Interacciones de las bacterias de la flora con el sistema inmune intestinal

La hipótesis de los estudios que constituyen esta tesis es que las bacterias no patógenas interactúan de manera cepa-específica con la mucosa intestinal humana induciendo un cambio o modulación en el patrón de secreción de citoquinas tanto en tejido normal como inflamado y que en el tejido intestinal inflamado, determinadas bacterias ejercen un efecto antiinflamatorio. Para ello se han realizado dos estudios que han sido publicados en revistas del área de gastroenterología. Estudio 1: «Effects of nonpathogenic bacteria on cytokine secretion by human intestinal mucosa.» N.Borruel, F.Casellas, M.Antolín, M.Llopis, M.Carol, E.Espín, J.Naval, F.Guarner, J.R.Malagelada. American Journal of Gastroenterology 2003;98:865-870. El objetivo de este estudio fue estudiar el efecto «ex vivo» de diferentes bacterias no patógenas sobre la secreción de citoquinas pro y anti-inflamatorias en la mucosa colónica normal. Estudio 2: «Increased mucosal tumor necrosis factor ? production in Crohn's disease can be downregulated ex-vivo by probiotic bacteria.» N.Borruel, M.Carol, F.Casellas, M.Antolín, F.De Lara, E.Espín, J.Naval, F.Guarner, J.R.Malagelada. Gut 2002;51:659-664. El objetivo del segundo estudio fue estudiar el efecto antiinflamatorio de diferentes bacterias no patógenas en la mucosa intestinal de pacientes con enfermedad de Crohn. Las conclusiones de los estudios son las siguientes: -Las bacterias no patógenas interactúan con la mucosa colónica normal e inducen cambios en la secreción de citoquinas que son cepa-específicos. Así: Lactobacillus casei DN 114 001 induce una disminución de la liberación de TNF? e IL-8; Lactobacillus casei DN 114 056 induce una disminución de la liberación de TNF?, ningún cambio en la liberación de IL-8 y una estimulación TNF?-independiente de la IL-10;Lactobacillus casei ATCC 334 induce una disminución de la liberación de TNF? sin cambios en el resto de citoquinas; Lactobacillus bulgaricus LB10 no induce cambios en la liberación de citoquinas y Escherichia coli ECOR-26 induce un incremento en la liberación de TNF? y un estímulo de la liberación de IL-10 TNF?-independiente. -La mucosa ileal inflamada de pacientes con enfermedad de Crohn presenta una producción aumentada de TNF? cuando se compara con ileon normal o no inflamado. Lactobacillus casei DN 114 001 y Lactobacillus bulgaricus LB10 inducen un potente efecto antiinflamatorio en la mucosa ileal inflamada mediante la inhibición de la liberación de TNF?. La incubación de la mucosa ileal inflamada con L.casei DN114 001 y L. bulgaricus LB10 induce además una disminución del número de linfocitos intraepiteliales y de la proporción de linfocitos activados tanto en el compartimiento intraepitelial como en la lámina propia.The hypothesis of the studies that constitute this thesis is that nonpathogenic bacteria interact in a strain-specific manner with human intestinal mucosa inducing a change or modulation in the cytokine secretion profile both in normal and inflamed tissue and that in inflamed intestinal tissue, certain bacteria exert an anti-inflammatory effect. To this purpose, it has been performed two studies published in gastroenteroloy area journals. Study 1: «Effects of nonpathogenic bacteria on cytokine secretion by human intestinal mucosa.» N.Borruel, F.Casellas, M.Antolín, M.Llopis, M.Carol, E.Espín, J.Naval, F.Guarner, J.R.Malagelada. American Journal of Gastroenterology 2003;98:865-870. The aim of this study was to investigate the effect «ex vivo» of different nonpathogenic bacteria on pro and antiinflammatory cytokine secretion by normal colonic mucosa. Study 2: «Increased mucosal tumor necrosis factor ? production in Crohn's disease can be downregulated ex-vivo by probiotic bacteria.» N.Borruel, M.Carol, F.Casellas, M.Antolín, F.De Lara, E.Espín, J.Naval, F.Guarner, J.R.Malagelada. Gut 2002;51:659-664. The aim of the second study was to investigate the anti-inflammatory effect of different nonpathogenic bacteria on the intestinal mucosa from patients with Crohn's disease. The conclusions of both studies were: -Nonpathogenic bacteria interact with normal colonic mucosa and induce changes on cytokine secretion that are strain-specific: Lactobacillus casei DN 114 001 induces an inhibition on TNF? and IL-8 release; Lactobacillus casei DN 114 056 induces an inhibition of TNF? release, no changes on IL-8 release and a TNF?-independient stimulation of IL-10 release; Lactobacillus casei ATCC 334 induces an inhibition of TNF? release without changes in other cytokines; Lactobacillus bulgaricus LB10 does not induce any changes on cytokine release and Escherichia coli ECOR-26 induces a stimulation on TNF? release and a TNF?-independent increase on IL-10 release. -Inflamed ileal mucosa from patients with Crohn's disease has an increased production of TNF? as compared with normal ileal mucosa or non-inflammed mucosa. Lactobacillus casei DN 114 001 and Lactobacillus bulgaricus LB10 induce a potent anti-inflammatory effect on inflamed ileal mucosa by the inhibition of TNF? release. Incubation of ileal inflamed mucosa with L.casei DN114 001 and L. bulgaricus LB10 induces a decrease in the number of intraepithelial lymphocytes and in the rate of activated lymphocytes both in the epithelium and in the lamina propria

