Tocilizumab en pacientes con artritis reumatoide activa y respuesta inadecuada a fármacos antirreumáticos modificadores de la enfermedad o antagonistas del factor de necrosis tumoral: subanálisis de los datos españoles de un estudio abierto cercano a la práctica clínica habitual / Tocilizumab in patients with active rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs or tumor necrosis factor inhibitors: Subanalysis of Spanish results of an open-label study close to clinical practice

Objetivos: Analizar la experiencia española en un estudio internacional para evaluar tocilizumab en pacientes con artritis reumatoide (AR) con respuesta insuficiente al tratamiento con fármacos antirreumáticos modificadores de la enfermedad convencionales (FAME) o anti-TNF en condiciones cercanas a la práctica clínica habitual. Material y métodos: Subanálisis de 170 pacientes con AR que participaron en España en un ensayo clínico, internacional abierto de fase iiib, que presentaban una respuesta inadecuada al tratamiento con FAME o anti-TNF. Los pacientes recibieron 8 mg/kg de tocilizumab cada 4 semanas en combinación con FAME o en monoterapia durante un periodo de 20 semanas. Se evaluaron la seguridad y la eficacia de tocilizumab distinguiendo entre pacientes con fallo a FAME o anti-TNF y, dentro de estos, entre los que habían hecho o no periodo de lavado del anti-TNF. Resultados: Los acontecimientos adversos más frecuentes fueron infecciones (25%) y elevación de colesterol total (38%) y transaminasas (15%). Cinco pacientes abandonaron el estudio por un acontecimiento adverso. El 71/50/30% de los pacientes cumplía criterios de respuesta ACR 20/50/70 a los 6 meses del inicio del tratamiento con tocilizumab. Los pacientes naïve para anti-TNF presentaron una mayor respuesta ACR20: el 76% frente a un 64% en el grupo anti-TNF con lavado previo y el 66% en el grupo anti-TNF sin lavado previo. Conclusiones: Se confirma el perfil de seguridad de tocilizumab en pacientes con AR y fallo a FAME o anti-TNF. Tocilizumab es más eficaz en pacientes que no responden de forma satisfactoria al tratamiento con FAME convencionales que con anti-TNF (AU)

Objectives: To analyze the Spanish experience in an international study which evaluated tocilizumab in patients with rheumatoid arthritis (RA) and an inadequate response to conventional disease-modifying antirheumatic drugs (DMARDs) or tumor necrosis factor inhibitors (TNFis) in a clinical practice setting. Material and methods: Subanalysis of 170 patients with RA from Spain who participated in a phase IIIb, open-label, international clinical trial. Patients presented inadequate response to DMARDs or TNFis. They received 8 mg/kg of tocilizumab every 4 weeks in combination with a DMARD or as monotherapy during 20 weeks. Safety and efficacy of tocilizumab were analyzed. Special emphasis was placed on differences between failure to a DMARD or to a TNFi and the need to switch to tocilizumab with or without a washout period in patients who had previously received TNFi. Results: The most common adverse events were infections (25%), increased total cholesterol (38%) and transaminases (15%). Five patients discontinued the study due to an adverse event. After six months of tocilizumab treatment, 71/50/30% of patients had ACR 20/50/70 responses, respectively. A higher proportion of TNFi-naive patients presented an ACR20 response: 76% compared to 64% in the TNFi group with previous washout and 66% in the TNFi group without previous washout. Conclusions: Safety results were consistent with previous results in patients with RA and an inadequate response to DMARDs or TNFis. Tocilizumab is more effective in patients who did not respond to conventional DMARDs than in patients who did not respond to TNFis (AU)

Tocilizumab in patients with active rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs or tumor necrosis factor inhibitors: subanalysis of Spanish results of an open-label study close to clinical practice.

