Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis.

Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.

Aminooxy analog of histamine is an efficient inhibitor of mammalian L-histidine decarboxylase: combined in silico and experimental evidence.

Histamine plays highlighted roles in the development of many common, emergent and rare diseases. In mammals, histamine is formed by decarboxylation of L-histidine, which is catalyzed by pyridoxal-5'-phosphate (PLP) dependent histidine decarboxylase (HDC, EC 4.1.1.22). The limited availability and stability of the protein have delayed the characterization of its structure-function relationships. Our previous knowledge on mammalian HDC, derived from both in silico and experimental approaches, indicates that an effective competitive inhibitor should be capable to form an "external aldimine-like structure" and have an imidazole group, or its proper mimetic, which provides additional affinity of PLP-inhibitor adduct to the HDC active center. This is confirmed using HEK-293 cells transfected to express human HDC and the aminooxy analog of histidine, 4(5)-aminooxymethylimidazole (O-IMHA, IC50 ≈ 2 × 10(-7) M) capable to form a PLP-inhibitor complex (oxime) in the enzyme active center. Taking advantage of the availability of the human HDC X-ray structure, we have also determined the potential interactions that could stabilize this oxime in the active site of mammalian HDC.

Correction: Emerging pollutants in the Esmeraldas watershed in Ecuador: discharge and attenuation of emerging organic pollutants along the San Pedro-Guayllabamba-Esmeraldas rivers.

Correction for 'Emerging pollutants in the Esmeraldas watershed in Ecuador: discharge and attenuation of emerging organic pollutants along the San Pedro-Guayllabamba-Esmeraldas rivers' by A. Voloshenko-Rossin et al., Environ. Sci.: Processes Impacts, 2015, 17, 41-53, https://doi.org/10.1039/C4EM00394B.

A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project.

OBJECTIVE: AMELIA (OsteoArthritis Modifying Effects of Long-term Intra-articular Adant) was designed to compare against placebo the efficacy and safety of repeated injections of hyaluronic acid (HA) and its effect on disease progression over 40 months. METHODS: A multicentre, randomised, patient and evaluator-blinded, controlled study in 306 patients fulfilling American College of Rheumatology criteria for knee osteoarthritis, radiological grades II-III (Kellgren-Lawrence) and joint space width ≥ 2 mm. Patients received four cycles of five intra-articular HA or placebo injections with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles. Osteoarthritis Research Society International (OARSI) 2004 responder criteria were used to assess efficacy. The consumption of rescue medication was a secondary outcome. Adverse events were recorded for safety purposes. RESULTS: At the 40-month visit significantly more patients responded to HA compared with placebo (OARSI 2004, p=0.004). The number of responders to HA increased through the study, whereas those to placebo did not change. Significant differences were also found in favour of HA for each individual component of the OARSI 2004. No safety problems were recorded. CONCLUSIONS: The results of AMELIA offer pioneer evidence that repeated cycles of intra-articular injections of HA not only improve knee osteoarthritis symptoms during the in-between cycle period but also exert a marked carry-over effect for at least 1 year after the last cycle. In this respect, it is not possible to establish if this carry-over effect reflects true osteoarthritis remission or just a modification of the disease's natural course. ClinicalTrials.gov number, NCT00669032.

Synthesis and biological properties of C12,13-cyclopropyl-epothilone A and related epothilones.

BACKGROUND: The epothilones are natural substances that are potently cytotoxic, having an almost identical mode of action to Taxoltrade mark as tubulin-polymerization and microtubule-stabilizing agents. The development of detailed structure-activity relationships for these compounds and the further elucidation of their mechanism of action is of high priority. RESULTS: The chemical synthesis of the C12,13-cyclopropyl analog of epothilone A and its C12,13-trans-diastereoisomer has been accomplished. These compounds and several other epothilone analogs have been screened for their ability to induce tubulin polymerization and death of a number of tumor cells. Several interesting structure-activity trends within this family of compounds were identified. CONCLUSIONS: The results of the biological tests conducted in this study have demonstrated that, although a number of positions on the epothilone skeleton are amenable to modification without significant loss of biological activity, the replacement of the epoxide moiety of epothilone A with a cyclopropyl group leads to total loss of activity.

