Terapias biológicas y tuberculosis en pediatría / Biological therapies and tuberculosis in pediatrics

En los últimos años, ha habido un aumento sostenido del uso de terapias inmunomoduladoras como las terapias biológicas y en un período más reciente, de las terapias con moléculas pequeñas. Estos tratamientos constituyen un factor de riesgo más para enfermar de tuberculosis en adultos y aunque en menor grado, también en niños, especialmente con el uso de anti TNF-α, por lo que antes de iniciar una terapia biológica, hay que descartar la tuberculosis activa y la latente. En el tratamiento de una tuberculosis activa producida por un biológico se debe prolongar la etapa de continuación a 9 meses. Es importante el seguimiento clínico prolongado en años de quienes usan o han completado el uso de estas terapias. Hay que posponer la vacunación BCG en los hijos de madres que usaron terapias biológicas durante la gestación hasta la edad 6 a 12 meses de los niños. El foco de esta revisión está centrado en la tuberculosis por progresión de una forma latente a una activa o por un contacto estrecho con una persona con tuberculosis pulmonar en pacientes que reciben terapias biológicas anti TNF alfa de uso inmunoreumatológico.

In recent years, there has been a sustained increase in the use of immunomodulatory therapies such as biologic therapies and, more recently, small molecule therapies. Those therapies have become another risk factor for tuberculosis in adults and, although to lesser degree, also in children, especially some of them, such as anti-TNF α. Before starting biological therapy, active tuberculosis and latent tuberculosis must be ruled out. In the treatment of active tuberculosis caused by a biologic, the continuation stage should be extended to 9 months. Long-term clinical follow-up in years of those who use them or have completed their use, is important. BCG vaccine should be postponed in children of mother who used biologic therapies during pregnancy until the children ́s age 6 to 12 months. The focus of this review is centered on tuberculosis due to progression from a latent to an active form or due to close contact with a person with pulmonary tuberculosis in patients receiving anti-TNF alpha biological therapies for immunorheumatology use.

Riesgo de infección en pacientes con enfermedades inmunológicas y oncológicas tratados con biológicos: revisión panorámica

Biological medications are effective for the treatment of cancer and inflammatory diseases. The aim of this review is to summarize the available evidence in systematic reviews or meta-analyses about the risk of infection in patients with cancer, arthritis, psoriasis and inflammatory bowel disease who use biological medications. We included systematic reviews or meta-analyses of controlled clinical trials and case/control studies that analyze infections during and after treatment with FDA-approved biological medications for the treatment of cancer, arthritis, inflammatory bowel disease and psoriasis, both in adults and children. The following databases were consulted: PubMed, Epistemonikos, Crochrane reviews, JIB, and Prospero. A quality guideline (AMSTAR) was applied to the selected studies. We included 26 studies. The risk of infections in patients with solid organ cancer is consistent in the literature. In psoriasis there is a risk of non-serious infections. In arthritis and other inflammatory diseases there is a risk of serious infections. In inflammatory bowel disease there is a risk for opportunistic infections. In conclusion, in patients with cancer and inflammatory diseases use biological medications entails a risk of infection. The evidence is different depending on the underlying disease of each patient.

Terapias biológicas en tiempos de COVID-19 / Biological therapies in times of COVID-19

La infección por el virus SARS-CoV-2 (COVID-19) ha planteado importantes de-safíos para pacientes con enfermedades reumatológicas autoinmunes en tratamiento con agentes biológicos. Actualmente no hay evidencia contundente sobre cómo esta terapia afecta el riesgo de adquirir esta infección o su evolución. Sin embargo, hay datos sobre el riesgo de infecciones virales con agentes biológicos en pacientes con enfermedades reumatológicas y específicamente cuál ha sido la experiencia de pacientes inmunosuprimidos con otros coronavirus. Además, ya se han publicado algunos estudios observacionales que han examinado la incidencia y severidad de COVID-19 en pacientes usuarios de biológicos. Por último, el cre-ciente conocimiento sobre la fisiopatología de la infección por SARS-CoV-2 está paradójicamente apoyando el papel beneficioso de algunos agentes biológicos como los inhibidores de IL-6 (Tocilizumab) e IL-1 (Anakinra) en COVID-19 grave. Se revisará la evidencia disponible para el manejo de pacientes reumatológicos con terapias biológicas en tiempos de pandemia.

