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Treatment with low-dose glucocorticoids (GCs) (≤7.5 mg prednisolone) in combination with standard care is highly effective in rheumatoid arthritis (RA), but despite 70 years of clinical experience, evidence-based information on its balance of benefit and harm is incomplete. This leads to an ongoing debate, with under- and over-use of GCs as result. The GLORIA pragmatic trial was developed to assess harm, benefit and costs of low-dose GCs added to the standard treatment of older RA patients. The objective of this abstract is to document the baseline status and frequency of comorbid conditions in the GLORIA study population. The results of the unblinded data will be submitted as late-breaking abstract. This double-blind, randomized, placebo-controlled, multicenter trial (1) was open for patients with RA according to the 1987 or 2010 (2) criteria, age ≥65 years, and disease activity score of 28 joints (DAS28) of ≥2.6. Patients were recruited from rheumatology clinics in Germany, Hungary, Italy, The Netherlands, Portugal, Romania and Slovakia. Eligible patients were randomized to two years of treatment with daily 5 mg prednisolone or matching placebo. All other medication was allowed, except for GCs. The presented data are blinded because the database is not closed yet. The population consists of 451 patients with mean disease duration 10.6 (Q1-Q3: 3-15) years. The majority (70%) is female, mean age is 72.5 (Q1-Q3: 68-76, range: 65-88) years, 66% were positive for rheumatoid factor and 56% for ACPA. Patients had a mean of 4.3 (SD 2.8) comorbidities besides RA (3.4 active) and therefore used multiple concomitant medications (3.9 (SD 3.4)) (Table 1). The most common comorbidities (provisional data of 161 patients with complete coding) in this older population are: vascular disorders (58%), musculoskeletal and connective tissue disorders (57%) and a history of surgical and medical procedures (45%). Patients were most frequently on beta blocking agents (22%, mainly metoprolol) and HMG CoA reductase inhibitors (20%, mainly simvastatin). Most patients also have an extensive history of anti-rheumatic treatment. At the start of the trial most patients (82%) were on cDMARD treatment; 15% were on bDMARDs/tsDMARDs. Almost half of the patients previously had been treated with GCs, with a mean duration of 3.4 years and a mean last dose of 4.6 mg/day. The baseline data shows that we have an older study population who have relatively many other comorbidities next to RA and who are almost all treated with multiple concomitant medications in addition to the study medication. Therefore, we expect to report a high adverse event rate. Research among older patients is urgently needed, but the frailty of this population as represented by the multiple comorbidities and concomitant medications have to be taken into account in the analyses and interpretation of the results. [1]Hartman L, Rasch LA, Klausch T, Bijlsma HWJ, Christensen R, Smulders YM, et al. Harm, benefit and costs associated with low-dose glucocorticoids added to the treatment strategies for rheumatoid arthritis in elderly patients (GLORIA trial): study protocol for a randomised controlled trial. Trials. 2018;19:67. [2]Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:2569-81. The GLORIA project is funded by the European Union's Horizon 2020 research and innovation programme under the topic ‘‘Personalizing Health and Care“, grant agreement No 634886. None declared Table 1Comorbidities and concomitant medications at baseline in theGLORIA trial.MeanSDRangeComorbidities4.32.80-15Active3.4Past1.9Concomitant medications (count)3.93.40-15Beta blocking agents (%)22HMG CoA reductase inhibitors (%)20Platelet aggregation inhibitors (%)16ACE inhibitors (%)12Angiotensin II antagonists (%)11DAS284.521.05DAS28CRP4.060.97HAQ (0-3)1.20.7RA treatmentCurrent (%)Previous (%)cDMARD8492bDMARD/tsDMARD1522NSAID5129Glucocorticoids049