Adalimumab for treating rheumatoid arthritis.

BACKGROUND: Adalimumab is a fully human anti-TNFalpha monoclonal antibody. Published studies indicate that its use in patients with RA can be effective and safe. OBJECTIVES: The aim of this review was to assess the efficacy and safety of adalimumab in the treatment of RA. SEARCH STRATEGY: Electronic databases were searched up to August, 2004: MEDLINE, CINAHL, EBM Reviews (CDSR, ACP Journal Club, DARE and CENTRAL) and Health STAR. Conference proceedings were hand searched and pharmaceutical companies were contacted to obtain additional unpublished data from published trials. Adalimumab was searched as a text word as it is not currently indexed. The search was not limited by language, year of publication or type of publication. SELECTION CRITERIA: All randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing adalimumab alone or in combination with DMARDs to placebo or other DMARDs. DATA COLLECTION AND ANALYSIS: Two reviewers independently collected the data in a standardized form and assessed the methodological quality of the trial using validated criteria. Outcome measures included ACR and EULAR responses, DAS 28 and components of ACR response and radiographic data. Safety data were also included. Continuous data were reported as weighted mean difference (WMD) with 95% confidence interval (95%CI), absolute benefit (AB) and relative difference (RD). Dichotomous outcomes were reported as relative risk (RR) with 95% CI, absolute risk difference (ARD) or risk difference (RDiff) with 95%CI and number needed to treat (NNT) or to harm (NNH). When significant heterogeneity was not found, data were pooled. MAIN RESULTS: Six studies with 2381 patients were included in this review. Two comparisons were done: A. adalimumab subcutaneously (sc) + methotrexate (or DMARDs) versus placebo sc + methotrexate (or DMARDs). B. adalimumab sc in monotherapy versus placebo sc. In the comparison A, with adalimumab 40 mg every other week (e.o.w.), the RR to achieve an ACR 20 response at 24 weeks ranged in the included studies from 1.52 to 4.63, and the NNT ranged from 1.9 to 5.4. The RR (95%CI) to achieve an ACR 50 response was 4.63 (3.04-7.05), and the NNT was 3.0 (95%CI 2.0-6.0). The RR (95%CI) to achieve an ACR 70 response was 5.14 (3.14-8.41) and the number needed to treat was 7.0 (95%CI 5.0-13.0). At 52 weeks, the RRs (95%CI) to achieve an ACR 20, 50, and 70 response were 2.46 (1.87-3.22), 4.37 (2.77-6.91), and 5.15 (2.60-10.22), with NNTs of 2.9, 3.1, and 5.3, respectively. At 52 weeks, adalimumab 40 mg e.o.w. and 20 mg every week (e.w.) significantly slowed the radiological progression including Sharp modified index, erosion score, and joint space score (only with 40 mg e.o.w.). In the comparison B, with adalimumab 40 mg e.o w. , the RRs to achieve an ACR 20, 50, and 70 response at 24/26 weeks were 1.91 (1.17-3.10), 2.84 (1.58-5.12), and 7.33 (2.25-33.90) with NNTs of 5.0 (95%CI 3.0-9.0), 7.0 (4.0-20.0), and 9.0 (3.0-38.0), respectively. In most of the analysed studies and comparisons, there were not significant differences in safety outcomes between adalimumab and control groups. The development of positive antinuclear antibodies was significantly more frequent in adalimumab patients than in placebo patients. Serious infections were significantly more frequent in adalimumab patients in only one study (Keystone 2004) with a RR (95%CI) of 7.64(1.02-57.18) and a NNH of 30.2. AUTHORS' CONCLUSIONS: On the basis of the studies reviewed here, adalimumab in combination with methotrexate is efficacious and safe in the treatment of the rheumatoid arthritis. Adalimumab 40 mg sc e.o.w. and 20 mg e.w. slows the radiographic progression at 52 weeks. Adalimumab in combination with DMARDs other than methotrexate is also efficacious and safe, even though data from one only study are available and the number of patients in each group is low. Adalimumab in monotherapy is efficacious and safe in the treatment of the rheumatoid arthritis but the effect size is lower than with combined therapy.

