Urinary serpin-A3 is an early predictor of clinical response to therapy in patients with proliferative lupus nephritis.

We have previously reported that urinary excretion of serpin-A3 (uSerpA3) is significantly elevated in patients with active lupus nephritis (LN). Here, we evaluated the course of uSerpA3 during the first year of treatment and its association with response to therapy in patients with proliferative LN. The observational longitudinal study included 60 Mexican adults with proliferative LN followed during the first year after LN flare. uSerpA3 was detected by Western blot analysis at flare and after 3, 6, and 12 mo. The response to therapy was determined 1 yr after the LN flare. We evaluated the correlation between uSerpA3 and histological parameters at LN flare. The temporal association between uSerpA3 and response to therapy was analyzed with linear mixed models. uSerpA3 prognostic performance for response was evaluated with receiver-operating characteristic curves. Among the 60 patients studied, 21 patients (35%) were class III and 39 patients (65%) were class IV. uSerpA3 was higher in class IV than in class III LN (6.98 vs. 2.89 dots per in./mg creatinine, P = 0.01). Furthermore, uSerpA3 correlated with the histological activity index (r = 0.29, P = 0.02). There was a significant association between the temporal course of uSerpA3 and response to therapy. Responders showed a significant drop in uSerpA3 at 6 mo compared with LN flare (P < 0.001), whereas nonresponders persisted with elevated uSerpA3. Moreover, uSerpA3 was significantly lower at flare in responders compared with nonresponders (2.69 vs. 6.98 dots per in./mg creatinine, P < 0.05). Furthermore, uSerpA3 was able to identify nonresponders since 3 mo after LN flare (area under the curve: 0.77). In conclusion, uSerpA3 is an early indicator of kidney inflammation and predictor of the clinical response to therapy in patients with proliferative LN.NEW & NOTEWORTHY LN requires aggressive immunosuppression to improve long-term outcomes. Current indicators of remission take several months to normalize, prolonging treatment regiments in some cases. Serpin-A3 is present in urine of patients with proliferative LN. We evaluated the excretion of serpin-A3 in serial samples of patients with proliferative LN during the first year after flare. We found that uSerpA3 correlates with kidney inflammation and its decline at early points predicts the response to therapy 1 yr after flare.

Spanish COPD guidelines (GesEPOC) 2021: updated pharmacological treatment of stable COPD [Pré-print]

The Spanish COPD Guidelines (GesEPOC) were first published in 2012, and since then have undergone a series of updates incorporating new evidence on the diagnosis and treatment of COPD. GesEPOC was drawn up in partnership with scientific societies involved in the treatment of COPD and the Spanish Patients' Forum. Their recommendations are based on an evaluation of the evidence using GRADE methodology, and a narrative description of the evidence in areas in which GRADE cannot be applied. In this article, we summarize the recommendations on the pharmacological treatment of stable COPD based on 9 PICO questions. COPD treatment is a 4-step process: 1) diagnosis; 2) determination of the risk level; 3) initial and subsequent inhaled therapy; and 4) identification and management of treatable traits. For the selection of inhaled therapy, high-risk patients are divided into 3 phenotypes: non-exacerbator, eosinophilic exacerbator, and non-eosinophilic exacerbator. Some treatable traits are general and should be investigated in all patients, such as smoking or inhalation technique, while others affect severe patients in particular, such as chronic hypoxemia and chronic bronchial infection. COPD treatment is based on long-acting bronchodilators with single agents or in combination, depending on the patient's risk level. Eosinophilic exacerbators must receive inhaled corticosteroids, while non-eosinophilic exacerbators require a detailed evaluation to choose the best therapeutic option. The new GesEPOC also includes recommendations on the withdrawal of inhaled corticosteroids and on indications for alpha-1 antitrypsin treatment. GesEPOC offers a more individualized approach to COPD treatment tailored according to the clinical characteristics of patients and their level of complexity.

