Exogenous glucocorticoids to improve extinction learning for post-traumatic stress disorder patients with hypothalamic-pituitary-adrenal-axis dysregulation: a study protocol description.

Background: Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients - potentially with substantial exposure to early-life adversity (ELA) - show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories.Objective: We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration.Method: The observational study (n = 160 PTSD group, n = 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study (n = 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts.Conclusion: The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies.Trial registration: The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30.

This protocol reports a proof-of-concept study for glucocorticoids as an enhancer for PTSD treatment.The study examines whether glucocorticoids enhance the strength and generalization of extinction memory.A further aim is to identify HPA-axis-related PTSD subgroups that may particularly benefit.

Development of a care protocol in pregnancy and chronic inflammatory arthritis, in a multidisciplinary work group.

OBJECTIVE: To design a care protocol in Chronic Inflammatory Arthritis during the pre-conceptional period, pregnancy, postpartum and lactation. This protocol aims to be practical and applicable in consultations where patients with chronic inflammatory rheumatological diseases are treated, thus helping to better control these patients. Likewise, recommendations are offered on when patients could be consulted/referred to a specialized center by the physician. METHODS: A multidisciplinary panel of expert physicians from different specialties identified the key points, analyzed the scientific evidence, and met to develop the care protocol. RESULTS: The recommendations prepared have been divided into three blocks: rheumatology, gynecology and pediatrics. The first block has been divided into pre-pregnancy, pregnancy and postpartum visits. CONCLUSIONS: This protocol tries to homogenize the follow-up of the patients from the moment of the gestational desire until the year of life of the infants. It is important to perform tests in patients of childbearing age and use drugs compatible with pregnancy. If appropriate, the patient should be referred to specialized units. Multidisciplinarity (rheumatology, gynecology and pediatrics) is essential to improve the control and monitoring of these patients and their offspring.

[Translated article] Physicochemical and microbiological stability study of two new preservative-free methylprednisolone eye drops.

OBJECTIVE: To study the physicochemical and microbiological stability over 90 days of two preservative-free methylprednisolone sodium succinate (MTPSS) 1 and 10 mg/mL eye drops for use in ocular pathologies such as Sjögren's syndrome and dry eye syndrome. METHOD: The two eye drops were prepared from injectable MTPSS (Solu-moderin® and Urbason®), water for injection and normal saline solution. In accordance with ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) guidelines, they were then stored in triplicate under refrigerated conditions (5±3 °C), at room temperature (25±2 °C), and at 40 °C (±2 °C). In accordance with the USP (United States Pharmacopeia), physicochemical controls of the active ingredient content were carried out by HPLC-UV (High Performance Liquid Chromatography with Ultraviolet detection), together with controls of pH, osmolality, and visual examination. Microbiological sterility was also tested under refrigerated conditions up to 30 days in open containers and up to 90 days in closed ones. RESULTS: The eye drops stored at 5 °C were the most stable; in the 1 mg/mL eye drops, degradation of the drug fell below 90% from day 21, and in the 10 mg/mL eye drops, from day 42. pH change did not vary by ≥1 unit in formulations stored at 5 °C, unlike the other formulations. Changes in osmolality did not exceed 5% on day 90 in any storage conditions. Samples of non refrigerate eye drops at 10 mg/mL, presented a white precipitate from day 14 and 28, respectively. Non-refrigerated 1 mg/mL eye drops presented suspended particles on day 90. There were no color changes. Microbiological analysis showed that sterility was maintained for over 90 days in the closed containers, although microbial contamination was detected from day 21 in the open containers. CONCLUSIONS: 1 mg/mL MTPSS eye drops show physicochemical and microbiological stability for 21 days under refrigeration, compared to 42 days for 10 mg/mL eye drops stored under the same conditions. However, since they do not include preservatives in their composition, they should not be used for more than 7 days after opening.

Physicochemical and microbiological stability study of two new preservative-free methylprednisolone eye drops. / Estudio de estabilidad fisicoquímica y microbiológica de dos nuevos colirios de metilprednisolona sin conservantes.

OBJECTIVE: To study the physicochemical and microbiological stability over 90 days of two preservative-free methylprednisolone sodium succinate (MTPSS) 1 mg/ml and 10 mg/ml eye drops for use in ocular pathologies such as Sjögren's syndrome and dry eye syndrome. METHOD: The two eye drops were prepared from injectable MTPSS (Solu-moderin® and Urbason®), water for injection and normal saline solution. In accordance with ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines, they were then stored in triplicate under refrigerated conditions (5 ±3 °C), at room temperature (25 ± 2 °C), and at 40 °C (±2 °C). In accordance with the USP (United States Pharmacopeia), physicochemical controls of the active ingredient content were carried out by HPLC-UV (High Performance Liquid Chromatography with Ultraviolet detection), together with controls of pH, osmolality, and visual examination. Microbiological sterility was also tested under refrigerated conditions up to 30 days in open containers and up to 90 days in closed ones. RESULTS: The eye drops stored at 5 °C were the most stable; in the 1 mg/ml eye drops, degradation of the drug fell below 90% from day 21, and in the 10 mg/ml eye drops, from day 42. pH change did not vary by ≥1 unit in formulations stored at 5 °C, unlike the other formulations. Changes in osmolality did not exceed 5% on day 90 in any storage conditions. Samples of non refrigerate eye drops at 10 mg/ml, presented a white precipitate from day 14 and 28 respectively. Non-refrigerated 1 mg/ml eye drops presented suspended particles on day 90. There were no color changes. Microbiological analysis showed that sterility was maintained for over 90 days in the closed containers, although microbial contamination was detected from day 21 in the open containers. CONCLUSIONS: 1 mg/ml MTPSS eye drops show physicochemical and microbiological stability for 21 days under refrigeration, compared to 42 days for 10 mg/ml eye drops stored under the same conditions. However, since they do not include preservatives in their composition, they should not be used for more than 7 days after opening.