The infection caused by SARS-CoV-2 (COVID-19) has posed significant challenges for patients with autoimmune rheumatic diseases being treated with biological agents. There is currently no conclusive evidence on how this therapy affects the risk of acquiring this infection or its outcomes. However, there are data on the risk of viral infections with biological agents in patients with rheumatologic diseas-es, and specifically what has been the experience of immunosuppressed patients with other coronaviruses. In addition, some observational studies have already been published that have examined the incidence and severity of COVID-19 in pa-tients using biologics. Finally, the growing knowledge about the pathophysiology of SARS-CoV-2 infection is paradoxically supporting the beneficial role of some biological agents such as IL-6 (Tocilizumab) and IL-1 (Anakinra) inhibitors in severe COVID-19. The available evidence for the management of rheumatology patients with biological therapies in times of pandemic will be reviewed.

Consenso sobre riesgo de complicaciones infecciosas en pacientes usuarios de medicamentos biológicos seleccionados. Parte I / Consensus of infectious complications in patients treated with selected biological therapies: first Part

Resumen La incorporación de terapias biológicas ha significado un gran avance en el manejo de diversas patologías de origen autoinmune, neoplásico u otros. Si bien su uso ha implicado mejoras significativas en el pronóstico de estas enfermedades, no está exento de complicaciones, entre estas, las infecciosas. El objetivo de este consenso fue evaluar el perfil de seguridad, desde la mirada infectológica, de las terapias biológicas de uso más frecuente y dar recomendaciones para la prevención de infecciones en pacientes tratados con ellas, basándose en la evidencia de mayor calidad disponible para los biológicos seleccionados. El consenso cuenta de dos manuscritos. Esta primera parte detalla los riesgos de desarrollar complicaciones infecciosas dependiendo del tipo de biológico utilizado para determinada patología. La revisión incluyó búsqueda amplia en MEDLINE y Epistemonikos de revisiones sistemáticas y meta-análisis de estudios clínicos controlados y caso/control que examinaban infecciones posteriores al tratamiento con anti-TNF alfa, anti-CD20, anti-CD52, CTLA4-Ig y anti-integrinas. Esta búsqueda se complementó con revisión de cohortes multicéntricas de usuarios de biológicos, del MMWR del CDC, Atlanta, E.U.A. y de registros nacionales y/o de sociedades científicas en la que se hiciera mención a complicaciones infecciosas derivadas del uso de biológicos.

The use of biological therapies has meant a great improvement in the management of several conditions like autoimmune, neoplastic or others diseases. Although its use has implied significant improvements in the prognosis of these diseases, it is not exempt from complications: infectious diseases as one of them. The objective of this consensus was to evaluate, from an infectious viewpoint, the safeness of the most frequently used biological therapies and give recommendations for the prevention of infections in patients treated with these drugs. These recommendations were based on the highest quality evidence available for the selected biologics. The consensus counts of two manuscripts. This first part details the risks of developing infectious complications depending on the type of biological used for a certain pathology. This evaluation included a broad search in MEDLINE and Epistemonikos of systematic reviews and meta-analyzes of controlled clinical trials and casecontrol examining post-treatment infections with anti-TNF alpha, anti-CD20, anti-CD52, CTLA4-Ig and anti-integrins. The research was complemented by a review of: multicentre cohorts of biological users, the MMWR of the CDC, Atlanta, U.S.A., and national registers and scientific societies in which infectious complications derived from the use of biological therapies were mentioned.

Consenso sobre riesgo de complicaciones infecciosas en pacientes usuarios de medicamentos biológicos seleccionados. Parte II: Guía clínica chilena de Prevención de Infecciones Asociadas al Uso de Terapias Biológicas (PREVITEB) / Consensus of infectious complications in patients treated with selected biological therapies. Screening of hepatitis B in high risk Chilean and immigrant pregnant women: Management of mother to child transmission Second part: Chilean Guidelines for Prevention of Infections associated to use of Biological Therapies (PREVITEB)

Resumen La incorporación de terapias biológicas ha significado un gran avance en el manejo de diversas patologías de origen autoinmune, neoplásico u otros. Si bien su uso ha implicado mejoras significativas en el pronóstico de estas enfermedades, no está exento de complicaciones, entre éstas, las infecciosas. El objetivo de este consenso fue evaluar el perfil de seguridad, desde la mirada infectológica, de las terapias biológicas de uso más frecuente y dar recomendaciones para la prevención de infecciones en pacientes tratados con ellas, basándose en la evidencia de mayor calidad disponible para los biológicos seleccionados. El consenso cuenta de dos manuscritos. Esta segunda parte corresponde a la guía clínica que detalla estas recomendaciones mediante estrategias de cribado, terapias profilácticas e indicación de vacunas, según corresponde, para infecciones bacterianas, y por micobacterias en particular, virus, hongos y parásitos, tanto para adultos como para niños.

