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The therapeutic armamentarium for rheumatoid arthritis has increased substantially over the last 20 years. Historically antirheumatic treatment was started late in the disease course and frequently included prolonged high-dose glucocorticoid treatment which was associated with accelerated generalised bone loss and increased vertebral and non-vertebral fracture risk. Newer biologic and targeted synthetic treatments and a combination of conventional synthetic DMARDs prevent accelerated systemic bone loss and may even allow repair of cortical bone erosions. Emerging data also gives new insight on the impact of long-term conventional synthetic DMARDs on bone health and fracture risk and highlights the need for ongoing studies for better understanding of “established therapeutics”. An interesting new antirheumatic treatment effect is the potential of erosion repair with the use of biologic DMARDs and janus kinase inhibitors. Although several newer anti-rheumatic drugs seem to have favorable effects on bone mineral density in RA patients, these effects are modest and do not seem to influence the fracture risk thus far. We summarize recent developments and findings of the impact of anti-rheumatic treatments on localized and systemic bone integrity and health.

Given the link between systemic inflammation, body composition and insulin resistance (IR), anti-inflammatory therapy may improve IR and body composition in inflammatory joint diseases. This study assesses the IR and beta cell function in rheumatoid arthritis (RA) patients with active disease compared to osteoarthritis (OA) patients and investigates the effect of anti-TNF treatment on IR, beta cell function and body composition in RA. 28 Consecutive RA patients starting anti-TNF treatment (adalimumab), and 28 age, and sex-matched patients with OA were followed for 6 months. Exclusion criteria were use of statins, corticosteroids, and cardiovascular or endocrine co-morbidity. Pancreatic beta cell function and IR, using the homeostasis model assessment (HOMA2), and body composition, using dual-energy X-ray absorptiometry (DXA) were measured at baseline and 6 months. At baseline, IR [1.5 (1.1–1.8) vs. 0.7 (0.6–0.9), 100/%S] and beta cell function (133% vs. 102%) were significantly (p < 0.05) higher in RA patients with active disease as compared to OA patients. After 6 months of anti-TNF treatment, IR [1.5 (1.1–1.8) to 1.4 (1.1–1.7), p = 0.17] slightly improved and beta cell function [133% (115–151) to 118% (109–130), p <0.05] significantly improved. Improvement in IR and beta cell function was most pronounced in RA patients with highest decrease in CRP and ESR. Our observations indicate that IR and increased beta cell function are more common in RA patients with active disease. Anti-TNF reduced IR and beta cell function especially in RA patients with highest decrease in systemic inflammation and this effect was not explained by changes in body composition.

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

Background:Adherence is a serious problem in treatment of inflammatory diseases. To measure adherence, caps that record medication bottle openings may be superior to capsule counts (1). In the ongoing two-year GLORIA trial on the addition of low-dose (5 mg) prednisolone or placebo to standard of care in elderly patients (65+ years) with rheumatoid arthritis, adherence was measured in both ways during the whole trial.Objectives:To describe adherence patterns, and to compare adherence as assessed with adherence caps and with capsule counts in the GLORIA trial.Methods:The recorded adherence patterns of patients (blinded for treatment group) were classified according to descriptive categories. Overall adherence according to number of bottle openings was compared with adherence according to the capsule count. Good adherence was defined as 80%: i.e. for caps 80% of days one opening recorded, and for counts less than 20% of prescribed tablets returned at the subsequent visit. Each patient has a maximum of 8 periods of 90 days.Results:Trial inclusion has closed in 2018 at 452 patients; the current dataset contains adherence data of 385 patients. Mean number of recorded 90-day periods per patient was 4 (range 1-8). Based on capsule counts over all periods, 90% of the patients met the 80% threshold of adherence; based on cap data only 31% met this criterion.The four adherence patterns are shown in a calendar matrix, with yellow for zero, green for one and blue for ≥two openings on a day (Figure 1). Bottles were supposed to be opened once a day.Patients were categorized according to the opening pattern seen in at least 50% of assessed periods:32% non-use(<20% of the days an opening);26% stable use(≥80% of the days 1 opening);40% irregular use(different adherence patterns, in or between periods);2% weekly use(1 opening per week).Conclusion:In our trial of elderly rheumatoid arthritis patients, patients appeared to be mostly adherent according to conventional capsule counts. Results from adherence caps were highly discrepant with the capsule counts, with patterns suggesting patients did not use the bottle for daily dispensing, despite specific advice to do so.References:[1] El Alili M, Vrijens B, Demonceau J, Evers SM, Hiligsmann M. A scoping review of studies comparing the medication event monitoring system (MEMS) with alternative methods for measuring medication adherence. Br J Clin Pharmacol 2016;82:268-79.Acknowledgments: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.Disclosure of Interests:Linda Hartman: None declared, Sabrina Paolino: None declared, Reinhard Bos: None declared, Daniela Opris-Belinski Speakers bureau: as declared, Marc R Kok Grant/research support from: BMS and Novartis, Consultant of: Novartis and Galapagos, Hanneke Griep-Wentink: None declared, Ruth Klaasen: None declared, Cornelia Allaart: None declared, George Bruyn: None declared, Hennie Raterman Grant/research support from: UCB, Consultant of: Abbvie, Amgen, Bristol-Myers Sqibb, Cellgene and Sanofi Genzyme, Marieke Voshaar Grant/research support from: part of phd research, Speakers bureau: conducting a workshop (Pfizer), Nuno Gomes: None declared, Rui Pinto: None declared, Thomas Klausch: None declared, WIllem Lems Grant/research support from: Pfizer, Consultant of: Lilly, Pfizer, Maarten Boers: None declared