Lineamientos para la prevención y el tratamiento de la osteoporosis inducida por glucocorticoides en pediatría / Guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis in pediatrics

Objetivo. Proporcionar un marco para profesionales de la salud que tratan a pacientes pediátricos bajo terapia con glucocorticoides (GC) y desarrollar recomendaciones para la prevención y el tratamiento de la osteoporosis inducida por GC en la población pediátrica. Métodos. Un panel de expertos en enfermedades óseas y pediátricas generó una serie de preguntas PICO que abordan aspectos relacionados con la prevención y el tratamiento de osteoporosis en pacientes bajo tratamiento con GC. Siguiendo la metodología GRADE, se realizó una revisión sistemática de la literatura, se resumieron las estimaciones del efecto y se calificó la calidad de la evidencia. Luego se procedió a la votación y a la formulación de las recomendaciones. Resultados. Se desarrollaron 7 recomendaciones y 6 principios generales para osteoporosis inducida por GC en población pediátrica. Conclusión. Estas recomendaciones proporcionan orientación para los médicos que deben tomar decisiones en pacientes pediátricos bajo tratamiento con GC.

Objective. To provide a framework for healthcare professionals managing pediatric patients who are on active glucocorticoid (GC) therapy and to develop recommendations for the prevention and treatment of GC-induced osteoporosis in the pediatric population. Methods. A panel of experts on bone and pediatric diseases developed a series of PICO questions that address issues related to the prevention and treatment of osteoporosis in patients on GC therapy. In accordance with the GRADE approach, we conducted a systematic review of the literature, summarized effect estimations, and classified the quality of the evidence. Then, voting and the formulation of recommendations followed. Results. Seven recommendations and six general principles were developed for GC-induced osteoporosis in the pediatric population. Conclusion. These recommendations provide guidance for clinicians who must make decisions concerning pediatric patients undergoing treatment with GC.

Determining the Associations Between Glucocorticoid Use During Hematologic Chemotherapy Treatment and New-onset Diabetes and Hyperglycemia and Mortality: A Population-based Cohort Study.

OBJECTIVES: The aim of this study was to determine the associations between glucocorticoid administration during chemotherapy for hematologic malignancy and hyperglycemia, new-onset diabetes, and mortality in Ontario, Canada. Hospitalization and emergency room utilization during the chemotherapy treatment period were also described. METHODS: We conducted a retrospective cohort study using health administrative data from ICES, Ontario, to assess risk of new-onset diabetes, new-onset hyperglycemia, and hyperglycemia for individuals with leukemia, non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL) receiving glucocorticoids during chemotherapy between 2006 and 2016. Using multivariable regression models, we determined the associations between glucocorticoid exposure and our outcomes of interest, controlling for age, sex, marginalization, and comorbidities. RESULTS: Our cohort included 19,530 individuals; 71.1% (n=13,893) received a glucocorticoid. The highest proportion of hyperglycemia occurred with leukemia (25.4%, n=1,301). Of the 15,580 individuals with no history of diabetes, those with leukemia had the highest rate of new-onset diabetes (7.1%, n=279) and new-onset hyperglycemia (18.1%, n=641), and glucocorticoid exposure increased the risk of new-onset diabetes (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.01 to 1.64, p=0.04) and new-onset hyperglycemia (HR 1.28, 95% CI 1.09 to 1.5, p=0.003). Hyperglycemia during chemotherapy increased the risk of all-cause mortality for the combined (HR 1.18, 95% CI 1.09 to 1.27, p<0.0001) and NHL (HR 1.16, 95% CI 1.04 to 1.28, p=0.007) cohorts. CONCLUSIONS: Hyperglycemia is common during hematologic chemotherapy treatment and is associated with a modest increased risk of all-cause mortality. Routine screening, monitoring, and management of hyperglycemia should be an integral part of treatment plans for leukemia, NHL, or HL, with or without glucocorticoid administration.

Características clínico-oftalmológicas y evolución de los pacientes con oftalmopatía tiroidea activa moderada severa tratados con bolos de metilprednisolona que acuden al Hospital Central del Instituto de Previsión Social, Paraguay / Clinical-ophthalmological characteristics and evolution of patients with moderately severe active thyroid ophthalmopathy treated with methylprednisolone boluses who attended the Central Hospital of the Instituto de Previsión Social, Paraguay

