Search

INTRODUCTION: Romosozumab is a monoclonal antibody that binds to sclerostin (an inhibitor of the Wingless-related integration site (Wnt) signaling pathway). It is a new osteoanabolic drug that simultaneously increases bone formation and decreases bone resorption. It has recently been approved by the US and EU authorities in postmenopausal women with at high risk of fractures.AREAS COVERED: The literature on romosozumab in preclinical and in phase II and III clinical studies has been reviewed about the effect on bone, bone markers, and fracture reduction and its safety.EXPERT OPINION: Compared to antiresorptive agents, its unique mechanism of action results in a quicker and greater increase in bone mineral density, it repairs and restores trabecular and cortical bone microarchitecture, and reduces fracture risk more rapidly and more effectively than alendronate, with persisting effects for at least two years after transition to antiresorptive agents. This finding has introduced the concept that, in patients at very high risk of fractures, the optimal sequence of treatment is to start with an osteoanabolic agent, followed by a potent AR drug. Recent national and international guidelines recommend the use of romosozumab as an initial treatment in patients at very high fracture risk without a history of stroke or myocardial infarction.

Spondyloarthropathies (SpA) are common systemic inflammatory rheumatic diseases, in which, as in other rheumatic diseases, levels of markers of bone resorption are elevated, leading to bone loss and elevated risk of vertebral fractures. However, the diseases are also associated with new bone formation in the spine, the so-called syndesmophytes. We tried to unravel the pathogenesis of formation and growth of syndesmophytes and evaluated new diagnostic and treatment options. After a successful meeting of the Working Group on Rheumatic Diseases at the ECTS 2020, we (WL and CR) were excited about the quality of the speakers (CM, JH, AG, and GL) and their complimentary lectures. Given the relative lack of reviews on spondyloarthropathies and bone, we decided to work together on a comprehensive review that might be interesting for basic scientists and clinically relevant for clinicians. Radiographic progression in axSpA is linked to several risk factors, like male sex, smoking, HLA-B-27, increased levels of CRP, presence of syndesmophytes, and marked inflammation on MRI. The potential role of mechanical stress in the context of physically demanding jobs has been also suggested to promote structural damages. Different treatment options from NSAIDs to biologic agents like TNF inhibitors (TNFi) or IL-17inhibitors (IL-17i) result in a reduction of inflammation and symptoms. However, all these different treatment options failed to show clear and reproducible results on inhibition on syndesmophyte formation. The majority of data are available on TNFi, and some studies suggested an effect in subgroups of patients with ankylosing spondylitis. Less information is available on NSAIDs and IL-17i. Since IL-17i have been introduced quite recently, more studies are expected. IL-17 inhibitors (Il-17i) potently reduce signs and symptoms, but serum level of IL-17 is not elevated, therefore, IL-17 probably has mainly a local effect. The failure of anti-IL-23 in axSpA suggests that IL-17A production could be independent from IL-23. It may be upregulated by TNFα, resulting in lower expression of DKK1 and RANKL and an increase in osteogenesis. In active AS markers of bone resorption are increased, while bone formation markers can be increased or decreased. Bone Turnover markers and additional markers related to Wnt such as DKK1, sclerostin, and RANKL are valuable for elucidating bone metabolism on a group level and they are not (yet) able to predict individual patient outcomes. The gold standard for detection of structural lesions in clinical practice is the use of conventional radiographics. However, the resolution is low compared to the change over time and the interval for detecting changes are 2 years or more. Modern techniques offer substantial advantages such as the early detection of bone marrow edema with MRI, the fivefold increased detection rate of new or growing syndesmophytes with low-dose CT, and the decrease in 18F-fluoride uptake during treatment with TNFα-inhibitors (TNFi) in a pilot study in 12 AS patients. Detection of bone involvement by new techniques, such as low-dose CT, MRI and 18-Fluoride PET-scans, and bone turnover markers, in combination with focusing on high-risk groups such as patients with early disease, elevated CRP, syndesmophytes at baseline, male patients and patients with HLA-B27 + are promising options for the near future. However, for optimal prevention of formation of syndesmophytes we need more detailed insight in the pathogenesis of bone formation in axSpA and probably more targeted therapies.