Co Treatment With Biologic Agents and Immunotherapy in the Setting of irAEs of Difficult Management

Adverse drugs reaction; Immune check-point inhibitors therapy; Immunosuppression therapyReacción adversa a medicamentos; Terapia con inhibidores del punto de control inmunitario; Terapia inmunosupresoraReaccions adverses als fàrmacs; Teràpia amb inhibidors del punt de control immune; Teràpia d'immunosupressióIn recent years, immunotherapy has become an important pillar of cancer treatment, with high response rates regardless of tumor histology or baseline mutations, sometime in patients without any alternative of treatment. Moreover, these treatments are moving from later line therapies to front-line therapies in the metastasic setting. However, immune activation associated with immune check-point inhibitors (ICI) is not selective and a large variety of immune-related adverse events, with an increasing frequency, have been associated with anti-PD1, anti-PD-1/L-1 and anti-CTLA-4 agents. In clinical trials, and sometimes also in real life practice, patients who develop severe toxicities on ICI-based therapies are usually not allowed to resume ICI once their disease progresses, because of the chance of developing severe irAEs on rechallenge with immunotherapies. Moreover, patients with irAEs suffer important side effects due to the high dose corticosteroids that are used to treat them. Therapy with ICI is sometimes the only alternative for certain patients, and for this reason co treatment with classic (DMARDS) or biologic immunosuppression therapy and ICI must be considered. Co-treatment with this type of immunosuppressant drugs, apart from allowing the maintenance of ICI therapy, drive to a lesser use of corticosteroids, with an improvement of the safety and quality of life of the patients. Such a tailored scheme of treatment is mostly an expert opinion based on recommendation and currently there is scarce evidence supporting it. Herein we present comprehensive, current recommendations and real-world data on the use of co-treatment with ICI and DMARDS and biologic immunosuppression