Introducción: La oftalmopatía tiroidea (OT) es un trastorno debilitante en pacientes con enfermedad tiroidea autoinmune, principalmente enfermedad de Graves, que se desarrolla entre el 30 a 50% de los casos. Objetivos: Describir las características clínico-oftalmológicas y la evolución de los pacientes con oftalmopatía tiroidea activa moderada severa tratados con bolos de metilprednisolona que acuden al Hospital Central del Instituto de Previsión Social en el tiempo comprendido entre enero de 2018 y setiembre de 2021. Materiales y métodos: Investigación de diseño observacional, con estudio descriptivo, retrospectivo. Resultados: Se revisaron fichas de 34 pacientes con OT activa moderada severa que recibieron bolos de metilprednisolona basado en las guías EUGOGO 2016, de los cuáles se excluyeron 3 pacientes por tener fichas incompletas y otros 3 pacientes ya que requirieron tratamiento de segunda línea previo al término del esquema de 12 sesiones. De los 28 pacientes estudiados, la edad promedio fue de 43,6 ±13,1 años, el 89% de sexo femenino y el 28,5%, fumadores. En cuanto a la función tiroidea de la población previo al tratamiento, se constató hipertiroidismo en el 82%, hipotiroidismo en el 11% y eutiroidismo en el 7%; y posterior al tratamiento, se constató hipertiroidismo en el 78,6% (subclínico), eutiroidismo en el 17,9% e hipotiroidismo en el 3,5%. La mayoría (92.6%) contaba con anticuerpos contra el receptor de TSH positivo, con un promedio de 18 ± 9,9 mIU/Ml. Respecto a la actividad de la oftalmopatía según la escala CAS, se constató un promedio de 4,1 ±1,0 previo al tratamiento y posterior 1,2 ±1,4; de ellos el 46,4% presentó un estado leve según escala de gravedad, 39% sin criterios de gravedad y 14 % persistió en moderada -severa. Se constató mejoría de la agudeza visual tras el tratamiento (57,1%), el promedio de exoftalmía previo al tratamiento fue 22,2 mm y posterior 21,1 mm; se presentó diplopía en el 7,1% previo al tratamiento y en el 3,6% posterior al tratamiento. Conclusión: El tratamiento con glucocorticoides endovenosos en la oftalmopatía de Graves moderada-severa (esquema EUGOGO 2016) fue muy efectivo, revirtiendo la actividad y consecuentemente ayudando a disminuir la gravedad, en la gran mayoría de nuestros pacientes. Esto podría explicarse porque la oftalmopatía era incipiente y por el alto grado de adherencia de los pacientes en el contexto de un manejo multidisciplinar bien protocolizado.

Introduction: Graves' orbitopathy (GO) is a debilitating disorder in patients with autoimmune thyroid disease, mainly Graves' disease, which develops in 30 to 50% of cases. Objectives: To describe the clinical-ophthalmological characteristics and evolution of patients with moderate-to- severe active GO treated with methylprednisolone boluses who attended the Central Hospital of the Institute of Social Security between January 2018 and September 2021. Materials and methods: Observational design research, descriptive, retrospective study. Results: Records of 34 patients with active moderate-to-severe GO who received boluses of methylprednisolone based on the EUGOGO 2016 guidelines, were reviewed, of which 3 patients were excluded due to having incomplete records and another 3 patients since they required second-line treatment prior to end the 12-session scheme. Of the 28 patients studied, the average age was 43.6 ±13.1 years, 89% were female and 28.5% were smokers. Regarding the thyroid function of the population prior to treatment, hyperthyroidism was found in 82%, hypothyroidism in 11% and euthyroidism in 7%; and after treatment, hyperthyroidism was found in 78.6% (subclinical), euthyroidism in 17.9% and hypothyroidism in 3.5%. The majority (92.6%) had positive thyrotropin receptor antibodies, with an average of 18 ± 9.9 mIU/Ml. Regarding the activity of orbitopathy according to the CAS scale, an average of 4.1 ±1.0 was found before treatment and 1.2 ±1.4 after; Of them, 46.4% presented a mild condition according to the severity scale, 39% without severity criteria and 14% persisted in moderate-severe. Improvement in visual acuity was noted after treatment (57.1%), the average exophthalmia before treatment was 22.2 mm and after 21.1 mm; Diplopia occurred in 7.1% before treatment and in 3.6% after treatment. Conclusion: Treatment with intravenous glucocorticoids in moderate-severe Graves' orbitopathy (EUGOGO 2016 scheme) was very effective, reversing the activity and consequently helping to reduce the severity, in the vast majority of our patients. This could be explained because the orbitopathy was incipient and by the high degree of patient adherence in the context of well-protocolized multidisciplinary management.

Comparación clínica en el manejo remoto del asma bronquial durante la pandemia COVID-19 entre dos terapias controladoras: fluticasona y beclometasona / Clinical comparison in the remote management of bronchial asthma during the COVID-19 pandemic between two controller therapies: Fluticasone and beclomethasone

RESUMEN Objetivo: Comparar el nivel de control del asma mediante el uso del Asthma Control Test (ACT) y manifestaciones clínicas en dos grupos de pacientes tratados con diferentes corticosteroides inhalados (GCI): fluticasona y beclometasona. Materiales y métodos. Se realizó un estudio observacional, comparativo y prospectivo en 521 niños del programa de asma del Hospital III Yanahuara. Durante el periodo de junio de 2020 a diciembre de 2021, se evaluó el nivel de control del asma mediante consultas remotas utilizando el ACT y la recopilación de hallazgos clínicos. Los pacientes se agruparon según el tipo de GCI que se encontraban utilizando. Se registraron los datos en dos momentos diferentes para cada paciente, con un intervalo de 4 meses entre cada control, durante la pandemia de COVID-19 y se comparó el nivel de control mediante la puntuación obtenida en el ACT y las manifestaciones clínicas entre ambos grupos de pacientes en ambos momentos del estudio. Resultados . Ambos grupos tuvieron un control óptimo al inicio como al final del estudio. En las manifestaciones clínicas no hubo diferencia estadística (P > 0.05) a favor de ningún medicamento en ninguno de los dos controles. Sin embargo, en el segundo control (egreso) se encontró una diferencia significativa de la fluticasona frente a la beclometasona (p = 0.030). Conclusiones . Se encontró que la Fluticasona tuvo una superioridad en el nivel de control del asma frente a la beclometasona. Sin embargo, el factor determinante para lograr un buen control es el uso continuo de cualquier GCI.

