Abstract 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.
Abstract Context There are contradictory findings about the relationship between various animal protein sources and the risk of gestational diabetes mellitus (GDM). Objective The purpose of our study was to understand better the associations between total protein, animal protein, and animal protein sources and the risk of developing GDM. Data Sources A systematic literature search was conducted in PubMed, Scopus, and Web of Science encompassing the literature up until August 2022. A random-effects model was used to combine the data. For estimating the dose–response curves, a one-stage linear mixed-effects meta-analysis was conducted. Data Extraction Data related to the association between animal protein consumption and the risk of GDM in the general population was extracted from prospective cohort studies. Data Analysis It was determined that 17 prospective cohort studies with a total of 49 120 participants met the eligibility criteria. It was concluded with high certainty of evidence that there was a significant association between dietary animal protein intake and GDM risk (1.94, 95% CI 1.42 to 2.65, n = 6). Moreover, a higher intake of total protein, total meat, and red meat was positively and significantly associated with an increased risk of GDM. The pooled relative risks of GDM were 1.50 (95% CI: 1.16, 1.94; n = 3) for a 30 g/d increment in processed meat, 1.68 (95% CI: 1.25, 2.24; n = 2) and 1.94 (95% CI: 1.41, 2.67; n = 4) for a 100 g/d increment in total and red meat, and 1.21 (95% CI: 1.10, 1.33; n = 4) and 1.32 (95% CI: 1.15, 1.52; n = 3) for a 5% increment in total protein and animal protein, respectively. GDM had a positive linear association with total protein, animal protein, total meat consumption, and red meat consumption, based on non-linear dose–response analysis. Conclusion Overall, consuming more animal protein–rich foods can increase the risk of GDM. The results from the current study need to be validated by other, well-designed prospective studies. Systematic Review Registration PROSPERO registration no. CRD42022352303.
To develop an operational definition of contextual factors (CF) [1].Based on previously conducted interviews, we presented three CF types in a Delphi survey; Effect Modifying -, Outcome Influencing - and Measurement Affecting CFs. Subsequently, a virtual Special Interest Group (SIG) session was held for in depth discussion of Effect Modifying CFs.Of 161 Delphi participants, 129 (80%) completed both rounds. After two rounds, we reached consensus (≥70% agreeing) for all but two statements. The 45 SIG participants were broadly supportive.Through consensus we developed an operational definition of CFs, which was well received by OMERACT members.
To explore which core domain is best associated with the American College of Rheumatology (ACR) 20% response in trials assessing the effect of targeted interventions in rheumatoid arthritis (RA).
Radiographic joint damage progresses in 20-30% of rheumatoid arthritis (RA) patients despite fulfilling clinical remission criteria [1]. Osteitis assessed on MRI predicts subsequent bone damage progression [2]. Therefore, targeting absence of osteitis combined with clinical remission may improve long-term radiographic outcomes.
Objectives
To investigate whether a 2-year MRI treat-to-target (MRI T2T) strategy targeting absence of osteitis combined with clinical remission, compared to a conventional T2T strategy targeting clinical remission only, could reduce radiographic joint damage progression over 5 years in RA patients.
Methods
IMAGINE-more was designed as a three-year observational extension study of the 2-year IMAGINE-RA randomized clinical trial [3]. IMAGINE-RA included 200 RA patients in clinical remission (DAS28-CRP<3.2 and no swollen joints), with erosive disease (bone erosion on conventional radiography), and treated with csDMARDs. The objective was to investigate whether an MRI T2T strategy targeting absence of osteitis combined with clinical remission (DAS28-CRP≤3.2 and no swollen joints) as compared to a conventional T2T strategy, targeting clinical remission only, could improve remission rates and prevent radiographic joint damage progression. If treatment target was not met, treatment was intensified stepwise starting with increment in csDMARDs and subsequently adding biologics. Participants in the IMAGINE-more study were managed in routine clinical practice in outpatient clinics. Clinical examinations and radiographs of hands and feet (also obtained at baseline, year 1 and 2 in IMAGINE-RA) were done year 3, 4 and 5. The primary endpoint was the proportion of patients with no radiographic progression (increase in total van der Heijde-modified Sharp score (vdHSS) ≤0) from baseline to year 5. Secondary endpoints were 0-5 years changes in total vdHSS, vdHSS erosion and joint space narrowing (JSN) scores. Dichotomous endpoints were estimated by logistic regression, while median differences were calculated for the continuous outcome measures.
