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Maria Cevey,1 Jaime Calvo-Alén,2 Carlos Crespo,3 Angel Robles-Marhuenda,4 Lee Smolen,5 Josefina Cortés-Hernández6 1Department of Market Access, GlaxoSmithKline SA, Madrid, Spain; 2Department of Rheumatology, University Hospital Araba, Vitoria, Spain; 3Department of Genetics, Microbiology and Statistics, Statistics Section, University of Barcelona, Barcelona, Spain; 4Department of Internal Medicine, Hospital La Paz, Madrid, Spain; 5Modeling & Analytics, Medical Decision Modeling Inc, Indianapolis, IN, USA; 6Department of Internal Medicine, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, SpainCorrespondence: Josefina Cortés-HernándezDepartment of Internal Medicine, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron University Hospital Research Institute, Passeig Vall d’Hebron 119-129, Barcelona 08035, SpainTel +34 934893000Fax +34 934894438Email fina.cortes@vhir.orgObjective: To evaluate the budget impact and the direct costs of the introduction of subcutaneous belimumab (SC) into the Spanish National Health Service (NHS) for patients with systemic lupus erythematosus (SLE) in Spain.Methods: This study was conducted from the Spanish NHS perspective with a time horizon of 3 years. The budget impact analysis compared the cost difference between two scenarios: current market (standard therapy (ST) and intravenous belimumab (IV)) and other market in which patients switched from belimumab IV to belimumab SC until reaching 17% of the total market share. The eligible population was calculated to receive treatment with belimumab, applying the EPISER (study of the prevalence of rheumatic diseases in adult population in Spain) prevalence (91 per 100,000 inhabitants), Autoimmune Systemic Diseases Study Group (GEAS) incidence (2 per 100,000 inhabitants), and the risk of annual mortality to the Spanish adult population. Patients with severe active lupus nephritis and with severe active CNS lupus were excluded. Patients’ characteristics, flare rates and severity, and healthcare resource consumption were evaluated based on data from the literature and interviews with an expert panel. A sensitivity analysis was performed.Results: Currently, there is an estimated 34,697 adult patients with SLE in Spain and 3849 patients who are eligible to be treated with belimumab. The introduction of belimumab SC into the Spanish NHS could generate savings in direct healthcare costs of 6 million euros over the 3 years.Conclusion: The introduction of belimumab SC shows direct savings for the Spanish NHS. These savings could contribute to sustainability and decision-making.Keywords: belimumab, budget impact, Spanish National Health Service, NHS, Systemic Lupus Erythematosus

Ilona Steigerwald,1 Matthias Müller,1 Jolanta Kujawa,2 Jean-Charles Balblanc,3 Jaime Calvo-Alén,41Medical Affairs Europe & Australia, Grünenthal GmbH, Aachen, Germany; 2Medical University of Lodz, Medical Rehabilitation Clinic, Lodz, Poland; 3Department of Rheumatology, General Hospital of Belfort, Belfort, France; 4Hospital Universitario Sierrallana and IFIMAV Research Institute, Universidad de Cantabria, Cantabria, SpainAbstract: This open-label, phase 3b study (ClinicalTrials.gov Identifier: NCT00983073) evaluated the effectiveness, and tolerability of tapentadol for severe, chronic osteoarthritis knee pain that was inadequately managed with World Health Organization (WHO) Step I or II analgesics or co-analgesics, or that was not treated with regular analgesics. Prior to starting study treatment, patients discontinued any WHO Step II analgesics, while Step I analgesics and/or co-analgesics were continued at the same dose. Patients received tapentadol prolonged release (50–250 mg bid) during a 5-week titration period and a 7-week maintenance period. Doses of tapentadol immediate release 50 mg (≤twice/day; ≥4 hours apart) were permitted throughout the study (total daily dose of tapentadol prolonged and immediate release, ≤250 mg bid). The primary endpoint was the change in pain intensity on an 11-point numerical rating scale-3 (NRS-3; recalled average pain intensity [11-point NRS] during the last 3 days) from baseline to Week 6, using the last observation carried forward (LOCF) to impute missing pain intensity scores. The mean (standard deviation) change from baseline to Week 6 (LOCF) in pain intensity was -3.4 (2.10; P < 0.0001) for all patients evaluated for effectiveness (n = 195). Significant decreases in pain intensity were also observed at Weeks 6, 8, and 12 (all P < 0.0001) using observed-case analysis. Corresponding significant improvements from baseline to Weeks 6 and 12 were observed in the Western Ontario and McMaster Universities osteoarthritis index, the EuroQol-5 Dimension health status questionnaire, the Short Form-36 health survey, and the Hospital Anxiety and Depression Scale (all P ≤ 0.0103). Treatment-emergent adverse events were in line with those observed in previous studies of tapentadol prolonged release. Overall, the results of this study indicate that tapentadol treatment results in significant improvements in pain intensity, health-related quality of life, and function in patients with inadequately managed, severe, chronic osteoarthritis knee pain.Keywords: tapentadol, osteoarthritis, chronic pain, opioid