ABSTRACT Objective: To compare the level of asthma control using the Asthma Control Test (ACT) and clinical manifestations in two groups of patients treated with different inhaled corticosteroids (ICG): fluticasone and beclometasone. Materials and methods: An observational, comparative and prospective study was conducted in 521 children in the asthma program of Hospital III Yanahuara. During the period from June 2020 to December 2021, the level of asthma control was assessed by remote consultations using ACT and collection of clinical findings. Patients were grouped according to the type of ICG they were using. Data were recorded at two different time points for each patient, with a 4-month interval between each control, during the COVID-19 pandemic and the level of control was compared by ACT score and clinical manifestations between the two groups of patients at both time points of the study. Results: Both groups had optimal control at baseline and at the end of the study. In clinical manifestations there was no statistical difference (P > 0.05) in favor of either drug in either control. However, in the second control (discharge) a significant difference was found for fluticasone versus beclometasone (P = 0.030). Conclusions: Fluticasone was found to have superiority in the level of asthma control over beclomethasone. However, the determining factor in achieving good control is the continuous use of any IGC.

Bone effects of epidural and intra-articular glucocorticoids: a systematic literature review / Efectos óseos de los glucocorticoides epidurales e intraarticulares: revisión sistemática de la literatura

Osteoporosis and vertebral and non-vertebral fractures are common in glucocorticoids (GC) treated patients. Oral GC treatment leads to bone loss, particularly of trabecular bone. The benefits of GC used in rheumatological and traumatological disorders are known but they would have possible negative effects on bone. This systematic review aimed to evaluate the effects of epidural steroid injections (ESI), and intra-articular and intramuscular GC administration on bone mineral density (BMD) and fragility fractures. A systematic review of Medline/PubMed, Cochrane, and LILACS up to November 2020 was conducted. Meta-analyses, systematic reviews, randomized and non-randomized controlled trials, and prospective and retrospective studies comparing the effect of ESI, intra-articular or intramuscular GC used compared to a control group or baseline measurements were included. Results: A total of 8272 individuals were included among the 13 selected articles (10 about ESI and 3 about intra-articular GC; no article was found evaluating intramuscular GC). Only a few studies showed a negative effect of ESI on bone in the qualitative analysis considering osteopenia and osteoporosis in lumbar spine, femoral neck and total hip and BMD as surrogate outcomes. On the other hand, the qualitative analysis showed that most studies found an increased risk of fragility fracture. However, only two studies could be included in the quantitative analysis, in which there were no differences between patients exposed to ESI versus controls in all evaluated regions. In conclusion, there was insufficient evidence to suggest that ESI and intra-articular GC, unlike oral GC, negatively affect bone mass. Longitudinal studies are needed to obtain more knowledge regarding the effect of ESI or intra-articular GC on BMD and fragility fractures. (AU)

La osteoporosis y las fracturas vertebrales y no vertebrales son comunes en pacientes tratados con glucocorticoides (GC). El tratamiento oral con GC conduce a la pérdida ósea, particularmente del hueso trabecular. Los beneficios de los GC utilizados en patologías reumatológicas y traumatológicas son conocidos, pero tendrían posibles efectos negativos sobre el hueso. Esta revisión sistemática tuvo como objetivo evaluar los efectos de las inyecciones epidurales de esteroides (ESI), GC intraarticulares e intramusculares sobre la densidad mineral ósea (DMO) y las fracturas por fragilidad. Se realizó una revisión sistemática de Medline/PubMed, Cochrane y LILACS hasta noviembre de 2020. Se incluyeron metanálisis, revisiones sistemáticas, ensayos controlados aleatorizados y no aleatorizados, estudios prospectivos y retrospectivos que compararon el efecto de ESI, GC intraarticular o intramuscular utilizado en comparación con un grupo de control o mediciones iniciales. Resultados: Se incluyeron un total de 8272 individuos entre los 13 artículos seleccionados (10 sobre ESI y 3 sobre GC intraarticular; no se encontró ningún artículo que evaluara GC intramuscular). Solo unos pocos estudios mostraron un efecto negativo del ESI sobre el hueso en el análisis cualitativo considerando la osteopenia y la osteoporosis en la columna lumbar, el cuello femoral y la cadera total y la DMO como un resultado indirecto. Por otro lado, el análisis cualitativo mostró que la mayoría de los estudios encontraron un mayor riesgo de fractura por fragilidad. Sin embargo, solo dos estudios pudieron incluirse en el análisis cuantitativo, en los que no hubo diferencias entre los pacientes expuestos a ESI versus los controles en todas las regiones evaluadas. En conclusión, no hallamos datos suficientes para sugerir que la ESI y los GC intraarticulares, a diferencia de los GC orales, afectan negativamente a la pérdida ósea. Se necesitan estudios longitudinales para obtener más conocimiento sobre el efecto de ESI o GC intraarticular en la DMO y las fracturas por fragilidad. (AU)

Effects of prenatal exposure to the 1944-45 Dutch famine and glucocorticoid receptor polymorphisms on later life PTSD susceptibility.