Results
Informed consent to participation in IMAGINE-more was obtained from 131 patients (59 from the original MRI T2T group). Of these, 14 patients (24%) in the MRI T2T group and 19 patients (26%) in the conventional T2T group had no radiographic progression from baseline to year 5 (OR 0.70 [0.28 to 1.71]). As illustrated in the Table 1 and Figure 1, the median progression in total vdHSS from baseline to 5 years was low, with no differences between treatment groups.
Conclusion
A 2-year combined MRI T2T and clinical T2T strategy, compared with a conventional clinical T2T strategy alone, did not result in reduced radiographic progression in the long term over 5 years in RA patients with erosive disease in clinical remission.
References
[1]Lillegraven et al. Ann Rheum Dis 2012 [2]Brown et al. Arthritis Rheum 2008 [3]Møller-Bisgaard et al. JAMA 2019
Acknowledgements:
NIL.
Disclosure of Interests
Signe Møller-Bisgaard Grant/research support from: Study support from AbbVie, Kim Hørslev-Petersen: None declared, Lykke Midtbøll Ørnbjerg: None declared, Bo Ejbjerg: None declared, Merete Lund Hetland: None declared, Jakob Møllenbach Møller: None declared, Robin Christensen: None declared, Sabrina Mai Nielsen: None declared, Daniel Glinatsi: None declared, Mikael Boesen Shareholder of: Minority shareholder in Image Analysis Group LTD, London UK, Speakers bureau: AbbVie, Celgene, Eli Lilly, Image Analysis Group, Novartis, Pfizer, UCB and Esaote, Paid instructor for: Novartis and Eli Lilly, Consultant of: Novartis, Grant/research support from: AbbVie, Celgene, Novo Nordisk and Novartis, Kristian Stengaard-Pedersen Consultant of: Pfizer, AbbVie, Grant/research support from: Roche, Pfizer, AbbVie and Medoc., Ole Madsen: None declared, Bente Jensen: None declared, Jan Alexander Villadsen: None declared, Ellen Margrethe Hauge Shareholder of: Novartis, AbbVie, Sanofi, Sobi, Grant/research support from: esearch funding to Aarhus University Hospital from Novo Nordic Foundation, Danish Rheumatism Association, Danish Regions Medicine Grants, Roche, Novartis, AbbVie, Oliver Hendricks Speakers bureau: Pfizer, Lilly, Novartis, Hanne Merete Lindegaard: None declared, Niels Steen Krogh: None declared, Anne Grethe Jurik: None declared, Henrik Thomsen: None declared, Mikkel Østergaard Speakers bureau: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Galapagos, Gilead, Hospira, Janssen, MEDAC, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB, Grant/research support from: Abbvie, BMS, Merck, Novartis and UCB.
There is growing interest in collecting outcome information directly from patients in clinical trials. This study evaluates what patients with rheumatic and musculoskeletal diseases (RMDs) consider important to know about symptomatic side effects they may experience from a new prescription drug.
Background: Perioperative antibiotic prophylaxis is routinely applied in total hip arthroplasty (THA) to reduce the risk of surgical site infections (SSI). The superiority of antibiotic duration in preventing serious adverse events (SAEs) including SSIs remains uncertain. We aimed to examine the comparative effectiveness of antibiotic prophylaxis durations in preventing SAEs within one year following THA. Methods: The study employed network meta-analysis of randomized controlled trials. MEDLINE, EMBASE, Cochrane CENTRAL databases, and Clinicaltrials.gov were searched from inception to December 22nd, 2022. Trials examining the effect of antibiotic prophylaxis on SAEs in patients undergoing primary THA were included. SAEs considered were prosthetic joint infections, other serious infections, major cardiovascular events, venous thromboembolisms, and mortality. Our main network meta-analysis was based on mixed-effects logistic regression models. The odds ratio (OR, with 95% confidence interval [95% CI]) was the primary measure. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. This study was registered with PROSPERO, CRD42022385597. Findings: The search generated 6,131 studies, of which 10 trials were included involving 9,106 patients; all 2-group comparisons. Trial arms (20) were grouped into five prespecified antibiotic prophylaxis durations: placebo (3), single-dose (3), multiple-dose ≤ 24 hours (6), multiple-dose over more days (>1 day) (6), and antibiotic-enriched bone cement (antibiotic cement) (2). Compared to placebo, all antibiotic prophylaxis durations except multiple-dose >1 day, demonstrated superior efficacy in reducing SAEs: OR (single-dose) = 0·11 (95%CI: 0·01 to 0·84; CINeMA estimates of certainty: low), OR (multiple-dose ≤ 24 hours) = 0·12 (0·02 to 0·69; low), OR (antibiotic cement) = 0·07 (0·01 to 0·69; low), OR (multiple-dose > 1 day) = 0·27 (0·06 to 1·16; low). Compared to single-dose, multiple-doses were not superior in reducing SAEs: OR (multiple-dose ≤ 24 hours) = 0·87 (0·20 to 3·73; very low) nor over