Crisis adrenal asociada al uso de modafinilo / Adrenal crisis associated with modafinil use

Resumen La crisis adrenal es la forma más extrema de presentación de la insuficiencia adrenal y representa una urgencia endocrinológica que llega a poner en riesgo la vida. Esta situación puede ser des encadenada por diferentes causas, entre las cuales se incluye el uso de fármacos inductores del CYP3A4, que aceleran la depuración de la hidrocortisona. Describimos el caso de una mujer de 85 años, con antecedentes de insuficiencia adrenal secundaria y enfermedad renal crónica, que presentó síntomas compatibles con crisis adrenal (astenia, adinamia, hiponatremia grave con síntomas neurológicos e hipotensión arterial) luego de nueve días del inicio de tratamiento con modafinilo. El cuadro clínico mejoró rápidamente con la suspensión del modafinilo y la administración de hidrocortisona endovenosa. Luego de descartar las posibles causas desencadenantes (infecciosas, isquémicas, tromboembolismo pulmonar y omisión en la toma de hidrocortisona), se interpretó que el modafinilo precipitó los síntomas de insuficiencia adrenal al aumentar la depuración del corticoide. El modafinilo tiene la capacidad de inducir la actividad del CYP3A4 y, en consecuencia, disminuir la biodisponibilidad de la hidrocortisona. Recalcamos la necesidad de ajustar la dosis de reemplazo de corticoides en sujetos que reciben fármacos inductores del metabolismo.

Abstract Adrenal crisis is the most extreme presentation form of adrenal insufficiency and represents a life-threatening endocrinological emergency. This situation can be triggered by different causes including the use of CYP3A4-inducing drugs, which accelerate hydrocortisone clearance. We describe the case of an 85-year-old woman with secondary adrenal insufficiency and chronic renal disease, who presented symptoms compatible with adrenal crisis (asthenia, adynamia, severe hyponatremia associated with neurological symptoms and hypotension) nine days after the start of modafinil treat ment. The clinical picture improved rapidly with the suspension of modafinil and the administration of intravenous hydrocortisone. After ruling out the possible triggering causes (infectious, ischemic, pulmonary thromboembo lism and failure to take hydrocortisone), it was interpreted that modafinil precipitated the symptoms of adrenal insufficiency by increasing the steroid clearance. Modafinil has the ability to induce the activity of CYP3A4 and consequently decrease the bioavailability of hydrocortisone. We emphasize the need to adjust steroid dose re placement in subjects receiving metabolism-inducing drugs.

Adverse drug reactions associated with treatment in patients with chronic rheumatic diseases in childhood: a retrospective real life review of a single center cohort

Abstract Background: Adverse drug reactions (ADRs) are the sixth leading causes of death worldwide; monitoring them is fundamental, especially in patients with disorders like chronic rheumatic diseases (CRDs). The study aimed to describe the ADRs investigating their severity and associated factors and resulting interventions in pediatric patients with CRDs. Methods: A retrospective, descriptive and analytical study was conducted on a cohort of children and adolescents with juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM). The study evaluated medical records of the patients to determine the causality and the management of ADRs. In order to investigate the risk factors that would increase the risk of ADRs, a logistic regression model was carried out on a group of patients treated with the main used drug. Results: We observed 949 ADRs in 547 patients studied. Methotrexate (MTX) was the most frequently used medication and also the cause of the most ADRs, which occurred in 63.3% of patients, followed by glucocorticoids (GCs). Comparing synthetic disease-modifying anti-rheumatic drugs (sDMARDs) vs biologic disease-modifying antirheumatic drugs (bDMARDs), the ADRs attributed to the former were by far higher than the latter. In general, the severity of ADRs was moderate and manageable. Drug withdrawal occurred in almost a quarter of the cases. In terms of risk factors, most patients who experienced ADRs due to MTX, were 16 years old or younger and received MTX in doses equal or higher than 0.6 mg/kg/week. Patients with JIA and JDM had a lower risk of ADRs than patients with JSLE. In the multiple regression model, the use of GCs for over 6 months led to an increase of 0.5% in the number of ADRs. Conclusions: Although the ADRs highly likely affect a wide range of children and adolescents with CRDs they were considered moderate and manageable cases mostly. However, triggers of ADRs need further investigations.(AU)