Background: Exposure to adversity in utero is thought to increase susceptibility to develop posttraumatic stress disorder (PTSD) following later life trauma, due to neurobiological programming effects during critical developmental periods. It remains unknown whether effects of prenatal adversity on PTSD susceptibility are modulated by genetic variations in neurobiological pathways implicated in PTSD susceptibility.Objective: We investigated whether genetic variation in the glucocorticoid receptor (GR) modulated effects of prenatal famine exposure on late adulthood PTSD symptom severity after trauma exposure in childhood and mid-to-late adulthood.Method: We included N = 439 term-born singleton adults (mean age: 72 years, 54.2% women) from the Dutch Famine Birth Cohort, born around the time of the Dutch Famine of 1944/1945, divided into exposure and control groups based on timing of the famine during gestation. Participants filled out self-report questionnaires on childhood (Childhood Trauma Questionnaire) and mid-to-late adulthood (Life Events Checklist for DSM-5) trauma, and current PTSD symptom severity (PTSD Checklist for DSM-5). GR haplotypes were determined from four functional GR single nucleotide polymorphisms (ER22/23EK, N363S, BclI and exon 9ß) in previously collected DNA. Linear regression analyses were performed to investigate associations of GR haplotype and prenatal famine exposure in conjunction with later life trauma on PTSD symptom severity.Results: We observed a significant three-way interaction between the GR Bcll haplotype, famine exposure during early gestation, and adulthood trauma exposure on PTSD symptom severity in late adulthood. Only participants exposed to famine during early gestation without the GR Bcll haplotype showed a significantly stronger positive association between adulthood trauma and PTSD symptom severity than non-exposed participants, indicating increased PTSD susceptibility.Conclusions: Our results illustrate the importance of integrated approaches considering genetics and environmental contexts throughout various life periods, including the rarely investigated prenatal environment, to elucidate how PTSD susceptibility evolves throughout life.HIGHLIGHTS Adversity during pregnancy is thought to increase offspring's PTSD risk following later life trauma, but exact neurobiological mechanisms underlying this process remain unknown.We found that effects of prenatal famine exposure on PTSD symptom severity were influenced by genetic variation in the glucocorticoid receptor, which signals effects of the stress hormone cortisol.Integrated approaches considering genetics and environmental contexts throughout both early and later life are important to understand how PTSD risk evolves throughout life.

Paraccocidiomicosis sistémica en consumidor crónico de corticoides

La Paracoccidiomicosis es una infección endémica. Junto con la histoplasmosis, son las infecciones micóticas más frecuentes en Latinoamérica. Esta micosis puede ser de afección local o sistémica, con un marcado trofismo por los pulmones, órganos linfoides, hígado, glándulas suprarrenales, piel y mucosa. Presentamos el caso de un varón adulto, consumidor crónico de corticoides, que desarrolla una paracoccidiomicosis sistémica con afección pulmonar y de glándulas suprarrenales con buena repuesta a la terapéutica antifúngica.

Paracoccidiomycosis is an endemic infection, together with histoplasmosis, they are the most frequent fungal infections in Latin America. This mycosis can be of local or systemic affection, with a marked trophism by the lungs, lymphoid organs, liver, adrenal glands, skin and mucosa. We present the case of an adult male, chronic steroid user, who develops systemic paracoccidiomycosis with pulmonary and adrenal gland involvement with good response to antifungal therapy.

Vasculitis del sistema nervioso central

La vasculitis primaria del Sistema Nervioso Central (VPSNC) se refiere a un grupo de enfermedades que resultan de la inflamación y destrucción de los vasos sanguíneos de la médula espinal, encéfalo y meninges, tanto en el sector venoso como arterial, esto puede conducir a la oclusión o formación de aneurismas, con las consiguientes alteraciones isquémico-hemorrágicas.1 La presentación es heterogénea y poco sistematizable. El diagnóstico se establece con un cuadro clínico compatible, una angiografía o biopsia del parénquima encefálico y/o meninges que evidencien vasculitis. Presentamos el caso de un paciente portador de retrovirus con probable VPSNC con clínica compatible, hallazgos imagenológicos sugestivos, con escasa alteración de LCR y EEG.2

Primary vasculitis of the Central Nervous System (VPSNC) refers to a group of diseases that result from inflammation and destruction of the blood vessels of the spinal cord, brain and meninges, both in the venous and arterial sector, this can lead to the occlusion or formation of aneurysms, with the consequent ischemic-hemorrhagic alterations.1 The presentation is heterogeneous and little systematizable. The diagnosis is established with a compatible clinical picture, an angiography or biopsy of the brain parenchyma and/or meninges that show vasculitis. We present the case of a patient with a retrovirus with probable NCPSV with compatible symptoms, suggestive imaging findings, with little CSF and EEG alteration.2

Threshold based on bone mineral density for therapeutic decision-making in postmenopausal women and men over 50 years old under glucocorticoid therapy.

