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Vitamin D has shown to play a role in multiple diseases due to its skeletal and extraskeletal actions. Furthermore, vitamin D deficiency has become a worldwide health issue. Few supplementation guidelines mention calcifediol treatment, despite being the direct precursor of calcitriol and the biomarker of vitamin D status. This 1-year, phase III-IV, double-blind, randomized, controlled, multicenter clinical trial assessed the efficacy and safety of calcifediol 0.266 mg soft capsules in vitamin D-deficient postmenopausal women, compared to cholecalciferol. Results reported here are from a prespecified interim analysis, for the evaluation of the study's primary endpoint: the percentage of patients with serum 25-hydroxyvitamin D (25(OH)D) levels above 30 ng/ml after 4 months. A total of 303 patients were enrolled, of whom 298 were included in the intention-to-treat (ITT) population. Patients with baseline levels of serum 25(OH)D

Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p

To describe the clinical and therapeutic management of rheumatoid arthritis (RA) patients with biological disease-modifying antirheumatic drugs (bDMARDs), alone or in combination with conventional synthetic DMARDs (csDMARDs), as well as analysing changes over time in bDMARD use. An observational, retrospective, multicentre study was conducted in the rheumatology departments of 10 public Spanish hospitals. Patients with RA treated with bDMARDs at baseline who had medical records available in the data collection period 2013-2016 were included. All visits to rheumatology departments recording any type of bDMARD modification (dose, etc.) were collected. Clinical characteristics, concomitant treatment, resource use, work productivity and quality of life (QoL) were recorded. 128 patients were included: 81 received first-line bDMARD treatment, 28 second-line bDMARD treatment and 19 received third or later lines. Mean study follow-up was 4.1 years. Assessment of DAS28 was available in 54.6% of visits. At baseline, 48.7% of patients had moderate-high disease activity. At final observation, 69.5% of patients continued with the first bDMARD. Tumour necrosis factor blockers were administered to 85.2% of patients in first line, 45.7% in second line and 18.1% in third or later lines. At final observation, 80.2% of patients still felt pain/discomfort. As expected, those with higher disease activity had higher loss of work productivity and lower QoL, as assessed by DAS28, than patients with lower disease activity. Drugs represented 82.6% of the total cost. In this Spanish cohort of 128 patients, most patients remained on the first prescribed bDMARD, despite remaining signs and symptoms.

The different sets of criteria for diagnosis or classification of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) lead to numerous overlapping and reclassified diagnoses in clinical practice. We designed this study to assess the difficulties in classifying patients with AAV. As a secondary objective, different variables were tested to predict prognosis. We conducted a retrospective chart review in a Western Spain multicentre survey. A total of 115 adult patients diagnosed with AAV from 2002 to 2013 and followed for at least 3 years were included. They were classified according to (1) Chapel Hill Consensus Conference (CHCC), (2) European Medicines Agency algorithm and (3) French Vasculitis Study Group/European Vasculitis Society phenotypes. Fifty-three patients (46%) had neither distinctive histopathological data of a single AAV definition nor any surrogate markers for granulomatous inflammation and thus did not fulfill any diagnostic criteria. Ocular, ear, nose, throat, skin, and lung involvement were more frequent with proteinase 3 (PR3) antibodies, whereas peripheral neuropathy was more frequent with myeloperoxidase (MPO) antibodies. When the disease was severe at diagnosis, the HR for mortality was 10.44. When induction treatment was not given in accordance with the guidelines, the HR for mortality was 4.00. For maintenance treatment, the HR was 5.49 for mortality and 2.48 for relapse. AAV classification is difficult because many patients had neither specific clinical data nor distinctive histological features of a single CHCC definition. A structured clinical assessment of patient severity is the best tool to guide the management of AAV.

Objective Describe the objectives, methods and results of the first year of the new version of the Spanish registry of adverse events involving biological therapies and synthetic drugs with an identifiable target in rheumatic diseases (BIOBADASER III). Methodology Multicenter prospective registry of patients with rheumatic inflammatory diseases being treated with biological drugs or synthetic drugs with an identifiable target in rheumatology departments in Spain. The main objective of BIOBADASER phase III is the registry and analysis of adverse events; moreover, a secondary objective was added consisting of assessing the effectiveness by means of the registry of activity indexes. Patients in the registry are evaluated at least once every year and whenever they experience an adverse event or a change in treatment. The collection of data for phase III began on 17 December 2015. Results During the first year, 35 centres participated. The number of patients included in this new phase in December 2016 was 2664. The mean age was 53.7 years and the median duration of treatment was 8.1 years. In all, 40.4% of the patients were diagnosed with rheumatoid arthritis. The most frequent adverse events were infections and infestations. Conclusions BIOBADASER phase III has been launched to adapt to a changing pharmacological environment, with the introduction of biosimilars and small molecules in the treatment of rheumatic diseases. This new stage is adapted to the changes in the reporting of adverse events and now includes information related to activity scores.