ObjectiveTo investigate the pharmacokinetics of methotrexate polyglutamate (MTX-PG) accumulation in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) in patients with early rheumatoid arthritis (RA) after oral and subcutaneous MTX treatment.MethodsIn a clinical prospective cohort study (Methotrexate Monitoring study), newly diagnosed patients with RA were randomised for oral or subcutaneous MTX. At 1, 2, 3 and 6 months after therapy initiation, blood was collected and RBCs and PBMCs were isolated. MTX-PG1-6concentrations were determined by mass spectrometry methods using stable isotopes of MTX-PG1-6as internal standards.Results43 patients (mean age: 58.5 years, 77% female) were included. PBMCs and RBCs revealed disparate pharmacokinetic profiles in both absolute MTX-PG accumulation levels and distribution profiles. Intracellular MTX-PG accumulation in PBMCs was significantly (p1(PG1>PG2>PG3). Remarkably, the distribution profile in PBMCs remained constant over 6 months. RBCs accumulated mainly MTX-PG1and lower levels of MTX-PG2-5at t=1 month. After 3 months, MTX-PG3was the main PG-moiety in RBCs, a profile retained after 6 months of MTX therapy. Subcutaneous MTX administration results in higher RBC drug levels than after oral administration, especially shortly after treatment initiation.ConclusionsThis is the first study reporting disparate MTX-PG accumulation profiles in RBCs versus PBMCs in newly diagnosed patients with RA during 6 months oral or subcutaneous MTX administration. This analysis can contribute to improved MTX therapeutic drug monitoring for patients with RA.Trial registration numberNTR 7149.

Long-term glucocorticoid (GC) therapy is frequently indicated to treat autoimmune and chronic inflammatory diseases in daily clinical practice. Two of the most devastating untoward effects are bone loss and fractures. Doses as low as 2.5 mg of prednisone for more than 3 months can impair bone integrity. Population at risk is defined based on the dose and duration of GC therapy and should be stratified according to FRAX (Fracture Risk Assessment Tool), major osteoporotic fracture, prior fractures, and bone mineral density values (BMD). General measures include to prescribe the lowest dose of GC to control the underlying disease for the shortest possible time, maintain adequate vitamin D levels and calcium intake, maintain mobility, and prescribe a bone acting agent in patients at high risk of fracture. These agents include oral and intravenous bisphosphonates, denosumab, and teriparatide.

BackgroundResearch on the disease severity of COVID-19 in patients with rheumatic immune-mediated inflammatory diseases (IMIDs) has been inconclusive, and long-term prospective data on the development of SARS-CoV-2 antibodies in these patients are lacking.MethodsAdult patients with rheumatic IMIDs from the Amsterdam Rheumatology and Immunology Center, Amsterdam were invited to participate. All patients were asked to recruit their own sex-matched and age-matched control subject. Clinical data were collected via online questionnaires (at baseline, and after 1–4 and 5–9 months of follow-up). Serum samples were collected twice and analysed for the presence of SARS-CoV-2-specific antibodies. Subsequently, IgG titres were quantified in samples with a positive test result.FindingsIn total, 3080 consecutive patients and 1102 controls with comparable age and sex distribution were included for analyses. Patients were more frequently hospitalised compared with controls when infected with SARS-CoV-2; 7% vs 0.7% (adjusted OR: 7.33, 95% CI: 0.96 to 55.77). Only treatment with B-cell targeting therapy was independently associated with an increased risk of COVID-19-related hospitalisation (adjusted OR: 14.62, 95% CI: 2.31 to 92.39). IgG antibody titres were higher in hospitalised compared with non-hospitalised patients, and slowly declined with time in similar patterns for patients in all treatment subgroups and controls.InterpretationWe observed that patients with rheumatic IMIDs, especially those treated with B-cell targeting therapy, were more likely to be hospitalised when infected with SARS-CoV-2. Treatment with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and biological DMARDs other than B-cell targeting agents is unlikely to have negative effects on the development of long-lasting humoral immunity against SARS-CoV-2.