INTRODUCTION AND AIM: T-score bone mineral density (BMD) thresholds may influence guidance for treatment in patients under glucocorticoid (GC) therapy. Different BMD thresholds have been described but there is no international consensus. The aim of this study was to find a threshold to help in treatment decision-making in the population under GC therapy. METHODS: A working group representing three scientific societies from Argentina was convened. The first team was formed by specialists with expertise in glucocorticoid-induced osteoporosis (GIO) who voted according to summary of evidence. The second team was constituted by a methodology group who coordinated and supervised each stage. We conducted two systematic reviews to synthesize the evidence. The first included trials of drugs used in GIO to analyze the BMD cut-off used as inclusion criteria. In the second, we analyzed the evidence regarding the densitometric thresholds to discriminate between fractured and non-fractured patients under GC treatment. RESULTS: In the first review, 31 articles were included for qualitative synthesis and more than 90% of the trials included patients regardless of their densitometric T-score or range of osteopenia. In the second review, 4 articles were included and more than 80% of the T-scores were in the range -1.6 to -2.0. The summary of findings was analyzed and put to a vote. CONCLUSIONS: With more than 80% agreement of the voting expert panel, a T-score≤-1.7 was considered the most appropriate for treatment in postmenopausal women and men over 50 years of age under GC therapy. This study could help in treatment decision-making in patients under GC therapy without fractures but other fracture risk factors should certainly be considered.

Threshold based on bone mineral density for therapeutic decision-making in postmenopausal women and men over 50 years old under glucocorticoid therapy / Umbral densitométrico de densidad mineral ósea para considerar tratamiento en pacientes mujeres posmenopáusicas y hombres mayores de 50 años en tratamiento con glucocorticoids

Introduction and aim: T-score bone mineral density (BMD) thresholds may influence guidance for treatment in patients under glucocorticoid (GC) therapy. Different BMD thresholds have been described but there is no international consensus. The aim of this study was to find a threshold to help in treatment decision-making in the population under GC therapy. Methods: A working group representing three scientific societies from Argentina was convened. The first team was formed by specialists with expertise in glucocorticoid-induced osteoporosis (GIO) who voted according to summary of evidence. The second team was constituted by a methodology group who coordinated and supervised each stage. We conducted two systematic reviews to synthesize the evidence. The first included trials of drugs used in GIO to analyze the BMD cut-off used as inclusion criteria. In the second, we analyzed the evidence regarding the densitometric thresholds to discriminate between fractured and non-fractured patients under GC treatment. Results: In the first review, 31 articles were included for qualitative synthesis and more than 90% of the trials included patients regardless of their densitometric T-score or range of osteopenia. In the second review, 4 articles were included and more than 80% of the T-scores were in the range −1.6 to −2.0. The summary of findings was analyzed and put to a vote. Conclusions: With more than 80% agreement of the voting expert panel, a T-score≤−1.7 was considered the most appropriate for treatment in postmenopausal women and men over 50 years of age under GC therapy. This study could help in treatment decision-making in patients under GC therapy without fractures but other fracture risk factors should certainly be considered.(AU)

Introducción y objetivo: Los umbrales del T-score de densidad mineral ósea (DMO) podrían influir en el tratamiento de pacientes bajo terapia con glucocorticoides (GC). Se han descrito diferentes umbrales, pero no existe un consenso internacional. El objetivo de este trabajo fue encontrar un umbral que ayude en la decisión terapéutica en la población bajo tratamiento con GC. Métodos: Se convocó un grupo de trabajo en representación de tres sociedades científicas de Argentina. El primer equipo estuvo formado por especialistas con experiencia en osteoporosis inducida por glucocorticoides (OIG), quienes estuvieron a cargo de la votación basada en la evidencia. El segundo equipo estuvo a cargo de la metodología coordinando y supervisando cada etapa. Realizamos dos revisiones sistemáticas: la primera incluyó ensayos de fármacos utilizados en OIG para analizar el T-score considerado como criterio de inclusión. En la segunda, analizamos la evidencia sobre umbrales densitométricos para la discriminación de pacientes fracturados y no fracturados bajo tratamiento con GC. Resultados: En la primera revisión se incluyeron 31 artículos donde se halló que más de 90% de los ensayos incluyeron pacientes independientemente del T-score o en el rango de osteopenia. En la segunda revisión se incluyeron cuatro artículos donde observamos que más de 80% de los valores de T-score se encontraban entre -1,6 y -2,0. Conclusiones: Con un acuerdo superior a 80% del panel de expertos, un T-score ≤ -1,7 se consideró el más adecuado para el tratamiento en mujeres posmenopáusicas y hombres mayores de 50 años bajo tratamiento con GC. Este estudio podría ayudar en la decisión terapéutica en pacientes bajo tratamiento con GC sin fracturas, pero ciertamente deberían considerarse otros factores de riesgos de fracturas complementarios.(AU)

Outcome of tocilizumab treatment in corticosteroid-resistant thyroid eye disease / Resultados del tratamiento con tocilizumab en la enfermedad ocular tiroidea resistente a glucocorticoides

Introduction: Thyroid eye disease (TED) is a complex and incompletely understood rare autoimmune disorder.ObjectivesTo analyze the experience and the outcomes obtained with the use of intravenous tocilizumab in the treatment of TED.MethodsA retrospective analysis of adult patients diagnosed with active TED resistant to intravenous corticosteroids treated in a tertiary hospital between May 2012 and May 2021.ResultsEleven patients were included with a mean age of 52±12 (range 35–67) years. Nine patients were female and two were male. Patients received a median of 5±3.2 doses. Twenty out of twenty-four eyes achieved inactivation of TED at week 16. Proptosis response was achieved in 6/8 patients and diplopia response in 3/8 patients. The GO-QOL questionnaire showed clinically significant improvement in 9/11 patients. No serious adverse effects were reported during tocilizumab treatment. One patient required decompressive surgery 15 months after tocilizumab therapy.ConclusionThe results obtained show that the use of tocilizumab in the treatment of this pathology can be a good alternative. (AU)