Paget¿s disease of bone (PDB) is characterized by increased bone resorption followed by an excessive compensatory bone formation, with an abnormal bone structure with altered mechanical properties. Pagetic bone also has a higher vascularization and marrow fibrosis. Despite of pagetic bone being a highly vascularized tissue, there are no studies on the plasma levels of angiogenic mediators in the different states of the disease; moreover, the effect of PDB treatment on plasma levels of these angiogenic mediators is not very well known. The aim of this study was to analyse plasma levels of cytokines implicated in the increased bone turnover (OPG, RANKL, sclerostin) and hypervascularization (VEGF, PGF, ENG) observed in PDB and their evolution and response to zoledronic acid treatment in 70 PDB patients, 29 with an active disease measured by plasma alkaline phosphatase (ALP). Plasma ALP concentration was higher in active PDB than in inactive PDB patients, whereas there were no differences in OPG, RANKL, sclerostin, VEGF, PGF and ENG plasma levels between active and inactive PDB patients. ALP decreased at 3 and 12 months after zoledronic acid treatment. RANKL levels were reduced and sclerostin levels were increased after 12 months of treatment. PGF levels were lower 12 months after zoledronic acid treatment, whereas there were no differences in plasma VEGF and ENG after zoledronic acid treatment. Summarizing, zoledronic acid treatment is associated to decreases in plasma levels of ALP, RANKL, sclerostin and P1GF in active PDB patients. This treatment may reduce bone turnover and might reduce the pathological vascularisation typical of pagetic bone., This work was supported by grants from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, PI12/00959, PI13/01741, PI15/01055, Kidney Research Network REDINREN RD012/0021/0032 and RD016/0009/0025, co-funded by FEDER) and Junta de Castilla y León (Ministry of Health, GRS 969/A/14).

BACKGROUND: Bisphosphonates are considered to be the treatment of choice for people with Paget's disease of bone. However, the effects of bisphosphonates on patient‐centred outcomes have not been extensively studied. There are insufficient data to determine whether reducing and maintaining biochemical markers of bone turnover to within the normal range improves quality of life and reduces the risk of complications. OBJECTIVES: To assess the benefits and harms of bisphosphonates for adult patients with Paget's disease of bone. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ISI Web of Knowledge and trials registers up to March 2017. We searched regulatory agency published information for rare adverse events. SELECTION CRITERIA: Randomised controlled trials (RCTs) of bisphosphonates as treatment for Paget's disease in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, extracted data and assessed studies for risk of bias. We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 20 trials (25 reports, 3168 participants). Of these, 10 trials (801 participants) compared bisphosphonates (etidronate, tiludronate, ibandronate, pamidronate, olpadronate, alendronate, risedronate, zoledronate) versus placebo, seven compared two bisphosphonates (992 participants), one trial compared a bisphosphonates with a bisphosphonate plus calcitonin (44 participants), and two studies, the largest trial (1331 participants) and its interventional extension study (502 participants), compared symptomatic treatment and intensive treatment where the goal was to normalise alkaline phosphatase. Most studies were assessed at low or unclear risk of bias. Six of 10 studies comparing bisphosphonates versus placebo were assessed at high risk of bias, mainly around incomplete outcome data and selective outcome reporting. Participant populations were reasonably homogeneous in terms of age (mean age 66 to 74 years) and sex (51% to 74% male). Most studies included participants who had elevated alkaline phosphatase levels whether or not bone pain was present. Mean follow‐up was six months. Bisphosphonates versus placebo Bisphosphonates tripled the proportion (31% versus 9%) of participants whose bone pain disappeared (RR 3.42, 95% confidence interval (CI) 1.31 to 8.90; 2 studies, 205 participants; NNT 5, 95% CI 1 to 31; moderate‐quality evidence). This result is clinically important. Data were consistent when pain change was measured as any reduction (RR 1.97, 95% CI 1.29 to 3.01; 7 studies, 481 participants). There was uncertainty about differences in incident fractures: 1.4% fractures occurred in the bisphosphonates group and none in the placebo group (RR 0.89, 95% CI 0.18 to 4.31; 4 studies, 356 participants; very low‐quality evidence). None of the studies reported data on orthopaedic surgery, quality of life or hearing thresholds. Results regarding adverse effects and treatment discontinuation were uncertain. There was a 64% risk of mild gastrointestinal adverse events in intervention group participants and 48% in the control group (RR 1.32, 95% CI 0.91 to 1.92; 6 studies, 376 participants; low‐quality evidence). The likelihood of study participants discontinuing due to adverse effects was slightly higher in intervention group participants (4.4%) than the control group (4.1%) (RR 1.01, 95% CI 0.41 to 2.52; 6 studies, 517 participants; low‐quality evidence). Zoledronate was associated with an increased risk of transient fever or fatigue (RR 2.57, 95% CI 1.21 to 5.44; 1 study, 176 participants; moderate‐quality evidence). Bisphosphonates versus active comparator More participants reported pain relief with zoledronate than pamidronate (RR 1.30, 95% CI 1.10 to 1.53; 1 study, 89 participants; NNT 5, 95% CI 3 to 11) or risedronate (RR 1.36, 95% CI 1.06 to 1.74; 1 study, 347 participants; NNT 7, 95% CI 4 to 24; very low quality evidence). This result is clinically important. There was insufficient evidence to confirm or exclude differences in adverse effects of bisphosphonates (RR 1.05, 95% CI 0.95 to 1.76; 2 studies, 437 participants; low‐quality evidence) and treatment discontinuation (2 studies, 437 participants) (RR 2.04, 95% CI 0.43 to 9.59; 2 studies, 437 participants; very low‐quality evidence). Intensive versus symptomatic treatment There was no consistent evidence of difference to response in bone pain, bodily pain or quality of life in participants who received intensive versus symptomatic treatment. Inconclusive results were observed regarding fractures and orthopaedic procedures for intensive versus symptomatic treatment (intensive treatment for fracture: RR 1.84, 95% CI 0.76 to 4.44; absolute risk 8.1% versus 5.2%; orthopaedic procedures: RR 1.58, 95% CI 0.80 to 3.11; absolute risk 5.6% versus 3.0%; 1 study, 502 participants; low‐quality evidence). There was insufficient evidence to confirm or exclude an important difference in adverse effects between intensive and symptomatic treatment (RR 1.05, 95% CI 0.79 to 1.41; low‐quality evidence). There was insufficient evidence to confirm or exclude an important difference of risk of rare adverse events (including osteonecrosis of the jaw) from the regulatory agencies databases. AUTHORS' CONCLUSIONS: We found moderate‐quality evidence that bisphosphonates improved pain in people with Paget's disease of bone when compared with placebo. We are uncertain about the results of head‐to‐head studies investigating bisphosphonates. We found insufficient evidence of benefit in terms of pain or quality of life from intensive treatment. Information about adverse effects was limited, but serious side effects were rare, and rate of withdrawals due to side effects was low.

SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome is a cluster of osteo-cutaneous manifestations that can lead to serious complications such as thrombosis of the subclavian vein or superior vena cava, mainly in patients with significant inflammatory involvement of the anterior chest wall. The objective of this study was to review the cases published in the medical literature related with the presence of thrombotic complications in patients diagnosed with SAPHO syndrome and to try to determine their possible pathogenic mechanism and risk factors. We analyzed 11 published reports of isolated clinical cases or case series, a total of 144 patients, which described a total of 15 cases of venous thrombosis. The clinical characteristics of these patients, evaluated to determine whether they meet the ASAS criteria for axial and peripheral spondyloarthritis, are analyzed and the need for early diagnosis and treatment is highlighted.

Hyperprolactinemia is an underappreciated/unknown adverse effects of antipsychotics. The consequences of hyperprolactinemia compromise therapeutic adherence and can be serious. We present the consensus recommendations made by a group of experts regarding the management of antipsychotic-induced hyperprolactinemia. The current consensus was developed in 3 phases: 1, review of the scientific literature; 2, subsequent round table discussion to attempt to reach a consensus among the experts; and 3, review by all of the authors of the final conclusions until reaching a complete consensus. We include recommendations on the appropriate time to act after hyperprolactinemia detection and discuss the evidence on available options: decreasing the dose of the antipsychotic drug, switching antipsychotics, adding aripiprazole, adding dopaminergic agonists, and other type of treatment. The consensus also included recommendations for some specific populations such as patients with a first psychotic episode and the pediatric-youth population, bipolar disorder, personality disorders and the elderly population.

IntroductionPaget’s disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget’s disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carrySQSTM1mutations.Methods and analysisPeople with a family history of PDB aged >30 years who test positive forSQSTM1mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events.Ethics and disseminationThe study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals withSQSTM1mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable.Trial registration numberISRCTN11616770

Paget's disease of bone (PDB) has a strong genetic component. Here, we investigated possible associations between genetic variants that predispose to PDB and disease severity. Allelic variants identified as predictors of PDB from genome-wide association studies were analyzed in 1940 PDB patients from the United Kingdom, Italy, Western Australia, and Spain. A cumulative risk allele score was constructed by adding the variants together and relating this to markers of disease severity, alone and in combination with SQSTM1 mutations. In SQSTM1-negative patients, risk allele scores in the highest tertile were associated with a 27% increase in disease extent compared with the lowest tertile (p

Context Several studies have suggested that the prevalence and severity of PDB have fallen in recent years. The magnitude of this trend and its globalization have not been well established. Objective The objective of this study is to estimate the pooled magnitude of the changes in the prevalence of PDB and as a secondary objective, to make up a world atlas of PDB prevalence. Methods A systematic review of English and non-English articles using MEDLINE (1946 to 2013) and EMBASE (1980 to 2013) was the method used. Search terms included epidemiology, incidence, prevalence, cohort studies, osteitis deformans or Paget's disease of bone. Studies with incidence and/or prevalence rate for PDB were included. Two authors independently extracted the data using predefined data fields and quality assessment. A pooled analysis based on random-effects models was carried out for secular trends. Results Twenty-eight articles documented the prevalence of PDB; four articles the incidence and two articles the rate of new referrals. The prevalence of PDB varied greatly between the different countries, from 0.00028% in Japan to 5.4% in the UK. There were available data on changes in prevalence from two different surveys over two different time frames in Europe and New Zealand. In all but one city (Turin), a drop in the prevalence of PDB was recorded (pooled OR 0.64; 95% CI 0.45–0.91). Conclusion The incidence and prevalence rates of PDB vary widely between populations but both have decreased in most regions over recent years. The changes are heterogeneous however and within countries, the largest changes have been in areas that previously had a high prevalence. The reasons for these changes remain unclear at present but are likely to be due to an interaction between genetic factors and environmental triggers which may differ in different regions.