La Guía Española de la EPOC (GesEPOC) se publicó por primera vez en 2012 y desde entonces ha experimentado una serie de actualizaciones que incorporan las nuevas evidencias sobre el diagnóstico y tratamiento de la EPOC. GesEPOC es una guía de práctica clínica elaborada con la colaboración de las sociedades científicas implicadas en el tratamiento de la EPOC y del Foro Español de Pacientes. Sus recomendaciones se basan en una evaluación de la evidencia mediante la metodología GRADE y en una descripción narrativa de la evidencia en aquellas cuestiones en que la aplicación de GRADE no es posible. En este artículo se resumen las recomendaciones sobre el tratamiento farmacológico de la EPOC estable basadas en la elaboración de 9 preguntas PICO. El proceso de tratamiento de la EPOC comprende cuatro etapas: 1) diagnóstico; 2) determinación del nivel de riesgo; 3) tratamiento inhalado inicial y de continuación y 4) identificación y abordaje de los rasgos tratables. Para la elección del tratamiento inhalado los pacientes de alto riesgo se dividirán en tres fenotipos: no agudizador, agudizador eosinofílico y agudizador no eosinofílico. Los rasgos tratables comprenden unos de tipo general, que deben investigarse en todos los pacientes, como el tabaquismo o la técnica inhalatoria y otros más específicos, que afectan sobre todo a los pacientes graves, como la hipoxemia crónica o la infección bronquial crónica. La base del tratamiento de la EPOC la constituyen los broncodilatadores de larga duración en monoterapia o en combinación según el nivel de riesgo del paciente. Los pacientes agudizadores eosinofílicos deben recibir corticosteroides inhalados y los no eosinofílicos requieren una evaluación detallada para elegir la mejor opción terapéutica. La nueva GesEPOC también incluye recomendaciones sobre la retirada de corticosteroides inhalados y sobre la indicación de tratamiento con alfa-1 antitripsina. GesEPOC supone una aproximación al tratamiento de la EPOC más individualizada según las características clínicas de los pacientes y su nivel de riesgo o de complejidad.

Tratamiento sustitutivo con alfa 1 antitripsina para el enfisema pulmonar / Alpha-1 antitrypsin augmentation therapyfor pulmonary emphysema