OBJECTIVES: To analyze the Spanish experience in an international study which evaluated tocilizumab in patients with rheumatoid arthritis (RA) and an inadequate response to conventional disease-modifying antirheumatic drugs (DMARDs) or tumor necrosis factor inhibitors (TNFis) in a clinical practice setting. MATERIAL AND METHODS: Subanalysis of 170 patients with RA from Spain who participated in a phase IIIb, open-label, international clinical trial. Patients presented inadequate response to DMARDs or TNFis. They received 8mg/kg of tocilizumab every 4 weeks in combination with a DMARD or as monotherapy during 20 weeks. Safety and efficacy of tocilizumab were analyzed. Special emphasis was placed on differences between failure to a DMARD or to a TNFi and the need to switch to tocilizumab with or without a washout period in patients who had previously received TNFi. RESULTS: The most common adverse events were infections (25%), increased total cholesterol (38%) and transaminases (15%). Five patients discontinued the study due to an adverse event. After six months of tocilizumab treatment, 71/50/30% of patients had ACR 20/50/70 responses, respectively. A higher proportion of TNFi-naive patients presented an ACR20 response: 76% compared to 64% in the TNFi group with previous washout and 66% in the TNFi group without previous washout. CONCLUSIONS: Safety results were consistent with previous results in patients with RA and an inadequate response to DMARDs or TNFis. Tocilizumab is more effective in patients who did not respond to conventional DMARDs than in patients who did not respond to TNFis.

[Prevalence of symptoms of anxiety and depression in patients with psoriatic arthritis attending rheumatology clinics]. / Prevalencia de síntomas de ansiedad y de depresión en pacientes con artritis psoriásica en consultas de reumatología.

UNLABELLED: FUNDAMENTAL AND OBJECTIVE: Psychological impairment is frequent in patients with rheumatic diseases. The aim of the study was to assess the prevalence of symptoms of anxiety and depression in patients with psoriatic arthritis attending rheumatology clinics. PATIENTS AND METHOD: Multicentre cross-sectional study conducted in rheumatology clinics. Patients with psoriatic arthritis were recruited; variables retrieved were sociodemographic, clinical and patient centered (Hospital Anxiety and Depression scale o HADs, EQ-5D questionnaire, etc.). Prevalence in the study population was calculated as anxiety or depression symptoms by an HADs score ≥11 or those receiving pharmacological treatment. A logistics regression model was used to know which variables were related to symptoms of anxiety or depression. RESULTS: A total of 495 patients were included, 42.8% were women and median (SD) age was 50.4 (12.7) years. Prevalence of symptoms of anxiety were 29.7% and prevalence of symptoms of depression was 17,6%. Patients with anxiety or depression symptoms had all EQ-5D dimensions affected (p<0.01). Higher prevalence of anxiety was related to being a woman, a mixed onset pattern with respect to peripheral joints and those treated with DMARD alone with respect to DMARD+NSAID or biologic alone. A higher depression prevalence was related to being a woman and a mixed onset pattern with respect to peripheral joints. CONCLUSION: The prevalence of anxiety symptoms and the prevalence of depression symptoms are high among patients suffering psoriatic arthritis in the studied population.

High-dose etanercept in ankylosing spondylitis: results of a 12-week randomized, double blind, controlled multicentre study (LOADET study).

OBJECTIVES: Etanercept 50 mg a week is approved in the treatment of AS. Increasing the etanercept dose to 100 mg/week improves efficacy in cutaneous psoriasis, a clinical manifestation related to the spondylarthritis family, while maintaining its safety profile. The purpose of this study was to evaluate the efficacy and safety of etanercept 100 vs 50 mg/week in patients with AS. METHODS: Adult patients with AS were randomized to receive etanercept 50 mg twice a week (biw), or etanercept 50 mg once a week (qw) for 12 weeks. The primary efficacy endpoint was Ankylosing Spondylitis Assessment Study (ASAS20) response at Week 12; secondary endpoints included ASAS40, ASAS50, ASAS70 and ASAS5/6 responses, partial remission and quality of life. Safety was assessed until 15 days after the last visit. RESULTS: A total of 108 patients were randomly selected and treated, 54 in each arm. At 12 weeks, ASAS20 response was achieved by 34 (71%) out of 48 patients of the etanercept 50 mg biw group and by 37 (76%) out of 49 patients of the etanercept 50 mg qw group (not statistically significant differences). Other efficacy variables improved significantly over time, but not between treatment groups. Fifty-six patients experienced at least one adverse event (generally, infections and infestations, gastrointestinal disorders and injection site reactions), most of them mild or moderate. CONCLUSIONS: High-dose (100 mg/week) etanercept in the treatment of AS for 12 weeks is as safe as the standard dose (50 mg/week). However, it does not significantly increase its efficacy. Trial Registration. Clinicaltrials.gov, http://clinicaltrials.gov/, NCT00873730.