Introducción: La orbitopatía tiroidea (OT) es una enfermedad rara autoinmune compleja que no se conoce completamente.ObjetivosAnalizar la experiencia y los resultados obtenidos con el uso de tocilizumab intravenoso en el tratamiento de la OT.MétodosAnálisis retrospectivo de pacientes adultos diagnosticados de OT activa resistente a glucocorticoides por vía intravenosa tratados en un hospital terciario entre mayo del 2012 y mayo del 2021.ResultadosSe incluyó a 11 pacientes con una edad media de 52±12 (rango 35 a 67) años. Nueve pacientes eran mujeres y 2, hombres. Los pacientes recibieron una mediana de 5±3,2 dosis. Veinte de 24 ojos lograron la inactivación de la OT en la semana 16. Se logró respuesta a la proptosis en 6/8 pacientes y respuesta a diplopía en 3/8 pacientes. El cuestionario GO-QoL mostró una mejora clínicamente significativa en 9/11 pacientes. No se notificaron efectos adversos graves durante el tratamiento con tocilizumab. Un paciente requirió cirugía descompresiva 15 meses después del tratamiento con tocilizumab.ConclusionesLos resultados obtenidos muestran que el uso de tocilizumab en el tratamiento de esta enfermedad puede ser una buena alternativa. (AU)

Development of a web tool to calculate the cumulative dose of glucocorticoids.

INTRODUCTION: Glucocorticoids are associated with serious side effects related to dosing and time of use. Unfortunately, there is no standard method for determining glucocorticoid exposure, especially in patients undergoing long-term treatment. OBJECTIVE: The aim of this work was to create a free and easy-to-use web application to calculate, in a systematic way, the total cumulative dose of corticosteroids. METHODS: The total cumulative dose is calculated as the sum of all periods of treatment with different doses of corticosteroids, and is expressed as the equivalent dose of prednisone in mg. Glucocorticoid doses during periods in which the available information is missing or incomplete are estimated by systematic assumptions. RESULTS: A simulation exercise using standard patterns of steroid use in polymyalgia rheumatica, and giant cell arteritis showed that even when the period of no information reached 50% of the time, the accuracy of the calculator had a mean absolute percentage error (MAPE)<7%. CONCLUSION: This tool simplifies and standardizes the glucocorticoids cumulative dose calculation, thereby minimizing bias in the assessment of glucocorticoid cumulative dose.

Brief review of pathophysiological disorders as consequence of psychological stress / Breve revisión de los trastornos fisiopatológicos como consecuencia del estrés psicológico

Background: Psychological stress is a reaction to an unexpected situation that favours adaptation and response to the event. However, when psychological stress is chronic or very intense, it can induce changes in various systems and tissues, causing diseases or aggravating existing ones. Objective: To briefly analyse the pathophysiological conditions caused by psychological stress. Method: A narrative review of the scientific literature on pathophysiological conditions as a consequence of psychological stress was performed. Results: Psychological stress can induce various conditions at the gastrointestinal, immune and cardiovascular levels. This is mainly due to the neurobiological and endocrine response because when faced with a stressful stimulus, a deregulated release of glucocorticoids and catecholamines is generated, altering the normal physiology of the organism. Gastrointestinal disorders are mainly due to goblet cell dysfunction, resulting in intestinal hyperpermeability, inflammation and infection. Changes at the immune level lead to an increase in inflammatory responses but a decrease in the protective activities of the immune system. Finally, cardiovascular conditions include atherosclerosis, increased blood pressure and stroke. Conclusion: Psychological stress can induce real physiological pathologies and, in some cases, fatal ones. Some of the molecular mechanisms involved in these pathologies have already been studied and identified. Knowledge of these molecular mechanisms can help clinicians and therapists to improve the treatment and therapy of patients.

Introducción: El estrés psicológico es una respuesta a una situación inesperada que favorece la adaptación y la respuesta ante dicho evento. Sin embargo, cuando el estrés psicológico es crónico o muy intenso, se pueden desencadenar afecciones en diversos sistemas y tejidos, generando enfermedades o empeorando las ya existentes. Objetivo: Analizar brevemente las afecciones fisiopatológicas causadas por el estrés psicológico. Método: Se realizó una revisión narrativa con la literatura científica sobre las afecciones fisiopatológicas debidas al estrés psicológico. Resultados: El estrés psicológico puede desencadenar diversas afecciones a nivel gastrointestinal, inmunitario y cardiovascular. Esto se debe principalmente a la respuesta neurobiológica y endócrina, ya que ante estímulos estresores, se genera una liberación desregulada de glucocorticoides y catecolaminas que alteran la fisiología normal del organismo. Las afecciones a nivel gastrointestinal se deben principalmente a la disfunción de las células caliciformes, dando como consecuencia hiperpermeabilidad intestinal, inflamación e infecciones. Las alteraciones a nivel inmunitario generan un aumento en las respuestas inflamatorias pero una reducción en las actividades protectoras del sistema inmune. Por último, las afecciones cardiovasculares incluyen ateroesclerosis, aumento de la presión arterial y derrames cerebrales, entre otros. Conclusión: El estrés psicológico puede causar patologías fisiológicas reales y, en algunos casos, mortales. Algunos de los mecanismos moleculares implicados en estas patologías ya han sido estudiados y establecidos. Conocer estos mecanismos moleculares puede ayudar a los médicos y terapeutas a mejorar el tratamiento y la terapia del paciente.