Emerging pollutants in the Esmeraldas watershed in Ecuador: discharge and attenuation of emerging organic pollutants along the San Pedro-Guayllabamba-Esmeraldas rivers.

Water quality characteristics and emerging organic pollutants were sampled along the San Pedro-Guayllabamba-Esmeraldas River and its main water pollution streams in the summer of 2013. The annual flow rate of the stream is 22 000 Mm(3) y(-1) and it collects the wastewater of Quito-Ecuador in the Andes and supplies drinking water to the city of Esmeraldas near the Pacific Ocean. The most persistent emerging pollutants were carbamazepine and acesulfame, which were found to be stable along the San Pedro-Guayllabamba-Esmeraldas River, whereas the concentration of most other organic emerging pollutants, such as caffeine, sulfamethoxazole, venlafaxine, O-desmethylvenlafaxine, and steroidal estrogens, was degraded to a large extent along the 300 km flow. The mass rate of the sum of cocaine and benzoylecgonine, its metabolite, was increased along the stream, which may be attributed to coca plantations and wild coca trees. This raises the possibility of using river monitoring as an indirect way to learn about changes in coca plantations in their watersheds. Several organic emerging pollutants, such as venlafaxine, carbamazepine, sulphamethoxazole, and benzoylecgonine, survived even the filtration treatment at the Esmeraldas drinking water system, though all except for benzoylecgonine are found below 20 ng L(-1), and are therefore not likely to cause adverse health effects. The research provides a way to compare drug consumption in a major Latin American city (Quito) and shows that the consumption of most sampled drugs (carbamazepine, venlafaxine, O-desmethylvenlafaxine, sulphamethoxazole, ethinylestradiol) was below their average consumption level in Europe, Israel, and North America.

Bone mass after long-term euthyroidism in former hyperthyroid women treated with (131)I influence of menopausal status.

The objective of this study was to assess bone mineral density (BMD) and bone markers in former hyperthyroid females after long-term euthyroidism (>4 yr) following (131)I therapy, as well as the potential influence of the timing of menopause. Twenty-six females ages 57 +/- 8 yr previously diagnosed with hyperthyroidism and treated with (131)I who were euthyroid for a minimum of the last 4 yr (10 +/- 5 yr) were studied. Eighteen patients (69%) were on levothyroxine (LT(4)) replacement therapy for 9 +/- 4 yr. BMD (g/cm(2) and Z-score) was measured by dual X-ray absorptiometry in the lumbar spine, femoral neck, and Ward's triangle. BMD (Z-score) was lower than the normal reference values for the Spanish population in all sites (lumbar spine: -0.65 +/- 1.13; femoral neck: -0.47 +/- 0.95; Ward's triangle: -0.37 +/- 0.88). No differences were found between BMD values according to the etiology of the hyperthyroidism or current LT(4) therapy. Current postmenopausal patients (n = 21) showed lower BMD than current premenopausal patients in the lumbar spine and femoral neck (p < 0.05). Those women who were postmenopausal at the time of the (131)I therapy (n = 15) also had lower lumbar spine BMD than premenopausal patients (p = 0.01), while no significant difference in BMD was seen according to the menopausal status when hyperthyroidism was diagnosed. Former hyperthyroid patients after long-term euthyroidism following (131)I therapy showed reduced BMD at the lumbar spine and proximal femur. Menopausal women showed a greater reduction in bone density. The menopausal status at the time of diagnosis did not seem to have long-term effects in bone density; nevertheless, an early therapeutic intervention in premenopause is suggested to reduce bone loss.

