resveratrol might attenuate AP and its complications. Mechanistically, resveratrol exerts its pharmacological effects through anti-inflammatory and antioxidant mechanisms via interaction with different signaling molecules and transcription factors. Indeed, resveratrol might prove to be an effective therapeutic component for AP treatment in the future. In this review, we shed light on potential most recent pathways through which resveratrol might impact the management and control of AP.

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.

Systematic reviews with meta-analyses are powerful instruments to synthesize research. If done correctly, they may constitute the highest level of evidence by combining several individual studies. As high-quality evidence is scarce in the field of complementary medicine, meta-analyses of randomized trials may shed new light on both efficacy and safety, but they must be properly conducted. In this commentary to a recently published paper we elaborate on methodological pitfalls in meta-analysis that every researcher should avoid to gain true high-quality evidence.

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)