Background:One of the well-known characteristics of rheumatoid arthritis (RA) is generalized bone loss.1–2 Although rituximab is a frequently prescribed biologic disease-modifying anti-rheumatic drug (bDMARD) for the treatment of RA, data regarding changes in bone mineral density (BMD) in RA patients during rituximab therapy are limited.Objectives:To study the extent of BMD loss at lumbar spine and hip in patients with active rheumatoid arthritis treated with rituximab.Methods:Consecutive RA patients with an active disease status (DAS28>3.2) starting rituximab treatment were enrolled in a prospective cohort study. BMD of the lumbar spine and hip was measured before treatment and after one year using dual energy X-ray absorptiometry (DXA) to assess BMD changes. Clinical response was defined using the European League Against Rheumatism (EULAR) response criteria.Results:A total of 43 subjects (18.6% men) with mean age of 53.6 (SD 10.7) years were included in the study. Median disease duration was 9.5 (IQR 0.7–40.2) years and baseline mean DAS28 was 5.6 (SD 1.3). In responders, the DAS28 decreased with 1.97 points (SD 0.78) 95% CI 1.67 – 2.28 p<0.001; and in non-responders, the DAS28 decreased with 0.01 points (SD 0.67) 95% CI -0.35 – 0.37 p=0.945. All changes in BMD were not statistically significant (table 1).Table 1BMD change after one year categorized by EULAR responseConclusions:The findings of this study indicate that patients with active RA treated with rituximab have arrest of bone loss at both the lumbar spine and hip. Moreover, these results suggest that rituximab has bone-saving abilities even in the absence of clinical response.References[1] McInnes IB, et al. The New England journal of medicine2011;365:2205–2219.[2] Firestein GS, et al. Nature2003;423:356–361.Disclosure of Interest:None declared