Intercellular mediators in bone remodeling regulation in the experimental renal pathology / Mediadores intercelulares de la regulación de la remodelación ósea en un modelo experimental de patología renal

Bone metabolism disorders are characterized by an imbalance of bone resorption and formation in the bone remodeling process. Glucocorticoids that are used to treat kidney diseases exacerbate these disorders. P-selectin and galectin-3 are molecules involved in the sclerotic process in kidney, whereas bone resorption is regulated by the interaction between the nuclear factor activator kappa b receptor (RANK), its ligand (RANKL) and the RANKL decoy receptor osteoprotegerin (OPG). The aim of this study was to investigate the cellular and molecular mechanisms of disruption of bone remodeling regulation processes, reflected by intercellular mediators (RANKL, OPG, P-selectin and galectin-3) in chronic kidney disease experimental model treated with glucocorticoids. Rats were divided into four groups of 10 animals each. The first group, the control group, included intact animals. The second group consisted of rats with impaired bone remodeling resulting from chronic kidney disease (experimental group (CKD). The third group was a group of animals with impaired bone remodeling due to exposure to glucocorticoids (experimental group (GCs)). The fourth group consisted of rats with impaired bone remodeling in chronic kidney disease, followed by exposure to glucocorticoids (experimental group (CKD + GCs)). The effects of CKD and glucocorticoid were evaluated biochemically, histologically and by measuring bone density. An enzymelinked immunoassay was used to measure intercellular mediator levels in the serum. The bone density in the experimental groups was reduced compared to the control group. RANKL levels in animals of three experimental groups were higher than in intact animals. Serum levels of OPG were higher in CKD and GCs groups than in intact animals. At the same time, in the animals' blood serum of the CKD + GCs group, the levels of OPG were lower, than those in animals from the control group. The levels of galectin-3 in the serum of the experimental groups GCs and CKD + GCs were lower than in intact animals. The serum levels of galectin-3 in animals of the CKD group were higher than those in animals from the control group. The levels of P-selectin were lower in the serum of the GCs group than in intact animals. At the same time, the levels of P-selectin were higher in the CKD and CKD + GCs groups, than those in animals from the control group. In conclusion, the study of the complex system of bone remodeling regulation, which includes many factors and their interactions, may lead to the development of new methods for treating patients with chronic kidney disease in order to prevent osteoporosis in the future. (AU)

Las enfermedades metabólicas óseas se caracterizan por un desequilibrio en el proceso de remodelación ósea en los que participan mediadores tales como receptor del activador del factor nuclear- kappa- b (RANK), su ligando (RANKL) y la osteoprotegerina (OPG). Los glucocorticoides, recuentemente empleados en el tratamiento de la enfermedad renal crónica, exacerban este desequilibrio. En la enfermedad esclerótica renal, las moléculas de adhesión celular P-selectina and galectina-3 tienen un rol fundamental. El objetivo de esta trabajo fue estudiar las alteraciones en los mediadores de la remodelación ósea (RANKL, OPG, P-selectina and galectina-3) en un modelo de enfermedad renal crónica con tratamiento glucocorticoideo. Ratas Wistar hembras fueron divididos en 4 grupos: control (C); enfermedad renal crónica con afección de la remodelación ósea (ERC); animales con afección de la remodelación ósea expuestos a glucocorticoides (GC); enfermedad renal crónica con afección de la remodelación ósea tratados con glucocorticoides (ERC+GC). Los efectos de la ERC y los GC fueron evaluados bioquímicamente, histológicamente y por medición de la densidad ósea. RANKL, OPG, Pselectina and galectina-3 se cuantificaron en muestras de sangre venosa empleando enzimoinmuno análisis. En los 3 grupos experimentales la densidad ósea se evidenció reducida y los niveles séricos de RANKL elevados respecto al grupo control. Los niveles de OPG en los grupos ERC y GC fueron superiores mientras que en el grupo ERC+GC menores respecto a los animales controles. Galectina 3 plasmática en GC y ERC+GC se encontró reducida y aumentada en los animales ERC, en comparación con los animales controles. La concentración sérica de P-selectina sérica fue mayor en los grupos ERC y ERC+GC, y menor en los animales GC respecto a los niveles plasmáticos de los animales intactos. El avance del conocimiento sobre la regulación de la remodelación ósea a través de la interacción de mediadores sistémicos, en un futuro, puede conducir al desarrollo de nuevas estrategias terapéuticas para la prevención de la osteoporosis en pacientes con enfermedad renal crónica. (AU)