Prevalencia de síntomas de ansiedad y de depresión en pacientes con artritis psoriásica en consultas de reumatología / Prevalence of symptoms of anxiety and depression in patients with psoriatic arthritis attending rheumatology clinics

Fundamento y objetivo. Las alteraciones psicológicas son frecuentes entre pacientes con enfermedades reumáticas. El objetivo del estudio fue conocer la prevalencia de los síntomas de ansiedad y depresión en pacientes con artritis psoriásica que acuden a consultas de reumatología. Pacientes y método. Estudio transversal multicéntrico en consultas de reumatología. Se seleccionaron pacientes con artritis psoriásica; se recogieron variables sociodemográficas, clínicas y centradas en el paciente (Escala Hospitalaria de Ansiedad y Depresión o HADs, cuestionario EQ-5D, etc.). Se calculó la prevalencia de síntomas de ansiedad y depresión en esta población según una puntuación ≥11 en HADs o estar recibiendo tratamiento farmacológico. Se utilizó un modelo de regresión logística para conocer las variables relacionadas con la presencia de síntomas de ansiedad o depresión. Resultados. Se incluyeron 495 pacientes, 42,8% mujeres y edad media (DE) de 50,4 (12,7) años. La prevalencia de síntomas de ansiedad fue 29,7% y 17,6% de depresión. Los pacientes con síntomas de ansiedad o depresión presentaron mayor afectación en todas las dimensiones del EQ-5D (p<0,01). La mayor prevalencia en la población de estudio de ansiedad se relacionó con ser mujeres, patrón de debut mixto respecto al periférico y en tratamiento con FAME en monoterapia respecto a FAME+AINES o biológico en monoterapia. La mayor prevalencia de depresión se relacionó con ser mujeres y patrón de debut mixto respecto al periférico. Conclusión. La prevalencia de síntomas de ansiedad y de depresión es elevada en pacientes con artritis psoriásica en la población de este estudio (AU)

Fundamental and Objective. Psychological impairment is frequent in patients with rheumatic diseases. The aim of the study was to assess the prevalence of symptoms of anxiety and depression in patients with psoriatic arthritis attending rheumatology clinics. Patients and method. Multicentre cross-sectional study conducted in rheumatology clinics. Patients with psoriatic arthritis were recruited; variables retrieved were sociodemographic, clinical and patient centered (Hospital Anxiety and Depression scale o HADs, EQ-5D questionnaire, etc.). Prevalence in the study population was calculated as anxiety or depression symptoms by an HADs score ≥11 or those receiving pharmacological treatment. A logistics regression model was used to know which variables were related to symptoms of anxiety or depression. Results. A total of 495 patients were included, 42.8% were women and median (SD) age was 50.4 (12.7) years. Prevalence of symptoms of anxiety were 29.7% and prevalence of symptoms of depression was 17,6%. Patients with anxiety or depression symptoms had all EQ-5D dimensions affected (p<0.01). Higher prevalence of anxiety was related to being a woman, a mixed onset pattern with respect to peripheral joints and those treated with DMARD alone with respect to DMARD+NSAID or biologic alone. A higher depression prevalence was related to being a woman and a mixed onset pattern with respect to peripheral joints. Conclusion. The prevalence of anxiety symptoms and the prevalence of depression symptoms are high among patients suffering psoriatic arthritis in the studied population (AU)

Psychomotor and intellectual development (Neurocognitive Function) of children born small for gestational age (SGA). Transversal and longitudinal study.