Background:Cardiovascular (CV) disease and osteoporosis (OP) have become increasing challenges in the ageing population, even more in patients with inflammatory rheumatic diseases, such as rheumatoid arthritis (RA) and spondyloarthropathies. Both RA and ankylosing spondylitis (AS) have been associated with generalized and localized bone loss, accelerated atherosclerosis, increased CV morbidity and mortality.Objectives:Bone and vascular biomarkers and parameters along with the effect of one-year anti-TNF therapy on these markers were assessed in order to determine correlations between vascular pathophysiology and bone metabolism in RA and AS.Methods:Fifty-three patients including 36 RA patients treated with etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study. Bone and vascular markers were assessed by ELISA. Bone density was assessed by DXA and quantitative CT (QCT). Flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and pulse-wave velocity (PWV) were assessed by ultrasound. The effects of vascular markers on bone and bone effects on vasculature undergone statistical analysis.Results:Serum levels of vascular endothelial growth factor (VEGF), PDGF-BB, angiopoietin 2 (Ang2) and cathepsin K (CathK) decreased, procollagen type 1 N-propeptide (P1NP) and sclerostin (SOST) levels increased, soluble receptor activator nuclear kappa B ligand (sRANKL) and osteoprotegerin (OPG) levels showed no differences. When bone and vascular markers were correlated with each other, at baseline, OPG correlated with Ang2 and adiponectin. SOST correlated positively with ccIMT. DXA L2-4 BMD, DXA L1 BMD and DXA femoral neck (FN) BMD correlated with FMD and CRP. QCT trabecular BMD correlated with ccIMT and PON1. According to the univariate analysis, FMD correlated with OPG, ccIMT correlated with SOST and QCT trabecular BMD. Ang1, Ang2 and PDGF-BB showed correlation with Dickkopf-1 (DKK1). Ang2 also correlated with OPG. As suggested by the multivariate analysis, OPG determined FMD; DKK1 was an independent predictor of Ang1, Ang2 and PDGF-BB. OPG was a predictor of Ang2.Conclusion:In our study of anti-TNF treated RA and AS patients, vascular and bone parameters showed numerous correlations. The therapy was clinically effective, it halted further bone loss over 1 year and reduced the production of angiogenic markers.Acknowledgments:This research was supported by an investigator-initiated research grant from Pfizer.Disclosure of Interests:Monika Czókolyová: None declared, Katalin Gulyás: None declared, Ágnes Horváth: None declared, Edit Végh: None declared, Zsófia Pethö: None declared, Szilvia Szamosi: None declared, Attila Hamar: None declared, Anita Pusztai: None declared, Emese Balogh: None declared, Nóra Bodnár: None declared, Levente Bodoki: None declared, Agnes Szentpetery: None declared, Harjit Pal Bhattoa: None declared, György Kerekes: None declared, Katalin Hodosi: None declared, Andrea Domjan: None declared, Sándor Szántó: None declared, Gabriella Szücs: None declared, Hennie Raterman Grant/research support from: UCB, Consultant of: Abbvie, Amgen, Bristol-Myers Sqibb, Cellgene and Sanofi Genzyme, WIllem Lems Grant/research support from: Pfizer, Consultant of: Lilly, Pfizer, Zoltán Szekanecz Grant/research support from: Pfizer, UCB, Consultant of: Sanofi, MSD, Abbvie, Pfizer, Roche, Novertis, Lilly, Gedeon Richter, Amgen

Objective:Rheumatoid arthritis (RA) patients have an increased risk of developing cardiovascular diseases (CVD). Other autoimmune diseases such as hypothyroidism are also associated with an enhanced risk for CVD. Our objective was to determine first, the prevalence of hypothyroid disorders in RA patients, and second, the risk of CVD in RA patients with hypothyroid abnormalities.Methods:Subjects were RA patients who participated in an ongoing prospective cohort study of cardiovascular mortality and morbidity (n = 358) in which hypothyroid abnormalities were assessed. CVD was defined as a verified medical history of coronary, cerebral or peripheral arterial disease.Results:Clinical hypothyroidism was observed in 16 of 236 female RA patients (6.8%), which is significantly higher than in the general population of The Netherlands. Subclinical hypothyroidism was detected in 6 out of 236 RA women (2.5%). In female RA patients, CVD was present in 6 out of 16 (37.5%) of all hypothyroid women. The odds ratio for CVD comparing female hypothyroid RA patients with female euthyroid RA patients was 4.1 (95% CI 1.2–14.3) after adjustment for sex, age, diabetes, smoking (ever), hypertension and statin use.Conclusions:Clinical hypothyroidism was observed three times more often in female RA patients than females in the general population. In female RA patients, clinical hypothyroidism was associated with a fourfold higher risk of CVD in comparison with euthyroid female RA patients independently of the traditional risk factors.