CONTEXTO CLÍNICO: El déficit de alfa 1 antitripsina (DAAT) es una enfermedad congénita que predispone al desarrollo de enfermedades pulmonares y hepáticas. La prevalencia de la deficiencia severa de alfa 1 antitripsina (AAT) es de 1 en 1.600 a 5.000 nacidos vivos. La AAT ayuda a regular la actividad de las proteasas, enzimas que al no ser reguladas de manera apropiada causan daño tisular. La AAT es producida por el hígado y es el inhibidor de proteasas más abundante del suero humano. Se comporta como una molécula antiinflamatoria de amplio espectro cuya función es modular las reacciones inflamatorias que se producen en el cuerpo. El gen de la AAT se transmite de manera autosómica codominante mediante dos alelos, uno de cada progenitor. El conjunto de variantes del gen se denomina sistema Pi. El alelo normal se denomina PiM, los alelos deficientes más frecuentes son PiS y PiZ. Los alelos S y Z codifican proteínas anormales, el 80-90% de las moléculas producidas por los alelos Z y el 40-50% de las producidas por los alelos S son retenidas dentro de las células hepáticas y degradadas. La mayor causa de morbimortalidad entre las personas con DAAT es la enfermedad pulmonar obstructiva crónica (EPOC, tanto en su forma de enfisema pulmonar como la bronquitis crónica), seguida por la cirrosis hepática. Los fumadores con DAAT tienen aumentado el riesgo de sufrir enfisema, así como aquellos individuos con herencia homocigota lo desarrollarán siendo adultos jóvenes. El enfisema pulmonar se caracteriza por la pérdida de tejido pulmonar y por un aumento de los espacios alveolares. El tratamiento de los pacientes con enfisema pulmonar por DAAT debe comprender las medidas habituales de tratamiento de los pacientes con EPOC. Pacientes graves seleccionados podrían ser candidatos a trasplante pulmonar. Se propone el tratamiento sustitutivo con AAT para pacientes con déficit congénito homocigota (PiZZ) y enfisema pulmonar con el objetivo de retrasar el deterioro de la función pulmonar causado por la destrucción tisular. TECNOLOGÍA: La AAT utilizada para el tratamiento sustitutivo se obtiene mediante purificación del plasma de donantes. Se la encuentra en forma de polvo liofilizado que debe ser reconstituido, o en forma de solución activa lista para ser administrada, ambas formas farmacéuticas se administran de modo endovenoso. Las marcas autorizadas por ANMAT para su comercialización en Argentina son Prolastin-C®, Aralast® y Trypsan® en forma de polvo y Glassia® en forma de solución. OBJETIVO: El objetivo primario fue evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura de la terapia de sustitución con alfa 1 antitripsina en pacientes con déficit congénito y enfisema pulmonar. El objetivo secundario fue evaluar la evidencia existente acerca de la eficacia y seguridad comparada entre diferentes marcas comerciales. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas (incluyendo Medline, Cochrane y CRD), en buscadores genéricos de Internet, agencias de evaluación de tecnologías sanitarias y financiadores de salud utilizando la siguiente estrategia: ((alpha 1-Antitrypsin [Mesh] OR "alpha 1-Antitrypsin proteinase inhibitor" [Tiab] OR aralast [Tiab] OR Glassia [tiab] OR Prolastin* [tiab] OR Zemaira [tiab] OR Trypsan [tiab] OR Alfalastin [tiab] OR Pulmolast [tiab] OR Trypsone [tiab]) AND ("alpha 1-Antitrypsin Deficiency"[Mesh] OR "alpha 1-Antitrypsin Deficiency"[Tiab])). Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS) y económicas (EE), guías de práctica clínica (GPC) y políticas de cobertura de otros sistemas de salud cuando estaban disponibles. RESULTADOS: Se hallaron un meta-análisis y siete ECAs, tres GPC, ocho políticas de cobertura y tres ETS. CONCLUSIONES: Escasa evidencia de alta calidad muestra que la terapia de reemplazo con alfa 1 antitripcina (AAT) no detiene el deterioro de la función pulmonar en pacientes con enfisema y déficit de AAT. En los estudios clínicos el uso de AAT ha mostrado reducir levemente la pérdida de volumen pulmonar, pero no se observan en desenlaces clínicos en términos de mortalidad, número de internaciones, exacerbaciones o calidad de vida. Los estudios comparativos existentes han mostrado que los diferentes productos son bioequivalentes y con similar perfil de seguridad, no existiendo evidencia de superioridad entre ellos. Varias sociedades científicas coinciden en recomendar su uso únicamente en pacientes seleccionados con enfisema progresivo panacinar, pérdida acelerada de la función pulmonar durante al menos un año, déficit grave de AAT (concentraciones menores al 35% de lo normal), no fumadores y con fenotipos deficitarios homocigotas, mientras que las políticas de cobertura no son homogéneas.

Longitudinal evaluation of the complexed-to-total prostate specific antigen ratio in men with prostate disease. Effect of treatment.