Rheumatoid arthritis and sleep quality / Artrite reumatoide e qualidade do sono

ABSTRACT Background: Sleep disturbances are common in rheumatoid arthritis (RA) patients and contribute to loss of life quality. Objective: To study associations of sleep quality with pain, depression and disease activity in RA. Methods: This is a transversal observational study of 112 RA patients submitted to measurement of DAS-28, Epworth scale for daily sleepiness, index of sleep quality by Pittsburg index, risk of sleep apnea by the Berlin questionnaire and degree of depression by the CES-D (Center for Epidemiologic Studies Depression scale) questionnaire. We also collected epidemiological, clinical, serological and treatment data. Results: Only 18.5% of RA patients had sleep of good quality. In univariate analysis a bad sleep measured by Pittsburg index was associated with daily doses of prednisone (p = 0.03), DAS-28 (p = 0.01), CES-D (p = 0.0005) and showed a tendency to be associated with Berlin sleep apnea questionnaire (p = 0.06). In multivariate analysis only depression (p = 0.008) and Berlin sleep apnea questionnaire (p = 0.004) kept this association. Conclusions: Most of RA patients do not have a good sleep quality. Depression and risk of sleep apnea are independently associated with sleep impairment.

RESUMO Antecedentes: Os distúrbios do sono são comuns em pacientes com artrite reumatoide (AR) e contribuem para a perda da qualidade de vida. Objetivo: Estudar as associações entre a qualidade do sono e a dor, depressão e atividade da doença na AR. Métodos: Estudo observacional transversal com 112 pacientes com AR submetidos à avaliação do DAS-28, escala de Epworth para sonolência diurna, qualidade do sono pelo índice de Pittsburg, risco de apneia do sono pelo questionário de Berlim e grau de depressão pelo questionário CES-D (Center for Epidemiologic Studies Depression). Também foram coletados dados epidemiológicos, clínicos, sorológicos e de tratamento. Resultados: Apenas 18,5% dos pacientes com AR tinham uma boa qualidade do sono. Na análise univariada, um sono ruim medido pelo índice de Pittsburg esteve associado à dose diária de prednisona (p = 0,03), DAS-28 (p = 0,01), CES-D (p = 0,0005) e mostrou uma tendência a estar associado à apneia do sono pelo questionário de Berlim (p = 0,06). Na análise multivariada, somente a depressão (p = 0,008) e a apneia do sono pelo questionário de Berlim (p = 0,004) mantiveram essa associação. Conclusões: A maior parte dos pacientes com AR não tem uma boa qualidade de sono. A depressão e o risco de apneia do sono estão independentemente associados ao comprometimento do sono.

Doença óssea induzida pelos glicocorticoides: mecanismos e importância na prática pediátrica / Glucocorticoid-induced bone disease: mechanisms and importance in pediatric practice

RESUMO Objetivo: Descrever os mecanismos pelos quais os glicocorticoides provocam osteoporose, com risco consequente de fraturas, integrando esse conhecimento a uma possível mudança de conduta dos profissionais de saúde. Fontes de dados: Foi realizada pesquisa aprofundada nas bases de dados (SciELO, PubMed, Medline e Scopus), buscando consensos, artigos de revisão, incluindo revisões sistemáticas e meta-análises, publicados em inglês, entre 2000 e 2016. As palavras-chaves utilizadas na busca foram glicocorticoides, esteroides, fraturas, osteoporose, saúde óssea, crianças e adolescentes. Síntese dos dados: A revisão foi dividida em quatro tópicos principais: 1) introdução, com breve enfoque nas fraturas em pediatria; 2) osteoporose em crianças e adolescentes, destacando-a como causa silenciosa de fraturas; 3) glicocorticoides e doença óssea secundária, com a descrição dos mecanismos deletérios desse grupo de esteroides na estrutura óssea; 4) efeitos moleculares do excesso de glicocorticoides no osso, com o detalhamento dos mecanismos nocivos a nível molecular do tecido ósseo. Conclusões: Os glicocorticoides em excesso determinam doença óssea precoce, favorecendo a ocorrência de fraturas. Dessa forma, uma criança ou adolescente que requer corticoterapia, sobretudo crônica e sistêmica, mas também em ciclos repetidos com doses cumulativas altas, necessita de cuidados e orientações relacionados à saúde óssea logo ao início do tratamento. Por outro lado, aqueles com fratura, mesmo entrelaçada a um trauma, podem sinalizar fragilidade óssea subjacente e desconhecida, incluindo a secundária ao uso de glicocorticoides e à deficiência de vitamina D.