Background: Cases of renal tubular dysfunction have been reported in patients with hepatitis B and in patients with human immunodeficiency virus who are undergoing tenofovir treatment. However, little is known about the impact on tubular function in patients with chronic hepatitis B (CHB) under long-term use of entecavir (ETV) and tenofovir disoproxil fumarate (TDF). We evaluated markers of renal tubular function and bone turnover in patients with CHB treated with ETV or TDF. Patients and Methods: A multicenter, cross-sectional study was performed on markers of renal tubular function and bone turnover in hepatitis B virus-monoinfected patients on long-term treatment with Entecavir or Tenofovir (the MENTE study). The analyzed parameters were: retinol-binding protein/creatinine, neutrophil gelatinase-associated lipocalin/creatinine, excretion of phosphates, uric acid excretion, glomerular filtrate, protein/creatinine, albumin/ creatinine, serum creatinine, phosphate, CTX, P1NP, vitamin D, and parathormone. Results: A total of 280 patients (ETV: 89, TDF: 69, control: 122) were included in this study. The TDF group was associated with altered levels of retinol-binding protein (RBP)/creatinine (TDF 25% vs. 7% ETV and control; P < 0.001). Protein/creatinine, uric acid excretion, P1NP1, and parathormone were higher in the TDF group. The proportion of patients with serum phosphate < 2.5 mg/dL was higher in both the ETV and the TDF groups compared with the control. The multivariate analysis showed that the use of TDF was independently associated with a higher risk of altered excretion of RBP/creatinine (4.4; interquartile range: 1.4 to 14; P = 0.013). Conclusions: We found an independent association between TDF use and altered RBP excretion. This finding indicates subclinical tubular damage. Because tubular dysfunction can precede the decline of renal function, close monitoring of RBP levels in patients with CHB on nucleos(t)ide analog treatment must be performed for early detection of TDF-related renal toxicity. In this study, these differences in tubular function were not associated with concomitant changes in markers of bone turnover.

The management of postmenopausal osteoporosis (PMO) in routine clinical practice differs considerably from guideline recommendations. The objective of our study was to reach a consensus on the management of PMO, considering prevention, diagnosis, treatment and follow-up, according to expert opinion in Spain.A two-round Delphi technique was conducted, including 38 experts. The questionnaire contained 35 sections, each one including 1-10 questions (n = 308) based on a literature review and contributions from the scientific steering committee. Each question was scored by experts from the current (1 = no occurrence, 9 = occurrence in all cases), wish (1 = total rejection; 9 = wish) and prediction (1 = no occurrence at all; 9 = occurs with maximum probability) perspectives. Consensus (wish and prediction perspectives) was considered when ≥75% of experts scored 7-9 (agreement) or 1-3 (disagreement).Overall, consensus was achieved on 75% of questions. While protocols of clinical management and consultation/referral should be followed, their implementation is unlikely. Furthermore, the medical specialties currently involved in PMO management are poorly defined. PMO patients without fracture should be managed (prevention, diagnosis, treatment and follow-up) in both primary care and rheumatology settings; however, experts predicted that only treatment and follow-up will be assumed by these specialties. A multidisciplinary team should be involved in patients with fracture. No assessment tools are usually applied, and prediction indicated that they will not be used.Efforts should be focused on questions with high divergence between wishes and predictions, defining actions that will improve PMO management. Collaboration between scientific societies and health authorities to address the identified opportunities of improvement is proposed.Amgen S.A.

Objective Due to increasing improvement in the diagnosis, evaluation and management of osteoporosis and the development of new tools and drugs, the Spanish Society of Rheumatology (SER) has promoted the development of recommendations based on the best evidence available. These recommendations should be a reference to rheumatologists and other health professionals involved in the treatment of patients with osteoporosis. Methods Recommendations were developed following a nominal group methodology and based on a systematic review. The level of evidence and the degree of recommendation were classified according to the model proposed by the Center for Evidence Based Medicine at Oxford. The level of agreement was established through Delphi technique. Evidence from previous consensus and available clinical guidelines was used. Results We have produced recommendations on diagnosis, evaluation and management of osteoporosis. These recommendations include the glucocorticoid-induced osteoporosis, premenopausal and male osteoporosis. Conclusions We present the SER recommendations related to the biologic therapy risk management.