ObjectivesTo investigate whether patients with rheumatoid arthritis (RA) can discontinue glucocorticoids (GC) after GC ‘bridging’ in the initial treatment step and to identify factors that may affect this.MethodsData from 7 clinical trial arms (with 1653 patients) that included a GC bridging schedule, previously identified in a systematic literature search, were combined in an individual patient data meta-analysis. Outcomes were GC use (yes/no) at predefined time points (1/3/6/12/18 months after bridging had ended), cumulative GC dose and continuous (≥3 months) GC use after bridging had ended. Age, sex, ACPA status, initial GC dose, duration of bridging schedule, oral versus parenteral GC administration and initial co-treatment were univariably tested with each outcome.ResultsThe probability of using GC 1 month after bridging therapy had ended was 0.18, decreasing to 0.07 from 6 until 18 months after bridging had ended. The probability of continuous GC use after bridging had ended was 0.18 at 1 year and 0.30 at 2 years of follow-up. In oral GC bridging studies only, the probabilities of later and continuous GC use and the cumulative GC doses were higher compared to the combined analyses with also parenteral GC bridging studies included. A higher initial dose and a longer GC bridging schedule were associated with higher cumulative GC doses and more patients on GC at 18 months after bridging had ended.ConclusionsBased on these RA clinical trial arms with an initial GC bridging schedule, the probability of subsequent ongoing GC use following bridging is low.

Objectives:Early microvascular damage and dysfunction are clinically mirrored in Raynaud’s phenomenon (RP). Currently, nailfold capillaroscopy (NC) is applied to differentiate between primary RP (PRP) and secondary RP (PRP), associated with connective tissue disease. However, abnormal morphology can also be caused due to age-related changes and cardiovascular disease. Thermography (TG) is a non-invasive technique which enables quantification of cutaneous vascular function. An approach using both NC and TG could improve the differentiation between PRP and SRP. Methods:Thirty RP patients (PRP, n = 21; SRP, n = 9) underwent nailfold capillaroscopy and thermography. Morphologic features were scored and patients were categorized according to the guidelines of EULAR Study group on Microcirculation in Rheumatic Diseases. TG of the hand was performed before, directly and ten minutes after a cold challenge test. Baseline images and rewarming curves were analyzed. Results:Capillary abnormalities with NC were found in all SRP patients (9/9) and in 48% (10/21) of PRP patients. Out of 10 PRP patients with altered capillary morphology, 9 (90%) had a cardiovascular disease. For all patients mean temperature was significantly higher 10 minutes after cold induction than before (p < 0,01). The gradient of the rewarming curve was significantly lower in patients with SRP compared to PRP patients (p = 0.015). Conclusions:Nailfold capillaroscopy and thermography can reliably be used to measure microvascular damage and dysfunction. Additional thermography can assist in differentiating between PRP and SRP, especially in elderly patients or in presence of a cardiovascular disease. Keywords:Raynaud’s phenomenon; Nailfold capillaroscopy; Thermography

Medication adherence, which is the extent to which patients take their medication as prescribed, is essential in treating chronic inflammatory diseases such as rheumatoid arthritis (RA). Therefore, we nested a subproject in the two-year multicenter Glucocorticoid Low-dose Outcome in Rheumatoid Arthritis (GLORIA) trial to add a low-dose prednisolone (5 mg/day) or placebo to the standard care in older people (65+ years) with RA. Adherence was measured with an electronic monitoring cap that recorded bottle openings in all patients. In the subproject, we performed an adherence intervention with an advanced cap that could communicate with an application on the smart device via Bluetooth. We randomized patients with a smart device to receive or not to receive adherence reminders on the smart device for three months. Multiple problems emerged that precluded an answer to the research question: sample size (overly optimistic estimates of older patients with a smart device), logistic issues (availability of smartcaps, data extraction), randomization and treatment allocation errors (despite training of personnel), and low quality of the data in the intervention group (hardware failure, discovered too late because data was read in batches). For future trials planning to include a subproject, we recommend keeping it simple, starting with a field test before the actual study starts, and monitoring data from the beginning of the study.Keywords: medication adherence, electronic caps, rheumatoid arthritis, nested trial, randomization

In the field of rare bone diseases in particular, a broad care team of specialists embedded in multidisciplinary clinical and research environment is essential to generate new therapeutic solutions and approaches to care. Collaboration among clinical and research departments within a University Medical Center is often difficult to establish, and may be hindered by competition and non-equivalent cooperation inherent in a hierarchical structure. Here we describe the “collaborative organizational model” of the Amsterdam Bone Center (ABC), which emerged from and benefited the rare bone disease team. This team is often confronted with pathologically complex and under-investigated diseases. We describe the benefits of this model that still guarantees the autonomy of each team member, but combines and focuses our collective expertise on a clear shared goal, enabling us to capture synergistic and innovative opportunities for the patient, while avoiding self-interest and possible harmful competition.