ABSTRACT Objective: To describe mechanisms by which glucocorticoids cause osteoporosis, with fracture risk, combining this learning with a possible professional behavior change. Data sources: A systematic search on SciELO, PubMed, Scopus, and Medline databases was carried out for consensus, review articles, including systematic reviews and meta-analysis, which were published in English, between 2000 and 2016. Keywords used on the search were the following: glucocorticoids, fractures, osteoporosis, bone health, vitamin D, children, and adolescents. Data synthesis: The review was divided into four topics: 1) introduction, with a brief focus on pediatric fractures; 2) osteoporosis in children and adolescents, highlighting it as a silent cause of fractures; 3) glucocorticoids and secondary bone disease, describing deleterious mechanisms of this steroids group on bone structure; 4) molecular effects of glucocorticoids excess on bone, with details about the harmful mechanisms on bone molecular level. Conclusions: Glucocorticoids excess determines early bone disease, favoring the occurrence of fractures. Thus, a child or an adolescent who uses glucocorticoids, especially systemically and chronically, but also repeats cycles at high cumulative doses of the medication, needs care and guidance related to bone health at the onset of treatment. On the other hand, the presence of fractures, even if related to trauma, can be a sign of underlying and unknown bone fragility, which may be secondary to the use of glucocorticoids and/or vitamin D deficiency.

Eficacia y seguridad del uso de tocilizumab para el tratamiento de artritis idiopatica juvenil en pacientes con falla alt ratamiento con aines, glucocorticoides y farmes / Efficacy and safety of the use of tocilizumab for the treatment of juvenile idiopathic arthritis in patients with failure to treat with aines, glucocorticoids and pharmacies

INTRODUCCIÓN: Antecedentes: El presente dictamen responde a la solicitud de evaluación del uso fuera del petitorio de tocilizumab para el tratamiento de pacientes con Artritis Idiopática Juvenil refractarios a tratamiento con FARMES. La Artritis Idiopática Juvenil (AIJ) engloba varios tipos de artritis crónica cuyo inicio se da antes de los 16 años, y está dada de manera general por un mal funcionamiento del sistema inmune que resulta en producción excesiva de moléculas pro-inflamatorias dirigidas principalmente a la membrana (revestimiento de las articulaciones). Tecnologia Sanitaria de Interés: Tocilizumab, con nombre comercial Actemra, es un anticuerpo monoclonal recombinante humanizado contra el receptor de interleucina-6 (IL-6). Este anticuerpo se une a los receptores de IL-6 que se encuentran en las membranas celulares o disueltos en el plasma, interrupiendo la unión de la IL-6 con su receptor en los tejidos. La IL-6 es una citoquina pro-inflamatoria secretada por células del sistema inmune, y que participa en diversas patologias asociadas a procesos inflamatorios. Tocilizumab ejerce su acción bloqueando los receptos de IL-6 de tal manera que no pued ser activada la cascada de señalización intracelular que lleva a la inflamación de los tejidos. METODOLOGÍA: Estrategia de Busqueda: Se utilizó el motor de búsqueda Pubmed empleando el algoritmo mostrado en la subsección B y los filtros correspondientes a meta-análisis, revisiones sistemáticas y ensayos clínicos, en línea con los criterios de elegibilidad. Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad de tocilizumab para el tratamiento de Artritis Idiopática Juvenil de varidad sistémica. La búsqueda se inició revisando la información sobre el uso del medicamento de acuerdo con entidades reguladoras como la Food And Drug Administration (FDA), la European Medicines Agency (EMA) y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriormente, se revisaron las bases de datos de PubMed, TRIPDATABASE y www.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas wev de grupos dedicados a la invstigación y educación en salud en general como The National Institute for Health and Care Excellence (NICE); y especializados en Enfermedades Reumatoides como el American College or Rheumatology (ACR). RESULTADOS: Sinopsos de la Evidencia: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de tocilizumab como tratamiento de pacientes con Artritis Idiopática Juvenil varidad sistémica refractaria a tratamiento convencional con AINEs, corticoides y FARMEs. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: La GPC y la ETS recomiendan el uso de tocilizumab como una alternativa de tratamiento de AIJ sistémica en niños mayores de 2 años quienes han presentado una respuesta inadecuada a AINEs, corticosteroides sistémicos y metotrexato (FARME). Tocilizumab presenta una mayor frecuencia de eventos adversos moderados y severos en comparación con placebo. Sin embargo, estos son controlables. Tocilizumab no está recomendado para el tratamiento de pacientes mayores de 2 años con AIJ que responden al tratamiento con metotrexato o no han sido tratados con metotrexato previamente. El Instituto de Evaluaciones de Tecnologías en Salud e Investigación-IETSI, aprueba el uso de tocilizumab para el manejo de los pacientes con diagnóstico de AIJ variedad sistémica refractaria a AINEs corticosteroides y FARMEs.