Background and Objectives: Systemic lupus erythematosus (SLE) is an autoimmune condition that can highly impact patients' quality of life (QoL). However, there is a lack of knowledge about SLE, affecting the general population and health care professionals (HCPs) alike. This lack of knowledge has negative implications for patients and the healthcare system, worsening prognosis, negatively impacting QoL, and increasing healthcare utilization. The aim of this paper is to draw attention, according to the perspective of the participants of this study, to the lack of awareness of SLE and its consequences in Spain, and to suggest improvements., Patients and Methods: This qualitative, descriptive, observational, multicenter, and cross-sectional study included 40 patients with moderate or severe SLE, recruited during their routine visits in six university hospitals in Spain. The study also included 11 caregivers and 9 HCPs. All participants were individually interviewed. Data from the interviews were coded and analyzed thematically by two anthropologists following a phenomenological perspective., Results: Our study identified a lack of disease awareness among primary care physicians, emergency medicine doctors, and other specialists treating SLE symptomatology. This led to diagnostic delays, which had a clinical and emotional impact on patients. Furthermore, symptom awareness was found to be context dependent. Differences in symptom awareness between HCPs and patients led to a mismatch between the severity evaluation made by doctors and patients. Some HCPs did not consider the limitations of the current severity evaluation of SLE, and therefore attributed symptoms potentially caused by SLE to the unfavorable socioeconomic conditions patients lived in. Finally, a lack of social awareness among friends, family members, and romantic partners led to lower social support, increased isolation, and negative physical and emotional impact for patients. Gender differences in the provision of support were identified., Conclusion: This study highlights the need to increase SLE awareness among patients, HCPs, and the broader public in order to improve patient QoL. Being aware of the clinical and emotional impact of such lack of awareness, as well as the role played by context on the patient experience of SLE, is a crucial step towards achieving this goal., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RRR and CSM are employees of A Piece of Pie and have received research funding from AstraZeneca to conduct this study. JSH, MG, and NBR are employees of AstraZeneca. ERA has received honoraria from GSK. All other authors report no competing interests.

