Patrones de tratamiento, sobrevida y efectividad a largo plazo de agentes biológicos en pacientes con Artritis Psoriásica / Patterns of treatment, survival and long-term effectiveness of biological agents in patients with Psoriatic Arthritis

Objetivos: Evaluar los patrones de tratamiento de las DME-b (Drogas Modificadoras de la Enfermedad-biológicas), su sobrevida acumulada y su eficacia a largo plazo en pacientes con Artritis Psoriásica (APs) utilizando el índice LUNDEX. Materiales y métodos: Estudio multicéntrico retrospectivo. Se incluyeron pacientes con diagnóstico de APs que hayan iniciado tratamiento con DME-b. Se recolectaron datos sociodemográficos y clínicos. Se consignaron fechas de inicio de DME-b, tratamiento concomitante, suspensión o cambio de tratamiento, y razones de suspensión. La respuesta terapéutica se definió acorde a MDA (Minimal Disease Activity), a los 6, 12 meses y anualmente a partir del inicio de DME-b. Análisis estadístico: Test de Student y Chi². Curvas de Kaplan Meier y Log Rank. Análisis de regresión de Cox. Resultados: Se incluyeron 72 pacientes con APs, 39 (54,2%) de sexo masculino. La edad mediana fue de 54,5 años (RIC 45-61) y el tiempo mediano de evolución de la enfermedad de 11 años (RIC 6-15). 71,2% (n=42) presentaron comorbilidades. El primer DME-b fue en orden decreciente de frecuencia: Adalimumab (45,8%), Etanercept (36,1%), Certolizumab (5,6%), Infliximab (4,2%), Ustekinumab (4,2%), Abatacept (2,7%) y Golimumab (1,4%). 15 pacientes (25,4%) recibieron DME-b en monoterapia. La sobrevida media fue de 82 meses (DE±7,4). El LUNDEX del primer biológico fue 24,7% a los 6 meses y 44,3% al año. La sobrevida media de Adalimumab fue de 90 meses (DE±10,4) y de Etanercept 79 meses (DE±12). Los pacientes añosos presentaron menor sobrevida de la droga [≥55 años: X59,8 (DE±10,5) vs <55 años: X101,2 (DE±9,7), p=0,006]. Luego de ajustar por diferentes confundidores, la edad ≥55 años se mantuvo significativamente a menor sobrevida [HR=1,064 (IC=1,01-1,11) p=0,005]. El LUNDEX fue menor en obesos vs no obesos (16% vs 66% al año, p=0,89; 10,5 vs 74,9% a los 2 años, p=0,011 y 5,9 vs 81,8% a los 3 años, p=0,005). Conclusiones: La sobrevida promedio del primer DME-b fue de 6,8 años. La única variable asociada a menor sobrevida fue la mayor edad.

Objectives: To evaluate the treatment patterns of DME-b (Disease-Modifying Drugs-biological), their accumulated survival and their long-term efficacy in patients with psoriatic arthritis (PsA) using the LUNDEX index. Materials and methods: Retrospective multicentre study. We included patients diagnosed with PsA who started treatment with DME-b. Sociodemographic and clinical data were collected. BMI-D start dates, concomitant treatment, suspension or change of treatment, and reasons for suspension were recorded. The therapeutic response was defined according to MDA (Minimal Disease Activity), at 6, 12 months and annually from the beginning of DME-b. Statistical analysis: Student test and Chi². Curves of Kaplan Meier and Log Rank. Cox regression analysis. Results: We included 72 patients with PsA, 39 (54.2%) male. The median age was 54.5 years (IQR 45-61) and the median time of evolution of the disease was 11 years (IQR 6-15). 71.2% (n=42) presented comorbidities. The first DME-b was in decreasing order of frequency: Adalimumab (45.8%), Etanercept (36.1%), Certolizumab (5.6%), Infliximab (4.2%), Ustekinumab (4.2%), Abatacept (2.7%) and Golimumab (1.4%). 15 patients (25.4%) received DME-b monotherapy. The mean survival was 82 months (SD±7.4). The LUNDEX of the first biological was 24.7% at 6 months and 44.3% per year. The mean survival of Adalimumab was 90 months (SD±10.4) and Etanercept 79 months (SD±12). Older patients had a lower survival of the drug [≥55 years: X59.8 (SD±10.5) vs <55 years: X101.2 (SD±9.7), p=0.006]. After adjusting for different confounders, age ≥55 years was significantly maintained at lower survival [HR=1.064 (CI=1.01-1.11) p=0.005]. The LUNDEX was lower in obese vs. non-obese (16% vs. 66% per year, p=0.89, 10.5 vs 74.9% at 2 years, p=0.011 and 5.9 vs 81.8% at 3 years, p=0.005). Conclusions: The average survival of the first DME-b was 6.8 years. The only variable associated with lower survival was the older age.

