Identification of gene expression biomarkers to predict clinical response to methotrexate in patients with rheumatoid arthritis.

OBJECTIVES: To identify biomarkers at the gene expression level to predict response to methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: MTX-naïve patients with RA were started on MTX and followed up over three months. The disease activity score 28 (DAS28) was used to classify patients into responders and non-responders. Genome-wide gene expression analysis was performed in CD4 + and CD14 + mononuclear cells sampled from whole blood at baseline to identify differentially expressed genes in responders versus non-responders. Gene selection methods and prediction modelling obtained the most relevant differentially expressed genes. A logistic regression prediction model was subsequently constructed and validated via bootstrapping. The area under the receiver operating characteristic (AUC) curve was calculated to judge model quality. RESULTS: Seventy-nine patients with RA (53.4 ± 13.9 years, 74.7% females) were enrolled, and 70 finished the study with a documented treatment EULAR response (77.1% responders). Forty-six differentially expressed genes were found. The most promising genes were KRTAP4-11, LOC101927584, and PECAM1 in CD4 + cells and PSMD5 and ID1 in CD14 + cells. The final prediction model using these genes reached an AUC of 90%; the validation set's AUC was 82%. CONCLUSIONS: Our prediction model constructed via genome-wide gene expression analysis in CD4 + and CD14 + mononuclear cells yielded excellent predictions. Our findings necessitate confirmation in other cohorts of MTX-naïve RA patients. Especially if used in conjunction with previously identified clinical and laboratory (bio)markers, our results could help predict response to MTX in RA to guide treatment decisions. Key Points • Patients with rheumatoid arthritis may or may not respond to treatment with methotrexate, which is the recommended first-line drug in guidelines around the world. • In non-responders, valuable time is lost until second-line treatments are started. • This study aimed at predicting response to methotrexate by identifying differentially expressed genes from peripheral blood samples. • The final prediction model yielded excellent prognostic values, but validation in other cohorts is necessary to corroborate these findings.

Incidence Rate and Factors Associated With Fractures Among Medicare Beneficiaries With Ankylosing Spondylitis in the United States.

OBJECTIVE: We evaluated the incidence rate and factors associated with fractures among adults with ankylosing spondylitis (AS). METHODS: We performed a retrospective cohort study with data from the Rheumatology Informatics System for Effectiveness registry linked to Medicare claims from 2016 to 2018. Patients were required to have two AS International Classification of Diseases codes 30 or more days apart and a subsequent Medicare claim. Then, 1 year of baseline characteristics were included, after which patients were observed for fractures. First, we calculated the incidence rate of fractures. Second, we constructed logistic regression models to identify factors associated with the fracture, including age, sex, race and ethnicity, body mass index, Medicare/Medicaid dual eligibility, area deprivation index, Charlson comorbidity index, smoking status, osteoporosis, historical fracture, and use of osteoporosis treatment, glucocorticoids, and opioids. RESULTS: We identified 1,426 adults with prevalent AS. Mean ± SD age was 69.4 ± 9.8 years, 44.3% were female, and 77.3% were non-Hispanic White. Fractures occurred in 197 adults with AS. The overall incidence rate of fractures was 76.7 (95% confidence interval [CI] 66.4-88.6) per 1,000 person-years. Older age (odds ratio [OR] 2.8, 95% CI 1.39-5.65), historical fracture (OR 5.24, 95% CI 3.44-7.99), and use of more than 30 mg morphine equivalent (OR 1.86, 95% CI 1.08-3.19) conferred increased odds of fracture. CONCLUSIONS: In this large sample of Medicare beneficiaries with AS, increasing age, historical fracture, and use of opioids had higher odds of fracture. Men and women were equally likely to have a fracture. Because opioid use was associated with fracture in AS, this high-risk population should be considered for interventions to mitigate risk.

Continuing versus tapering low-dose glucocorticoids in patients with rheumatoid arthritis and systemic lupus erythematosus in states of low disease activity or remission: A systematic review and meta-analysis of randomised trials.

OBJECTIVES: To study the benefit and harm associated with continuing versus tapering low-dose glucocorticoids (GCs) in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) who have achieved low disease activity/remission. METHODS: A protocolised (PROSPEROCRD42022325175) systematic review and meta-analysis of randomised trials was performed. Trials compared, in patients with low disease activity/remission and GCs at baseline, continued low-dose GCs (≤7.5 mg/d prednisone equivalent) with a taper. Co-primary outcomes were time to flare and adverse events (AEs), accompanied by secondary benefit and harm outcomes. We performed meta-analyses and evaluated risk of bias and quality of evidence (QoE). Subgroup analyses were conducted for patients with RA. RESULTS: Four trials (three: RA; one: SLE; study duration 24-104 weeks) with 472 participants were included. Tapering GCs resulted in a shorter time to flare (hazard ratio 3.41 [95 %-CI 1.96-5.93]; p<0.01; very low QoE). The risks of AEs, serious AEs, and withdrawal due to AEs were similar in both groups (very low to low QoE). There were more withdrawals due to lack of efficacy with tapered GCs (risk ratio 3.02 [1.56-5.87]; low QoE). In RA, the disease activity score-28 was lower with continued GCs (mean difference 0.49 [0.07-0.91]; low QoE). One of 238 patients in the tapering groups experienced adrenal insufficiency. Subgroup analyses yielded consistent results. CONCLUSION: In RA and SLE with low disease activity, continuing low-dose GCs may provide better sustained disease control, but QoE is insufficient. Adrenal insufficiency is very rare when tapering low-dose GCs. Longer-term safety concerns for GCs remain.