Tenosinovitis química de dedo medio por corticoides intraarticulares con evolución a síndrome compartimental en paciente con lupus eritematoso sistémico / Chemical tenosynovitis in middle finger after intra-articular corticosteroids infiltration evolving to compartment syndrome in a patient with systemic lupus erythematosus

Tenosynovitis is the inflammation of the tendon and synovial sheath. It is commonly affects hands and wrist. The etiology may be infectious or inflammatory. In patients with Systemic Lupus Erythematosus (SLE) the periarticular and tendinous commitment is frequent. Intra-articular corticosteroids (CO) are effective as adjuvant of the systemic therapy. Complications of use are infrequent. The case of a female patient is presented, 32 years old, with SLE and chronic renal failure secondary to lupus nephritis, chronic user of oral CO. She is infiltrates with intra-articular deposit betamethasone in metacarpal-phalangeal (MCP), because of articular edema. Twelve days later evolves with Compartment Syndrome (SC). Fasciotomy show findings compatible with chemical synovitis by betamethasone crystals. Currently there are quite few reports in the literature of CS with presentation in fingers. The diagnosis is mainly clinical. The common use of intra-articular CO is not without risk and should be planned and diagnosed early...

Tenosinovitis es la inflamación del tendón y vaina sinovial. Es más frecuente en manos y muñecas. Su etiología es infecciosa o inflamatoria. En pacientes con Lupus Eritematoso Sistémico (LES) el compromiso periarticular y tendíneo es frecuente. Los corticoides (CO) intraarticulares son efectivos como adyuvante de terapia sistémica. Las complicaciones de su uso son infrecuentes. Se presenta el caso de paciente sexo femenino, 32 años, con LES e insuficiencia renal crónica secundaria a nefropatía lúpica, usuaria de CO orales. Por edema articular se le infiltra betametasona de depósito intraarticular en metacarpo-falángica (MCF). Evoluciona doce días después con Síndrome Compartimental (SC). Durante la fasciotomía se evidencian hallazgos compatibles con sinovitis química por cristales de betametasona. Existe escaso reporte en la literatura de SC en dedos de la mano. El diagnóstico es principalmente clínico. El uso común de CO intraarticulares no está exento de riesgos y deben ser previstos y diagnosticados precozmente...

Infecciones en pacientes reumatológicos asociadas a corticosteroides y antagonistas del factor de necrosis tumoral α / Infections in patients affected by rheumatologic diseases associated to glucocorticoid use or tumor necrosis factor-alpha inhibitors

A great diversity of infectious agents can affect patients that use steroids at immunosuppressive doses or tumor necrosis factor α (TNF-α) antagonists. The list of participating microorganisms is more restricted in the case of anti TNF-α blockers. Overlapping agents include intracellular bacteria, Mycobacterium tuberculosis, geographic fungal agents that have the ability to establish granulamotous infections, herpes zoster, and reactivation of chronic hepatitis B virus infection. An important conceptual issue for these infections is the existence of a threshold prednisone daily dose for the emergence of opportunistic infections but higher levels of immunosuppression and cofactors are required in the case of Pneumocystis jiroveci and cytomegalovirus infections. In order to prevent these threats, a detailed medical evaluation is needed before prescription to detect potential risks and manage them properly. Prevention rules must be prescribed in every case, that include common sense behaviors, vaccines, and in selected cases, chemoprophylaxis for latent tuberculosis (TB) infection, P. jiroveci pneumonia (PCP) or other specific requirements. Latent TB infection is probable and requires chemoprophylaxis in the case of remote or recent exposure to a patient with lung TB, a positive tuberculin or interferon-gamma release assay result or residual lung scars in a chest x-ray exam. PCP prevention is suggested when the patient reaches a daily dose of prednisone of 30 mg but might be needed at lower doses in case of other concomitant immunosuppressive drugs or when lymphopenia arises shortly after prednisone initiation.