Altered TDP-43-dependent splicing in HSPB8-related distal hereditary motor neuropathy and myofibrillar myopathy.

BACKGROUND AND PURPOSE: Mutations in the small heat-shock protein 22 gene (HSPB8) have been associated with Charcot-Marie-Tooth disease type 2L, distal hereditary motor neuropathy (dHMN) type IIa and, more recently, distal myopathy/myofibrillar myopathy (MFM) with protein aggregates and TDP-43 inclusions. The aim was to report a novel family with HSPB8K141E -related dHMN/MFM and to investigate, in a patient muscle biopsy, whether the presence of protein aggregates was paralleled by altered TDP-43 function. METHODS: We reviewed clinical and genetic data. We assessed TDP-43 expression by qPCR and alternative splicing of four previously validated direct TDP-43 target exons in four genes by reverse transcriptase-polymerase chain reaction. RESULTS: The triplets and their mother presented in the second to third decade of life with progressive weakness affecting distal and proximal lower limb and truncal muscles. Nerve conduction study showed a motor axonal neuropathy. The clinical features, moderately raised creatin kinase levels, selective pattern of muscle involvement on magnetic resonance imaging and pathological changes on muscle biopsy, including the presence of protein aggregates, supported the diagnosis of a contemporary primary muscle involvement. In affected muscle tissue we observed a consistent alteration of TDP-43-dependent splicing in three out of four TDP-43-target transcripts (POLDIP3, FNIP1 and BRD8), as well as a significant decrease of TDP-43 mRNA levels. CONCLUSIONS: Our study confirmed the role of mutated HSPB8 as a cause of a combined neuromuscular disorder encompassing dHMN and MFM with protein aggregates. We identified impaired RNA metabolism, secondary to TDP-43 loss of function, as a possible pathological mechanism of HSPB8K141E toxicity, leading to muscle and nerve degeneration.

Tratamiento de la artritis psoriásica con ustekinumab en diferentes escenarios clínicos. Casos reales y revisión de la literatura / Treatment of psoriatic arthritis with ustekinumab in different clinical scenarios. Real cases anda literature review

El tratamiento de la Artritis Psoriásica (APs) se basa en suprimir los signos y síntomas en todos los componentes de la enfermedad (articular, piel, entesis, compromiso axial). Dentro de las opciones terapéuticas contamos con los antinflamatorios no esteroideos (AI-NEs), corticoides, drogas modificadoras de la enfermedad (DMARs) entre ellas el metotrexato y leflunomida, y los anti-TNF. Estas últimas han demostrado actualmente amplia eficacia a largo plazo y buen perfil de seguridad. Fueron el único mecanismo de acción para el tratamiento de la APs; sin embargo en el último año fue aprobado en varios países, ustekinumab, un inhibidor de la subunidad p40 de la IL12 y 23. Esta revisión presenta una serie de 6 casos clínicos donde hemos utilizado esta opción terapéutica en diferentes escenarios

Estrategia para la derivación oportuna: experiencia en un centro de referencia en reumatología / Strategy for temely referral: experience in a reference center in rheumatology