ObjectiveTo determine whether macrophage positron emission tomography (PET)/computed tomography (CT) imaging using (R)-[11C]PK11195 at 0 and 2 weeks is associated with clinical response at 13 weeks in patients with early rheumatoid arthritis (RA).MethodsWhole-body (R)-[11C]PK11195 PET/CT scans were performed at baseline and after 2 weeks of COBRA-light (combination therapy of methotrexate and prednisone) treatment in 35 patients with clinically active early RA. Clinical assessment (Disease Activity Score of 44 joints (DAS44)) was performed at 0, 2 and 13 weeks of treatment. PET/CT scans were assessed visually by two blinded, experienced readers, and by calculating standardised uptake values (SUVs) for shoulders, elbows, hips, knees, and hand and feet joints. Clinical and PET variables were compared using (multivariate) linear regression.Results18 males and 17 females were included (baseline DAS44=3.2 ± 1.0). 171 out of 1470 joints were visually PET positive at baseline, decreasing to 100 joints after 2 weeks. In general, small feet joints showed the highest uptake at baseline, and the largest decrease after 2 weeks (Δ0-2). Neither baseline nor Δ0-2 PET measures correlated with DAS44 at 13 weeks. However, at 2 weeks, average SUV of the feet significantly correlated with DAS44 at 13 weeks (R2=0.14, p=0.04). In a multivariable model, DAS44 and average SUV of the feet at 2 weeks showed substantial combined predictive value (combined R2=0.297, pConclusionQuantitative macrophage PET assessment of feet joints, together with DAS44, after 2 weeks of COBRA light treatment in patients with early RA correlates with clinical response after 3 months of treatment.

In the published article the author name Maritza Vidal Wilman was processed incorrectly and now it has been rectified. The original article has been updated.

Background:Patients with rheumatoid arthritis have an increased risk for developing cardiovascular diseases (CVD) compared to the general population, similar to the CVD risk in patients with diabetes mellitus. However, there are no controlled studies investigating the incidence of cardiovascular (CV) events in RA patients with follow up of more than 20 years.Objectives:The objectives of the current study were to investigate the incidence rates of CV events in a long-term follow up cohort of RA patients, and to compare these to a similar cohort representing the general population, ie. The Hoorn study.Methods:The CARRÉ study is an ongoing prospective cohort study, which started in 2001, investigating CV mortality and morbidity in 353 randomly selected patients with RA. Primary endpoints, i.e. verified medical history of coronary, cerebral or peripheral arterial disease, were determined at baseline, and after three, ten, fifteen and twenty years of follow up. Patients were censored at the date of an experienced CV event or their death. Incidence density rates per 100 patient years were calculated. Data were compared to results from the Hoorn study, a Dutch cohort study of glucose metabolism and other CV risk factors that began in 1989. All 2,484 participants were subject to an extensive and repeated CV screening program similar to that used in the CARRÉ study.Results:After 20 years of follow up 118 patients (33%) developed at least one CV event in the Carré group. Mean (SD) follow up time was 11 (6) years with a total of 3,500 years at risk and an incidence rate of 3.4 per 100 patient-years; this is slightly up from the figure reported at 15 years, i.e. 3.2 per 100 patient-years. A CV event-free survival curve is shown in figure 1. After 30 years of follow up, 295 participants of the Hoorn study had developed a CV event, during a mean follow up time 20 (8) years. Total time at risk was 50,000 years, with an incidence rate of 0.6 CV events per 100 patient years.Conclusion:In our cohort the incidence rate of CV events in RA patients has remained consistently high when compared with the general population, despite better control of RA inflammation in recent years. This again confirms the need for timely CVD-risk screening and management.References:[1]Agca R, Hopman L, Laan KJC, van Halm VP, Peters MJL, Smulders YM, et al. Cardiovascular Event Risk in Rheumatoid Arthritis Compared with Type 2 Diabetes: A 15-year Longitudinal Study. J Rheumatol. 2020;47(3):316-24.Figure 1.Survival curve of participants with rheumatoid arthritis. RA = rheumatoid arthritisDisclosure of Interests:None declared

Background: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.Objectives: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.Methods: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.Results: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.Conclusion: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.References:[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.Table 1.Comorbidities and concomitant medications at baseline in the GLORIA trial.MeanSDRangeComorbidities 4.32.8 0-15 Active 3.4 Past 1.9Concomitant medications (count) 3.93.4 0-15 Beta blocking agents (%)22 HMG CoA reductase inhibitors (%)20 Platelet aggregation inhibitors (%)16 ACE inhibitors (%)12 Angiotensin II antagonists (%)11DAS28 4.521.05DAS28CRP 4.060.97HAQ (0-3) 1.20.7RA treatmentCurrent (%)Previous (%) cDMARD8492 bDMARD/tsDMARD1522 NSAID5129 Glucocorticoids 049Acknowledgements: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:None declared

