Methylprednisolone therapy induces differential metabolic trajectories in severe COVID-19 patients.

IMPORTANCE: The SARS-CoV-2 virus infection in humans induces significant inflammatory and systemic reactions and complications of which corticosteroids like methylprednisolone have been recommended as treatment. Our understanding of the metabolic and metabolomic pathway dysregulations while using intravenous corticosteroids in COVID-19 is limited. This study will help enlighten the metabolic and metabolomic pathway dysregulations underlying high daily doses of intravenous methylprednisolone in COVID-19 patients compared to those receiving placebo. The information on key metabolites and pathways identified in this study together with the crosstalk with the inflammation and biochemistry components may be used, in the future, to leverage the use of methylprednisolone in any future pandemics from the coronavirus family.

Inmunoglobulina humana para el tratamiento de pacientes pediátricos con encefalitis autoinmune, que no mejoran con respuesta a pulsos de metilprednisolona y/o plasmaféresis / Human immunoglobulin for the treatment of pediatric patients with autoimmune encephalitis, who do not improve with response to pulses of methylprednisolone and/or plasmapheresis

INTRODUCCIÓN: Este informe de ETS-R corta se realizó a solicitud del Seguro Integral de Salud; el cual motivó la formulación de la pregunta PICO conjuntamente con médicos y especialistas del Instituto Nacional del Niño de Breña, P: pacientes pediátricos con encefalitis autoinmune que no mejoran con respuesta a pulsos de metilprednisolona y/o plasmaféresis; I: IgIV más metilprednisolona; C: mejor terapia de soporte (continuar con pulsos de metilprednisolona); O: mejoría clínica, recaída, calidad de vida, numero de crisis convulsivas, tiempo de estancia hospitalaria, frecuencia de infecciones y eventos adversos. a. Cuadro clínico: La encefalitis autoinmune incluye un grupo heterogéneo de trastornos de tipo autoinmunitario en los que el sistema inmune reacciona frente a antígenos propios expresados en el sistema nervioso central. Los anticuerpos anti neuronales pueden estar dirigidos a la superficie celular (antígenos sinápticos en neuronas y glía) o a antígenos intracelulares. Los principales autoanticuerpos presenten en la encefalitis autoinmune son aquellos contra las moléculas NMDAR, GABAa, GABAb, AMPA, receptores de glicina, LGI1, CASPR2, GAD, entre otros. Las manifestaciones clínicas incluyen convulsiones, trastornos del movimiento, cambios de comportamiento y estado de ánimo, psicosis, deterioro cognitivo, disfunción autonómica y alteración del nivel de conciencia. La encefalitis por anticuerpos anti-NMDAR es la más prevalente en la población pediátrica. Las opciones terapéuticas consideradas como primera línea incluyen a los corticoides, la inmunoglobulina humana intravenosa (IgIV) y/o la plasmaféresis. b. Tecnología sanitária: La IgIV es una solución estéril de inmunoglobulinas humanas concentradas derivadas de donantes sanos; más del 90% de la preparación de IgIV corresponde a la IgG siendo el componente principal requerido para el efecto terapéutico. El mecanismo de acción de la IgIV aún no está claro, pero se presume que tienen un efecto inmunomodulador y antinflamatorio. Los efectos secundarios graves incluyen meningitis aséptica, shock anafiláctico, trombosis, accidente cerebrovascular y deterioro de la función renal; y el 6 % de los pacientes reportan eventos adversos serios. Dado su potencial mecanismo de acción, la IgIV ha sido utilizada en indicaciones fuera de etiqueta, tales como la encefalitis autoinmune. Actualmente, la IgIV cuenta con la aprobación de la Food and Drug Administration (FDA) para el tratamiento de inmunodeficiencia humoral primaria (IgIV al 5 %) y/o para el tratamiento de púrpura trombocitopénica inmune crónica en pacientes de 15 años o más; o polineuropatía desmielinizante inflamatoria crónica en adultos (IgIV al 10 %). A pesar de no contar con indicación para el uso en encefalitis autoinmune, se ha reportado su uso en pacientes pediátricos con esta condición. La dosis de IgIV para el tratamiento de la encefalitis autoinmune se establece empíricamente en 2 mg/kg seguido de una dosis mensual de mantenimiento de 1 g/kg que se ajusta según la respuesta clínica del paciente; o en 0.4 g/kg/día durante 5 días con o sin esteroides. OBJETIVOS: Describir la evidencia científica disponible sobre la eficacia y seguridad de la Inmunoglobulina Intravenosa (IgIV) para el tratamiento de encefalitis autoinmune en pacientes pediátricos que no mejoran con respuesta a pulsos de metilprednisolona y/o plasmaféresis. METODOLOGÍA: Se realizó una búsqueda sistemática en Medline/PubMed, The Cochrane Library y LILACS utilizando la estrategia de búsqueda descrita en el Anexo 01. Ésta se complementó con la búsqueda de evidencia en páginas institucionales de agencias gubernamentales y buscadores genéricos. Se priorizó la identificación y selección de ensayos clínicos aleatorizados controlados (ECA), revisiones sistemáticas (RS) de ECA, estudios observacionales comparativos, guías de práctica clínica (GPC), evaluaciones de tecnología sanitaria (ETS) y evaluaciones económicas (EE) de América Latina. La calidad de la evidencia se valoró usando: AMSTAR 2 para revisiones sistemáticas, la herramienta de la colaboración Cochrane para ensayos clínicos, la escala Newcastle-Ottawa para estudios no aleatorizados incluyendo cohortes y estudios de casos y controles, y AGREE II para valorar el rigor metodológico de las GPC. RESULTADOS: Tras la búsqueda sistemática se identificaron 207 artículos de los cuales 11 pararon a revisión a texto completo. De estos 11 documentos solo uno (GPC) correspondió con la pregunta PICO de interés. No se identificaron ECA o estudios observacionales comparativos, evaluaciones económicas, ni ETS que respondieran a la pregunta PICO de interés. CONCLUSIONES: Se revisó la mejor evidencia disponible sobre la eficacia y seguridad de la IgIV más metilprednisolona en pacientes pediátricos con encefalopatía autoinmune no mejoran con respuesta a pulsos de metilprednisolona y/o plasmaféresis (población objetivo). Se identificó solo una GPC que brinda recomendaciones para la población objetivo basada únicamente en consenso de expertos. Esta guía recomienda tanto la intervención como el comparador (prolongar el uso de metilprednisolona). No se cuenta con evidencia procedente de estudios tipo ECA u observacionales comparativos que evalúen la eficacia y seguridad de IgIV más metilprednisolona en la población objetivo, incluso ni en el contexto de primera línea. No se disponen de ETS ni evaluaciones económicas que respondan a la pregunta PICO de la presente revisión. Se espera que los resultados de ensayos clínicos en curso puedan brindar nueva información que permita responder a la pregunta de la presente revisión.