[IgM, IgG and IgA rheumatoid factors in rheumatoid arthritis]. / Factores reumatoides IgM, IgG e IgA en la artritis reumatoide.

The IgM, IgG and IgA rheumatoid factors (RF) were studied by ELISA in the serum of 122 patients with rheumatoid arthritis (RA) associating the Waaler-Rose test results, with the clinical and radiological aspects of the disease. 75 patients (61%) had RF IgM positive according to the Waaler-Rose test while the ELISA showed positive in 104 (85%). The RF (IgG was positive in 64 cases (52%) and RF IgA in 82 (67%). The levels of RF IgA were correlated to RF IgM levels, determined by the Waaler-Rose test (p < 0.01) and ELISA (p < 0.001), while RF IgG levels were not correlated to RF IgM or IgA. There was a significant correlation between RF IgA titles and Lansbury's index (p < 0.01), and between RF IgG and sedimentation rate (p < 0.01). In patients with extraarticular disease high levels of RF have been observed, especially RF IgM and IgA. We concluded that the ELISA technique is the preferred method to measure the RF.

Dose escalation of the anti-TNF-alpha agents in patients with rheumatoid arthritis. A systematic review.

OBJECTIVE: To estimate the proportion of rheumatoid arthritis (RA) patients on anti-tumour necrosis factor (anti-TNF) who require dose escalation. METHODS: Systematic review of the scientific literature. Infliximab, etanercept and adalimumab studies in RA were considered. Primary outcome was the proportion of patients requiring dose escalation. American College Rheumatology (ACR) and Disease activity score (DAS) responses post-escalation were assessed when available. RESULTS: From 1801 references, 16 studies with 8510 patients were included. Of all the infliximab patients, 53.7% underwent dose escalation. Fourty-four per cent of the infliximab patients experienced dose increase and 8.3%, frequency increase. The ACR20 response to dose escalation ranged from 27 to 36% and DAS28 improved from 5.2 to 4.5 in one study and from 4.1 to 3.7 in another. Of the etanercept patients, 17.5% experienced a dose increase but changes on the mean dose were not statistically significant. CONCLUSIONS: Dose escalation is common in patients treated with infliximab, and less frequent with etanercept. In a proportion of patients, the dose escalation seems effective. The design and evidence level of the available studies limit the strength of the conclusions.

[Cross-cultural adaptation and validation of a Spanish version of a specific instrument to measure health-related quality of life in patients with ankylosing spondylitis]. / Adaptación transcultural y validación de una versión en español de un instrumento específico para medir calidad de vida relacionada con la salud en pacientes con espondilitis anquilosante: el ASQoL.

OBJECTIVE: To make a cross-cultural adaptation and validation of a version in Spanish of the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) for assessing the health-related quality of life (HRQL) of patients with Ankylosing Spondylitis (AS). PATIENTS AND METHODS: A cross-sectional study with test-retest. AS patients (modified New York criteria) were included. Cross-cultural adaptation was done. Construct validity was assessed comparing the ASQoL scores with the SF-36 and EuroQol scores and diseaserelated variables. Internal consistency and reliability (test-retest) were assessed. Feasibility was assessed by the time spent to complete the questionnaire and the number of items without answer. Spearman correlation coefficient, Mann-Whitney U test, and Kruskal-Wallis test were used in the statistical analysis. Cronbach́alpha coefficient and statistic kappa were used for assessing internal consistency and reliability. RESULTS: Fifty-four patients, 37 males (68.5%), with age (mean±SD) 40.5±10.5 years, were included. The ASQoL global score was 6.8±4.7 (median, 7; range, 0-17). The ASQoL scores had high correlations with physical (rho = 0.79) and mental (0.69) SF-36 components, the SF-36 domains pain (0.82), vitality (0.75), and role-physical (0.68), and the most of the disease-related variables. The ASQoL scores were significantly different between patients with different response levels in the health profile of the EuroQol. The Cronbach́alpha coefficient was 0.86. The reliability had kappa = 1 in 12 items and rho = 0.98. The time spent to complete the ASQoL was from 2 to 5 minutes and there only was a missing answer in one patient. CONCLUSION: The Spanish ASQoL is valid, reliable, and feasible instrument for assessing the HRQL of the AS patients.