Background:Clinical assessment of arthritis is the cornerstone in the diagnosis and treatment of rheumatoid arthritis (RA). Nevertheless, reliable determination of (sub)clinical arthritis can be difficult, especially in the feet. Advanced imaging techniques may contribute to early diagnosis and therapy monitoring through sensitive detection and (quantitative) monitoring of synovitis. Previously, it has been demonstrated that macrophage imaging using (R)-[11C]PK11195 positron emission tomography (PET) allows for highly sensitive and specific imaging of RA disease activity in the hands.(1,2)Whole body macrophage PET imaging that includes the feet has not yet been evaluated in RA.Objectives:To compare whole body macrophage PET imaging to clinical assessment of arthritis activity in clinically active, early RA patients.Methods:Thirty-five previously untreated RA patients (age 54 ± 12, 51% male) with at least two clinically inflamed joints were included. They underwent a whole body (R)-[11C]PK11195 PET/computed tomography (CT) scan in addition to standard clinical assessment of number of tender and swollen joints (TJC and SJC, respectively). Two readers blinded to clinical assessment (GZ and CvdL) visually scored intensity of uptake in joints on a 0 to 3 scale. A PET positive joint score was defined at ≥ 1. Additionally, (R)-[11C]PK11195 uptake in joints was assessed quantitatively as standardized uptake values (SUV). Visual parameters were compared to clinical parameters using Cohen’s kappa, and quantitative parameters were analyzed using an independent T-test.Results:All patients showed enhanced tracer uptake in one or more joints (Figure 1). A total of 168 joints were visually PET positive, with the following distribution: 16% in the wrists, 14% in the metacarpophalangeal joints, 25% in the proximal interphalangeal joints, 4% in the ankles, 37% in the metatarsophalangeal joints. Positivity in other large joints was rare (4%). The number of discrepant findings between PET and clinical outcome (TJC and/or SJC) varied based on anatomic localization; more joints were clinically active in the hands, and more joints were active on the PET scan in the feet. Consequently, agreement between visual PET positivity and clinical activity was low, with only moderate agreement found in the ankles (κ = 0.46 and 0.41 for SJC and TJC respectively). Quantitative PET data showed a trend towards higher SUV values in joints that were clinically tender and/or swollen, reaching a significant difference in the feet (ankles + MTPs) versus SJC (Figure 2; 0.7 vs 1.0,p< 0.001). However, parts of the clinically non-affected joints also depicted moderately increased SUV values, and vice versa.Figure 1.Visual PET uptake in the left MTP5-joint.Figure 2.(R)-[11C]PK11195 (SUV) in both clinically affected and non-affected feet joints (defined as swollen yes or no).Conclusion:Whole body macrophage PET imaging showed clear uptake of (R)-[11C]PK11195 in several joints of clinically active, early RA patients, especially in MTP-joints. The best correlation between quantitative PET data and clinical assessment of swelling was observed in the feet. In general, however, PET also provided distinct information from clinical assessment, which may provide a means for detecting subclinical synovitis. We are performing longitudinal studies to further assess the value of macrophage PET in RA.References:[1]Elzinga EH, et al. J Nucl Med. 2011; 52(1): 77-80.[2]Gent YY, et al. J Rheumatology. 2014; 41: 2145-52Acknowledgments:We thank ReumaNederland and Pfizer for financial support of this investigator initiated study.Disclosure of Interests:Nicki J.F. Verweij: None declared, Marieke ter Wee: None declared, Jerney de Jongh: None declared, Gerben C.J. Zwezerijnen: None declared, Maqsood Yaqub: None declared, Maarten Boers: None declared, Alexandre Voskuyl: None declared, Adriaan A. Lammertsma: None declared, WIllem Lems Grant/research support from: Pfizer, Consultant of: Lilly, Pfizer, Conny J. van der Laken: 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 Conclusions: 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 Systemic lupus erythematosus (SLE) is associated with an increased risk of fractures1. However, data on the incidence of vertebral and peripheral fractures are limited. In particular, data on (morphometric) vertebral fracture incidence and determinants of such fractures are scarce and show conflicting results. Objectives To assess the incidence of fractures in a population of patients with SLE, and to identify determinants that predict incident vertebral and peripheral fractures. Methods A prospective longitudinal cohort study in 145 patients with SLE was performed. Serial bone mineral density (BMD) measurements using dual x-ray absorptiometry, and radiographs of the thoracic and lumbar spine were performed at inclusion and after a median of 5 years (IQR 3–5) follow-up. Demographic and clinical data were also collected. Vertebral fractures were scored according to the semi-quantitative method by Genant et al. Reported peripheral fractures were confirmed by x-rays. Analyses were performed with logistic regression (forward selection procedure, p-value of 0.05 as cut-off level). The outcome measures were incident fracture in general (yes/no), vertebral fracture (yes/no), and peripheral fracture (yes/no). Results Of the 145 included patients, 131 (90%) were females and 100 (69%) Caucasian. The mean age was 41 years (SD 12) at baseline, and median follow-up was 7.2 years (IQR 6–12). A total of 42 incident fractures (vertebral and peripheral) occurred during 998 patient years. The incidence rate of vertebral and peripheral fractures was 2.0 per 100 patient years (95% CI 1.30–3.13), and 2.20 per 100 patient years (95% CI 1.45–3.35), respectively. Any fracture (both vertebral and peripheral) was predicted by postmenopausal status and Caucasian ethnicity. Vertebral fractures were predicted by age, in which the older the SLE patient, the higher the odds of getting vertebral fractures. Peripheral fractures were predicted by history of stroke, postmenopausal status and moderate alcohol use (1–12 units per week). Use of higher dosages of alcohol (>13 units per week) did not reduce peripheral fracture occurrence. Table 1 shows the final prediction models. Conclusions The results of our study suggest a twofold increased risk of both vertebral and peripheral fractures in SLE patients compared to the general population1,2. Age, Caucasian ethnicity and postmenopausal status are important risk factors for incident fractures in SLE. In addition, special attention should be paid to SLE patients with a history of stroke since this subgroup of patients is at high risk of peripheral fractures. References [1] Bultink IEM, et al. Osteoporos Int2014;25:1275–83. [2] Ballane G, et al. Osteoporos Int2017;28:1531–42. Disclosure of Interest F. El Hadiyen: None declared, M. Tsang-A-Sjoe: None declared, M. ter Wee: None declared, A. Voskuyl: None declared, W. Lems: None declared, I. Bultink Speakers bureau: Lilly Netherlands, MSD, Amgen BV, UCB Pharma BV, Sanofi Genzyme BV