Hepatotoxicidad por metilprednisolona. Reporte de un caso / Methylprednisolone-induced hepatotoxicity. A case report / Hepatotoxicidade por metilprednisolona. Relato de um caso

Resumen: Introducción: la hepatotoxicidad inducida por fármacos y otros agentes es una forma frecuente de injuria hepática, superando en algunos países a las hepatitis virales. La presentación es variable, desde una alteración aislada del funcional hepático hasta formas graves con fallo hepático agudo fulminante. Se presenta un caso de lesión hepática aguda luego de un ciclo corto con altas dosis de metilprednisolona intravenosa. Caso clínico: sexo femenino, 45 años. Antecedentes personales de esclerosis múltiple, con último empuje 40 días previo a la consulta, tratada con bolos de metilprednisolona intravenosa. Consulta por ictericia de una semana de evolución, dolor abdominal, vómitos, anorexia, astenia y adinamia en el último mes. De la paraclínica se destaca: hiperbilirrubinemia mixta, elevación de las transaminasas, tiempo de protrombina descendido. Se descarta etiología viral, autoinmune y metabólica. Se plantea hepatotoxicidad por metilprednisolona que se confirma con la evolución favorable, y normalización a los 3 meses del enzimograma hepático y tiempo de protrombina tras la suspensión del tratamiento con metilprdnisolona. Discusión: el primer paso para el diagnóstico de hepatotoxicidad es descartar otras causas de injuria hepática. En segundo lugar, se debe demostrar la relación temporal entre la exposición al fármaco y el daño hepático. Por último, la suspensión del medicamento suele acompañarse de mejoría del cuadro clínico y analítico. Para diagnosticar esta entidad es necesario tener un alto índice de sospecha. El tratamiento con dosis altas de metilprednisolona puede inducir hepatitis severa que recurre con la re-exposición a la droga. Los pacientes con enfermedades autoinmunes tienen mayor riesgo de desarrollar hepatotoxicidad, lo que plantea un desafío terapéutico.

Summary: Introduction: drug induced hepatotoxicity and toxicity induced by other agents is a frequent form of liver injury, accounting for larger number of cases than viral hepatitis in some countries. Presentation may be variable, from an isolated alteration in the liver function test to severe forms of acute fulminant liver failure. The study presents a case of severe liver injury following a short cycle with high doses of intravenous methylprednisolone. Clinical case: 45 year-old female patient. Personal history of multiple sclerosis, with relapse 40 days prior to the consultation, treated with intravenous methylprednisolone. The patient consulted for jaundice with one week of evolution, abdominal pain, vomiting, anorexia, asthenia, and adynamia in the last month. Paraclinical tests find mixed hyperbilirubinemia, increased transaminases and decreased prothrombin time (PT). Viral, autoimmune and metabolic etiology are ruled out and a hypothesis is made for methylprednisolone-induced hepatotoxicity. The latter is confirmed and evolution is favorable, liver enzymogram being normal after three months, the same as the prothrombin time upon the interruption of methylprednisolone therapy. Discussion: the first step to diagnose hepatotoxicity is excluding other causes of liver injury. Next, the temporal relationship between drug exposure and liver injury needs to be demonstrated. Last, withdrawing the drug is usually accompanied by clinical and tests improvement. A high degree of suspicion is necessary to diagnose this condition. Therapies with high doses of methylprednisolone may cause severe hepatitis, and it is recurrent upon re-exposure to the drug. Patients with autoimmune diseases have greater risks of developing hepatotoxicity, what results in a therapeutic challenge.