Vertebral fractures are associated with back pain and disability; however, relatively little is known about the impact of radiographic vertebral fractures on quality of life in population samples. The aim of this study was to determine the impact of a recent radiographic vertebral fracture on health-related quality of life (HRQoL). Men and women aged 50 years and over were recruited from population registers in 12 European centers. Subjects completed an interviewer-administered questionnaire and had lateral spine radiographs performed. Subjects in these centers were followed prospectively and had repeat spinal radiographs performed a mean of 3.8 years later. Prevalent deformities were defined using established morphometric criteria, and incident vertebral fractures by both morphometric criteria and qualitative assessment. For each incident fracture case, three controls matched for age, gender, and center were selected: one with a prevalent deformity (at baseline) and two without prevalent deformities. All subjects were interviewed or completed a postal questionnaire instrument which included Short Form 12 (SF-12), the EQ-5D (former EuroQol), and the quality of life questionnaire of the International Osteoporosis Foundation (QUALEFFO). The median time from the second spinal radiograph until the quality of life survey was 1.9 years. Comparison between cases and their matched controls was undertaken using the signed rank test. 73 subjects with incident vertebral fracture (cases), mean age 64.8 years (of whom 23 had a baseline deformity), and 196 controls, mean age 63.9 years (of whom 60 had a baseline deformity), were studied. There were strong correlations between the domain scores for each of the three instruments. There was no statistically significant difference in any of the domain scores between cases and those controls with a prevalent deformity. However, compared with the controls without a prevalent deformity the cases had significantly impaired quality of life as determined using the total QUALEFFO score (38.2 vs 33.7), the physical component score of the SF-12 (39.9 vs 43.7) and the health status score of the EQ-5D (62.3 vs 69.9). When the analysis was repeated after stratification of the cases by baseline deformity status (i.e., cases with and without a prevalent deformity at baseline), cases with a prevalent deformity had impaired quality of life compared with their matched controls, both with and without a prevalent deformity. In contrast there was no significant difference in quality of life among the cases without a prevalent deformity and either control group. In this population-based study a recent vertebral fracture was associated with impairment in quality of life, though this was mainly among those who had sustained a previous vertebral deformity.

Summary In 27 centres across Europe, the prevalence of deforming spinal Scheuermann’s disease in age-stratified population-based samples of over 10,000 men and women aged 50+ averaged 8 % in each sex, but was highly variable between centres. Low DXA BMD was un-associated with Scheuermann’s, helping the differential diagnosis from osteoporosis. Introduction This study aims to assess the prevalence of Scheuermann’s disease of the spine across Europe in men and women over 50 years of age, to quantitate its association with bone mineral density (BMD) and to assess its role as a confounder for the radiographic diagnosis of osteoporotic fracture. Methods In 27 centres participating in the population-based European Vertebral Osteoporosis Study (EVOS), standardised lateral radiographs of the lumbar and of the thoracic spine from T4 to L4 were assessed in all those of adequate quality. The presence of Scheuermann’s disease, a confounder for prevalent fracture in later life, was defined by the presence of at least one Schmorl’s node or irregular endplate together with kyphosis (sagittal Cobb angle >40° between T4 and T12) or a wedged-shaped vertebral body. Alternatively, the (rare) Edgren-Vaino sign was taken as diagnostic. The 6-point-per-vertebral-body (13 vertebrae) method was used to assess osteoporotic vertebral shape and fracture caseness. DXA BMD of the L2–L4 and femoral neck regions was measured in subsets. We also assessed the presence of Scheuermann’s by alternative published algorithms when these used the radiographic signs we assessed. Results Vertebral radiographic images from 4486 men and 5655 women passed all quality checks. Prevalence of Scheuermann’s varied considerably between centres, and based on random effect modelling, the overall European prevalence using our method was 8 % with no significant difference between sexes. The highest prevalences were seen in Germany, Sweden, the UK and France and low prevalences were seen in Hungary, Poland and Slovakia. Centre-level prevalences in men and women were highly correlated. Scheuermann’s was not associated with BMD of the spine or hip. Conclusions Since most of the variation in population impact of Scheuermann’s was unaccounted for by the radiological and anthropometric data, the search for new genetic and environmental determinants of this disease is encouraged.