Background Methotrexate (MTX) is a widely applied anti-rheumatic and anti-leukemic drug. For its intracellular retention and pharmacologic activity, MTX relies on the enzymatic activity of folylpolyglutamate synthetase (FPGS) to convert MTX into its polyglutamate forms (MTX-PG2–6). Loss of FPGS activity is associated with reduced MTX activity and although red blood cell (RBC) MTX-PGn levels correlate with disease activity in RA patients,1 it is anticipated to be more relevant to measure MTX-PGn in peripheral blood mononuclear cells (PBMCs). Thus, the aim of our study was to develop a LC-MS/MS method to 1) measure FPGS activity replacing laborious radioactive assays, and 2) to measure MTX-PGn in PBMCs.2 Objectives To validate a rapid, sensitive and non-radioactive assay to measure FPGS activity and MTX-PGn in PBMCs based on LC-MS/MS technology. Methods Protein extracts (n=5) of PBMCs of MTX-treated RA patients were incubated for 2 hours at 37°C in FPGS assay buffer (pH8.8) containing 250 µM MTX and 4 mM l-glutamic acid as substrates. Next, MTX-PG2 formation was analysed with AB Sciex 4000 Q Trap tandem mass spectrometer coupled to an Acquity Ultra Performance LC system. Measurement of PBMC-MTX-PGn (n=5) was performed by extraction of MTX-PGn from PBMCs by perchloric acid precipitation. Quantification was performed with 13C515N-labelled MTX-PG1–5 internal standards. In FPGS activity and MTX-PG validation studies, human CCRF-CEM leukaemia cells, CEM/R30dm (a FPGS-deficient, MTX-resistant subline of CCRF-CEM), and human acute lymphoblastic leukemic (ALL) cells served as reference. Results In CCRF-CEM, the FPGS enzymatic assay showed linearity with protein input (10–250 µg) and incubation time (0.5–3 hours). Substrate affinity parameters (Km) for MTX (65 µM) and l-glutamic acid (2.2 mM) were consistent with earlier reports.3 FPGS activity in CEM/R30dm was Conclusions A sensitive LC-MS/MS based method was developed for the measurement of FPGS activity and MTX-PGn levels in PBMCs of RA patients. This method holds promise to guide future MTX-therapy response evaluations. References [1] de Rotte MC, et al. Ann Rheum Dis2015;74:408–414. [2] Jansen G, et al. Oncology Res1992;4:299–305. [3] Liani E, et al. Int. J. Cancer2003;103:587–599. Disclosure of Interest None declared