Resumo: Introdução: a hepatotoxicidade induzida por drogas e outros agentes é uma forma frequente de lesão hepática, superando as hepatites virais em alguns países. A apresentação é variável, desde uma alteração isolada da função hepática até formas graves com insuficiência hepática aguda fulminante. Um caso de lesão hepática aguda após um curto curso de metilprednisolona intravenosa em altas doses é apresentado. Caso clínico: sexo feminino, 45 anos. Antecedentes pessoais de esclerose múltipla, com último impulso 40 dias antes da consulta, tratados com bolus de metilprednisolona endovenosa. Consulta por icterícia de uma semana de evolução, dor abdominal, vômitos, anorexia, astenia e adinamia no último mês. Dos exames paraclínicos, destacam-se: hiperbilirrubinemia mista, transaminases elevadas, tempo de protrombina diminuído. A etiologia viral, autoimune e metabólica é descartada. Foi sugerida hepatotoxicidade por metilprednisolona, confirmada pela evolução favorável, e normalização aos 3 meses da enzima hepática e do tempo de protrombina após a interrupção do tratamento com metilprednisolona. Discussão: o primeiro passo no diagnóstico de hepatotoxicidade é descartar outras causas de lesão hepática. Em segundo lugar, a relação temporal entre a exposição à droga e o dano hepático deve ser demonstrada. Por fim, a suspensão do medicamento costuma ser acompanhada de melhora do quadro clínico e analítico. Para diagnosticar esta entidade é necessário ter um alto índice de suspeição. O tratamento com altas doses de metilprednisolona pode induzir hepatite grave que se repete na reexposição ao medicamento. Pacientes com doenças autoimunes apresentam risco aumentado de desenvolver hepatotoxicidade, o que representa um desafio terapêutico.

SARS-CoV-2 and Aspergillus section Fumigati coinfection in an immunocompetent patient treated with corticosteroids.

BACKGROUND: Patients with severe viral pneumonia are likely to receive high-dose immunomodulatory drugs to prevent clinical worsening. Aspergillus species have been described as frequent secondary pneumonia agents in severely ill influenza patients receiving steroids. COVID-19 patients admitted to Intensive Care Unit (ICU) are receiving steroids as part of their treatment and they share clinical characteristics with other patients with severe viral pneumonias. COVID-19 patients receiving steroids should be considered a putative risk group of invasive aspergillosis. CASE REPORT: We are reporting a SARS-CoV-2/Aspergillus section Fumigati coinfection in an elderly intubated patient with a history of pulmonary embolism treated with corticosteroids. The diagnosis was made following the ad hoc definitions described for patients admitted to ICU with severe influenza, including clinical criteria (fever for 3 days refractory to the appropriate antibiotic therapy, dyspnea, pleural friction rub, worsening of respiratory status despite antibiotic therapy and need of ventilator support), a radiological criterion (pulmonary infiltrate) and a mycological criterion (several positive galactomannan tests on serum with ratio ≥0.5). In addition, Aspergillus section Fumigati DNA was found in serum and blood samples. These tests were positive 4 weeks after the patient was admitted to the ICU. The patient received voriconazole and after two month in ICU his respiratory status improved; he was discharged after 6 weeks of antifungal treatment. CONCLUSIONS: Severely ill COVID-19 patients would be considered a new aspergillosis risk group. Galactomannan and Aspergillus DNA detection would be useful methods for Aspergillus infection diagnosis as they allow avoiding the biosafety issues related to these patients.

Corticosteroid associated lupus pancreatitis.

The relationship between acute pancreatitis and the administration of glucocorticoids is unclear because most reported cases have been diagnosed with systemic vascular diseases, such as systemic lupus erythematosus, which may be responsible for pancreatitis. A 22-year-old woman with eye involvement of a newly diagnosed systemic lupus erythematosus was admitted to our hospital. Pulse intravenous methylprednisolone therapy was given at 1mg/kg day for 3 days, and oral prednisolone at 40 mg/day thereafter. During pulse steroid therapy, she had abdominal pain, back pain, distention, nausea, and vomiting. Her physical examination was compatible with acute abdomen and peritonitis. Abdomen Computerized Tomography scan revealed diffuse liquid perihepatic and perisplenic area with heterogeneity around the mesentery. Due to the symptoms of acute abdomen, explorative laparotomy was performed. There was diffuse free fluid in the abdomen and edematous changes were observed around the pancreas. Amylase and lipase from intraabdominal fluid were studied and found to be high. The postoperative prednol dose was reduced carefully. On the sixth postoperative day, the drain was removed, and the patient was discharged without any problem. Physicians should keep in mind that acute pancreatitis may also be a cause of differential diagnosis of newly developed abdominal pain in patients receiving pulse steroid therapy with a normal level of serum amylase and lipase.