Introducción: En los últimos años se ha reconocido la importancia del diagnóstico precoz de la artritis reumatoidea y las espondiloartritis. Aún existen barreras que impiden la derivación precoz de estos pacientes. Objetivo: Evaluar si existe un aumento significativo en el número de derivaciones al Servicio de Reumatología luego de implementar una estrategia de concientización a otros especialistas. Material y métodos: Estudio observacional, retrospectivo. Resultados: Durante el primer período, el servicio realizó un total de 1027 consultas, de las cuales 130 fueron derivaciones. Las consultas efectuadas luego de la implementación del plan de derivación fueron 1199 con 202 derivaciones (17% IC 95 14,7-19); la diferencia entre ambos períodos fue estadísticamente significativa (p 0,003). Conclusión: La implementación de estrategias de derivación fue valiosa, puesto que encontramos un incremento en el número de derivaciones realizadas. Consideramos que estas intervenciones deben perdurar en el tiempo para mejorar el diagnóstico precoz.

Introduction: In recent years, the importance of early diagnosisof rheumatoid arthritis and spondyloarthritis has been recognized. However, there are still barriers that obstruct the early referral ofthese patients. Objective: To evaluate whether there is a significant increase in thenumber of referrals to the department of Rheumatology after implementinga strategy of awareness to other specialists. Material and methods: Observational and retrospective study. Results: During the first period, the service conducted a total of1027 consultations, of which 130 were referrals. Consultations made after the implementation of the derivation strategy were 1199 of which 202 were referrals (17% CI 95 14.7-19); the difference between the two periods was statistically significant (p 0.003). Conclusion: The implementation of this strategy was valuable, since we found an increase in the number of referrals made. Weconsider that these interventions should last over time to improveearly diagnosis.

Tocilizumab en artritis psoriásica ante la falla a los bloqueantes del factor de necrosis tumoral alfa: experiencia en dos casos / Tocilizumab in psoriatic artritis in patients falling anti-tumor necrosis factor: experience in two cases

En artritis psoriásica (APs), los bloqueantes del factor de necrosis tumoral alfa (anti-TNF) son la opción más adecuada ante la falla a drogas modificadoras. La eficacia y la seguridad de los anti-TNF están ampliamente fundamentadas en la literatura; sin embargo, en algunos casos, pueden presentarse eventos adversos o no se logra la eficacia deseada. Las alternativas terapéuticas en dichos pacientes son acotadas, la inhibición de la interleuquina 6 (IL-6) podría ser una opción. Presentamos dos casos clínicos de pacientes con APs resistentes a anti-TNF que recibieron tocilizumab, en los cuales podemos observar diferencias importantes en el perfil de eficacia de esta droga

In psoriatic arthritis, the blocking of tumor necrosis factor alpha (anti-TNF) is the most suitable option when modifying antirheumatic drugsfail. The efficacy and safety of anti-TNF are largely supported by theliterature; however, in some cases, adverse events may occur or thedesired efficiency is not achieved. Therapeutic alternatives in thesepatients are bounded; inhibition of interleukin 6 could be an option.We present two cases of patients with resistant anti-TNF receivingtocilizumab, in which we can observe significant differences in theefficacy profile of the drug.

Monoterapia biológica en pacientes con artritis reumatoidea en Argentina / Biological monotherapy in patients with rheumatoid arthritis in Argentina

Introducción: La utilización de agentes biológicos para el tratamiento de la Artritis Reumatoidea (AR) es habitualmente usada en aquellos pacientes con enfermedad activa que no hayan respondido al tratamiento con drogas modificadoras de la Artritis Reumatoidea convencionales (DMARD, por sus siglas en inglés) o que hayan presentado intolerancia a las mismas. Al estado actual de la evidencia, la terapia combinada de agentes biológicos más un DMARD convencional (principalmente metotrexato) constituye el estándar de tratamiento. Sin embargo existen algunos escenarios como la intolerancia, la falta de adherencia y la aparición de eventos adversos a las DMARDs convencionales donde la monoterapia biológica emerge como una opción terapéutica válida. Según los distintos registros a nivel internacional, la frecuencia de utilización de agentes biológicos en monoterapia oscila entre 12 a 39%. Debido a la ausencia de estos datos a nivel local decidimos realizar este estudio para conocer el porcentaje de pacientes que se encuentran en monoterapia biológica y analizar las causas que llevaron a este tipo de tratamiento. Materiales y métodos: Estudio de tipo corte transversal donde se invitó a participar a diferentes centros reumatológicos distribuidos a lo largo de Argentina. Cada centro revisó las historias clínicas de los últimos 30 a 50 pacientes consecutivos vistos con AR, mayores de 18 años, que habían presentado inadecuada respuesta al tratamiento con DMARDs y que estaban bajo tratamiento biológico. Se completaba una ficha por cada paciente incluido, registrando datos demográficos, de la enfermedad y tratamientos previos. Resultados: Se incluyeron 32 centros y se evaluaron 1148 historias clínicas de pacientes con AR durante el mes de octubre y noviembre del 2012. Un 21,4% (246) de los pacientes al momento del estudio se encontraba bajo tratamiento biológico en monoterapia...