more days (>1 day) OR = 0·40 (0·07 to 2·42; very low) nor was multiple-dose >1 day superior to multiple-dose ≤ 24 hours, OR = 0·46 (0·11 to 1·90; very low). Interpretation: We found that most antibiotic prophylaxis durations relative to placebo prevent SAEs up to one year after THA. This analysis found no evidence suggesting any superior antibiotic prophylaxis duration. Thus, there is no trial evidence to guide the preferable prophylaxis duration.Study Registration: This study was registered with PROSPERO, CRD42022385597.Funding: There is no financial or other support explicitly donated for this specific systematic review and network meta-analysis. The study was indirectly funded by the Novo Nordisk Foundation (NNF20OC0065693), Medicine Fund of the Danish Regions (Regionernes Medicin- og Behandlingspulje; EMN-2020-00030), and The Danish Rheumatism Association (Gigtforeningen; R201-A7259). Section for Biostatistics and Evidence-Based Research, the Parker Institute, Bispebjerg, and Frederiksberg Hospital are supported by a core grant from the Oak Foundation (OCAY-18-774-OFIL). The funders of the source had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.Declaration of Interest: CV reported receiving travel expenses from Stryker paid to the institution and with no relevance to the present study. RC reported receiving payments made directly to RC as an individual for providing consulting advice on biostatistical matters: Image Analysis Ltd, trading as IAG, Image Analysis Group (UK) and providing consulting advice on statistical measures and clinical epidemiology matters: Compass Communications Ltd, and for being a statistical editor at Osteoarthritis and Cartilage, Acta Orthopaedica and Specialty Chief Editor of Rheumatic Drug Safety: (Frontiers in Drug Safety and Regulation). RC is also a Leading member of OMERACT (Outcome Measures in Rheumatology), a member of the GRADE Working Group and Editor at the Cochrane Collaboration with no payments involved. SO reported receiving institutional grants from Heraeus for lectures and course moderation and received personal payment from J&J for lectures. No other disclosures were reported. All other authors report no conflicts of interest.
Spinal manipulative therapy (SMT) is a widely used manual treatment, but many reviews exist with conflicting conclusions about the safety of SMT. We performed an overview of reviews to elucidate and quantify the risk of serious adverse events (SAEs) associated with SMT. We searched five electronic databases from inception to December 8, 2015. We included reviews on any type of studies, patients, and SMT technique. Our primary outcome was SAEs. Quality of the included reviews was assessed using a measurement tool to assess systematic reviews (AMSTAR). Since there were insufficient data for calculating incidence rates of SAEs, we used an alternative approach; the conclusions regarding safety of SMT were extracted for each review, and the communicated opinion were judged by two reviewers independently as safe, harmful, or neutral/unclear. Risk ratios (RRs) of a review communicating that SMT is safe and meeting the requirements for each AMSTAR item, were calculated. We identified 283 eligible reviews, but only 118 provided data for synthesis. The most frequently described adverse events (AEs) were stroke, headache, and vertebral artery dissection. Fifty-four reviews (46%) expressed that SMT is safe, 15 (13%) expressed that SMT is harmful, and 49 reviews (42%) were neutral or unclear. Thirteen reviews reported incidence estimates for SAEs, roughly ranging from 1 in 20,000 to 1 in 250,000,000 manipulations. Low methodological quality was present, with a median of 4 of 11 AMSTAR items met (interquartile range, 3 to 6). Reviews meeting the requirements for each of the AMSTAR items (i.e. good internal validity) had a higher chance of expressing that SMT is safe. It is currently not possible to provide an overall conclusion about the safety of SMT; however, the types of SAEs reported can indeed be significant, sustaining that some risk is present. High quality research and consistent reporting of AEs and SAEs are needed. PROSPERO CRD42015030068 .
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 < 0.001) and the type of intervention (surgical interventions averaging the highest retention; psychological interventions averaging the lowest retention: p < 0.001) were associated with trial retention. Post hoc analyses allowing for interaction revealed a small statistically significant association between the PE and trial retention in pharmacological (retention increasing with the PE) and physical/physiotherapeutic (retention decreasing with the PE) interventions. Further sensitivity analyses showed no significant associations between attrition due to LoE or AE and the PE in any model.
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