Objective: To draft recommendations on interleukin 6 (IL-6) blockade in rheumatoid arthritis (RA), based on best evidence and experience., Methods: A group of 10 experts on IL-6 blockade in RA was selected. The 2 coordinators formulated 23 questions about IL-6 blockade (indications, efficacy, safety, etc.). A systematic review was conducted to answer the questions. Using this information, inclusion and exclusion criteria were established, as were the search strategies (Medline, EMBASE and the Cochrane Library were searched). Two different reviewers selected the articles. Evidence tables were created. At the same time, European League Against Rheumatism and American College of Rheumatology abstracts were evaluated. Based on this evidence, the coordinators proposed preliminary recommendations that the experts discussed and voted on in a nominal group meeting. The level of evidence and grade of recommendation were established using the Oxford Centre for Evidence Based Medicine and the level of agreement with the Delphi technique (2 rounds). Agreement was established if at least 80% of the experts voted yes (yes/no)., Results: The 8 preliminary recommendations were accepted after the Delphi process. They covered aspects such as the use of these therapies in monotherapy, in combination, in patients with refractory disease or intolerant patients, response evaluation, optimization and risk management., Conclusions: The manuscript aims to solve frequently asked questions and aid in decision making strategies when treating RA patients with IL-6 blockade., (Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Objective: To develop recommendations for the use of parenteral methotrexate (MTX) in rheumatic diseases, mainly rheumatoid arthritis, based on best evidence and experience., Methods: A group of 21 experts on parenteral MTX use was selected. The coordinator formulated 13 questions about parenteral MTX (indications, efficacy, safety and cost-effectiveness). A systematic review was conducted to answer the questions. Using this information, inclusion and exclusion criteria were established, as were the search strategies (involving Medline, EMBASE and the Cochrane Library). Three different reviewers selected the articles. Evidence tables were created. Abstracts from the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) were evaluated. Based on this evidence, the coordinator proposed preliminary recommendations that the experts discussed and voted in a nominal group meeting. The level of evidence and grade of recommendation were established using the Oxford Center for Evidence-Based Medicine and the level of agreement with the Delphi technique (2 rounds). Agreement was established if at least 80% of the experts voted yes (yes/no)., Results: Most of the evidence involved rheumatoid arthritis. A total of 13 preliminary recommendations on the use of parenteral MTX were proposed; 11 of them were accepted. Two of the 13 were not voted and are commented on in the main text., Conclusions: The manuscript aims to solve frequent questions and help in decision-making strategies when treating patients with parenteral MTX., (Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Polymorphisms of cytokine genes have been investigated as susceptibility markers of giant cell arteritis (GCA). Here, we have reviewed the evidence to date and especially addressed the functional consequences of IL10 (-592C/A and -1082A/G) gene polymorphisms and their association with susceptibility to and disease phenotype in GCA. A total number of 71 patients with GCA and 124 age-matched controls were genotyped using allele-specific primers and restriction fragment length polymorphism analysis. As previous studies in GCA showed inconsistent results, a meta-analysis of the existing studies was also conducted by using both fixed and random-effects models. The levels of circulating IL10 and the production of IL10 by peripheral blood mononuclear cells after in vitro stimulation were studied by Cytometric Bead Array. Data showed no significant differences in genotype or allele frequency distribution between patients and controls. The clinical characteristics and prognosis of these patients were also unrelated to the presence of these polymorphisms. However, the meta-analysis found a significant association of IL10 -592C/A polymorphism with susceptibility to GCA (odds ratio 2.205 (95% confidence interval 1.074-4.524); p = 0.031). In both patients and age-matched controls, no differences in circulating IL10 levels or IL10 production were observed depending on the genotypes of the IL10 gene. In conclusion, although our cohort results do not support the impact of IL10 variants in susceptibility or clinical phenotype of GCA patients, the meta-analysis revealed a significant association of -592C/A polymorphism with susceptibility to GCA. In this population, no functional association was found between IL10 gene variants and IL10 production.

Objective: Toll-like receptor (TLR) 4 (+896 A/G) gene polymorphism has been reported to be associated with susceptibility to giant cell arteritis (GCA) with inconsistent results. To provide a more definitive conclusion, a cumulative meta-analysis of the association of TLR4 (+896 A/G) polymorphism with GCA susceptibility combining previous studies was performed., Methods: The cumulative meta-analysis included 3 case-control studies which provided a total of 437 patients and 1023 controls. Meta-analysis was conducted by fitting random effects models and checked for heterogeneity and publication bias. Combined odds ratio (OR) and associated 95% confidence intervals (CI) were obtained by using a DerSimonian and Laird random effects model., Results: Three studies, all from a South European ancestry, were identified through a literature search and included in this meta-analysis. The cumulative meta-analysis showed that the pooled random effects OR was non significant (OR: 1.46, 95% CI: 0.95-2.25; p = 0.082). There is some evidence suggestive of moderate-high heterogeneity between the three studies, I2 34.2% (95% CI: 0-55.2)., Conclusion: This cumulative meta-analysis does not demonstrate an association of TLR4 (+896 A/G) gene polymorphism with susceptibility to GCA. Further studies using larger samples and in populations from different geographic origins are needed to determine the exact role of TLR4 gene polymorphisms in GCA., (Copyright © 2011. Published by Elsevier B.V.)