The use of biological therapies has meant a great improvement in the management of several conditions like autoimmune, neoplastic or others diseases. Although its use has implied significant improvements in the prognosis of these diseases, it is not exempt from complications: infectious diseases as one of them. The objective of this consensus was to evaluate, from an infectious viewpoint, the safeness of the most frequently used biological therapies and give recommendations for the prevention of infections in patients treated with these drugs. These recommendations were based on the highest quality evidence available for the selected biologics. The consensus counts of 2 manuscripts. This second part is a guideline that details these recommendations through screening strategies, prophylactic therapies and vaccines indications for bacterial, mycobacterial, viral, fungal and parasitic infections, both for adults and children.

Valoración previa a la inmunosupresión farmacológica en Reumatología / (Pre-assessment of pharmacological immunosuppression in Rheumatology)

ResumenEn los últimos 15 años se han desarrollado terapias y esquemas terapéuticos para inducir la remisión a la gran mayoría de enfermedades reumatológicas. La mejoría clínica lograda se consigue a expensas de una inmunosupresión más agresiva y específica, lo que conlleva un aumento en el riesgo de infecciones. La principal causa de muerte de las enfermedades autoinmunes, en los primeros 5 años de evolución, es la infección secundaria a la inmunosupresión. El objetivo del presente trabajo fue elaborar un documento de consenso con el afán de reducir este riesgo, basado en la mejor evidencia médica disponible, utilizando los recursos disponibles en el hospital para disminuir la morbimortalidad de los pacientes que reciben estas terapias. Contar con un documento de consenso permitirá minimizar los efectos secundarios y mejorar la acción terapéutica, con mayores oportunidades de remisión y una más adecuada utilización del recurso institucional.

AbstractIn the last 15 years therapies and therapeutic schemes have been developed to induce remission to the vast majority of rheumatologic diseases. The clinical improvement achieved is at the cost of a more aggressive and specific immunosuppression, which leads to an increase in the risk of infections. The main cause of death of autoimmune diseases in the first 5 years of evolution is infection secondary to immunosuppression. The objective of the present study was to develop a consensus document with the aim of reducing this risk of infection, based on the best available medical evidence, using the resources available in our hospital to reduce the morbidity and mortality of patients receiving these therapies. Having a consensus document will allow us to minimize side effects and improve therapeutic action with greater opportunities for referral and better utilization of institutional resources.

Evolución de pacientes con artritis idiopática juvenil en terapia biológica que cursan infección por virus varicela zoster: a propósito de 4 casos / Outcomes of patients with juvenile idiopathic arthritis on biological therapy and have a varicella-zoster virus infection

En niños inmunocomprometidos, la infección por virus varicela puede producir una enfermedad grave. Existen pocos casos publicados de varicela en pacientes con artritis idiopática juvenil (AIJ) y terapia biológica. OBJETIVO: Describir la evolución de pacientes con AIJ con terapia biológica que adquirieron el virus varicela. CASOS CLÍNICOS: Se describe la historia clínica de 4 pacientes con AIJ, de entre 3 y 12 años de edad, que presentaron infección por virus varicela zoster estando con distintas terapias biológicas: 2 con anti TNF, uno con anti IL-6 y uno con bloqueador de la coestimulación del linfocito T. Dos de ellos habían recibido la vacuna contra la varicela. Todos recibieron diferentes terapias y evolucionaron sin complicaciones, no encontrando diferencias importantes en relación con el tipo de terapia biológica ni con el antecedente de haber sido vacunados. En todos los pacientes se suspendió el tratamiento biológico por al menos 2 semanas y se reinició sin reactivación de la artritis. CONCLUSIONES: En esta serie de pacientes con AIJ tratados con terapia biológica que cursaron con infección por VVZ no se observaron complicaciones graves.