Although much is now known about the effects of intrauterine growth retardation (IUGR) on children born SGA with regard to anthropometric and biochemical parameters and their treatment, there are still many gaps associated with its impact on neurocognitive functions. In our experience published several years ago, IUGR has a negative effect on neurocognitive development, regardless of whether these children showed evidence of catch-up growth or not or of the socio-economic conditions that might contribute to the situation. We have now accumulated a large number of cases, many of whom have been followed longitudinally, some for up to 7 years, many having been treated with GH from the time when this therapy was first approved by the EMA. Apart from the cases mentioned, other confounding factors such as gestational age, Apgar score, neonatal comorbidity and the possible effects of GH treatment have also been included. In addition and using our own reference standards, we now present our experience, which confirms what we had already noted in the past, that IUGR is in itself a condition that often causes psychomotorintellectual impairment, may be extremely severe and tends to worsen. This negative impact of IUGR on neurocognitive development does not depend on how the child grows,spontaneous growth is better and when growth is not altered by GH therapy. Later studies will be able to confirm whether early treatment with GH throughout the 2nd year of life, or an early specific stimulation programme, or the sum of both, can improve the neurocognitive development of these children. IUGR prevention, acting on causal factors that are partly avoidable such as smoking, working conditions and stress during pregnancy (see the corresponding article in this supplement) proves once again to be the best way to stop this negative impact on the IQ of many children born SGA.

Hematocrit influences immunoassay performance for the measurement of tacrolimus in whole blood.

The comparison between the MEIA II and the EMIT assays for tacrolimus measurement and the interference by the hematocrit were evaluated in 93 samples from routine therapeutic monitoring at tacrolimus concentrations less than 9 microg/L (group A). Additionally, the incidence of false-positive results were determined in samples (n=46) from patients who were not receiving the drug (group B). In group A, no statistical differences were observed between the mean+/-SD values obtained by MEIA II (5.14+/-2.28 microg/L) and EMIT (4.61+/-1.79 microg/L). The correlation coefficient and the regression equation (95% CI) between both assays, were 0.761 and EMIT=1.088 (0.90, 1.35) MEIA II -0.38 (-1.65, -0.46), respectively. When the samples were stratified according to the hematocrit, the median differences between the methods (MEIA II minus EMIT) were as follows: hematocrit35%, 0.25 microg/L (P=0.02). In group B, false-positive results (above the detection limit) were observed in 63.04% of samples analyzed by MEIA II and in 2.17% of samples analyzed by EMIT. The median differences in apparent tacrolimus results were significantly higher in the samples with the lowest hematocrit: 2.2 microg/L, 1.4 microg/L, and 0.0 microg/L in samples with hematocrit35%, respectively. In conclusion, the differences in the tacrolimus results obtained by MEIA and EMIT assays were higher in samples from patients with hematocrit less than 25%, and the MEIA assay demonstrated a high incidence of false-positive results.

Evaluation of a limited sampling strategy to estimate area under the curve of tacrolimus in adult renal transplant patients.

Limited sampling strategies have been developed to predict full AUCs. The goal of this study was to develop a limited sampling strategy to estimate the AUC of tacrolimus in adult renal transplant patients and to evaluate its predictive performance in an independent patient population. A total of 27 tacrolimus pharmacokinetic profiles were studied. Blood samples were collected before the dose (0) and at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. The study was divided into 2 phases. In phase 1, the goal was to obtain a sampling strategy from 14 pharmacokinetic profiles. In phase 2, the bias and precision of the model were evaluated in another 13 pharmacokinetic profiles. The best correlation was achieved at 4 hours after dose (r(2) = 0.790). Stepwise multiple regression analysis determined that the abbreviated AUC at 0, 1, and 4 hours could accurately predict total AUC (r(2) = 0.965). The following formula was developed: AUC = 8.90 + 4.0C0h+ 1.77C1h + 5.47C4h. No significant differences were found between calculated and estimated AUC (165.6 +/- 41.1 and 166.7 +/- 43.2 ng.h/mL, respectively). The mean prediction error (MPE), the relative prediction error (PE), and the mean squared error (MSE) were 0.48 ng.h/mL, 0.16%, and 40.0 ng.h/mL, respectively. The limited sampling with use of the 3 levels at 0, 1, and 4 hours postdose provides accurate, reliable determination of tacrolimus AUC in renal transplant patients.