Introduction: The use of biological agents for the treatment of rheumatoid arthritis (RA) is commonly used in patients with active disease who have not responded to treatment with conventional rheumatoid arthritis-modifying drugs (DMARDs) or Who have presented intolerance to them. At the present state of evidence, combined therapy of biological agents plus conventional DMARD (mainly methotrexate) is the standard of treatment. However, there are some scenarios such as intolerance, lack of adherence and the appearance of adverse events to conventional DMARDs where biological monotherapy emerges as a valid therapeutic option. According to different international registries, the frequency of use of biological agents in monotherapy ranges from 12 to 39%. Due to the absence of these data at the local level we decided to carry out this study to know the percentage of patients who are in biological monotherapy and to analyze the causes that led to this type of treatment. Materials and methods: A cross-sectional study where different rheumatologic centers throughout Argentina were invited to participate. Each center reviewed the medical records of the last 30 to 50 consecutive patients seen with RA, older than 18 years, who had inadequate response to treatment with DMARDs and who were under biological treatment. One card was completed for each patient included, recording demographic, disease and previous treatment data. Results: Thirty-two centers were included and 1148 clinical records of patients with RA were evaluated during October and November 2012. A total of 244 patients (246) at the time of the study were under monotherapy...

Time course of changes in adenosine 5'-monophosphate airway responsiveness with inhaled heparin in allergic asthma.

BACKGROUND: Recent studies have shown that inhaled heparin exerts a protective effect against various bronchoconstrictor stimuli in asthma, possible through an inhibition of mast cell activation. OBJECTIVE: Because adenosine 5'-monophosphate (AMP) elicits bronchoconstriction by augmenting mast cell mediator release, we have investigated the effect of inhaled heparin (15,000 units USP/ml, 4 ml) on the bronchoconstrictor response to this agonist and to methacholine in a randomized, double-blind, placebo-controlled study of 10 subjects with asthma. We also carried out a separate randomized, double-blind study in seven additional volunteers with asthma to examine in more detail the time-course of change in bronchial reactivity to inhaled AMP after treatment with nebulized heparin. RESULTS: Inhaled heparin significantly increased the provocative concentration of AMP causing a 20% decrease in forced expiratory volume in 1 second (PC20 FEV1-AMP) from the postplacebo treatment value of 22.3 mg/ml (range, 5.7 to 68.9 mg/ml) to 48.1 mg/ml (range, 5.1-196.8 mg/ml) (p < 0.01). When compared with placebo, inhaled heparin failed to alter the airway responsiveness to methacholine; the mean (range) PC20 methacholine values were 1.00 mg/ml (0.44 to 4.76 mg/ml) and 1.08 mg/ml (0.46 to 5.08 mg/ml), respectively. After placebo administration, the PC20 AMP values at 15, 60, and 180 minutes did not differ significantly from each other; their geometric mean (range) values were 26.1 mg/ml (5.9 to 85.8 mg/ml), 26.6 mg/ml (6.3 to 87.8 mg/ml), and 24.9 mg/ml (5.2 to 80.2 mg/ml), respectively. When compared with placebo, the PC20 values for AMP after administration of inhaled heparin were significantly increased up to 57.3 mg/ml (14.7 to 176.0 mg/ml) and to 52.7 mg/ml (13.9 to 90.8 mg/ml) at 15 minutes and 60 minutes, respectively. At 180 minutes, inhaled heparin failed to affect AMP airway responsiveness; the PC20 AMP was not significantly different from that of placebo, with a value of 30.6 mg/ml (4.8 to 93.3 mg/ml). CONCLUSION: Heparin administered by inhalation is effective in attenuating the airway response to AMP but not to methacholine. The time course of change in bronchial reactivity to AMP has a peak effect at 15 minutes and lasts up to 60 minutes. It is possible that the mechanism(s) underlying the protective effects of inhaled heparin in asthma may be related to an inhibitory modulation of mast cell activation.

