J. A. P. da Silva

Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data

Adverse effects of glucocorticoids have been abundantly reported. Published reports on low dose glucocorticoid treatment show that few of the commonly held beliefs about their incidence, prevalence, and impact are supported by clear scientific evidence. Safety data from recent randomised controlled clinical trials of low dose glucocorticoid treatment in RA suggest that adverse effects associated with this drug are modest, and often not statistically different from those of placebo.

The molecular basis for the effectiveness, toxicity, and resistance to glucocorticoids: focus on the treatment of rheumatoid arthritis

Glucocorticoids (GCs) have powerful and potent anti‐inflammatory and immunomodulatory effects in rheumatoid arthritis (RA) and many other diseases. These effects are mediated by up to four different mechanisms of action: cytosolic glucocorticoid receptor (cGCR)‐mediated classical genomic and rapid non‐genomic effects, membrane‐bound glucocorticoid receptor (mGCR)‐mediated non‐genomic effects and non‐specific non‐genomic effects. On the basis of this detailed knowledge of mechanisms there are currently interesting approaches being considered that may lead to the development of GC drugs and GCR ligands with an improved benefit to side‐effect ratio. Another interesting field of GC research is the phenomenon of GCR resistance. Several different mechanisms may mediate this phenomenon; among them are alterations in number, binding affinity, or phosphorylation status of the GCR. Other mechanisms of GC resistance being investigated are polymorphic changes and/or overexpression of (co‐)chaperones, the increased expression of inflammatory transcription factors, overexpression of the GCR beta isoform, the multidrug resistance pump, and an altered mGCR expression.

Lead Optimisation: Improving the Affinity of the Antiretrovirals Nelfinavir and Amprenavir for HIV-1 Protease

Nelfinavir (Viracept®, Pfizer), and Amprenavir (Ageneraze®, GlaxoSmithKline) are potent bioavailable inhibitors of the enzyme Protease (PR) of the Human Immunodeficiency Virus-1 (HIV-1), which have been developed by consistent structure-based drug design projects, and have been approved worldwide for the treatment of HIV infected patients. They act as competitive inhibitors, and tightly bind the active site of PR with high shape and electrostatic potential complementarity. However, the virus has shown the ability of fixating mutations which decrease the affinity of the antiretrovirals for the binding pocket of PR, although at the cost of decreasing (but to a minor extent) the affinity for the substrate. The consequent appearance of drug resistance compromised the long term efficacy of the drug. In this work we have extended such structure based drug design effort with computational methodologies, by performing very small substitutions in the inhibitors, directed at interacting with the most conserved amino acids. It is not possible to mutate the latter, at the cost of making the enzyme catalytically inactive. We show with a set of examples that significant increases in affinity can still be achieved without changing the overall structure, molecular mass and hydrophobicity of the inhibitors, thus preserving their very favourable ADME properties.

Multitarget therapy of mycophenolate mofetil and cyclosporine A for induction treatment of refractory lupus nephritis

Standard induction therapy for lupus nephritis (LN) with mycophenolate mofetil (MMF) or cyclophosphamide (CYC) is often ineffective. Evidence on rescue induction regimens is scarce. We analyzed efficacy and tolerability of multitarget immunosuppression with MMF and cyclosporine A (CsA) as induction treatment for LN (class III/IV/V) refractory to CYC and/or MMF. We included all six refractory LN patients (class IV = 3, class V = 2, class III = 1) from our 400-patient tertiary Lupus Clinic observed between 2012 and 2015. Four patients had previously received pulse CYC. All six received MMF as first or second induction therapy and CsA was added once failure to reach remission was established. Daily dose of MMF was 2–3 g and CsA was dosed up to 2.6–3.7 mg/kg/day. Mean proteinuria was reduced from 2407 mg/24 hours at the start of the MMF+CsA regimen to 544 mg/day after six months. The mean prednisolone dose was reduced from 17.5 to 6 mg/day after six months of MMF+CsA. Four patients achieved a complete renal response, one patient had a partial renal response and one failed to respond. None of the patients presented with adverse events. These data suggest that adding CsA to MMF can induce complete remission of refractory LN and is well tolerated.

Ultrasonography for the assessment of skin in systemic sclerosis: a systematic review

To identify and synthesize the best available evidence on the use of ultrasound to assess skin involvement in systemic sclerosis (SSc).