Background Glucocorticoid (GC)-induced osteoporosis (GIOP) remains the most common secondary cause of osteoporosis. Despite approved therapies, many subjects do not receive GIOP prevention or treatment. There is increased RANKL and decreased osteoprotegerin (OPG) expression in patients with GIOP. Denosumab (DMAb) is a monoclonal antibody to RANKL. This study was designed to assess the safety and efficacy of DMAb compared with risedronate (RIS) in GC-treated individuals, in whom treatment guidelines advocate a GIOP intervention. Objectives The primary objective was to demonstrate, in separate GC-continuing (GC-C) and GC-initiating (GC-I) subpopulations, that DMAb was not inferior to RIS with respect to percentage change from baseline (%Δ) in lumbar spine (LS) bone mineral density (BMD) at 12 months. Secondary objectives were to assess superiority of DMAb over RIS with respect to %Δ in LS and total hip (TH) BMD at 12 months. Methods This was a phase 3, randomized, double-blind, double-dummy, active-controlled study to evaluate DMAb vs. RIS in GC-treated individuals for 24 months. Eligible subjects were women and men ≥18 yrs receiving GC therapy at a dose ≥7.5 mg prednisone daily or its equivalent for ≥3 months or Results A total of 795 subjects (505 GC-C and 290 GC-I) enrolled in the study. Baseline characteristics were balanced between treatment groups (Table). Non-inferiority and superiority with DMAb were demonstrated for both the GC-C and GC-I subpopulations, as indicated by significantly greater BMD gains compared with RIS at the LS and TH in both subpopulations (Figure). The incidences of adverse events (AEs) and serious AEs, including serious AEs of infection, as well as fracture, were similar between treatment groups and consistent with the known safety profile of DMAb. Conclusions DMAb significantly increased BMD more than RIS at the spine and hip at 12 months. The overall safety profile was similar between treatment groups. DMAb has the potential to become another treatment option for patients newly initiating or continuing GC who are at risk for fracture. Acknowledgements The study was funded by Amgen. C Desborough (Amgen [Europe] GmbH) provided editorial support. Disclosure of Interest K. Saag Grant/research support from: Amgen, Merck, Consultant for: Amgen, Merck, Radius, R. B. Wagman Shareholder of: Amgen, Employee of: Amgen, P. Geusens Grant/research support from: Pfizer, Abbott, Lilly, Amgen, MSD, Will, Roche, UCB, BMS, Novartis, J. Adachi Grant/research support from: Amgen, Eli Lilly, Merck, Pfizer, Consultant for: Amgen, Eli Lilly, Merck, International Osteoporosis Foundation, Speakers bureau: Amgen, Eli Lilly, O. Messina Grant/research support from: Amgen, GSK, R. Emkey Speakers bureau: Amgen, R. Chapurlat Grant/research support from: Amgen, Merck, Chugai, Consultant for: Amgen, Eli Lilly, BMS, AbbVie, Pfizer, Chugai, UCB, N. Daizadeh Shareholder of: Amgen, Employee of: Amgen, N. Pannacciulli Shareholder of: Amgen, Employee of: Amgen, W. Lems Grant/research support from: Eli Lilly, Amgen, MSD, Novartis.

Evaluation of: Antoniucci DM, Vittinghof E, Palermo L et al.: Vitamin D insufficiency does not affect response of bone mineral density to alendronate. Osteoporos. Int. (2008) (Epub ahead of print). Earlier data have suggested that vitamin D deficiency may blunt the increase in bone mineral density during treatment with bisphosphonates (etidronate), and may lead to osteomalacia. Therefore, it is attractive that Antoniucci et al. analyzed data from 1000 randomly selected patients from the alendronate Phase III Trials, FIT 1 and FIT 2. All patients were treated with alendronate; patients who had a daily calcium intake of less than 1000 mg were supplied with 500 mg calcium and 250 IU cholecalciferol. The most important outcome was that there was hardly any difference in the change in bone mineral density of the lumbar spine and hips in those patients with vitamin D deficiency, vitamin D insufficiency and sufficient vitamin D levels at baseline. At first sight, it seems reassuring that baseline vitamin D level...