The longitudinal changes in the complexed-to-total prostate specific antigen (PSA) ratio were evaluated in 90 men with benign prostatic hyperplasia (BPH) and 50 men with prostate cancer. The influence of treatment on this ratio was studied in 45 BPH patients and 50 patients with prostate cancer. Using a cut-off of 0.80 for the complexed-to-total PSA ratio, the large majority of prostate cancer patients had a ratio above the cut-off before treatment in serial determinations, whereas most BPH patients had a ratio consistently below that value. However, the few prostate cancer patients who had a ratio < or = 0.80 showed this low ratio in serial determinations, as did BPH patients who had a ratio > or = 0.80. During treatment, the ratio significantly decreased in 43 of the 50 patients with prostate cancer in parallel with the decrease in total PSA, and 34 of the 41 patients that had a pretreatment ratio > 0.80 showed a ratio < or = 0.80 during hormonal therapy. Our results show that neither the physiological changes in total and complexed PSA nor the treatment of BPH patients change the diagnostic efficacy of the complexed-to-total PSA ratio, whereas in prostate cancer patients under hormonal therapy, the ratio decreased in parallel with the decrease in total PSA. This suggests that, apart from improving the diagnostic efficacy of total PSA, the complexed-to-total PSA ratio could also be used to monitor BPH patients for newly developed tumours or to monitor therapy in patients with prostate cancer.

Alpha-1-antichymotrypsin is an effective inhibitor of pancreatitis-induced lung injury.

BACKGROUND: Pancreatitis-induced adult respiratory distress syndrome (ARDS) may result from an imbalance between leucocyte proteases, produced by infiltrating neutrophils, and endogenous protease inhibitors. OBJECTIVE: The aim of this study was to evaluate the role of recombinant alpha-1-antichymotrypsin (rACT P3-P3'), an endogenous serine protease inhibitor, in ameliorating lung injury associated with pancreatitis. DESIGN: Sprague-Dawley rats were randomly divided into control (saline infusion) and pancreatitis groups, which were treated immediately with saline or rACT P3-P3' (50 mg/kg body weight). METHODS: Myeloperoxidase (MPO) was employed as a monitor of neutrophil traffic in the lung, and wet-dry lung weights as a measure of pulmonary endothelial permeability. Lungs were also evaluated histologically. RESULTS: Caerulein (5 micrograms/kg body weight/h) induced pancreatitis in all animals, with an increase in serum amylase from 1851 +/- 208 IU (control) to 5198 +/- 924 IU (pancreatitis), P < 0.05. Pancreatitis caused a significant increase in MPO activity (7.8 +/- 1.1 units compared with 2.08 +/- 0.5 units in controls, P < 0.001) and wet-dry lung weight ratios (12.8 +/- 3.3 compared with 3.2 +/- 0.1 in controls, P < 0.001), indicating significant pulmonary neutrophil influx and microvascular leakage, respectively. These increases in MPO activity and wet-dry ratios were decreased in the pancreatitis group treated with rACT P3-P3' (MPO 4.68 +/- 0.7 units, wet-dry ratio 4.2 +/- 0.5, P < 0.05 compared with the untreated pancreatitis group). CONCLUSION: These data support the hypothesis that deficient endogenous protease inhibition may be responsible for the neutrophil-mediated lung injury observed in pancreatitis and suggest that there may be a therapeutic role for recombinant protease inhibitors such as alpha-1 antichymotrypsin.

[Specific plasma sorption of proteinases--a new approach to the treatment of acute pancreatitis]. / Spetsificheskaia plazmosorptsiia proteinaz--novyi podkhod k lecheniiu ostrogo pankreatita.

The authors treated destructive forms of acute pancreatitis for the first time by means of specific plasma sorption of proteinases with the use of a proteinase plasma sorbent which is an acid-stable proteinase inhibitor immobilized on sepharose (ASI-Sepharose). Specific plasma sorption of proteinases on ASI-Sepharose was applied to the treatment of 29 patients with various forms of acute destructive pancreatitis. At the end of specific plasma sorption procedure the activity of blood plasma proteolytic enzymes in the patients reduced by 60-75%, which was attended by marked improvement of the condition in most cases; aggravation of the patients' condition was not encountered. The mortality in this group was 20.7% and was due to complications occurring during the development of the main disease. The mortality rate among patients treated by specific proteinase plasma sorption is much lower than that recorded in the USSR for destructive forms of acute pancreatitis which ranges from 30 to 75%.