Consensus of the definitions of the OMERACT glucocorticoid impact core domain set for people with rheumatic and musculoskeletal diseases.

BACKGROUND: The Outcome Measures in Rheumatology (OMERACT) Glucocorticoid (GC) Impact Working Group has been working to develop a core domain set to measure the impact of GCs on patients living with rheumatic and musculoskeletal diseases. The mandatory domains previously identified for inclusion in all clinical trials measuring the GC effects include infection, bone fragility, mood disturbance, hypertension, diabetes, weight, fatigue, and mortality. Before progressing to instrument selection, the Working Group sought to establish precise definitions of all mandatory domains within the core domain set. METHODS: OMERACT methodology was applied with the use of evidence and consensus-based decision making of all stakeholder groups (patient research partners, health care professionals, clinician researchers, industry members and methodologists) to develop detailed definitions for the broad domain, target domain and domain components, taking into consideration sources of variability that could affect measurement of the domain.  The working group synthesized prior qualitative studies, quantitative work, and results from Delphi rounds, to develop a rich definition of 'what' is to be measured. RESULTS: Between 2021 and 2023, the OMERACT Working Group on GC Impact conducted virtual meetings to establish domain definitions. First, we mapped each domain onto an OMERACT Core Area. All domains were primarily represented within the Pathophysiological Manifestations Core Area, except from Fatigue which was primarily Life Impact and Weight which spanned both Core Areas. Sources of variability included cultural factors, age, gender, education level, socioeconomic status, personal experiences, emotional state, and language barriers. The domain definitions will form the foundation for instrument selection and the initial step of domain / concept match and content validity in the OMERACT pillar of 'truth' before moving on to feasibility and discrimination. CONCLUSION: The OMERACT GC Impact Working Group has developed and agreed upon detailed domain definitions for core domains. Future steps of the working group are to select instruments and develop the core outcome measurement set for clinical trials measuring the impact of GC on patients with rheumatic and musculoskeletal diseases.

[Trabecular bone score in rheumatology : Are there benefits in comparison to bone densitometry alone?] / Trabecular Bone Score in der Rheumatologie : Gibt es einen Nutzen im Vergleich zur alleinigen Osteodensitometrie?

Patients with inflammatory rheumatic diseases have an increased risk of fractures due to the inflammatory potential of the disease and also because of the treatment with glucocorticoids that is often necessary. According to the current guidelines of the Governing Body on Osteology (DVO), the fracture risk can be assessed using dual energy X­ray absorptiometry and can also be supplemented by measuring the trabecular bone score (TBS). The assessment of the TBS offers additional advantages, for example in glucocorticoid-induced osteoporosis and in patients with osteoproliferative changes of the spine (spondylarthritis) and thus optimizes the fracture risk assessment in the rheumatological patient population.

The Effect of Low-Dose Glucocorticoids Over Two Years on Weight and Blood Pressure in Rheumatoid Arthritis: Individual Patient Data From Five Randomized Trials.

BACKGROUND: Weight gain and hypertension are well known adverse effects of treatment with high-dose glucocorticoids. OBJECTIVE: To evaluate the effects of 2 years of low-dose glucocorticoid treatment in rheumatoid arthritis (RA). DESIGN: Pooled analysis of 5 randomized controlled trials with 2-year interventions allowing concomitant treatment with disease-modifying antirheumatic drugs. SETTING: 12 countries in Europe. PATIENTS: Early and established RA. INTERVENTION: Glucocorticoids at 7.5 mg or less prednisone equivalent per day. MEASUREMENTS: Coprimary end points were differences in change from baseline in body weight and mean arterial pressure after 2 years in intention-to-treat analyses. Difference in the change of number of antihypertensive drugs after 2 years was a secondary end point. Subgroup and sensitivity analyses were done to assess the robustness of primary findings. RESULTS: A total of 1112 participants were included (mean age, 61.4 years [SD, 14.5]; 68% women). Both groups gained weight in 2 years, but glucocorticoids led, on average, to 1.1 kg (95% CI, 0.4 to 1.8 kg; P < 0.001) more weight gain than the control treatment. Mean arterial pressure increased by about 2 mm Hg in both groups, with a between-group difference of -0.4 mm Hg (CI, -3.0 to 2.2 mm Hg; P = 0.187). These results were consistent in sensitivity and subgroup analyses. Most patients did not change the number of antihypertensive drugs, and there was no evidence of differences between groups. LIMITATION: Body composition was not assessed, and generalizability to non-European regions may be limited. CONCLUSION: This study provides robust evidence that low-dose glucocorticoids, received over 2 years for the treatment of RA, increase weight by about 1 kg but do not increase blood pressure. PRIMARY FUNDING SOURCE: None.