Neutral endopeptidase inhibition with inhaled phosphoramidon: no effect on bronchial responsiveness to adenosine 5'-monophosphate (AMP) in asthma.

Part of the contractile response of adenosine in the asthmatic airways may be due to the activation of peptidergic pathways with subsequent local release of spasmogenic neuropeptides. At present, little is known about the potential role of lung peptidases in modulating adenosine-induced airway dysfunction in humans in vivo. We have, therefore, investigated the change in bronchial reactivity to adenosine 5'-monophosphate (AMP), after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double-blind, placebo-controlled, randomized study of 12 asthmatic subjects. Subjects attended on six separate occasions, during which concentration response studies with inhaled AMP and methacholine were carried out, initially in the absence of treatment and then after nebulized phosphoramidon sodium salt (10[-5] M) or matched placebo 5 min prior to a bronchoprovocation test with AMP or methacholine. Agonist responsiveness was expressed as the provocative concentration of AMP or methacholine producing a 20% fall in FEV1 from baseline (PC[20,AMP] or PC[20,meth], respectively). When compared to placebo, phosphoramidon failed to potentiate the airway response to AMP. The geometric mean (range) PC20 AMP value of 23.4 (4.4-190.6) mg x mL(-1) after placebo was not significantly different from that of 20.7 (45-100.9) mg x mL(-1) obtained after phosphoramidon. The lack of change in bronchial reactivity to adenosine 5'-monophosphate after phosphoramidon indicates that endogenous airway neutral endopeptidase may not be of physiological importance in modulating the contractile response of adenosine in the airways. Thus, the present data do not support the view that activation of peptidergic pathways with subsequent local release of spasmogenic neuropeptides is important in the airway response to adenosine

Inhaled lysine acetylsalicylate (L-ASA) attenuates the bronchoconstrictor response to adenosine 5'-monophosphate (AMP) in asthmatic subjects.

When administered by inhalation, adenosine 5'-monophosphate (AMP) provokes dose-related bronchoconstriction in asthmatic subjects by a mechanism believed to involve mast cell mediator release. However, little is known of the change in airway responsiveness to AMP after cyclo-oxygenase blockade. The aim of this study was to investigate the effect of the potent cyclo-oxygenase inhibitor, lysine acetylsalicylate (L-ASA) administered by inhalation, on AMP-induced bronchoconstriction in a group of nine asthmatic subjects. The subjects studied attended the laboratory on six separate occasions to receive nebulized L-ASA (solution of 90 mg.ml-1) or matched placebo (glycine solution, 30 mg.ml-1) 15 min prior to bronchoprovocation tests with AMP, histamine and methacholine in a randomized, double-blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and agonist responsiveness was expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). Administration of both L-ASA and glycine solution caused a small but significant acute fall in FEV1 from baseline, which returned to normal within 15 min. When compared to placebo, inhaled L-ASA reduced the airway responsiveness to AMP in all the subjects studied, the geometric mean (range) values for PC20 AMP increasing significantly from 36.3 (7.9-250.5) to 101.8 (27.2-1300) mg.ml-1 after placebo and L-ASA, respectively. Moreover, nebulized L-ASA induced a small but significant reduction in airway responsiveness to histamine, the geometric mean (range) PC20 values for histamine increasing from 2.77 (1.05-5.49) to 4.36 (1.69-11.24) mg.ml-1 after placebo and L-ASA, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

[Mast cell mediator release after endobronchial challenge with adenosine 5'-monophosphate in asthmatic subjects]. / Liberazione di mediatori mastocitari dopo challenge endobronchiale con adenosina 5'-monofosfato in soggetti asmatici.