Vertebral fractures are associated with back pain and disability. There are, however, few prospective data looking at back pain and disability following identification of radiographic vertebral fracture. The aim of this analysis was to determine the impact of radiographically identified vertebral fracture on the subsequent occurrence of back pain and disability. Women aged 50 years and over were recruited from population registers in 18 European centers for participation in the European Prospective Osteoporosis Study. Participants completed an interviewer-administered questionnaire which included questions about back pain in the past year and various activities of daily living, and they had lateral spine radiographs performed. Participants in these centers were followed prospectively and had repeat spine radiographs performed a mean of 3.7 years later. In addition they completed a questionnaire with the same baseline questions concerning back pain and activities of daily living. The presence of prevalent and incident vertebral fracture was defined using established morphometric criteria. The data were analyzed using logistic regression with back pain or disability (present or absent) at follow-up as the outcome variable with adjustment made for the baseline value of the variable. The study included 2,260 women, mean age 62.2 years. The mean time between baseline and follow-up survey was 5.0 years. Two hundred and forty participants had prevalent fractures at the baseline survey, and 85 developed incident fractures during follow-up. After adjustment for age, center, and the baseline level of disability, compared with those without baseline prevalent fracture, those with a prevalent fracture (odds ratio [OR] = 1.4; 95% confidence interval [CI] 1.0 to 2.0) or an incident fracture (OR = 1.7; 95% CI, 0.9 to 3.2) were more likely to report disability at follow-up, though the confidence intervals embraced unity. Those with both a prevalent and incident fracture, however, were significantly more likely to report disability at follow-up (OR = 3.1; 95% CI, 1.4 to 7.0). After adjustment for age, center, and frequency of back pain at baseline, compared with those without baseline vertebral fracture, those with a prevalent fracture were no more likely to report back pain at follow-up (OR = 1.2; 95% CI, 0.8 to 1.7). There was a small increased risk among those with a preexisting fracture who had sustained an incident fracture during follow-up (OR = 1.6; 95% CI, 0.6 to 4.1) though the confidence intervals embraced unity. In conclusion, although there was no significant increase in the level of back pain an average of 5 years following identification of radiographic vertebral fracture, women who suffered a further fracture during follow-up experienced substantial levels of disability with impairment in key physical functions of independent living.

BackgroundLow-dose glucocorticoid (GC) therapy is widely used in rheumatoid arthritis (RA) but the balance of benefit and harm is still unclear.MethodsThe GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) pragmatic double-blind randomised trial compared 2 years of prednisolone, 5 mg/day, to placebo in patients aged 65+ with active RA. We allowed all cotreatments except long-term open label GC and minimised exclusion criteria, tailored to seniors. Benefit outcomes included disease activity (disease activity score; DAS28, coprimary) and joint damage (Sharp/van der Heijde, secondary). The other coprimary outcome was harm, expressed as the proportion of patients with ≥1 adverse event (AE) of special interest. Such events comprised serious events, GC-specific events and those causing study discontinuation. Longitudinal models analysed the data, with one-sided testing and 95% confidence limits (95% CL).ResultsWe randomised 451 patients with established RA and mean 2.1 comorbidities, age 72, disease duration 11 years and DAS28 4.5. 79% were on disease-modifying treatment, including 14% on biologics. 63% prednisolone versus 61% placebo patients completed the trial. Discontinuations were for AE (both, 14%), active disease (3 vs 4%) and for other (including covid pandemic-related disease) reasons (19 vs 21%); mean time in study was 19 months. Disease activity was 0.37 points lower on prednisolone (95% CL 0.23, p<0.0001); joint damage progression was 1.7 points lower (95% CL 0.7, p=0.003). 60% versus 49% of patients experienced the harm outcome, adjusted relative risk 1.24 (95% CL 1.04, p=0.02), with the largest contrast in (mostly non-severe) infections. Other GC-specific events were rare.ConclusionAdd-on low-dose prednisolone has beneficial long-term effects in senior patients with established RA, with a trade-off of 24% increase in patients with mostly non-severe AE; this suggests a favourable balance of benefit and harm.Trial registration number NCT02585258.