Varicella virus infection may develop into severe disease in immunocompromised children. There are few studies that describe the clinical presentation of varicella infection in patients with Juvenile Idiopathic Arthritis when on biological therapy. OBJECTIVE: Describe the outcomes of patients with a diagnosis of Juvenile Idiopathic Arthritis, who acquired a varicella virus infection during treatment with biological therapy. CLINICAL CASES: A description is presented on 4 cases of Juvenile Idiopathic Arthritis in children between 3 and 12 years old, who developed a varicella-zoster infection during treatment with different biological therapies. Two patients were taking anti-TNF agents, one an Anti IL-6 agent, and one patient a T cell costimulatory blockade agent. Two of them received varicella vaccination prior to the start of biological therapy. All of them received different therapies and had favourable outcome without developing complications. No significant differences were found as regards the type of biological therapy or history of previous vaccination. Biological therapy was suspended for at least 2 weeks in all patients, and was restarted without reactivation of arthritis. CONCLUSIONS: No serious complications were observed in this patient series of children with JIA treated with biological therapy associated with VZV infection.

Desarrollo de neoplasia en pacientes con enfermedad inflamatoria intestinal / Development of malignant tumors in patients with inflammatory bowel disease

Background: The chronic inflammation of the intestinal mucosa, the extra-intestinal manifestations of the disease and the immunosuppressive treatment of inflammatory bowel disease may increase cancer risk. Aim: To report the demographic and clinical features of patients with IBD who developed a malignant tumor. Material and Methods: Retrospective analysis of an IBD patient registry of a private clinic, diagnosed between 1976 and 2014. Results: 437 subjects were included, aged 15-88 years (58% women). Seventy two percent of patients had ulcerative colitis. The median time of follow up was 6 years. Ten patients (2.3%) developed a malignant tumor. In four, the tumor could be related to IBD (two colorectal cancers, one cholangiocarcinoma and one chronic myeloid leukemia (CML)). Two of 45 patients treated with biological therapy developed a tumor (CML and hypernephroma). Three of 170 patients on immunosuppressive treatment developed tumors. Only one had a tumor possibly related with the use of azathioprine (non-melanoma skin cancer). In only two patients, the treatment was changed at the time of their cancer diagnosis, from immunosuppressive medications to mesalamine. Conclusions: Only a small proportion of these patients with IBD developed a malignant tumor. The treatment of IBD has to be determined by the severity of the disease and not by the fear of developing a neoplasia. Following recommendations is fundamental to decrease the possibility of developing this complication.

Trasplante de microbiota fecal: primer caso reportado en Chile y revisión de la literatura / Fecal microbiota transplantation: first case report in Chile and review

Clostridium difficile (CD) infection is increasing in frequency and severity in in-hospital and outpatient clinical settings, with a recurrence that can reach 30% after first episode. The recurrences are usually treated with longer courses of metronidazole or vancomycin. Other treatments have been used, such as probiotics, fidaxomicin, rifaximin, immunoglobulins and monoclonal antibodies against toxins A and B. Fecal microbiota transplantation (FMT) has emerged as a promising strategy in this group of patients, with effectiveness greater than 90%. We present the first case reported in Chile of this therapeutic strategy in a patient with Crohn's disease and recurrent CD infection who presented after the fecal transplantation an Escherichia coli bacteremia, suggesting the need for caution in the use of this strategy. 10 months after the FMT the patient presented a new episode of E. coli bacteremia and two episodes of diarrhea due to CD infection, treated both of them with vancomycin with good clinical response.

La infección por Clostridium difficile (CD) está aumentando en frecuencia y gravedad tanto a nivel intrahospitalario como ambulatorio, con una recurrencia que puede alcanzar hasta 30% después de un primer episodio. Los cuadros recurrentes son generalmente tratados con cursos prolongados de metronidazol y/o vancomicina. Otras terapias han sido sugeridas como el uso de probióticos, fidaxomicina, rifaximina, inmunoglobulina y anticuerpos monoclonales para toxina A y B. El trasplante de microbiota fecal (TMF) ha emergido como una estrategia promisoria en este grupo de pacientes con una efectividad mayor a 90%. Presentamos el primer caso reportado en Chile de esta estrategia terapéutica en un paciente con enfermedad de Crohn y CD recurrente, quien presentó una bacteriemia por Escherichia coli post-TMF, sugiriendo la necesidad de tener precaución con el uso de esta estrategia. El paciente presentó a los 10 meses post-TMF un nuevo episodio de bacteriemia por E. coli y dos episodios de diarrea por CD siendo tratados ambos cuadros con vancomicina con buena respuesta clínica.

Fecal transplantation: passing fashion or here to stay?