Two trials have shown that a single 5-mg infusion of zoledronic acid achieves much higher response rates in Paget disease of bone than risedronate. The duration of this effect is unknown. We have conducted an open follow-up of responders from the two trials (152 originally treated with zoledronic acid, 115 with risedronate) out to 6.5 years without further intervention. Endpoints were times to relapse (ie, return of serum total alkaline phosphatase activity to within 20% of the pretreatment value) or loss of response (response = normalization of alkaline phosphatase or 75% or greater reduction in its excess). Bone turnover markers were lower in the zoledronic acid group throughout follow-up, with mean alkaline phosphatase (ALP) remaining within the reference range in these patients, whereas the mean in the risedronate group was above normal from 1 year. Relapse rates were substantially greater in the risedronate group (23 of 115, 20%) than in those treated with zoledronic acid (1 of 152, 0.7%, p

Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by focal increases in bone turnover, which in some cases is caused by mutations in SQSTM1. To identify additional susceptibility genes, we performed a genome-wide association study in 750 individuals with PDB (cases) without SQSTM1 mutations and 1,002 controls and identified three candidate disease loci, which were then replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 near the CSF1 gene (P = 5.38 x 10(-24)). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 x 10(-13)) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 x 10(-13)). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.

Objectives The aim of this study was to compare the clinical and economic consequences of using subcutaneous methotrexate (Metoject®) with respect to oral methotrexate in the management of rheumatoid arthritis (RA) in Spain. Methods A cost-effectiveness analysis was performed to compare early treatment of RA using a Markov model. The model allowed us to estimate long term efficacy of RA treatment based on data from the literature and expert opinion, and to combine this data with costs of managing RA in Spain. The perspective of the study was from the National Health System point of view, using a time horizon of 5 years and patient lifetime. All costs were expressed in 2009 euros and a 3% discount rate was applied. Results The cost (only pharmacologic costs) per quality-adjusted life year (QALY) gained with Metoject® went from 25,173 to 35,807 € at 5 years and from 19,056 to 25,351 € for patient lifetime. When direct costs in RA treatment were considered, it was observed that cost-effectiveness at 5 years went from 29,682 to 42,175 €/QALY gained, and for patient lifetime from 22,514 to 29,848 €/QALY gained. Conclusions Additional costs of Metoject® with respect to oral methotrexate would be offset by their improved effectiveness, expressed in QALY, showing that Metoject® could be a cost-effective treatment option for RA in the Spanish Health System assuming a spanish threshold.

a b s t r a c t Objectives: To describe the clinical and epidemiological characteristics of patients included in the National Register of Paget's disease. Methods: A Register of patients with Paget disease (PD), radiologically confirmed, and pertaining to 25 hospitals was analyzed. Clinical and epidemiological data were collected, including age, sex, date, and presentations at time of diagnosis, treatment, quality of life (QL) (EuroQol 5D) and perceived health, environmental factors (profession, history of measles, contact with animals, dairy consumption, housing conditions, place of birth and address) and family history (PD history, origin of the ancestors, number of children). We conducted a statistical description of the data. Results: The register included 602 patients with an average age of 62 (11) years and a predominance of male (55%). Of the patients included, 79% showed symptoms at the time of diagnosis, mainly pain (83%); 82% had received treatment, mainly bisphosphonates (47% more than one drug). Despite treatment, a significant proportion had limitations in their QL, especially related to pain (64%), mobility (47%), and anxiety/depression (33%). Most of the patients had been exposed to situations which were considered as risk factors. Of the patients included, 14% had family history of PD and 1.5% had children with PD. The ancestors of the familial cases came more frequently from Avila, Salamanca, La Coruna, and Malaga. Conclusions: The pain and the limitation of mobility decrease the QL of patients with PD despite treatment. Frequently, patients have a history of exposure to risk factors

Fundamento y objetivo: Los estudios sobre la capacidad de los marcadores del remodelado oseo (MRO) para la prediccion de la perdida osea y sobre la correlacion de los MRO con la densidad mineral osea (DMO) han mostrado resultados dispares. Los objetivos del trabajo han sido evaluar la utilidad de los MRO para predecir la perdida de masa osea y estudiar la correlacion entre los MRO y la DMO en las mujeres posmenopausicas recientes. Sujetos y metodo: Seleccionamos al azar a 183 mujeres sanas de 50-55 anos, con menopausia natural en los ultimos 6-36 meses. En suero analizamos fosfatasa alcalina osea (FAO), osteocalcina intacta (OC) y C-telopeptido (sCTx), y en orina, calcio, deoxipiridinolina (DPD) y N-telopeptido (NTx). Realizamos una densitometria osea (L2-L4) basal y otra de control a los 2 anos. El analisis estadistico se ha hecho mediante la t de Student, ANOVA, prueba de x2 y curvas ROC. Resultados: Los MRO correlacionaron con la DMO y permitieron diferenciar entre osteoporosis, osteopenia y masa osea normal, principalmente OC y sCTx (p < 0,001). Segun las curvas ROC, la OC tuvo una sensibilidad del 77,8% y una especificidad del 80,6% para el diagnostico de osteoporosis, mientras que la de sCTx, fue del 83,3 y el 74,5%, respectivamente. En cuanto a la relacion con la perdida osea, solamente hubo diferencia entre el cuartil inferior y el superior de sCTx (p = 0,042). No encontramos asociacion entre recambio oseo alto y perdidas rapidas de masa osea. Conclusiones: Los MRO son de utilidad para la identificacion de mujeres posmenopausicas recientes con osteoporosis y osteopenia, principalmente OC y sCTx, pero respecto a la perdida osea tan solo sCTx tiene un valor predictivo debil.