SAT0197 Ultrasound Guided Musculoskeletal Procedures under Peripheral Nerve Block: A Pilot Controlled Study in Rheumatic Patients

Background Musculoskeletal Ultrasound (US) is a valuable tool in the diagnosis and monitoring of rheumatic diseases. Invasive musculoskeletal procedures under US guidance improve technical accuracy and efficacy. However, patients complain of considerable pain during these procedures, which may compromise patient cooperation and technical efficacy. Peripheral nerve blocks (PNBs) allow an effective local anaesthesia, without significant adverse effects. Objectives To investigate the feasibility of PNBs in patients undergoing US-guided invasive procedures and their impact upon the pain induced by the procedure and its efficacy. Methods Consecutive patients requiring US-guided invasive procedures were recruited. Patients were randomly allocated, in blocks of 5, to two treatment groups. Group 1 had a local peripheral nerve block using 5ml of lidocaíne cloridrate 2% and Group 2 had a topical anaesthetic applied before the US-guided procedure. Demographic and clinical parameters and current therapies were registered. US examination of the anatomical region of pain was performed and effusion, synovial hypertrophy, hipoechoic tendon halus and Power Doppler (PD) signal were evaluated (synovitis, defined as the presence of effusion and/or synovial hypertrophy, was scored in gray-scale from mild to severe;PD signal was scored in a 0-3 scale). US evaluation and pain assessment were performed at baseline and 2 weeks after the US-guided procedure. Patients were asked to score the pain spontaneously felt at the region of interest over the previous week, using a Visual Analog Scale (VAS;0-100mm). Pain caused by the procedure was evaluated as above, 5 minutes after its performance. Efficacy of the procedure was defined as a reduction ≥1 point in synovitis and/or PD score and as a reduction ≥15mm in patient pain VAS. Comparison between groups was performed through Chi2 or Independent Samples T test, as adequate. p<0.05 was considered significant in statistical analyses. Results Sixty-one patients were included (Group 1=36;Group 2=25). Rheumatoid arthritis was the most frequent underlying rheumatic disease (34.4%). In Group 1, deep peroneous nerve block and an association of radial and ulnar nerve blocks were the most commonly PNBs executed (52.7% and 38.9%, respectively). No postblock complications were reported. Demographic and clinical parameters and patient pain VAS (previous week) were similar in both groups, although initial US gray-scale findings were significantly higher in Group 1 (p=0.04). The difference in the nature of procedures performed in the two groups was close to statistical significance (p=0.06). Efficacy based on pain responder rates was similar in both groups (66.7% vs 52.6%;p=0.34). Efficacy of the US-guided procedure (at 2 weeks) using responder rates was also similar in both groups (58.3% vs 52.0%;p=0.13). Pain caused by the US-guided procedure was significantly lower in Group 1 (3.36±2.86 vs 5.08±2.41;p=0.017). Conclusions PNBs were superior to topical anaesthetic in relieving pain due to musculoskeletal US invasive procedures. PNBs are simple and fully acceptable by patients. The differences in the degree of baseline US inflammation and in the nature of the procedures performed in each group, together with the small sample size, preclude final conclusions regarding potential differences in efficacy of the procedures performed under nerve blocks vs local anaesthetic. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5575

Severe fatigue is highly prevalent in ALL rheumatic diseases : an international study

Background Fatigue is a common, disabling, and difficult to manage problem in rheumatic diseases. Prevalence estimates of fatigue within various rheumatic disease groups vary considerably. Data on the relative prevalence of severe fatigue across multiple rheumatic diseases using a similar instrument is missing. Objectives The aim of this study was to provide an overview of the prevalence of severe fatigue across a broad range of rheumatic diseases and to examine its relationship with clinical and demographic variables. Methods Online questionnaires were filled out by an international sample of 6120 patients (88% female, mean age 47) encompassing 30 different rheumatic diseases. Fatigue was measured with the RAND(SF)-36 Vitality scale. A score of ≤35 was taken as representing severe fatigue. This cut-off score is similar to the 10th percentile of the general population; it was found to have 90% sensitivity (90% of people with chronic fatigue syndrome according to established classification criteria was correctly identified as having chronic fatigue syndrome using this cut-off score) and 81% specificity (81% of the people not having chronic fatigue syndrome according to established classification criteria was correctly identified as not having chronic fatigue syndrome using this cut-off score). Results Severe fatigue was present in 41% to 57% of the patients with a single inflammatory rheumatic disease such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjögrens syndrome, psoriatic arthritis, and scleroderma. The percentage of patients with severe fatigue was 59% in patients with multiple rheumatic diseases without fibromyalgia. Severe fatigue was least prevalent in patients with osteoarthritis (35%) and most prevalent in patients with (comorbid) fibromyalgia (around 80%). In logistic regression analysis, severe fatigue was predicted by having (comorbid) fibromyalgia, having multiple rheumatic diseases without fibromyalgia, younger age, lower education, and linguistic background. Of Dutch, English, French, German, Portuguese and Spanish speaking patients, severe fatigue was most prevalent in French speaking patients and least prevalent in Dutch speaking patients. Conclusions Severe fatigue is very common in all rheumatic diseases. Our study indicates that about one out of every two patients with a rheumatic disease is severely fatigued. As severe fatigue can have devastating effects for the patient, the near environment, and society at large, unraveling the underlying mechanisms of fatigue and developing optimal treatment strategies should be top priorities in rheumatological research and practice. Acknowledgements Thanks to Isabel Lόpez-Chicheri García (Murcia, Spain), Ricarda Mewes & Winfried Rief (Marburg, Germany), Karoline Vangronsveld & Geert Crombez (Ghent, Belgium), Andreas AJ Wismeijer, Henriët van Middendorp & Johannes WJ Bijlsma (Tilburg & Utrecht, the Netherlands), and Mark A Lumley (Detroit, USA) for help in data collection. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.2399