Corticosteroid associated lupus pancreatitis

SUMMARY The relationship between acute pancreatitis and the administration of glucocorticoids is unclear because most reported cases have been diagnosed with systemic vascular diseases, such as systemic lupus erythematosus, which may be responsible for pancreatitis. A 22-year-old woman with eye involvement of a newly diagnosed systemic lupus erythematosus was admitted to our hospital. Pulse intravenous methylprednisolone therapy was given at 1mg/kg day for 3 days, and oral prednisolone at 40 mg/day thereafter. During pulse steroid therapy, she had abdominal pain, back pain, distention, nausea, and vomiting. Her physical examination was compatible with acute abdomen and peritonitis. Abdomen Computerized Tomography scan revealed diffuse liquid perihepatic and perisplenic area with heterogeneity around the mesentery. Due to the symptoms of acute abdomen, explorative laparotomy was performed. There was diffuse free fluid in the abdomen and edematous changes were observed around the pancreas. Amylase and lipase from intraabdominal fluid were studied and found to be high. The postoperative prednol dose was reduced carefully. On the sixth postoperative day, the drain was removed, and the patient was discharged without any problem. Physicians should keep in mind that acute pancreatitis may also be a cause of differential diagnosis of newly developed abdominal pain in patients receiving pulse steroid therapy with a normal level of serum amylase and lipase.

RESUMO A relação entre pancreatite aguda e a administração de glicocorticoides é incerta pois a maioria dos casos relatados foram diagnosticados com doenças vasculares sistêmicas, como lúpus eritematoso sistêmico, que pode causar pancreatite. Uma paciente de 22 anos com envolvimento ocular e lúpus eritematoso sistêmico recém-diagnosticado foi admitida em nosso hospital. Pulsoterapia intravenosa com metilprednisolona 1mg/kg foi administrada por 3 dias. Depois disso, a paciente foi tratada com prednisolona oral 40 mg/dia. Durante a pulsoterapia com corticoides, a paciente apresentava dor abdominal, dor nas costas, distensão, náusea e vômitos. O exame físico era compatível com quadro de abdome agudo e peritonite. Tomografia computadorizada do abdome revelou líquido difuso na região perihepática e periesplênica, com heterogeneidade ao redor do mesentério. Devido aos sintomas de abdome agudo, foi realizada laparotomia exploradora. Havia líquido livre difuso no abdome e alterações edematosas foram observadas em torno do pâncreas. A amilase e lipase do líquido intra-abdominal foram analisadas e consideradas elevadas. A dose pós-operatória de prednol foi reduzida com cuidado. No sexto dia de pós-operatório, o dreno foi retirado, e a paciente recebeu alta sem qualquer problema. Médicos devem lembrar que a pancreatite aguda também pode ser uma causa de diagnóstico diferencial para dor abdominal recém-desenvolvida em pacientes recebendo pulsoterapia com corticoides e com níveis normais de amilase e lipase séricas.

First Line Treatments for Newly Diagnosed Primary Immune Thrombocytopenia in Children: A Systematic Review and Network Meta-analysis.

BACKGROUND: The first-line interventions in immune thrombocytopenia (ITP) include intravenous polyclonal immunoglobulins (IVIg), corticosteroids and anti-D immunoglobulin (anti-D). OBJECTIVE: We aimed to compare the effectiveness and safety of first line treatments for newlydiagnosed primary ITP in children to increase the platelet count. METHODS: We searched MEDLINE, EMBASE, LILACS and the Cochrane Central register of Controlled Trials (CENTRAL); and included the clinical trials. We performed the statistical analysis in R. RESULTS: We included 12 studies for meta-analysis. Compared with IVIG 2g/kg, response rates were lower for prednisone 2mg/kg at 72 hours [RR 0.04 (95% CI 0.0 to 0.68)] and at 7 days [RR 0.23 (95% CI 0.08 to 0.67)]; at 48 hours, methylprednisolone 30mg/kg also showed lower response rates [RR 0.72 (95% CI 0.52 to 0.99)]. IVIG 2g/kg and 2.5g/kg had less adverse effects than Anti- D, methylprednisolone and IVIG 0.8g/kg. For rising platelet count, no statistical differences were found at 24 hours or in 7 days; at 48 hours, IVIG 2g/kg showed better results than Anti-D 75µg/kg [MD -58.84 (95% CI -87.02 to -25.66)]. After a month, platelet count with IVIG 2g/kg was higher than Anti-D 50 and 75µg/kg [-82.03 (95% CI -102.60 to -61.46) and -78.77 (95% CI -97.80 to - 59.74), respectively], but lower than methylprednisolone 50mg/kg [MD 118 (95% CI 3.88 to 232.12)]. CONCLUSION: The total platelet count rises higher in early and late phases with IVIG than Anti-D, but in long term it is higher with methylprednisolone. Additionally, IVIG causes less adverse effects than Anti-D and corticosteroids.