We conducted the current study to characterize the clinical presentation of primary Sjögren syndrome (SS) in a large cohort of Spanish patients and to determine whether epidemiologic, clinical, and analytical features modulate disease expression. Patients were from the GEMESS Study group, which was formed in 2005 and included 12 Spanish reference centers. By March 2007, the database included 1010 consecutive patients, recruited since 1994, both incident and prevalent cases. The cohort included 937 women and 73 men (ratio, 13:1), with a mean age of 53 years at diagnosis and 59 years at inclusion in the registry. Multivariate analysis showed that male patients had a lower frequency of thyroiditis, Raynaud phenomenon, and antinuclear antibodies. Young-onset patients had a low degree of sicca involvement (xerostomia and parotid enlargement) and a high frequency of immunologic markers (anti-Ro/SS-A and low C4 levels). Patients with disease duration of more than 10 years had a higher prevalence of xerophthalmia, parotid enlargement, lung involvement, and peripheral neuropathy in comparison with incident cases. The subset of patients with anti-Ro/La antibodies had the highest prevalence of most systemic, hematologic, and immunologic alterations (higher frequency of Raynaud phenomenon, altered parotid scintigraphy, positive salivary gland biopsy, peripheral neuropathy, thrombocytopenia, and rheumatoid factor). Hypocomplementemia was associated with a higher frequency of vasculitis and lymphoma, and cryoglobulins with a higher frequency of parotid enlargement, vasculitis, and leukopenia.Epidemiologic, clinical, and analytical features have a significant impact on the clinical presentation of primary SS, influencing the results of the main diagnostic tests, the prevalence and diversity of extraglandular involvement, and the frequency of the main immunologic markers. Primary SS should be considered as a systemic autoimmune disease that can express in many guises beyond sicca involvement.

Background Glucocorticoid (GC) therapy is associated with an increased risk of fractures. The main objective of this study was to determine the prevalence of undiagnosed vertebral fractures in women chronically using GC therapy for autoimmune disorders. We also determined the prevalence of non-vertebral fractures, and investigated whether factors such as quality-of-life and future fracture risk are associated with vertebral/non-vertebral fractures. Methods This was a multicenter cross-sectional study conducted in Spain. All women had rheumatoid arthritis (RA) and/or systemic lupus erythematosus (SLE). Radiological morphometric vertebral fractures were evaluated centrally (Genant semiquantitative method), whereas non-vertebral fractures were not assessed by radiography. Before radiography, patients were asked whether they had vertebral/non-vertebral fractures, hereafter referred to as ‘self-reported’ fractures. Assessment tools included the Disease Activity Score (DAS28), the SF-36 questionnaire, and FRAX®. Results Complete data were obtained for 576 outpatients with RA and/or SLE (83.3 % had RA); mean [SD] age 59.6 [15] years. Of all patients, 6.4 % had self-reported vertebral fractures, whereas 18.9 % had morphometric vertebral fractures (RA: 7.1 % self-reported vs. 20.0 % morphometric; SLE: 3.2 % self-reported vs. 13.7 % morphometric). Non-vertebral fractures were self-reported by 9.8 % of RA and 5.3 % of SLE patients. Low physical functioning was associated with morphometric vertebral fractures (mean [SD] SF-36 score 18.8 [6.0] when present vs. 20.1 [5.9] when absent; p = 0.028) and self-reported non-vertebral fractures (16.7 [5.2] when present vs. 20.1 [5.9] when absent; p

The objective of this article is to evaluate different T-score cut-off points in the calcaneus in order to establish the prevalence of osteoporosis in the general population and to evaluate the clinical value of bone mineral density at the calcaneus as a tool to identify patients with spine or hip osteoporosis. A total of 1455 people (727 women and 728 men) from the Hortega cohort were studied. The densitometric studies were carried out in the calcaneal region using a Peripheral Instantaneous X-ray Imaging (PIXI) Lunar bone densitometer. We established three cut-off points (−1.6, −2.0, −2.5). One-hundred twenty-five patients (67 men with a mean age of 47 ±13 yr and 58 women with a mean age of 66 ±8 yr) from internal medicine outpatient clinics who were undergoing densitometry of the calcaneus, spine, and hip were subsequently studied. The prevalence of osteoporosis in women with a calcaneus T-score −1.6 was 12.4%, which is comparable to the 12.7% obtained with an axial densitometer in a Spanish population. The prevalence in men was 7.8%, with a calcaneus T-score of −1.0 enables the diagnosis of the disease to be excluded, whereas a calcaneus T-score of