Sex and age do not modify the association between glucocorticoids and bone mineral density in patients with rheumatoid arthritis: a cross-sectional study.

BACKGROUND: It is unclear whether sex or age modify the association of glucocorticoid (GC) use with reduced bone mineral density (BMD) in patients with rheumatoid arthritis (RA). METHODS: We studied cross-sectional data of RA patients with current or previous GC treatment in a single center cohort study (Rh-GIOP cohort). Our primary outcome was the minimum T-score (measured by DXA) of either lumbar spine, total femur, or femoral neck. Current GC dose was the main exposure; cumulative GC dose and cumulative duration of GC use were also assessed. Following a predefined statistical analysis plan, linear regression analyses with adjustment for confounders assessed whether the association of GC use with BMD was modified by sex (men versus women) or age (≥ 65 versus < 65 years). RESULTS: Four hundred eighty-three patients with RA (mean age 64 ± 12 years, 80% women) were included. 33% were not currently taking GCs, 32% were treated with a dose of 5 mg/d prednisone equivalent and 11% with more than 7.5 mg/d. 23% of patients had osteoporosis by DXA (minimum T-score ≤ -2.5). The slope, i.e., the association between changes in minimum T-scores with 1 mg/d change in current GC dose, was similar in men and women (-0.07 and -0.04, respectively; difference -0.03 [-0.11 to 0.04]; p for interaction = 0.41). Slopes were also similar for elderly and non-elderly patients (-0.03 and -0.04, respectively; difference -0.01 [-0.06 to 0.05]; p for interaction = 0.77). Using cumulative dose and duration of use as exposures did not lead to substantial changes of these results. CONCLUSIONS: In our sample, the association of GC use with reduced BMD in RA was not modified by sex or age.

Safety and efficacy associated with long-term low-dose glucocorticoids in rheumatoid arthritis: a systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to assess the safety and efficacy of long-term low-dose glucocorticoids (GCs) in RA. METHODS: A 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). RESULTS: Six 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. CONCLUSION: There 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.

No association between methotrexate and impaired bone mineral density in a cohort of patients with polymyalgia rheumatica, giant cell arteritis, granulomatosis with polyangiitis and other vasculitides-a cross-sectional analysis with dose-response analyses.

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.

Digital health information on autoinflammatory diseases: a YouTube quality analysis.

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.

Optimising both disease control and glucocorticoid dosing is essential for bone protection in patients with rheumatic disease.

OBJECTIVES: Inflammatory 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. METHODS: Rh-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. RESULTS: Data from 1066 patients with iRMD were analysed. GC doses of <5 mg prednisone equivalent per day, cumulative dose and duration of GC therapy were not associated with negative effects on BMD. Dosages of ≥5 mg/day lost their negative association with BMD after adjustment for confounders. When subanalysing patients with exactly 5 mg/day, no negative effect was seen. For patients with rheumatoid arthritis (RA), 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). CONCLUSIONS: GCs 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 NUMBER: NCT02719314.

Systematic literature review of observational cohorts and clinical trials into the success rate of glucocorticoid discontinuation after their use as bridging therapy in patients with rheumatoid arthritis.

OBJECTIVE: To 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). METHODS: Systematic 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. RESULTS: The 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%). CONCLUSION: The 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.

Glucocorticoids Are Not Associated with Bone Mineral Density in Patients with Polymyalgia Rheumatica, Giant Cell Arteritis and Other Vasculitides-Cross-Sectional Baseline Analysis of the Prospective Rh-GIOP Cohort.

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 (ß(continuous model) = -0.01, 97.5% CI -0.02 to 0.01; p(all models) ≥ 0.49) nor cumulative (ß(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.

[Trends in the Results of Part II and III of the German Medical Licensing Examinations]. / Entwicklung der Ergebnisse des zweiten und dritten Abschnitts der Ärztlichen Prüfung ("M2" Und "M3") In Deutschland.

OBJECTIVE: Trend analysis of the results of the second clinical (written, "M2") and third clinical (oral, "M3") part of the German medical licensing examination. METHODS: 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. RESULTS: 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 ß=-0.82%; p < 0.01) and the percentage of participants with "very good" (ß=-1.17; p=0.04) and "good" (ß=-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). CONCLUSION: 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.

Altered molecular pathways and prognostic markers in active systemic juvenile idiopathic arthritis: integrated bioinformatic analysis.

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 naïve 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.

How to taper glucocorticoids in inflammatory rheumatic diseases? A narrative review of novel evidence in rheumatoid arthritis, systemic lupus erythematosus, and giant cell arteritis.

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.

Effects of Calcium and Vitamin D Co-supplementation on the Lipid Profile: A Systematic Review and Meta-analysis.

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.