Effects of immunotherapy induction on outcome and graft survival of kidney-transplanted patients with different immunological risk of rejection.

BACKGROUND: In kidney transplantation, immunotherapy with thymoglobulin (rATG) has been used to down-regulate the patient immune system. rATG is a powerful immunobiologic drug used to deplete lymphocytes to prevent early acute rejection. The aim of this research was to evaluate the effects of immunotherapy by rATG on graft suvival during a 9-year period in kidney-transplanted patients with different immunological profiles. METHODS: A sample of 469 patients were allocated into four groups (G) based on immunological risk of rejection: G1, low risk, not sensitized recipients, solid-phase immunoassay with single antigen beads (SPI-SAB) < 10%; G2, medium risk I, sensitized recipients, SPI-SAB ≥ 10 < 50%; G3, medium risk II sensitized (SPI-SAB ≥50%); and G4, high risk, sensitized recipients, SPI-SAB- donor-specific antibody positive (DSA+). Only patients from G3 and G4 received immunotherapy. RESULTS: Of 255 patients who received a kidney from a living donor (LD), 42 (16.47%) from all groups (G) had T-cell-mediated rejection (TCMR) and four (G1) lost their grafts, 8 (3.14%) had antibody-mediated rejection (AMR), and two lost their graft in G1 and G4. Of 214 patients who received a kidney from deceased donors (DD), 37 (17.29%) had TCMR with one lost graft in G1. AMR was shown in 13 (6.07%) patients, with three losses observed in G2. Statistical differences between the groups in the 9-year graft survival rate were found only in the comparison of G1 versus G2 (P = 0.005) and G2 versus G4 (P = 0.047) for DD. For LD, no statistical differences were found. CONCLUSION: This clinical retrospective study shows that immunotherapy induction was associated with improvement of outcomes, graft function, and survival in patients treated with immunotherapy in comparison with patients who did not received induction therapy. These findings strongly suggest that immunotherapy should be used for all patients transplanted with kidneys from deceased donors.

Guidelines of the Brazilian Society of Rheumatology for the treatment of systemic autoimmune myopathies.

BACKGROUND: Recommendations of the Myopathy Committee of the Brazilian Society of Rheumatology for the management and therapy of systemic autoimmune myopathies (SAM). MAIN BODY: The review of the literature was done in the search for the Medline (PubMed), Embase and Cochrane databases including studies published until June 2018. The Prisma was used for the systematic review and the articles were evaluated according to the levels of Oxford evidence. Ten recommendations were developed addressing the management and therapy of systemic autoimmune myopathies. CONCLUSIONS: Robust data to guide the therapeutic process are scarce. Although not proven effective in controlled clinical trials, glucocorticoid represents first-line drugs in the treatment of SAM. Intravenous immunoglobulin is considered in induction for refractory cases of SAM or when immunosuppressive drugs are contra-indicated. Consideration should be given to the early introduction of immunosuppressive drugs. There is no specific period determined for the suspension of glucocorticoid and immunosuppressive drugs when individually evaluating patients with SAM. A key component for treatment in an early rehabilitation program is the inclusion of strength-building and aerobic exercises, in addition to a rigorous evaluation of these activities for remission of disease and the education of the patient and his/her caregivers.

Guidelines of the Brazilian Society of Rheumatology for the treatment of systemic autoimmune myopathies

Abstract Background: Recommendations of the Myopathy Committee of the Brazilian Society of Rheumatology for the management and therapy of systemic autoimmune myopathies (SAM). Main body: The review of the literature was done in the search for the Medline (PubMed), Embase and Cochrane databases including studies published until June 2018. The Prisma was used for the systematic review and the articles were evaluated according to the levels of Oxford evidence. Ten recommendations were developed addressing the management and therapy of systemic autoimmune myopathies. Conclusions: Robust data to guide the therapeutic process are scarce. Although not proven effective in controlled clinical trials, glucocorticoid represents first-line drugs in the treatment of SAM. Intravenous immunoglobulin is considered in induction for refractory cases of SAM or when immunosuppressive drugs are contra-indicated. Consideration should be given to the early introduction of immunosuppressive drugs. There is no specific period determined for the suspension of glucocorticoid and immunosuppressive drugs when individually evaluating patients with SAM. A key component for treatment in an early rehabilitation program is the inclusion of strengthbuilding and aerobic exercises, in addition to a rigorous evaluation of these activities for remission of disease and the education of the patient and his/her caregivers.

Intravenous pulses of methylprednisolone to treat flares of immune-mediated diseases: how much, how long?