Objective.Ankylosing spondylitis (AS) is generally observed in young patients but can occur later in life or in persons ≥ 50 years of age. Our objective was to characterize the clinical features of late-onset AS in a large multicenter national cohort.Methods.We studied late-onset AS in the National Registry of Spondyloarthritis of the Spanish Society of Rheumatology (REGISPONSER database) cohort (n = 1257), of whom 3.5% had onset at age ≥ 50 years versus a control group with onset at < 50 years.Results.There were no differences between late-onset and early-onset AS according to sex and family history of spondyloarthropathies. Patients in the late-onset group more often showed involvement of the cervical spine (22.7% vs 9.7%; p = 0.03) and arthritis of the upper (13.6% vs 3.0%; p = 0.002) and lower limbs (27.3% vs 15.2%; p = 0.03) as first manifestations than did patients in the early-onset group. A higher percentage of mixed forms (axial and peripheral joint disease) during the course of the disease was also recorded in the late-onset group (50% vs 24%; p = 0.0001).Conclusion.Our study suggests that age at onset of AS affects the patients’ presenting clinical form. Arthritis of the upper limbs requires a differential diagnosis with other conditions frequent in patients over 50 years of age, such as rheumatoid arthritis or crystal-induced arthropathy.

Objective. There are limited data on the long-term prognosis of microscopic polyangiitis (MPA). A systematic review was performed to estimate the survival, renal survival and relapse rates in patients with MPA. Methods. Articles included in MEDLINE and EMBASE databases were reviewed. Randomized or nonrandomized trials, cohort, casecontrol and cases-series studies of patients with MPA diagnosed according to Chapel Hill Consensus Conference definitions, a high rate of biopsy-confirmed diagnosis, follow-up >1 year and follow-up losses

Ankylosing spondylitis (AS) is the prototype of diseases that belong to the category of spondyloarthropathies. AS usually affects the sacroiliac joints and invariably involves the axial skeleton. Peripheral joint involvement, enthesitis, and extraskeletal manifestations are also important clinical and radiographic features of the disease1,2. A 55-year-old man was diagnosed with …

Long-term prognoses of Wegener granulomatosis (WG) and Churg-Strauss syndrome (CSS) are known; however, few data exist on long-term prognoses for microscopic polyangiitis (MPA). Our aim was to analyse the prognoses of MPA.Cohort study with retrospective selection of patients. Twenty-two patients admitted to our Hospital (1990-2006) with biopsy-proven MPA were studied. The start date for entry into the study was the date of diagnosis. Statistical analysis was performed to look for prognostic factors for survival.MPA patients were followed-up for a median of 78 (5-131) months. MPA patients were treated with cyclophosphamide (Cy) plus corticosteroid (Cs) (59%) or Cs alone (41%). Seven MPA patients died. Cumulative MPA patient survival at 1, 5, and 10 years were 85% (75-95%), 85% (75-95%), and 74% (60-88%) in those treated with Cy plus Cs and 50% (32-68%), 36% (14-58%), and 0% (0-30%) in those treated with Cs alone, respectively (P=0.04). Disease extent index5 (P=0.02) and age65 years (P=0.02) were associated with improved survival rates in MPA patients treated with Cy. Five MPA (23%) patients relapsed after a median of 54 months (35-93). No variables were related to relapses. Despite treatment, 11MPA (50%) patients developed end-stage renal disease after a median of 9 months (0-53).Most MPA patients had life-threatening renal or lung involvement at diagnosis. Patients not treated with immunosuppressants had a poorer prognosis. The long-term prognosis of MPA patients who survived 6 months post diagnosis was good, although renal survival rates are low.

Adequate vitamin D levels are necessary for good vascular health. 1,25-dihydroxycholecalciferol activates CYP3A4, an enzyme of the cytochrome P450 system, which metabolizes atorvastatin to its main metabolites. The objective of this study was to evaluate the response of cholesterol and triglycerides to atorvastatin according to vitamin D levels. Sixty-three patients with acute myocardial infarction treated with low and high doses of atorvastatin were included. Levels of total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol were measured at baseline and at 12 months of follow-up. Baseline levels of 25-hydroxyvitamin D (25-OHD) were classified as deficient ( < 30 nmol/L), insufficient (30–50 nmol/L), and normal ( > 50 nmol/L). In patients with 25-OHD < 3 0 nmol/L, there were no significant changes in levels of total cholesterol ( 1 7 3 ± 4 7 mg/dL versus 1 6 4 ± 5 1 mg/dL), triglycerides ( 1 5 1 ± 4 9 mg/dL versus 1 7 7 ± 9 4 mg/dL), and LDL cholesterol ( 1 1 1 ± 4 8 mg/dL versus 92 4 5 ± mg/dL); whereas patients with insufficient (30–50 nmol/L) and normal vitamin D ( > 50 nmol/L) had a good response to atorvastatin. We suggest that vitamin D concentrations > 30 nmol/L may be required for atorvastatin to reduce lipid levels in patients with acute myocardial infarction.