BackgroundRituximab (RTX) is an effective treatment of rheumatoid arthritis (RA) after failure or intolerance to TNF blockers. Nevertheless, still 30–50% of RA patients does not respond. Therefore, identifying patients with favourable response to RTX is important in order to further optimize treatment for the individual patient. In vivo imaging of biodistribution of radiolabelled RTX in RA by Positron Emission Tomography (PET) might provide a tool to fulfil this unmet clinical need.ObjectivesTo investigate the association of in vivo biodistribution of Zirconium-89 (89Zr-)RTX in RA patients starting with RTX treatment and clinical response at 24 weeks post injection (p.i.).MethodsWe included 20 anti-B cell therapy naïve RA patients (female18/20; age 53±11; DAS28 5.4±1.2) who started RTX treatment according to standard clinical protocol (without methylprednisolone). The first RTX infusion (1000 mg) was directly followed by infusion of 10 mg-18 MBq 89Zr-RTX. Whole body and PET-CT images of wrists/hands (n=22 joints/patient) were performed three days p.i. After 24 weeks of therapy, response was defined according to the EULAR response criteria (DAS28 at endpoint ≤5.1 and/or deltaDAS28>0.6) (1). 89Zr-RTX uptake was assessed visually (blinded for clinical data) and quantitatively by drawing volumes of interest (VOI) on PET positive tissues/joints. Standardized uptake values (SUVs) were calculated and background ROIs were drawn on metacarpal bone to calculate target-to-background (T/B) ratios.ResultsAt 24 weeks 13/20 patients were moderate to good responders to RTX. Whole body PET images showed 89Zr-RTX distribution in liver, spleen, kidneys, blood pool, lymph nodes (LN) (9/20pts) and in shoulders/elbows (9/20pts), without statistically significant SUV differences between responders and non-responders. Detailed hand images showed PET positive joints in 18/20 patients (ranging 1–20 joints/patient). Clinical responders had significantly higher 89Zr-RTX uptake in visually positive joints than non-responders (SUV: 3.2±1.4 vs 2.1±1.1 [p=0.04]; T/B ratios 6.2±2.5 vs. 3.4±1.7 [p=0.015], respectively). Using a T/B cut-off value of 4.0, positive predictive value and negative predictive value for response were respectively 90% and 75%, at a sensitivity of 82% and specificity of 86% (Fig 1). In contrast, no association was found between any clinical disease or serological (including a-CCP/RF) parameters and clinical response at 24 weeks.Conclusions89Zr-RTX PET-CT clearly visualizes arthritic joints in RA patients. Significant differences in baseline quantitative 89Zr-RTX uptake in PET positive hand joints were found between responders and non-responders to RTX treatment at 24 weeks. Our data point at a promising clinical value of 89Zr-RTX PET to predict at baseline the therapeutic response to RTX and therefore has potential for stratification of RTX treatment in RA. Further validation is required in larger cohorts.ReferencesVan Gestel et al; Arthritis Rheum 1998AcknowledgementThis study was financially supported by Hoffmann-La-Roche,The NetherlandsDisclosure of InterestS. Bruijnen: None declared, M. Tsang-A-Sjoe: None declared, H. Raterman: None declared, T. Ramwadhdoebe: None declared, D. Vugts: None declared, G. Van Dongen: None declared, M. Huisman: None declared, O. Hoekstra: None declared, P. Tak Grant/research support from: P.P. Tak participated in this study from his position at the Academic Medical Center, Amsterdam, The Netherlands. GSK did neither sponsor this study nor supported this study otherwise. P.P.Tak also has affiliations at Cambridge and Ghent but his activities at these locations were not involved in the current study., A. Voskuyl: None declared, C. Van der Laken: None declared