Introduction Glucocorticoids are widely used in the treatment of immune-mediated diseases. Despite their widespread use, details on dosing, effectiveness and adverse effects are yet to be determined. Objective To know the current use of methylprednisolone (MTP) in the management of immune-mediated conditions, evaluating the relationship among doses, therapeutic response and adverse effects. Methodology A multicenter retrospective cohort study was designed, including patients who received intravenous pulses of MTP between 1 January 2013 and 12 December 2015 in three different hospitals in Uruguay. The patients included received MTP to treat systemic autoimmune diseases (SADs), hematological, nephrological and neurologic diseases and others. The following variables were analyzed: age, gender, MTP cumulative dose, duration of treatment, clinical response (complete, partial and no response) and adverse effects. Results In total, 164 cases were identified, of which 118 (72%) were female. The median age was 48.4 (SD: 18) years. The indications for MTP included: neuroimmune-mediated 92 (56.1%), SADs 29 (17.5%), hematological 15 (9.1%), nephrological 12 (7.3%) and others 16 (9.9%). The median dose to achieve complete response was 3.2 g (SD: 1.5); the median dose to accomplish a partial response was 3.5 g (SD: 1.25); the median dose for non-responders was 3.3 g (SD 1.2) ( p > 0.05). The median dose in those patients with adverse effects was 3.4 g (SD 1.5) and the median dose for those who did not experience adverse effects was 3.3 g (SD: 1.3) ( p > 0.05). The most frequent adverse effects were infectious (22/164, 13.4%). Diabetics were found to have the highest incidence of adverse effects (13/16, 81%) in comparison to non-diabetics, p < 0.05. Discussion Our study suggests a wide range of doses and duration of treatments with MTP. No major associations were found between clinical response and the use of high MTP doses, but the latter was associated with a large proportion of severe infections. No severe infections were identified with MTP doses lower than 1.5 g. The diabetic population is known to be at risk of experiencing varied adverse effects to MTP. These observations reinforce the need for protocolized use of MTP in order to achieve a better relationship among doses, effectiveness and safety profile.

Interventions for infantile haemangiomas of the skin.

BACKGROUND: Infantile haemangiomas (previously known as strawberry birthmarks) are soft, raised swellings of the skin that occur in 3% to 10% of infants. These benign vascular tumours are usually uncomplicated and tend to regress spontaneously. However, when haemangiomas occur in high-risk areas, such as near the eyes, throat, or nose, impairing their function, or when complications develop, intervention may be necessary. This is an update of a Cochrane Review first published in 2011. OBJECTIVES: To assess the effects of interventions for the management of infantile haemangiomas in children. SEARCH METHODS: We updated our searches of the following databases to February 2017: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, AMED, LILACS, and CINAHL. We also searched five trials registries and checked the reference lists of included studies for further references to relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of all types of interventions, versus placebo, active monitoring, or other interventions, in any child with single or multiple infantile haemangiomas (IHs) located on the skin. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary outcome measures were clearance, a subjective measure of improvement, and adverse events. Secondary outcomes were other measures of resolution; proportion of parents or children who consider there is still a problem; aesthetic appearance; and requirement for surgical correction. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included 28 RCTs, with a total of 1728 participants, assessing 12 different interventions, including lasers, beta blockers (e.g. propranolol, timolol maleate), radiation therapy, and steroids. Comparators included placebo, an active monitoring approach, sham radiation, and interventions given alone or in combination.Studies were conducted in a number of countries, including China, Egypt, France, and Australia. Participant age ranged from 12 weeks to 13.4 years. Most studies (23/28) included a majority of females and different types of IHs. Duration of follow-up ranged from 7 days to 72 months.We considered most of the trials as at low risk of random sequence generation, attrition bias, and selective reporting bias. Domains such as allocation concealment and blinding were not clearly reported in general. We downgraded evidence for issues related to risk of bias and imprecision.We report results for the three most important comparisons, which we chose on the basis of current use. Outcome measurement of these comparisons was at 24 weeks' follow-up.Oral propranolol versus placeboCompared with placebo, oral propranolol 3 mg/kg/day probably improves clinician-assessed clearance (risk ratio (RR) 16.61, 95% confidence interval (CI) 4.22 to 65.34; 1 study; 156 children; moderate-quality evidence) and probably leads to a clinician-assessed reduction in mean haemangioma volume of 45.9% (95% CI 11.60 to 80.20; 1 study; 40 children; moderate-quality evidence). We found no evidence of a difference in terms of short- or long-term serious adverse events (RR 1.05, 95% CI 0.33 to 3.39; 3 studies; 509 children; low-quality evidence), nor in terms of bronchospasm, hypoglycaemia, or serious cardiovascular adverse events. The results relating to clearance and resolution for this comparison were based on one industry-sponsored study.Topical timolol maleate versus placeboThe chance of reduction of redness, as a measure of clinician-assessed resolution, may be improved with topical timolol maleate 0.5% gel applied twice daily when compared with placebo (RR 8.11, 95% CI 1.09 to 60.09; 1 study; 41 children;low-quality evidence). Regarding short- or long-term serious cardiovascular events, we found no instances of bradycardia (slower than normal heart rate) or hypotension in either group (1 study; 41 children; low-quality evidence). No other safety data were assessed, and clearance was not measured.Oral propranolol versus topical timolol maleateWhen topical timolol maleate (0.5% eye drops applied twice daily) was compared with oral propranolol (via a tablet taken once per day, at a 1.0 mg/kg dose), there was no evidence of a difference in haemangioma size (as a measure of resolution) when measured by the proportion of patients with a clinician-assessed reduction of 50% or greater (RR 1.13, 95% CI 0.64 to 1.97; 1 study; 26 participants; low-quality evidence). Although there were more short- or long-term general adverse effects (such as severe diarrhoea, lethargy, and loss of appetite) in the oral propranolol group, there was no evidence of a difference between groups (RR 7.00, 95% CI 0.40 to 123.35; 1 study; 26 participants; very low-quality evidence). This comparison did not measure clearance.None of our key comparisons evaluated, at any follow-up, a subjective measure of improvement assessed by the parent or child; proportion of parents or children who consider there is still a problem; or physician-, child-, or parent-assessed aesthetic appearance. AUTHORS' CONCLUSIONS: We found there to be a limited evidence base for the treatment of infantile haemangiomas: a large number of interventions and outcomes have not been assessed in RCTs.Our key results indicate that in the management of IH in children, oral propranolol and topical timolol maleate are more beneficial than placebo in terms of clearance or other measures of resolution, or both, without an increase in harms. We found no evidence of a difference between oral propranolol and topical timolol maleate with regard to reducing haemangioma size, but we are uncertain if there is a difference in safety. Oral propranolol is currently the standard treatment for this condition, and our review has not found evidence to challenge this. However, these results are based on moderate- to very low-quality evidence.The included studies were limited by small sample sizes and risk of bias in some domains. Future trials should blind personnel and participants; describe trials thoroughly in publications; and recruit a sufficient number of children to deduce meaningful results. Future trials should assess patient-reported outcomes, as well as objective outcomes of benefit, and should report adverse events comprehensively. Propranolol and timolol maleate require further assessment in RCTs of all types of IH, including those considered problematic, as do other lesser-used interventions and new interventions. All treatments should be compared against propranolol and timolol maleate, as beta blockers are approved as standard care.