THU0371 A Frax Model for the Estimation of Osteoporotic Fracture Probability in Portugal

Background World Health Organization developed a fracture risk assessment tool, named FRAX1. FRAX is a computer-based algorithm (http://www.shef.ac.uk/FRAX) that provides an estimate of fracture probability in men and women over the subsequent ten years1. Since osteoporotic fracture rates vary greatly between countries, the FRAX algorithm is calibrated to the target population3. Objectives The objective of this study was to develop a Portuguese version of the World Health Organization (WHO) fracture risk assessment tool (FRAX®). Methods Age- and sex-stratified cases of hip fracture in patients aged 40 years of age or more were extractedfrom the Portuguese National Hospital Discharge Registerdata from 2006 to 2010. Age and sex- ranked population estimates and mortality rates were provided by the Portuguese Institute for National Statistics. Incidences were computed for each year in intervals of five years and the average of the five years under consideration was taken. Given the lack of reliable data regarding other major fractures in Portugal, rates for these were imputed from the epidemiology of Sweden as undertaken for the majority of FRAX® models. All the methodological aspects and results were submitted to critical appraisal by a wide panel of national experts and representatives of the different stakeholders, including patients, to enhance data quality assurance and foster the adoption of the tool. Results Hip fracture incidence rates were higher in women than in men and increased with age. The lowest incidence was observed in 40-44 years group (14.1 and 4.0 per 100,000 inhabitants for men and women, respectively). The highest rate was observed among the 95-100 age-group (2,577.6 and 3,551.8/100,000 inhabitants, for men and women, respectively). The estimated ten-year probability for major osteoporotic fracture or hip fracture increased with decreasing T-score and with increasing age. Portugal has one of the lowest fracture incidences among European countries, which was, reflected in the estimated 10-year probability for major osteoporotic fracture or hip fracture. All stakeholders involved in this project officially endorsed the Portuguese FRAX® model and co-authored this paper Conclusions The FRAX® tool can be used to estimate the ten-year risk of osteoporotic fractures. and applied to investigate the most appropriate intervention thresholds in Portugal. This is the first fracture prediction model that has been calibrated to the Portuguese population, using national data. Despite some limitationsof the FRAX® tool, its strengths and overall advantages are recognized worldwide. These qualities and the wide consensus obtained about its development and structure make the Portuguese FRAX® a good tool for implementation in clinical practice. References Kanis JA, Johnell O, Odén A, Johansson H, McCloskey E (2008) FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int19:385– 397. Kanis JA, Johnell O, De Laet C, Jonsson B, Odén A, Ogelsby AK (2002) International variations in hip fracture probabilities: implications for risk assessment. J Bone Miner Res17:1237– 1244. Disclosure of Interest None Declared

SAT0591-HPR Patient Education Programs (PEP) for Patients with Rheumatoid Arthritis (RA): an Updated Systematic Review