In women older than 60 years with clinical risk factors for osteoporosis but without osteoporosis based on bone mineral density (T-score a parts per thousand yenaEuro parts per thousand a'2.5), a systematic survey with X-rays of the spine identified previously unknown vertebral deformities in 21% of women. This study determines the prevalence of vertebral deformities in elderly women with clinical risk factors for osteoporosis but with BMD values above the threshold for osteoporosis (T-score a parts per thousand yenaEuro parts per thousand a'2.5). Bisphosphonate na < ve women older than 60 years attending 35 general practices in the Netherlands with a parts per thousand yen2 clinical risk factors for osteoporosis were invited for BMD measurement (DXA). In women with T-score a parts per thousand yenaEuro parts per thousand a'2.5 at both spine and the hips, lateral radiographs of the thoracic and lumbar spine were performed. Of 631 women with a DXA measurement, 187 (30%) had osteoporosis (T-score < -2.5 at the spine or the hip). Of the remaining 444 women with T-score a parts per thousand yenaEuro parts per thousand a'2.5 at both spine and hip, 387 had additional spine radiographs, of whom 80 (21%) had at least one vertebral deformity. In elderly women with clinical risk factors for osteoporosis but BMD T-score a parts per thousand yenaEuro parts per thousand a'2.5, addition of spine radiographs identified vertebral deformities in 21% (95% CI: 17-25). Since these women are at risk of future fractures, antiosteoporotic treatment should be considered.

Few data are available on the prevention of fracture in glucocorticoid-treated premenopausal women with autoimmune disorders such as systemic lupus erythematosus. In this setting, Okada et al. compared the effect of coadministration of alfacalcidol alone with that of alfacalcidol combined with alendronate. After 12 months of treatment, lumbar spine bone mineral density increased by 1.7% in the combination group, but decreased by 9.9% in the alfacalcidol-only group (P

To investigate in a randomized clinical trial setting with an aggressive combination-therapy arm and a mild-monotherapy arm, whether therapy-induced changes in urinary C-terminal crosslinking telopeptide of type I collagen (CTX-I) and type II collagen (CTX-II) predict 5-year radiographic progression in patients with rheumatoid arthritis (RA).Patients had participated in the COBRA (Combinatietherapie Bij Reumatoïde Artritis) trial comparing aggressive step-down combination therapy (the COBRA regimen, including temporary high-dose prednisolone, temporary low-dose methotrexate, and sulfasalazine [SSZ]) and mild monotherapy (SSZ). Urinary CTX-I and CTX-II levels were measured at baseline and 3, 6, 9, and 12 months after initiation of treatment. Radiographs were scored according to the modified Sharp/van der Heijde method (mean of 2 independent readers who were aware of the sequence). Individual long-term radiographic progression was estimated, using baseline radiographs and all radiographs obtained during the followup period, by simple linear regression analysis (curve fitting).Both COBRA therapy and SSZ monotherapy produced a significant decrease in urinary CTX-I and CTX-II levels at 3 months, and this decrease was amplified at 6 months. COBRA therapy suppressed CTX-II (change from baseline levels -36% and -43% at 3 and 6 months, respectively), but not CTX-I, significantly better than did SSZ (-17% and -21% at 3 and 6 months, respectively) at 3 and 6 months. The magnitude of the decrease in urinary CTX-II levels at 3 months significantly predicted long-term (5-year) radiographic progression (beta = 0.48 [95% confidence interval (95% CI) 0.13, 0.83]). This effect was independent of the change in disease activity and inflammation indices at 3 months. Patients whose CTX-II levels were normalized (150 ng/mmoles of urinary creatinine) at 3 months had a significantly higher chance of radiographic stability (no progression over 5 years) than did patients whose CTX-II levels were increased both at baseline and at 3 months (odds ratio 4.5 [95% CI 1.5, 13]).The individual CTX-II response measured after 3 months of therapy in patients with active RA who had increased CTX-II levels at baseline independently predicts long-term radiographic progression. Urinary CTX-II levels may be used as early markers of treatment efficacy in patients with RA.