Development of a web tool to calculate the cumulative dose of glucocorticoids / Desarrollo de una herramienta web para calcular la dosis acumulada de corticoides

Introduction: Glucocorticoids are associated with serious side effects related to dosing and time of use. Unfortunately, there is no standard method for determining glucocorticoid exposure, especially in patients undergoing long-term treatment. Objective: The aim of this work was to create a free and easy-to-use web application to calculate, in a systematic way, the total cumulative dose of corticosteroids. Methods: The total cumulative dose is calculated as the sum of all periods of treatment with different doses of corticosteroids, and is expressed as the equivalent dose of prednisone in mg. Glucocorticoid doses during periods in which the available information is missing or incomplete are estimated by systematic assumptions. Results: A simulation exercise using standard patterns of steroid use in polymyalgia rheumatica, and giant cell arteritis showed that even when the period of no information reached 50% of the time, the accuracy of the calculator had a mean absolute percentage error (MAPE)<7%. Conclusion: This tool simplifies and standardizes the glucocorticoids cumulative dose calculation, thereby minimizing bias in the assessment of glucocorticoid cumulative dose.(AU)

Introducción: Los glucocorticoides se asocian con efectos secundarios graves, relacionados con dosis y tiempo de uso. Desafortunadamente, no existe un método estándar disponible para determinar el nivel de exposición a glucocorticoides en tratamientos prolongados. Objetivo: Crear una aplicación web gratuita y fácil de usar para calcular, de forma sistematizada, la dosis acumulada de glucocorticoides. Métodos: La dosis acumulada se calcula como la suma de todos los períodos de tratamiento con diferentes dosis, y se expresa como la dosis equivalente de prednisona en mg. La dosis durante los períodos en los que la información no está disponible o está incompleta se estima mediante asunciones sistematizadas. Resultados: Un ejercicio de simulación utilizando patrones estándar de uso de esteroides en la polimialgia reumática y la arteritis de células gigantes demostró que, incluso cuando el período de ausencia de información alcanzaba el 50% del tiempo, la precisión de la calculadora tenía un porcentaje de error medio absoluto (MAPE)<7%. Conclusión: Esta herramienta simplifica y estandariza el cálculo de la dosis acumulativa de glucocorticoides, minimizando el sesgo del cálculo.(AU)

Outcome of tocilizumab treatment in corticosteroid-resistant thyroid eye disease.

INTRODUCTION: Thyroid eye disease (TED) is a complex and incompletely understood rare autoimmune disorder. OBJECTIVES: To analyze the experience and the outcomes obtained with the use of intravenous tocilizumab in the treatment of TED. METHODS: A retrospective analysis of adult patients diagnosed with active TED resistant to intravenous corticosteroids treated in a tertiary hospital between May 2012 and May 2021. RESULTS: Eleven patients were included with a mean age of 52±12 (range 35-67) years. Nine patients were female and two were male. Patients received a median of 5±3.2 doses. Twenty out of twenty-four eyes achieved inactivation of TED at week 16. Proptosis response was achieved in 6/8 patients and diplopia response in 3/8 patients. The GO-QOL questionnaire showed clinically significant improvement in 9/11 patients. No serious adverse effects were reported during tocilizumab treatment. One patient required decompressive surgery 15 months after tocilizumab therapy. CONCLUSION: The results obtained show that the use of tocilizumab in the treatment of this pathology can be a good alternative.

Osteonecrosis múltiple inducida por glucocorticoides / Multiple osteonecrosis induced bye glucocorticoids / Osteonecrose múltipla induzida por glicocorticóides

La osteonecrosis múltiple es una entidad poco frecuente que se define por el compromiso de al menos tres regiones diferentes. Es indispensable el abordaje multidisciplinario de los pacientes que la padecen tanto para el diagnóstico como el tratamiento oportuno. Presentamos el caso clínico de un paciente joven que presenta una osteonecrosis múltiple con compromiso de ambas caderas, hombros, rodillas, codo derecho y cuello de pie izquierdo. El principal factor de riesgo presente en nuestro caso es el consumo de glucocorticoides.

Multiple osteonecrosis is a rare entity that is defined by the involvement of at least three different regions. A multidisciplinary approach to patients who suffer from it is essential for both diagnosis and timely treatment. We present the clinical case of a young patient who presented multiple osteonecrosis with involvement of both hips, shoulders, knees, right elbow, and neck of the left foot. The main risk factor present in our case is the consumption of glucocorticoids.

A osteonecrose múltipla é uma entidade rara que se define pelo envolvimento de pelo menos três regiões diferentes. Uma abordagem multidisciplinar aos pacientes que sofrem com isso é essencial para o diagnóstico e tratamento oportuno. Apresentamos o caso clínico de um paciente jovem que apresenta osteonecrose múltipla envolvendo quadris, ombros, joelhos, cotovelo direito e pescoço do pé esquerdo. O principal fator de risco presente no nosso caso é o consumo de glicocorticóides.