Mediator release from activated mast cells is also likely to take place in the asthmatic airways in vivo during adenosine-induced bronchoconstriction. To test this hypothesis, we evaluated mast cell mediator release directly into the airways of 9 asthmatic subjects after endobronchial challenge with adenosine by bronchoalveolar lavage (BAL). The mediators measured were histamine, tryptase, and PGD2. When compared to the saline-challenged segment, the response to AMP instillation was characterized by a prompt reduction in airway calibre paralleled by a significant 4.2-fold increase in PGD2 levels in the BAL fluid (p = 0.004). There were also increases in median histamine (from 200.1 to 433.6 pg/mL) and tryptase levels (from 0.31 to 0.46 ng/mL) recovered after AMP challenge, although they were not significant. These findings support the view that acute bronchospastic response to AMP in asthmatic airways is paralleled by the local release of mast cells derived products, particularly PGD2.

Inhibition of neutral endopeptidase potentiates bronchoconstriction induced by neurokinin A in asthmatic patients.

The endogenous tachykinins exhibit a range of properties which may be relevant in the pathophysiology of asthma. Their effects on the airways seem to be modulated by a variety of lung peptidases, including neutral endopeptidase (NEP). In order to evaluate the potential role of endogenous NEP activity in modulating tachykinins-induced bronchoconstriction in man in vivo, six atopic asthmatic patients, with a mean FEV1 value of 3.38 +/- 0.76 l, and a histamine PD20 mean value of 0.024 mg, were studied. The influence of inhaled phosphoramidon (a potent NEP inhibitor) was examined against the NKA-induced bronchospasm in a double-blind, placebo-controlled randomized study. Changes in airway calibre were followed as FEV1 and agonists responsiveness expressed as PD20 and PD15 for histamine and NKA respectively. Patients received nebulized phosphoramidon sodium salt (10(-5) M) or a control solution 10 min prior to the bronchoprovocation test with NKA. No significant difference was noticed between any of the study days and after inhaled phosphoramidon on baseline FEV1 values (3.29 +/- 0.90 l) in comparison with the control solution (3.31 +/- 0.79 l). Inhaled NKA produced a dose-dependent fall in FEV1 values in all the subjects studied with a mean PD15 value of 20.91 x 10(-9) mol. Phosphoramidon administered by inhalation elicited a significant (P < 0.01 vs baseline and control solution) potentiation in the airway responsiveness to inhaled NKA, the NKA PD15 value decreasing to 9.45 x 10(-9) mol. The present study confirms that inhaled NKA induces a dose-related bronchoconstriction in asthmatic patients and demonstrates that inhaled phosphoramidon potentiates NKA-induced bronchoconstriction.

[Management of electron accelerators for radiotherapy. Data as of 31 December 1984]. / La gestione di acceleratori di elettroni per radioterapia. Dati aggiornati al 31 dicembre 1984.

Several italian radiotherapeutic centers have supplied the data analysed, regarding problems connected with the management of electron accelerators in the years 1982-1983-1984. The data concern 27 out of the 35 accelerators settled in Italy. The average cost of purchase has proved to be of 940 M pounds with an expense of annual allowance of 94 M pounds. We have then analysed the incidences of the allowance of the purchase expenditure of the machine (23%), the allowance of the expenses for the construction of the bunker (22%), the expenses of maintenance of the machine (5%), the cost of the staff (48%) and the cost of the power supply (2%) on the management costs (about pounds 820.000 per each handled patient). The duration of the various phases of the machinery installment, from the purchase to the beginning of the treatment, the charge of work supported in the three considered years, the daily use of the machinery and the problems deriving from days of time out of services due to failures or to periodical maintenance have then been studied. The analysis of the average values of the parameters studied and of the range of their variability allows us to find out the sector in which it is possible, also at present, to intervene in order to ameliorate the employment of a linear accelerator, regarding the costs and the performance.