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

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

Recruitment and Retention of Older People in Clinical Research: A Systematic Literature Review

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

Association Between Participant Retention and the Proportion of Included Elderly People in Rheumatology Trials: Results From a Series of Exploratory Meta‐Regression Analyses

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

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

Reducing the Toxicity of Long-Term Glucocorticoid Treatment in Large Vessel Vasculitis

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

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 (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

Zur Frage der Generalisierbarkeit randomisierter klinischer Studien zur rheumatoiden Arthritis und Arthrose

Ziel. Zu evaluieren, ob die Ergebnisse aktueller randomisierter klinischer Studien (RCT) zur rheumatoiden Arthritis (RA) und Arthrose auf die allgemeine Patientenpopulation bezüglich Alter und Geschlecht generalisierbar sind. Methoden. Dieses systematische Review mit Meta-Analyse wurde zu Beginn im internationalen Protokollregister für systematische Reviews, PROSPERO, registriert (Identifizierungscode CRD42018085409). Die medizinische Datenbank MEDLINE wurde systematisch nach RCT (Jahre 2016 und 2017) und populationsbasierten Studien (PBS; Jahre 2013 bis 2017) durchsucht. Zusätzlich wurde eine Handsuche nach relevanten Artikeln durchgeführt. Der Anteil älterer Menschen (definiert als ≥65 Jahre alt) wurde unter Annahme einer trunkierten Normalverteilung geschätzt, falls er nicht im Forschungsartikel berichtet wurde. Das Risiko für Bias der eingeschlossenen PBS wurde durch die Joanna Briggs Institute Critical Appraisal Checklist for Prevalence Studies beurteilt. Mithilfe von random-effects Meta-Analysen wurden der durchschnittliche Anteil älterer Menschen an den Studienpopulationen, das Durchschnittsalter, dessen Standardabweichung (SA) und der durchschnittliche Anteil an Frauen geschätzt – stratifiziert nach Krankheit (RA und Arthrose) und Studientyp (RCT und PBS). Diese stratifizierten Schätzungen wurden anschließend verglichen und mittels zwei-Stichproben Z-Tests auf signifikante Unterschiede geprüft. Zusätzlich wurde evaluiert, ob der Anteil älterer Menschen mit der Art der Studienfinanzierung und der Art der Intervention zusammenhängt. Ergebnisse. Es wurden 265 RCT und 53 PBS mit entsprechend 51.240 bzw. 523.630 Teilnehmern eingeschlossen. Sowohl RCT zur RA als auch zur Arthrose schlossen signifikant weniger ältere Menschen ein als PBS: Die Proportionen unterschieden sich um –0.18 (95% Konfidenzintervall –0.22 bis –0.13) bei RA und um –0.20 (–0.30 bis –0.09) bei Arthrose. Dementsprechend berichteten RCT auch niedrigere Durchschnittsalter: RA –5.2 Jahre (–6.8 bis –3.5); Arthrose –4.7 Jahre (–7.5 bis –2.0); und schmalere SA: RA –1.9 Jahre (–2.6 bis –1.3); Arthrose –2.7 Jahre (–4.2 bis –1.2); (alle Vergleiche: p ≤ 0.001). Der Anteil weiblicher Teilnehmer in RCT unterschied sich bei beiden Krankheiten nicht signifikant von den jeweiligen PBS. Die Art der Studienfinanzierung übte keinen Einfluss auf das Defizit an älteren Menschen in RCT aus, die Art der Intervention jedoch bei Studien zur RA (p = 0.02), nicht aber bei Studien zur Arthrose (p = 0.60). Fazit. Im Gegensatz zu Frauen sind ältere Menschen in klinischen Studien zur RA und Arthrose unterrepräsentiert. Aktuelle Evidenz ist daher nur begrenzt auf diese wachsende Patientengruppe generalisierbar. Es müssen mehr ältere Menschen in klinische Studien eingeschlossen werden; ebenso sollte der Einfluss des Patientenalters auf Outcomes untersucht werden.Objective. To assess whether the results of current trials in rheumatoid arthritis (RA) and osteoarthritis (OA) are generalizable to the general patient population with regard to age and sex. Methods. This systematic review and meta-analysis was preregistered with the international protocol registry for systematic reviews, PROSPERO (identifier CRD42018085409). MEDLINE was systematically searched for randomized controlled trials (RCT) on any intervention (years 2016 and 2017) and for population-based studies (PBS; years 2013 to 2017) in both RA and OA, complemented by a hand search. If not reported in the original research manuscript, the proportion of elderly people (defined as being ≥65 years old) was estimated from an assumed truncated normal distribution. The risk of bias of included PBS was evaluated with the Joanna Briggs Institute Critical Appraisal Checklist for Prevalence Studies. Random effects meta-analyses estimated the pooled proportion of elderly people, the mean age, its standard deviation (SD), and the proportion of women stratified by disease (RA and OA) and study type (RCT and PBS). These stratified estimates were subsequently compared by two-sample Z-tests. Additionally, the influence of the type of funding and intervention on the proportion of elderly people was assessed. Results. The search yielded 265 RCT and 53 PBS comprising 51,240 and 523,630 participants, respectively. In both diseases, RCT included significantly fewer elderly people than PBS: Proportions differed by –0.18 (95% confidence interval –0.22 to –0.13) in RA and –0.20 (–0.30 to –0.09) in OA. Correspondingly, RCT 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 did not differ significantly between RCT and PBS in both RA and OA. Funding source did not influence the deficit of elderly people in RCT, however, the type of intervention did in RA (p = 0.02) but not in OA (p = 0.60) trials. Conclusion. While adequate proportions of women are included, the elderly are underrepresented in RA and OA trials. Current evidence is thus only limitedly generalizable to this growing subgroup of patients. It is important to study age as a determinant for outcome and to improve the inclusion of elderly people in RA and OA clinical trials

Glucocorticoid-trials in rheumatoid arthritis mostly study representative real-world patients: A systematic review and meta-analysis

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

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

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