Objective: Coding variants in Toll-like receptor 4 (TLR4) have been reported to be associated with inflammatory diseases. The aim of this study was to determine whether two of these polymorphisms (+896 A/G and +1196 C/T) are associated with susceptibility and clinical features of GCA. We also attempted to correlate the functional consequences of these polymorphisms., Methods: A total of 72 patients with GCA and 126 age-matched controls were genotyped using allele-specific PCR and restriction fragment length polymorphism analysis. TLR4 expression was studied on peripheral blood mononuclear cells by flow cytometry and TLR4 function was assessed by stimulating monocytes in vitro with a specific ligand., Results: There was no significant difference in allele frequency or genotype of TLR4 (+896 A/G and +1196 C/T) between GCA patients and controls. The clinical characteristics of these patients were unrelated to the presence of these polymorphisms. Furthermore, we did not observe an association with TLR4 expression or a distinct phenotype of TLR4 response with the +896 A/G and +1196 C/T genotypes., Conclusion: Our results do not support the association of these TLR4 variants with GCA. Studies including a larger number of patients and patient populations from different geographical origin are needed.

Objectives: Coding variants in TLR4 gene have been reported to be associated with inflammatory diseases. The aim of this study was to determine whether two of these polymorphisms (Asp299Gly and Thr399Ile) of TLR4 contribute to the genetic background of polymyalgia rheumatica (PMR) and elderly-onset rheumatoid arthritis (EORA). Furthermore, we have attempted to correlate the functional consequences of these polymorphisms., Methods: 164 patients with PMR, 93 with EORA and 126 unrelated age-matched controls were genotyped. The TLR4 genotypes were determined using allele-specific primers and restriction fragment length polymorphism analysis. Association of genotypes and alleles with disease susceptibility and disease phenotypes were studied. TLR4 expression was assessed on PBMCs by flow cytometry and TLR4 function was assessed by stimulating PBMCs in vitro with LPS., Results: No significant difference in allele frequency or genotype between patients with elderly-onset inflammatory conditions and controls was observed. The Thr399Ile CC genotype was associated with a higher cumulative dose of corticosteroids in patients with PMR (p=0.031). We found no association with TLR4 expression on B cells, T cells or monocytes or a distinct phenotype of TLR4 response with the Asp299Gly or Thr399Ile genotypes., Conclusions: These results do not support the association of these TLR4 variants with two age-related inflammatory conditions. The value of determining Thr399Ile genotypes for disease prognosis in PMR should be confirmed in different populations.

Objective: To evaluate the utility of the duration of morning stiffness (MS), as a patient-reported outcome (PRO), in assessing rheumatoid arthritis (RA) disease activity., Methods: We acquired information on 5439 patients in QUEST-RA, an international database of patients with RA evaluated by a standard protocol. MS duration was assessed from time of waking to time of maximal improvement. Ability of MS duration to differentiate RA activity states, based on Disease Activity Score (DAS)28, was assessed by analysis of variance; and a receiver-operating characteristic (ROC) curve was plotted for discriminating clinically active (DAS28 > 3.2) from less active (DAS28 3.2)., Conclusion: MS duration has a moderate correlation with RA disease activity. Assessment of MS duration may be clinically helpful in patients with low RAPID3 scores.