Una gran diversidad de agentes infecciosos puede afectar a los pacientes que usan corticosteroides en dosis inmunosupresoras o antagonistas del factor de necrosis tumoral o (FNTα). La lista de microorganismos participantes es más restringida en el caso de los bloqueadores del FNTα. Los agentes que se sobreponen incluyen bacterias intracelulares, Mycobacterium tuberculosis, hongos geográficos que son capaces de establecer infecciones granulomatosas, herpes zoster y reactivación de hepatitis crónica por virus de hepatitis B. Existe una dosis umbral diaria de prednisona (o equivalente), sobre la cual emergen estas infecciones oportunistas, pero el nivel de inmunosupresión parece ser más alto en el caso de Pneumocystis jiroveci o citomegalovirus. Para prevenir estas amenazas, se requiere una evaluación médica detallada antes de su prescripción para detectar riesgos potenciales y manejarlos apropiadamente. Se deben indicar medidas de prevención en cada caso, las que incluyen conductas de sentido común y en casos seleccionados, quimioprofilaxis para infección latente por tuberculosis (TBC), neumonía por P. jiroveci u otros requerimientos específicos. La existencia de TBC latente es probable en el caso de exposición reciente o remota a un bacilífero pulmonar, prueba de tuberculina o de liberación de interferón γ positiva, o lesiones residuales en la radiografía de tórax. La prevención de neumonía por P. jiroveci se recomienda cuando se usan al menos 30 mg de prednisona al día pero puede ser necesario a dosis menores si se aplican otros fármacos inmunosupresores concomitantes o si aparece linfopenia poco después del inicio de los corticosteroides.

The impact of glucocorticoids and anti-cd20 therapy on cervical human papillomavirus infection risk in women with systemic lupus erythematosus

OBJECTIVE: To identify the prevalence and factors associated with cervical human papillomavirus infection in women with systemic lupus erythematosus METHODS: This cross-sectional study collected traditional and systemic lupus erythematosus-related disease risk factors, including conventional and biologic therapies. A gynecological evaluation and cervical cytology screen were performed. Human papillomavirus detection and genotyping were undertaken by PCR and linear array assay. RESULTS: A total of 148 patients were included, with a mean age and disease duration of 42.5±11.8 years and 9.7±5.3 years, respectively. The prevalence of squamous intraepithelial lesions was 6.8%. The prevalence of human papillomavirus infection was 29%, with human papillomavirus subtype 59 being the most frequent. Patients with human papillomavirus were younger than those without the infection (38.2±11.2 vs. 44.2±11.5 years, respectively; p = 0.05), and patients with the virus had higher daily prednisone doses (12.8±6.8 vs. 9.7±6.7 mg, respectively; p = 0.01) and cumulative glucocorticoid doses (14.2±9.8 vs. 9.7±7.3 g, respectively; p = 0.005) compared with patients without. Patients with human papillomavirus infection more frequently received rituximab than those without (20.9% vs. 8.5%, respectively; p = 0.03). In the multivariate analysis, only the cumulative glucocorticoid dose was associated with human papillomavirus infection. CONCLUSIONS: The cumulative glucocorticoid dose may increase the risk of human papillomavirus infection. Although rituximab administration was more frequent in patients with human papillomavirus infection, no association was found. Screening for human papillomavirus infection is recommended in women with systemic lupus erythematosus. .

Exercício físico previne alterações cardiometabólicas induzidas pelo uso crônico de glicocorticóides / Exercise prevents cardiometabolic alterations induced by chronic use of glucocorticoids