[Methylprednisolone for the treatment of Immune-mediates Diseases flares. Relationship between doses, effectiveness and safety. A pilot study]. / Metilprednisolona en brotes de enfermedades inmunomediadas: relación entre dosis, efectividad y seguridad. Estudio Piloto.

Background: Methylprednisolone (MTP) pulses have proved effectiveness for the treatment of severe manifestations of immune-mediated diseases (ID). However, the the relationship between doses, effectiveness and safety is not well established. Objective: To know MTP indications, doses, therapeutic response and safety in the clinical setting. Methodology: A retrospective review of records was performed in Hospital Pasteur of Uruguay, from patients who had received MTP during a ID flare. Variables studied: age, sex, MTP cumulative doses, duration of treatment, therapeutic response and adverse effects. Results: Thirty six cases were identified, 26 were female. The mean age was 41,5 (SD 15,5) years. The mean dose of MTP in cases of complete response was 3,6 (SD 2) grams, the mean dose in cases of partial response was 4 (SD 1,5) grams, and in cases of no response was 2,8 (SD 1,2) grams (p> 0,05). The mean dose in patients with adverse effects was 4,4 (SD 1,8) grams, and in cases without adverse effects was 3,2 (SD 1,6) grams (p<0,05). Conclusions: Our series does not confirm a relationship between higher doses and clinical response. However, an association between higher doses of MTP and adverse effects was observed. These finding should be thoroughly investigated.

INTRODUCCIÓN: Metilprednisolona (MTP) es una molécula con probada efectividad antiinflamatoria e inmunosupresora para la terapia en pulsos de brotes de enfermedades inmunomediadas (EI). Sin embargo, no se conoce con certeza la mejor relación entre dosis, efectividad y efectos adversos. OBJETIVO: Conocer los usos de MTP, dosis, respuesta terapéutica y efectos adversos. MATERIAL Y MÉTODOS: Se realizó un estudio retrospectivo de pacientes que recibieron MTP en el Hospital Pasteur de Uruguay. Se incluyeron pacientes que recibieron MTP en pulsos por una enfermedad inmunomediada. Se analizaron las siguientes variables: edad, sexo, dosis acumulada de MTP, duración del tratamiento con MTP, respuesta terapéutica, efectos adversos. RESULTADOS: Se identificaron 36 casos, 27 de sexo femenino. La media de edad fue 41,5 (DE: 15,5) años. La media de dosis en los casos de respuesta completa fue 3,6 (DE: 2) gramos; la media de dosis en los casos de respuesta parcial fue 4 (DE: 1,5) gramos; la media de dosis de no respuesta fue 2,8 (DE 1,2) gramos (p> 0,05). La media de dosis en los pacientes que presentaron efectos adversos fue 4,4 (DE: 1,8) gramos y la media de dosis de los que no presentaron efectos adversos fue 3,2 (DE: 1,6) gramos (p<0,05). DISCUSIÓN: Nuestra serie sugiere que no existe una clara relación entre dosis mayores y mejores respuestas terapéuticas. Sin embargo, existe una mayor tendencia a presentar efectos adversos con dosis más elevadas. Estos hallazgos refuerzan la necesidad de racionalizar las dosis de MTP y continuar estudiando este tema en con mayor número de pacientes.