[Resource utilization in a cohort of rheumatoid arthritis patients attended in rheumatology units in Spain]. / Utilización de recursos en una cohorte de pacientes con artritis reumatoide atendidos en área especializada de reumatología en España.

OBJECTIVE: To determine resource use over a 1-year period in patients with rheumatoid arthritis (RA) attended in rheumatology units in hospitals within the Spanish public health system. PATIENTS AND METHODS: An observational, longitudinal, prospective, multicenter, 1-year study was performed in randomly selected rheumatology units in hospitals of the Spanish public health system. Patients with RA were randomly selected in each hospital. Four visits (at baseline and every 4 months) were conducted by a rheumatologist not routinely involved in the care of the patient. Demographic and disease-related variables were collected. Patient diaries and systematic interviews were used to gather data on resource use. RESULTS: A total of 301 patients were included and 190 (83% females) completed the study. The mean age was 59 ± 13 years and the mean disease duration was 10 ± 10 years. The resources most heavily used were medical. All of the patients made medical visits with a median of four visits to rheumatologists (1-13). Ninetynine percent of the patients took at least one drug. The most frequent drugs were paracetamol (41%), deflaza-cort (32%), and methotrexate (24%). Laboratory tests were performed in all patients, and x-rays were performed in 59%. Sixty-one patients (32%) were hospitalized; 75% of these patients were non-surgical. The most frequently used non-medical direct resources were meals and home visits by non-medical staff (39%). Thirtyone patients (16%) had some type of work disability. CONCLUSIONS: AR is associated with substantial utilization of medical and non-medical resources related to the disease and work disability.

[Cost analysis in a cohort of rheumatoid arthritis patients managed in rheumatology units in Spain]. / Análisis de costes en una cohorte de enfermos con artritis reumatoide atendidos en área especializada de reumatología en España.

OBJECTIVE: To assess the annual costs of rheumatoid arthritis (RA) patients attended at rheumatology units in Spanish public hospitals. METHODS: A longitudinal, prospective, multicenter, observational, 1-year study was performed in the rheumatology units of randomly selected Spanish public hospitals. Randomly selected RA patients were included. The patients made four visits (at baseline and every 4 months). Resource use and costs were collected from patient diaries and structured questionnaires. RESULTS: A total of 301 patients were included and 190 (83% women) completed the study. The mean (± SD) age was 59±13 years and the mean disease duration was 10±10 years. The median annual cost per patient was 3,845 euros (318-36,783). The estimated total annual cost of the Spanish RA population managed in the rheumatology units of public hospitals was 590,110,000 euros. Of total costs, 74% were direct costs and 26% were indirect costs. Medical costs represented 81% of direct costs. The main components of medical costs were drugs (56%), medical visits (21%), complementary tests (12%), and hospitalizations (11%). Permanent work disability represented 66% of indirect costs. CONCLUSIONS: Direct costs were substantially higher than indirect costs. The main components of medical costs were drugs. There was high variability in resource use with a wide range of annual costs per patient.

Computerized tomographic evidence of cerebral atrophy in heavy drinkers.

Of 50 heavy drinkers referred for nonalcoholic psychiatric problems, 56% had computerized tomographic evidence of cerebral atrophy. This contrasted with a rate of 6% in patients with schizophrenia and affective illnesses who had taken psychotropic drugs for at least ten years. Further, the severity of atrophy was greater in the group of heavy drinkers. The results support a role for computerized tomography in assessment of patients with chronic alcoholic problems.