FUNDAMENTO: Cronicamente, os glicocorticóides induzem alterações cardiometabólicas adversas, incluindo resistência à insulina, diabete, dislipidemia, esteatose hepática e hipertensão arterial. OBJETIVOS: Avaliar o efeito da prática regular de exercício físico aeróbio sobre as alterações cardiometabólicas induzidas por administração crônica de dexametasona (Dex - 0,5 mg/kg/dia i.p) em ratos. MÉTODOS: Ratos Wistar machos (n = 24) foram divididos em quatro grupos: Grupo controle; Grupo treinado; Grupo tratado com Dex e Grupo tratado com Dex e treinado. O treinamento físico (iniciado 72 horas após a primeira dose de Dex) foi realizado 3 vezes por semana, até o final do tratamento. Ao final desse período, realizaram-se as seguintes avaliações bioquímicas: glicemia em jejum, teste de tolerância à glicose e análise do perfil lipídico no sangue que incluiu colesterol total (CT), LDL-c, HDL-c, VLDL-c e triglicerídeos (TG). O peso do músculo gastrocnêmio, análise histopatológica do fígado e os índices cardiometabólicos (CT/HDL-c, LDL-c/HDL-c e TG/HDL-c) também foram avaliados. RESULTADOS: Observou-se hiperglicemia, menor tolerância à glicose, elevação do CT, LDL-c, VLDL-c e TG, diminuição do HDL-c, presença de esteatose hepática, hipotrofia muscular e elevação dos índices CT/HDL-c, LDL-c/HDL-c e TG/HDL-c nos animais tratados com Dex. O exercício físico reduziu a hiperglicemia, melhorou a tolerância à glicose, reduziu a dislipidemia e preveniu a esteatose hepática , a hipotrofia muscular e reduziu os índices CT/HDL-c, LDL-c/HDL-c e TG/HDL-c. Entretanto, não houve efeito significante do treinamento físico sobre o HDL-c. CONCLUSÃO: O exercício físico aeróbio tem efeito protetor contra as alterações cardiometabólicas induzidas pelo uso crônico de glicocorticóides.

BACKGROUND: Chronically, glucocorticoids induce adverse cardiometabolic alterations including insulin resistance, diabetes, dyslipidemia, liver steatosis and arterial hypertension. OBJECTIVES: To evaluate the effect of regular practice of aerobic exercise on cardiometabolic alterations induced by chronic administration of dexamethasone (Dex - 0.5 mg/kg/day ip) in rats. METHODS: Male Wistar rats (n = 24) were divided in four groups: Control group; Trained group; Treated with Dex group and Treated with Dex and trained group. The exercise training (initiated 72 hours after the first dose of Dex) was carried out three times a week until the end of the treatment. At the end of this period, the following biochemical assessments were performed: fasting glycemia, oral glucose tolerance test and analysis of the blood lipid profile that included total cholesterol (TC), LDL-c, HDL-c, VLDL-c and triglycerides (TG). The weight of the gastrocnemius muscle, the histopathological analysis of the liver and cardiometabolic indices (TC/HDL-c, LDL-c/HDL-c and TG/HDL-c) were also performed. RESULTS: Hyperglycemia, lower glucose tolerance, increased TC, LDL-c, VLDL-c, TG, CT/HDL-c, LDL-c/HDL-c and TG/HDL-c, decreased HDL-c, presence of liver steatosis and muscular hypotrophy were observed in the animals treated with Dex. The exercise training reduced hyperglycemia, improved glucose tolerance, decreased dyslipidemia and prevented liver steatosis, muscular hypotrophy and reduced CT/HDL-c, LDL-c/HDL-c and TG/HDL-c ratios. However, there was no significant effect on HDL-c. CONCLUSION: The aerobic exercise training have a protective effect against the cardiometabolic alterations induced by the chronic use of glucocorticoids.

Tratamento com hrGH da baixa estatura induzida pelo uso crônico de glicocorticóide em crianças: [revisão] / hrGH treatment of glucocorticoid-induced short stature in children: [review]

O uso crônico de glicocorticóides no tratamento de doenças sistêmicas causa diminuição da velocidade de crescimento (VC), podendo acarretar perda estatural final. As interações entre o eixo adrenal e o eixo GH-sistema IGF têm sido descritas, podendo ocorrer em nível hipotalâmico-hipofisário e na regulação do sistema IGF, inclusive modulando o sinal do IGF-1R. Pode-se dizer que o quadro clínico deve ser considerado como estado de deficiência de Igf-1, absoluta e/ou funcional. As intervenções que possibilitam a normalização funcional do eixo GH-IGF poderiam reduzir a perda estatural destas crianças. Os estudos realizados em pacientes com artrite reumatóide juvenil em tratamento com corticóides mostraram aceleração da VC e diminuição da perda protéica com o uso de GH recombinante humano (hrGH). A aceleração da VC foi também descrita em pacientes sob corticoterapia crônica por causa da doença intestinal inflamatória ou do transplante renal após o uso de hrGH. A dose de hrGH guarda correlação positiva com a aceleração da VC e os resultados reforçam que esta deficiência funcional do eixo GH-IGF pode ser revertida com a administração de hrGH. O efeito do hrGH é restrito ao período de tratamento e depende do esquema de reposição do hrGH, do estado nutricional e das condições da doença de base.