Acute necrotising pancreatitis derived from low-dose corticosteroid use: an important reminder of clinical management.

Although the exact mechanism is unknown, incidence of drug-induced pancreatitis from corticosteroids is well established in the medical literature. Commonly reported in chronic steroid-dependent individuals who require large doses for a wide array of pathologies, the incidence of damage to the pancreas from low-doses have not been well described. We report a case of a 68-year-old woman who presented with severe abdominal pain, nausea and vomiting, 3 days after the initiation of low-dose methylprednisolone for osteoarthritis. Inpatient laboratory analysis revealed an elevated lipase of 1770 U/L and CT scan showing extensive necrotising pancreatitis involving the head, body and tail. Cessation of the causative medication and conservative treatment successfully led to resolution of symptoms. We present this case to inform clinicians of the precipitance of pancreatitis from modest strength corticosteroid management, so that more accurate and improved performance in pharmacological decisions can be made for patient care.

Administration of low-dose cyclosporine alone for the treatment of elderly patients with membranous nephropathy.

This study aimed to investigate the effects of administration of low-dose cyclosporine A (CsA) alone and the combination of low-dose CsA and a low-dose hormone for the treatment of elderly patients with membranous nephropathy. We divided 27 patients into two groups as follows: low-dose CsA group (group A) and the group receiving a combination of a low-dose hormone and low-dose CsA (group B). The treatment and follow-up times were ≥ 6 months. We observed no difference in gender, age, serum creatinine levels, estimated glomerular filtration rate (eGFR), and 24-h urinary protein levels between the two groups before treatment; in addition, the rates of complete and partial remission were not different 6 months after treatment. The rate of complications in group B was higher than that in group A (84.6 vs 35.7%, respectively; t = 0.018). While the pretreatment eGFR of patients who achieved remission was significantly higher than that of patients who did not achieve remission, the 24-h urinary protein levels and incidence of hypertension were significantly lower than those of patients who did not achieve remission (t = 0.042, 0.035 and 0.043, respectively). The efficacy of administration of low-dose CsA alone and in combination with a low-dose hormone was similar; the efficacy was related to eGFR, urinary protein levels, and the incidence of hypertension before the treatment. The side effects of administration of CsA alone were significantly lower than those of the combination treatment.

An unexpected temporary suppression of lactation after a local corticosteroid injection for tenosynovitis.

INTRODUCTION: Intra-lesional glucocorticosteroid (GCS) injections are used widely for painful musculoskeletal conditions in general practice. CASE: A 26 year old female, was given an intra-lesional injection of 24 mg methyl prednisolone acetate (MPA) with 15 mg lidocaine for treatment of DeQuervain's tenosynovitis. She was six weeks postpartum and predominantly breast feeding. Lactation was suppressed at approximately 30 h post injection and this persisted for a period of approximately 36 h before spontaneous resumption of milk production. Lactation returned to normal 90 h after the injection. DISCUSSION: Studies done in lactating animals have shown that injected GCS have led to a reduction of milk production, but there is limited data on these injections in lactating humans. The dose of GCS administered and the site of the GCS injection appear to contribute to this phenomenon. Very large doses of GCS have caused suppression of lactation in humans as opposed to low doses of GCS. Injections of GCS into areas of the body subjected to high activity level like the knee or wrist could lead to greater systemic absorption of GCS than GSC administered to body sites with lower physical activity like the shoulder. CONCLUSION: Local injection of MPA reversibly suppressed lactation in a young woman for a period of 24-48 h. Doctors using injectable GCS in lactating women should apprise patients of this possibility. Mothers can take precautions like expressing and storing enough breast milk to cover this period prior to receiving these injections.

Iatrogenic meningitis.

Iatrogenic meningitis can be caused by a number of mechanisms. The recent case reports of fungal meningitis after application of epidural methylprednisolone caused warning in the medical community. Cases were caused by contaminated lots of methylprednisolone from a single compounding pharmacy. Several medications can cause meningitis by probable hypersensitivity mechanism. Neurologists should be alert to the recent description of the use of lamotrigine and development of aseptic meningitis.

Iatrogenic meningitis / Meningites iatrogenicas

Iatrogenic meningitis can be caused by a number of mechanisms. The recent case reports of fungal meningitis after application of epidural methylprednisolone caused warning in the medical community. Cases were caused by contaminated lots of methylprednisolone from a single compounding pharmacy. Several medications can cause meninigitis by probable hypersensitivity mechanism. Neurologists should be alert to the recent description of the use of lamotrigine and development of aseptic meningitis.

As meningites iatrogênicas podem ser provocadas por uma série de mecanismos. Os recentes relatos de casos de meningite por fungos após a aplicação de injeção epidural de metilprednisolona causou alerta na comunidade médica. Os casos foram causados por lotes contaminados de metilprednisolona produzidos por uma única farmácia de produção. Diversos medicamentos podem causar meningite por provável mecanismo de hipersensibilidade. Neurologistas devem ficar alerta para a recente descrição do uso de lamotrigina e o desenvolvimento de meningite asséptica.