The aim of this population-based prospective study was to determine the incidence of limb fracture by site and gender in different regions of Europe. Men and women aged 50-79 years were recruited from population registers in 31 European centers. Subjects were invited to attend for an interviewer-administered questionnaire and lateral spinal radiographs. Subjects were subsequently followed up using an annual postal questionnaire which included questions concerning the occurrence of new fractures. Self-reported fractures were confirmed where possible by radiograph, attending physician or subject interview. There were 6451 men and 6936 women followed for a median of 3.0 years. During this time there were 140 incident limb fractures in men and 391 in women. The age-adjusted incidence of any limb fracture was 7.3/1000 person-years [pyrs] in men and 19 per 1000 pyrs in women, equivalent to a 2.5 times excess in women. Among women, the incidence of hip, humerus and distal forearm fracture, though not 'other' limb fracture, increased with age, while in men only the incidence of hip and humerus fracture increased with age. Among women, there was evidence of significant variation in the occurrence of hip, distal forearm and humerus fractures across Europe, with incidence rates higher in Scandinavia than in other European regions, though for distal forearm fracture the incidence in east Europe was similar to that observed in Scandinavia. Among men, there was no evidence of significant geographic variation in the occurrence of these fractures. This is the first large population-based study to characterize the incidence of limb fracture in men and women over 50 years of age across Europe. There are substantial differences in the descriptive epidemiology of limb fracture by region and gender.

The risk of low and moderate energy fracture is related to bone mineral density (BMD). Yet it is uncertain whether the epidemiologic determinants of fracture risk are the same as for low bone density. The European Vertebral Osteoporosis Study was a population-based prevalence study of vertebral deformity in 36 age-stratified population samples aged 50-80 years. In nearly 4000 subjects (13 centers), BMD measurements were also made at the spine, femoral neck and femoral trochanter. To investigate whether effects of reported physical activity on spine deformity risk were mediated through BMD, we modeled these and other risk factor data with BMD as the dependent variate after adjusting for age, center, sex and body mass index (BMI). The significant determinants of vertebral deformity risk were also entered into logistic models of deformity risk that included BMD measurements as covariates. Both current and lifetime physical activity were positively associated with BMD. This effect was stronger with hip BMD than with spine BMD. Lifetime smoking exposure was associated with reduced BMD. Type 2 diabetes mellitus was associated with increased BMD. Weak positive associations were found between consumption of dairy products and BMD at the three measured sites and these were strengthened by an interaction with measures of physical activity in men. Physical activity in women had the largest beneficial effect in lean women and in women exposed to hormone replacement therapy. When fracture risk was modeled with BMD as a covariate, the lifestyle and dietary determinants became less strongly related to vertebral deformity risk, suggesting that BMD may have acted as an intermediary variable. However, heavy physical activity in men still increased spine deformity risk after adjusting for BMD. It is concluded that physical activity in both genders and milk consumption in young women might protect against vertebral deformities in later life through their effects on bone density. The adverse effect of smoking on BMD was confirmed. Heavy physical activity in men might increase spine deformity risk even when BMD is normal.

The randomised placebo-controlled GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) trial evaluated the benefits and harms of prednisolone 5 mg/day added to standard care for 2 years in patients aged 65+ years with rheumatoid arthritis (RA). Here, we studied disease activity, flares and possible adrenal insufficiency after blinded withdrawal of study medication. Per protocol, patients successfully completing the 2-year trial period linearly tapered and stopped blinded study medication in 3 months. We compared changes in disease activity after taper between treatment groups (one-sided testing). Secondary outcomes (two-sided tests) comprised disease flares (DAS28 (Disease Activity Score 28 joints) increase >0.6, open-label glucocorticoids or disease-modifying antirheumatic drug (DMARD) increase/switch after week 4 of tapering) and symptoms/signs of adrenal insufficiency. In a subset of patients from 3 Dutch centres, cortisol and ACTH were measured in spot serum samples after tapering. 191 patients were eligible; 36 met treatment-related flare criteria and were only included in the flare analysis. Mean (SD) DAS28 change at follow-up: 0.2 (1.0) in the prednisolone group (n=76) vs 0.0 (1.2) in placebo (n=79). Adjusted for baseline, the between-group difference in DAS28 increase was 0.16 (95% confidence limit -0.06, p=0.12). Flares occurred in 45% of prednisolone patients compared with 33% in placebo, relative risk (RR) 1.37 (95% CI 0.95 to 1.98; p=0.12). We found no evidence for adrenal insufficiency. Tapering prednisolone moderately increases disease activity to the levels of the placebo group (mean still at low disease activity levels) and numerically increases the risk of flare without evidence for adrenal insufficiency. This suggests that withdrawal of low-dose prednisolone is feasible and safe after 2 years of administration.