BackgroundIn last decade rituximab (RTX), a B-cell targeted monoclonal antibody, has been introduced to treat rheumatoid arthritis (RA) patients but with variable response rates (30-50%). To increase treatment efficacy and reduce costs, treatment should be individualized to match the spectrum of RA. B-cell targeted therapy has been hypothesized to be most effective in a more B-cell mediated RA disease, possibly correlated to serological status (1). Whole body Positron Emission Tomography (PET) is capable to show B-cells targeting with high specificity in lymphoma patients using 89Zr-RTX (2). In addition, our group previously demonstrated the potential of PET for non-invasive visualization of immunological targets in RA (3).ObjectivesTo investigate the feasibility of non-invasive imaging of B-cells in RA patients who initiate RTX treatment by [89Zr]RTX PET-CT.MethodsAnti-B cell therapy naïve RA patients (n=20; female18/20; age 53±11; 65% IgM RF/a-CCP +) with clinical arthritis in at least two hand joints, who were eligible for RTX treatment, were included. Directly after the first therapeutic RTX infusion (1000 mg, without methylprednisolone), 18MBq [89Zr]-10 mg RTX was administered. Whole body PET-CT and detailed images of wrists and hands (22 joints/patient) were acquired at 3, and in addition, in a subpopulation at 6 days post-injection (p.i.). Thereafter, RTX treatment was continued according to standard clinical protocol. Areas of enhanced uptake on PET were defined and quantified as maximum standardized uptake values (SUVmax). Wrist and hand joints were clinically assessed for swelling and tenderness.ResultsVisually, all patients showed at least one hand joint with increased focal tracer uptake (87/440 joints; mean/patient ± SD 4.4±4.9) (Figure 1) with distribution: metacarpophalangeal (n=44/200), proximal interphalangeal (n=22/200) and wrist joints (n=21/40). Interestingly, 66% of PET-positive joints (57/87) corresponded to clinical findings of arthritis, while PET additionally displayed possible subclinical disease activity in another 30 joints (34%). Quantitative analysis showed high mean SUVmax values of hotspots in hand joints (2.98±1.46) which were up to 4 times higher than maximum background uptake, but varying between patients (range SUVmax 1.2-8.0), regardless of serological status. Stability of joint uptake was found over time (3-6 days p.i.) while the tracer cleared from circulation, pointing at specific binding in joints. Whole body PET-CT also demonstrated tracer uptake in extra-articular tissues especially in liver, spleen and in 5/20 patients slightly enhanced uptake in at least one peripheral lymph node.Conclusions[89Zr]RTX PET-CT seems to be a sensitive tool for in vivo identification of B-cells in arthritic joints and extra-articular tissues in RA patients. Whether quantitative differences in uptake (articular and body distribution) correlate to clinical and RTX response data is currently investigated in a prospective study.ReferencesIsaacs JD et al; Ann Rheum Dis 2013.Muylle K et al; Ann Oncol 2008.van der Laken CJ et al; Arthritis Rheum 2008.AcknowledgementsThis study was financially supported by Hoffmann-La-Roche,The NetherlandsDisclosure of InterestS. Bruijnen: None declared, M. Tsang-A-Sjoe: None declared, H. Raterman: None declared, T. Ramwadhdoebe: None declared, D. Vugts: None declared, G. Van Dongen: None declared, M. Huisman: None declared, O. Hoekstra: None declared, P. Tak Grant/research support from: P.P. Tak participated in this study from his position at the Academic Medical Center, Amsterdam, The Netherlands. GSK did neither sponsor this study nor supported this study otherwise. P.P.Tak also has affiliations at Cambridge and Ghent but his activities at these locations were not involved in the current study., A. Voskuyl: None declared, C. van der Laken: None declared

Objectives:Rheumatoid arthritis (RA) patients are at increased risk of cardiovascular disease (CVD), which is even more pronounced in hypothyroid RA patients. An unfavourable cardiovascular risk profile conferred by a higher prevalence of the metabolic syndrome (MetS) and a higher Framingham risk score might explain this amplified cardiovascular morbidity. This study compared first, MetS (features) and second, the Framingham 10-year CVD risk in RA patients with hypothyroidism compared with euthyroid RA patients.Methods:RA patients participating in the CARRÉ investigation were divided into two groups: hypothyroid and euthyroid RA patients. MetS according to the National Cholesterol Education Program Third Adult Treatment Panel criteria and the Framingham risk score was compared between hypothyroid and non-hypothyroid CVD event-free RA patients.Results:In total, 257 RA patients were included: 236 with RA (91.8%) and 21 with hypothyroid RA (8.2%), respectively. The prevalence of the MetS was significantly higher in hypothyroid RA patients (43%) compared with RA patients (20%). Moreover, female hypothyroid RA patients had a higher Framingham risk score compared with euthyroid RA patients. With RA patients as the reference category, the age and gender-adjusted prevalence odds ratio for the MetS was 3.5 (95% CI 1.3 to 9.1) in hypothyroid RA.Conclusions:Hypothyroid RA patients, particularly female patients, have a more unfavourable cardiovascular risk profile, reflected by an increased prevalence of the MetS and higher Framingham score, than euthyroid RA patients, suggesting a greater need for cardiovascular risk management in these patients to prevent future CVD events.