Several trillions of bacteria, distributed among more than 1,000 species, are natural inhabitants of the human intestinal tract and constitute what is now known as the gut microbiota. Although its composition varies within and between individuals with age, diet, and health status, it is becoming increasingly recognized that imbalances in the bacterial microbiota (dysbiosis) are linked to a number of conditions such as antibiotic-associated diarrhea, inflammatory bowel disease, and obesity, among others. Fecal transplantation where a preparation of stool from a microbiologically screened donor is administered into the colon of an affected recipient has been shown to be highly effective for the treatment of recurrent Clostridium difficile infection. Several trials of this therapy are now underway for gut dysbiosis in a number of patient disease groups raising concerns on the risk of transmission of infectious agents from donor to recipient, possible long-term adverse consequences of treatment, and effective regulation of the stool material used for the procedure. A worrying aspect is the emergence of private stool banks providing samples to the general public for self-administration.

Primer caso en Uruguay de tuberculosis asociada a terapia con agentes biológicos: reporte de un caso clínico / Tuberculosis associated with biological therapeutic agents: first case in Uruguay

Las terapias biológicas con anticuerpos monoclonales antifactor de necrosis tumoral alfa (TNF- ) revolucionaron el tratamiento de la artritis reumatoide. Su uso implica un riesgo elevado para el desarrollo de tuberculosis pulmonar por lo que exige una evaluación exhaustiva, tanto al inicio del tratamiento como en el seguimiento del paciente, descartando infección latente o tuberculosis activa. Se presenta el primer caso clínico descripto en Uruguay de tuberculosis pulmonar asociada a terapia con agentes biológicos (adalimumab).

Biologic therapies with anti-tumor necrosis factor alpha (TNF- ) monoclonal antibodies were a revolution in the treatment of rheumatoid arthritis. The use of antibodies implies a high risk of developing pulmonary tuberculosisand thus a thorough assessment is necessary, both upon the initiation of treatment and during patient follow up, to rule out a latent infection or active tuberculosis. The study presents the first clinical case of pulmonary tuberculosis associated with biologic therapydescribed in Uruguay (adalimumab).

As terapias biológicas com anticorpos monoclonais antifator de necrose tumoral alfa (TNF- ) revolucionaramo tratamento da artrite reumatoide. Seu uso implica um risco elevado para o surgimento de tuberculose pulmonarrazão pela qual é imprecindível a avaliação exaustiva, tanto no inicio do tratamento como durante o seguimentodo paciente para descartar infecção latente ou tuberculose ativa. Apresentamos o primeiro caso clínicodescrito no Uruguai de tuberculose pulmonar associada à terapia com agentes biológicos (adalimumab).

Biologicals in psoriasis

During the recent years, a new class of therapeutic agents has been introduced for the treatment of psoriasis and psoriatic arthritis. These agents target different inflammatory mediators involved in the pathogenesis of disease. The focus of this article is on the mechanism of action, side effect profile and dosing of the agents currently in use today for the treatment of psoriasis

Análise retrospectiva de 5 anos dos padrões de utilização do infliximab num hospital terciário em São Paulo, Brasil / A retrospective 5-year analysis of the infliximab use pattern in a tertiary hospital in São Paulo, Brazil

O objetivo foi analizar o uso e a eficácia do tratamento com infliximab no HIAE de 2001 a 2006. O método utilizado foi o questionário respondido por clínicos que prescreveram infliximab. Os dados clínicos de cada paciente foram encaminhados pelo reumatologista responsável segundo padrões individuais. A principal razão para a prescrição do infliximab foi falha na resposta a outras drogas anti-reumáticas que modificam a doença. Foi definido como escalada no tratamentoo aumento e/ou diminuição no intervalo entre as infusões de infliximab (intervalo interinfusional). Resultados: A duração média do tratamento foi 78 ± 54 semanas. A maioria dos que abandonaram a terapia o fizeram nos primeiros dois anos devido principalmente à ausência/perda de eficácia. O tempo do tratamento dos que ainda tomaram infliximab foi 92 ± 23 semanas. Ajustes de dose foram freqüentes, a maioria com aumento, porém alguns pacientes toleraram aumento do intervalo interinfusional.Estes dados confirmam a eficácia de infliximab para tratamento das artrites inflamatórias. Aproximadamente 50% dos pacientes desistiram do tratamento e um terço necessitou de ajuste de dose. Alguns pacientes toleraram um maior espaçamento entre as doses.