The gold-standard method for osteoporosis diagnosis is by dual-energy X-ray absorptiometry (DXA) of the lumbar spine and/or hip. DXA is expensive and alternative approaches are being analyzed. The objective of this study was to evaluate whether the Osteoporosis Self-Assessment Tool (OST) combined with calcaneal DXA improves the sensitivity and specificity of the DXA. One hundred and sixty-one (67 males and 94 females) outpatients referred due to suspected osteoporosis or lumbar pain were included. Hip, spinal, or calcaneal DXA was performed in all patients and the OST index was administered. The cutoff point for patients of high- or low-risk osteoporosis was 2 for women and 3 for men. The mean OST index value was 3.62 � 4.3. Twenty-seven percent of the patients were osteoporotic. Sixty-two percent presented a low risk and 38% a high risk. In men, the OST had a sensitivity of 39% and a specificity of 86%, whereas in women the sensitivity was 94% with a specificity of 59%. The combination of the calcaneal DXA with the OST index did not modify the validity of DXA in men. In women, the sensitivity of the different cutoff points was improved at the expense of a decrease in the specificity without modifying the area under the curve. The combination of the calcaneal DXA with the OST index did not improve the value of each of the separate techniques. The OST index is useful in women to facilitate the densitometry indication for hip and/or spine.

Background and aims: An association between the polymorphism for transcription factor Sp1 in the gene COL1A1 and low bone density (BMD) and osteoporotic fractures has been described but not confirmed for all races and ages. The aim of this preliminary work was to ascertain whether this association is present in women from the Canary Islands. Methods: Polymerase chain reaction RFLP was used to determine COL1A1 polymorphism Sp1 in 199 consecutive outpatient post-menopausal Caucasian women from the Canary Islands, aged 50–70 years. BMD was measured at lumbar spine and hip by DXA and at third lumbar vertebrae by QCT. Prevalent vertebral fractures were recorded on standard lateral X-ray film. Non-vertebral osteoporotic fractures were registered by medical record and self-reported history. Biochemical markers (serum osteocalcin, tartrate-resis-tant acid phosphatase), blood calcium and phosphate were also assessed. Results: Distribution genotypes were 113 (50.8%) GG homozygotes, 73 (36.7%) Ss heterozygotes and 7 (3.5%) TT homozygotes. All patients with osteoporotic fractures carried the GG allele more frequently than TT homozygotic women. The odds ratio was 3.01 (95% CI 1.6–5.7) for prevalent vertebral fractures (n=62) and 2.33 (95% CI 1.2–4.4) for all osteoporotic fractures (n=65) for the T-carrying allele vs TT homozygotic women. There was no difference in BMD measured by DXA or QCT, nor in bone markers, blood calcium or phosphate. Conclusions: This preliminary study confirmed that the presence of at least one copy of the T allele is associated with osteoporotic fractures, but not with low BMD, in women from the Canary Islands.

Introduction Osteoclasts are the most important cells involved in the pathogenesis of Paget disease of bone (PDB). Cytokines stimulate osteoclast differentiation and activation, with some of them over-expressed in pagetic osteoclasts. We have assessed whether genetic variability in genes coding of proteins from the IL1 pathway clustered in chromosome 2 is associated with clinical characteristics and the therapeutic response of patients with PDB. Methods We have studied − 511 C/T and + 3953 T/C polymorphisms of the IL1B gene, a HinfI polymorphism in the 5′UTR of the IL1R1 gene, and a variable number of tandem repeats (VNTR) in the intron 2 of the IL1RN gene, in 165 patients diagnosed as suffering from PDB and in 122 healthy controls. Distribution of genotypes and alleles was studied for association with clinical and laboratory data and response to bisphosphonate (BSP) treatment. Results No differences were observed in the distribution of genotypes or alleles between PDB patients and control subjects. We also failed to detect differences concerning epidemiological, clinical and laboratory data in the series of PDB patients. However, the − 511 CC genotype of the IL1B gene was associated with a higher percentage of resistance to BSP (49% vs. 20%; P = 0.00 for all BSP, 60% vs. 39%, P = 0.17 for etidronate, 50% vs. 37% P = 0.53 for clodronate, 48 vs. 34% P = 0.05 for tiludronate and 50% vs. 4% P = 0.01 for risedronate). Conclusions Our results suggest that the − 511 CC genotype of the IL1B gene could be related to resistance to bisphosphonates in patients with PDB.

To the Editor: The small-vessel vasculitides associated with antineutrophil cytoplasmic antibodies (AASV) are a group of rare conditions characterized by inflammation and necrosis of blood vessel walls. The etiology of these conditions is largely unknown, but genetic and environmental factors have been related with the pathogenesis of AASV. Clues to the role of the environmental factors have been obtained by comparison of the incidence of the various entities of the AASV in different regions of the world1,2. Although evidence suggests that the overall incidence of AASV is similar throughout Europe3,4, reports support the idea of a north-south gradient of the granulomatosis with polyangiitis (Wegener’s) (GPA)/microscopic polyangiitis (MPA) ratio. GPA would be more common in the northern regions of the continent1,2,4,5, and MPA more common in the southern regions1,2,6 … Address correspondence to Dr. L. Corral-Gudino, Department of Internal Medicine, Hospital el Bierzo, c/o Medicos sin Fronteras, 7, CP: 24411, Fuentesneuvas, Ponferrada, Leon, Spain. E-mail: lcorral{at}saludcastillayleon.es