The treatment of systemic diseases with glucocorticoids is often associated with decreased height velocity (HV), and can result in shorter final height. Interactions between adrenal and GH-IGF axis have been described and can occur at hypothalamic-pituitary level or at the regulation of IGF system, including the IGF1R signaling. The clinical state of these patients may be considered as an absolute and/or functional IGF-1 deficiency. Interventions aiming to restore the normal function of GH-IGF axis might reduce the glucocorticoids-induced growth suppression in these children. It has been shown that recombinant human GH (hrGH) induces an increase in HV and a decrease in protein loss in patients with juvenile idiopathic arthritis treated with glucocorticoids. Significant increment in HV was also described after hrGH treatment in children under glucocorticoid therapy due to inflammatory bowel disease or renal transplantation. There is a positive correlation between HV and the dose of hrGH. The results support that the IGF-1 deficiency in these children may be counteract by hrGH therapy. The effect of hrGH is observed only during the treatment period and depends on the replacement strategy, nutritional status and disease control.

Síndrome de Cushing exógena e retirada de glicocorticóides: [revisão] / Exogenous Cushing's syndrome and glucocorticoid withdrawal: [review]

Glicocorticóides são amplamente utilizados na prática clínica para o controle da atividade de doenças auto-imunes, inflamatórias, alérgicas e outras entidades nosológicas. Doses terapêuticas de glicocorticóides são muita vezes administradas inapropriadamente e isto é um problema particular, pois a terapia crônica tem muitos efeitos colaterais que se estendem desde a supressão do eixo hipotálamo-hipofisário-adrenal e síndrome de Cushing até infecções e alterações do status mental. Fatores que influenciam tanto nos efeitos adversos quanto nos terapêuticos dos glicocorticóides incluem propriedades farmacocinéticas do glicocorticóide, dose diária, diferenças individuais no metabolismo esteróide e duração do tratamento. Quando utilizados para o controle da atividade destas doenças, quatro aspectos da retirada de glicocorticóide merecem atenção especial. Primeiro, a doença tratada pelo esteróide pode recorrer. Segundo, o eixo hipotálamo- hipófise-adrenal pode permanecer suprimido por um longo período. Terceiro, muitas vezes desenvolve-se dependência psicológica a esses hormônios. Quarto, uma síndrome de retirada inespecífica pode desenvolver mesmo enquanto os pacientes estão recebendo doses de reposição fisiológica de glicocorticóides. A gravidade da síndrome de retirada depende da fase e o grau de dependência e inclui sintomas tais como anorexia, náusea, vômitos, perda de peso, fadiga, mialgias, artralgias, cefaléia, dor abdominal, letargia, hipotensão postural, febre e descamação da pele.

Glucocorticoids are widely used in clinical practice to control the activity of autoimmune, inflammatory, allergic diseases and other nosological entities. Therapeutic doses of glucocorticoids are often administered inappropriately and it is a particular problem because chronic therapy has many side effects, ranging from suppression of the hypothalamic-pituitary-adrenal axis and Cushing's syndrome to infections and changes in mental status. Factors influencing both the therapeutic and adverse effects of glucocorticoids include the pharmacokinetic properties of the glucocorticoid, daily dosage, individual differences in steroid metabolism and the duration of treatment. When used to control the activity of these diseases, four aspects of glucocorticoid withdrawal deserve special attention. First, the illness treated by steroids may relapse. Second, the hypothalamic-pituitary-adrenal axis may remain suppressed for a long time. Third, psychological dependence to these hormones often develops. Fourth, a nonspecific withdrawal syndrome may develop even while patients are receiving physiological replacement doses of glucocorticoids. The severity of the withdrawal syndrome depends on the phase and degree of dependence and includes many symptoms as anorexia, nausea, emesis, weight loss, fatigue, myalgias, arthralgias, headache, abdominal pain, lethargy, postural hypotension, fever, and skin desquamation.