[Serum osteocalcin and bone turnover in hyperthyroidism]. / Osteocalcina sérica y remodelado óseo en el hipertiroidismo.

In hyperthyroidism an increased bone turnover may appear, essentially due to a higher bone resorption. In order to evaluate this complication we have measured the serum levels of Osteocalcin (BGP) in 41 patients, mean age 43 +/- 18 (+/- SD) years. BGP is a protein synthesized by osteoblasts which may be employed as an specific and non-aggressive marker of bone turnover. Serum BGP was significantly increased in these patients with respect to normals (6.2 +/- 4.2 vs 3.7 +/- 1.3 ng/ml). The total group was divided according to BGP values higher and lower than 3.7 ng/ml, emerging two groups with BGP 7.9 +/- 3.8 (n = 30) y 2.2 +/- 1.2 ng/ml (n = 11), respectively. There were not differences between these two groups regarding to thyroid hormones or other data of mineral metabolism. In the total group, only serum BGP and T3 were correlated. Our results suggest the existence of a double effect of hyperthyroidism on bone, as well as a temporal dissociation between thyroid synthesis and bone metabolism.

[Rofecoxib versus non-steroidal anti-inflammatory drugs in arthrosis treatment: cost-effectiveness analysis for Spain]. / Rofecoxib frente a antiinflamatorios no esteroideos en el tratamiento de la artrosis: análisis coste-efectividad para España.

OBJECTIVE: Analyze the efficiency of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) versus rofecoxib prescription for arthrosis treatment in Spain through a theoretical model of cost-effectiveness. METHODOLOGY: A theoretical model of decision that evaluates the efficiency of the use of non-selective NSAIDs and rofecoxib in the treatment of patients > 65 years with arthrosis who were nonrespondent to the administration of acetaminophen 4 g/day. The analysis focuses on the estimate of the impact derived from the gastrointestinal (GI) adverse effects. Two alternative analysis contexts are considered: "customary clinical practice" and "rational use of GI drugs" with possible preventive use of gastroprotective (GP) drugs in both groups. The time horizon is 1 year. Direct expenses are estimated from the Spanish Health System perspective. The effectiveness parameter used is the number of severe GI complications prevented. RESULTS: Under the assumptions of the first context, with a 55% estimated combinated prescription of non-selective GP with NSAID, and 6% with rofecoxib, the percentage of cost compensation of rofecoxib is 72%. Under the assumptions of the second context, the cost of rofecoxib is totally compensated when the percentage of combinated prescription of GP with NSAIDs is 59%. CONCLUSION: The use of rofecoxib can be a cost-effective alternative with regard to the traditional non-selective NSAID in the arthrosis treatment, especially in context of higher preventive use of CI drugs.

Novel chemistry of alpha-tosyloxy ketones: applications to the solution- and solid-phase synthesis of privileged heterocycle and enediyne libraries.

New synthetic technologies for the preparation and elaboration of alpha-tosyloxy ketones in solution- and on solid-phase are described. Both olefins and ketones serve as precursors to these relatively stable chemical entities: olefins via a novel one-pot epoxidation, arylsulfonic acid displacement, and oxidation sequence, and ketones by direct exposure to arylsulfonic acids in the presence of diacetoxy iodobenzene. Reaction of these substrates with O-, S-, or N-centered nucleophiles leads to incorporation of the nucleophile with concomitant expulsion of the sulfonate, while exposure to bis-functional nucleophiles furnishes annulated heterocyclic systems. In addition, the reactions of carbon-centered nucleophiles with alpha-tosylyloxy ketones are also explored. The collated data for all these nucleophiles provide compelling evidence for the proposal that different reaction pathways are followed when alpha-tosyloxy ketones are engaged by "hard" versus "soft" nucleophiles. The accessibility and site-selectivity of the chemistry demonstrated herein offer the promise of an expanded use for this moiety in solid-phase library construction, in particular, and in the field of organic synthesis, in general.