Objective: To describe the clinical and immunologic characteristics of a large series of patients with systemic autoimmune diseases (SAD) associated with chronic hepatitis C virus (HCV) infection., Methods: The HISPAMEC Registry is a multicenter international study group dedicated to collecting data on patients diagnosed with SAD with serological evidence of chronic HCV infection. The information sources are cases reported by physicians of the HISPAMEC Study Group and periodic surveillance of reported cases by a Medline search updated up to December 31, 2007., Results: One thousand twenty HCV patients with SAD were included in the registry. Patients were reported from Southern Europe (60%), North America (15%), Asia (14%), Northern Europe (9%), South America (1%), and Australia (1%). Countries reporting the most cases were Spain (236 cases), France (222 cases), Italy (144 cases), USA (120 cases), and Japan (95 cases). The most frequently reported SAD were Sjögren's syndrome (SS; 483 cases), rheumatoid arthritis (RA; 150 cases), systemic lupus erythematosus (SLE; 129 cases), polyarteritis nodosa (78 cases), antiphospholipid syndrome (59 cases), inflammatory myopathies (39 cases), and sarcoidosis (28 cases). Twenty patients had 2 or more SAD. Epidemiological data were available in 677 cases. Four hundred eighty-seven (72%) patients were female and 186 (28%) male, with a mean age of 49.5 +/- 1.0 years at SAD diagnosis and 50.5 +/- 1.1 years at diagnosis of HCV infection. The main immunologic features were antinuclear antibody (ANA) in 61% of patients, rheumatoid factor (RF) in 57%, hypocomplementemia in 52%, and cryoglobulins in 52%. The main differential aspect between primary and HCV-related SAD was the predominance of cryoglobulinemic-related markers (cryoglobulins, RF, hypocomplementemia) over specific SAD-related markers (anti-ENA antibodies, anti-dsDNA, anti-cyclic citrullinated peptide) in patients with HCV., Conclusion: In the selected cohort, the SAD most commonly reported in association with chronic HCV infection were SS (nearly half the cases), RA and SLE. Nearly two thirds of SAD-HCV cases were reported from the Mediterranean area. In these patients, ANA, RF and cryoglobulins are the predominant immunological features.

Introduction: Gender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA)., Methods: The cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents., Results: Women had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies., Conclusions: In this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself.

Introduction: Temporal artery (TA) biopsy is required for the evaluation of several clinical scenarios because of the therapeutic implications of a positive result. We describe the experience of our department, which is the center for this technique in our hospital., Patients and Methods: A retrospective study was made of all TA biopsies performed in the Department of Otolaryngology, Hospital Sierrallana, from January 1995 to April 1997., Results: Thirty-four biopsies of the TA artery were performed in 33 patients for possible temporal arteritis. Mean age was 76 years (range: 61-87 years). Twelve were male and 21 female. Twenty-two patients (66.6%) had recent onset cephalalgia, 11 (33.3%) polymyalgia rheumatica, 5 (15.1%) mandibular claudication, and 8 (24.2%) ocular symptoms. In 75.8% ESR was elevated. An abnormal TA exam was observed in 9 cases (27.3%), 6 of which had a positive biopsy. Only 1 of the 15 patients without local findings at the physical examination had a positive TA biopsy. No information on the physical exam was recorded for the other 2 patients with a positive biopsy., Conclusions: TA biopsy is a relatively easy surgical procedure with a very low rate of complications. An abnormal physical TA examination correlates with a positive histopathological study.

Objective: To determine predictors of the occurrence of systemic lupus erythematosus (SLE) in patients with early (< or = 1 yr) undifferentiated connective tissue disease (CTD)., Methods: Analysis of a cohort of 213 patients with early undifferentiated CTD at entry, followed for 5 yrs at 11 tertiary centers. Baseline demographic, clinical, and laboratory data were compared using univariate and Cox multivariate regression analyses to identify possible predictive features for the subsequent occurrence of SLE., Results: 143 of 213 patients had ascertainable clinical status at 5 yrs. By univariate analyses those who evolved to SLE (13%) were more likely to be younger, African-American, and to have alopecia, serositis, discoid lupus, positive Coombs' test, positive anti-dsDNA and anti-Sm antibodies, positive ANA (homogeneous pattern), and/or a false positive test for syphilis. Discoid lupus (relative risk = 15.8), serositis (4.1), ANA-homogeneous (4.8), and anti-Sm positivity (28.2) were retained as predictors of the occurrence of SLE in the Cox regression model., Conclusion: Some clinical and laboratory features in patients with early undifferentiated CTD can predict the subsequent occurrence of SLE.