Background Patient education (PE) is broadly accepted as an integral part of the management of people with Rheumatoid arthritis (RA)(1), completing clinical care. However, previous reviews, till 2003,(2, 3) concluded that studies show small short-term results with lack of evidence of long-term benefits as well as updated results are not known on this evidence. Objectives To sistematically review the effectiveness of behavior and/or psychoeducational interventions on health status of patients with RA. Methods We searched on MEDLINE for randomized controlled trials (RCT’s), evaluating long term (≥1year) outcomes, controlled with standard care and published between 2003 (inclusion date of latest systematic review) and 2012. Keywords used were “rheumatoid arthritis” in conjunction with each of the following “education AND group intervention/programme”. Two reviewers examined and screened search results and evaluated their quality with a checklist (4). Results Forty-seven results were obtained. From thirteen RCT’s published after 2003, four studies were included. Exclusions were due to: outcome evaluation inferior to 1 year (three); other disease than (only) RA (three); no behaviour and/or psychoeducational intervention (two); parallel intervention comparison (one). Three studies showed that PEP was associated with positive results at long-term, mainly on: adherence to joint protection behaviour; coping; knowledge; quality of life (symptoms); care satisfaction; early morning stiffness duration, functional capacity (AIMS2). One of these studies hasn’t proved differences on functional capacity (HAQ). Only one study hasn’t showed any statistical significant difference between groups in any outcome [functional capacity (AIMS2), self efficacy]. Conclusions Long-term efficacy was proven in some outcomes. However, primary outcomes and measures differ frequently between studies. Standard interventions are also difficult to be homogeneous. Better methodological quality studies are needed, even if good ones are already published5, 6. One of the most important decisions for future studies is to decide what (main/primary) outcomes should be used. References - van Eijk-Hustings, Y., et al. (2012). EULAR recommendations for the role of the nurse in the management of chronic inflammatory arthritis. Annals of the Rheumatic Diseases, 71(1):13- 19. - Riemsma, R.P. et al. (2003). Patient education for adults with rheumatoid arthritis. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD003688. - Niedermann, K. et al. (2004). Gap Between Short- and Long-Term Effects of Patient Education in Rheumatoid Arthritis Patients: A Systematic Review. Arthritis & Rheumatism, 51:3, 388–398. - Kmet, L.; Lee, R.; Cook, S. (2004). Standard Quality Assessment Criteria for Evaluating Primary Research Papers from a Variety of Fields. Alberta, Edmonton: Alberta Heritage Foundation for Medical Research. - Niedermann, K. et al. (2012). Six and 12 months’ effects of individual joint protection education in people with rheumatoid arthritis: A randomized controlled trial. Scandinavian Journal of Occupational Therapy, 19: 360–9. - Quintrec, J. et al. (2007). Effect of a collective educational program for patients with rheumatoid arthritis: a prospective 12-month randomized controlled trial. J Rheumatol., 34(8):1684-91. Disclosure of Interest None Declared

THU0370 Hip Fractures in Portugal: 2006-2010 an Epidemiologic Analysis

Background Hip fractures are considered to be the most devastating consequence of osteoporosis. They require long hospitalizations and high health-care costs and represent an important cause of morbidity, disability, and mortality, especially in the elderly1. As patients are invariably hospitalized in most countries the epidemiology of hip fracture is well documented compared with other fracture outcomes and provides a surrogate for the total burden of osteoporosis2. Objectives To carry out an epidemiologic analyses of hip fractures incidence rates in Portugal. Methods All cases of hip fracture occurred at 40 years of age or above from 2006 to 2010 were extracted from the Portuguese National Hospital Discharge Register. Age and gender-stratified population data was collected from the Institute for National Statistics. Average annual incidences were computed for age and gender groups along with the associated mortality, length of hospital stay and destination of the patient after discharge. Statistical differences between genders were assessed trough IBM SPSS® 20 with 0.05 as level of significance. Results A total of 51701 hip fractures occurred in the period under analysis. Hip fracture incidence rates were higher in women than in men and increased with age. The lowest incidence was observed in the 40-44 age group (14.1 and 4.0 per 100,000 inhabitants for men and women, respectively). The highest rate was observed among the 95-100 age-group (2,577.6 and3,551.8/100,000 inhabitants, for men and women, respectively). The mean length of hospital stay was13.4 days for men and 14.2 days for women (t(19271.4)=6.731; p<0.05), respectively. We also found statistically significant differences between genders on patient’s destination after discharge (Chi Square(5)=253.099; p<0.05), the most frequent being: home 88.5% (men=85.3%; women=89.6%), mortality 5.1% (men=7.9%; women=4.3%), transferred for another hospital 3.9% (men=4.9%; women=3.7%), with homecare help 1.9% (men=1.2%; women=1.9%), discharge without medical consent 0.6%( men=0.7%; women=0.5%). Conclusions As expected women have a higher incidence of hip fractures. The Portuguese women are more likely to go home after being discharge of the hospital and have a lower mortality. Men are more likely to be transferred for another hospital. Further studies are necessary for access the mortality rates after discharge. References Kanis, J.A. & Johnell, O. (2005). Requirements for DXA for the management of osteoporosis in Europe. Osteoporos Int., 16:229–38. Cooper, C., Cole, Z.A., Holroyd, C.R., Earl, S.C., Harvey, N.C., Dennison, E.M., Melton, L.J., Cummings, S.R., & Kanis, J.A. (2011). Secular trends in the incidence of hip and other osteoporotic fractures. Osteoporos Int., 22:1277–88. Disclosure of Interest None Declared