JAK inhibitors: A new dawn for oral therapies in inflammatory bowel diseases

JAK inhibitors; Oral therapies; Small moleculesInhibidors de JAK; Teràpies orals; Molècules petitesInhibidores de JAK; Terapias orales; Moléculas pequeñasInflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract that requires chronic treatment and strict surveillance. Development of new monoclonal antibodies targeting one or a few single cytokines, including anti-tumor necrosis factor agents, anti-IL 12/23 inhibitors, and anti-α4β7 integrin inhibitors, have dominated the pharmacological armamentarium in IBD in the last 20 years. Still, many patients experience incomplete or loss of response or develop serious adverse events and drug discontinuation. Janus kinase (JAK) is key to modulating the signal transduction pathway of several proinflammatory cytokines directly involved in gastrointestinal inflammation and, thus, probably IBD pathogenesis. Targeting the JAK-STAT pathway offers excellent potential for the treatment of IBD. The European Medical Agency has approved three JAK inhibitors for treating adults with moderate to severe Ulcerative Colitis when other treatments, including biological agents, have failed or no longer work or if the patient cannot take them. Although there are currently no approved JAK inhibitors for Crohn’s disease, upadacitinib and filgotinib have shown increased remission rates in these patients. Other JAK inhibitors, including gut-selective molecules, are currently being studied IBD. This review will discuss the JAK-STAT pathway, its implication in the pathogenesis of IBD, and the most recent evidence from clinical trials regarding the use of JAK inhibitors and their safety in IBD patients

Perioperative management and early complications after intestinal resection with ileocolonic anastomosis in Crohn’s disease: analysis from the PRACTICROHN study

This study is aimed at describing the prevalence of and risk factors associated with early post-operative complications after Crohn’s disease-related intestinal resection. Methods: This was a retrospective analysis of data from the PRACTICROHN cohort. Adult Crohn’s disease patients who underwent ileocolonic resection with ileocolonic anastomosis between January 2007 and December 2010 were included. The complications evaluated included death, ileus, anastomotic leak, abscess, wound infection, catheter-related infection, digestive bleeding and other extra-abdominal infections that occurred in the 30 days after surgery.Results: A total of 364 patients (median age at surgery 38 years and 50% men) were included. Indication for surgery was: stricturing disease (46.4%), penetrating disease (31.3%), penetrating and stricturing disease (14.0%) or resistance to medical treatment (5.8%). Early complications were recorded in 100 (27.5%) patients, with wound infection, intra-abdominal abscess and anastomotic leakage being the most frequent complications. Median hospitalization duration was 16 days for patients with complications vs. 9 days without complications (P<0.001). Complications were more common among patients with penetrating disease (36/114, 31.6%) and those refractory to treatment (9/21, 42.9%) compared with stricturing disease (45/169, 26.6%) or stricturingþpenetrating disease (6/51, 11.8%) (P¼0.040). The rate of complications was higher among patients with diagnosis made at the time of surgery (15/31, 48.4%) compared with the rest (85/331, 25.7%) (P¼0.013). Medication received at the time of surgery did not affect the rate of complications. Conclusions: Almost a quarter of patients developed early complications after intestinal resection. Penetrating disease and urgent surgery were associated with an increased risk of complicationsThis study was supported by Merck Sharp and Dohme, Spai

Multidisciplinary, evidence-based consensus guidelines for human papillomavirus (HPV) vaccination in high-risk populations, Spain, 2016

High-risk populations; Human papillomavirus infection; VaccinesPoblacions d'alt risc; Virus del papil·loma humà; VacunesPoblaciones de alto riesgo; Virus del papiloma humano; VacunasINTRODUCTION: Although human papillomavirus (HPV) routine vaccination programmes have been implemented around the world and recommendations have been expanded to include other high-risk individuals, current recommendations often differ between countries in Europe, as well as worldwide. AIM: To find and summarise the best available evidence of HPV vaccination in high-risk patients aiding clinicians and public health workers in the day-to-day vaccine decisions relating to HPV in Spain. METHODS: We conducted a systematic review of the immunogenicity, safety and efficacy/effectiveness of HPV vaccination in high-risk populations between January 2006 and June 2016. HPV vaccination recommendations were established with levels of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: A strong recommendation about HPV vaccination was made in the following groups: HIV infected patients aged 9-26 years; men who have sex with men aged 9-26 years; women with precancerous cervical lesions; patients with congenital bone marrow failure syndrome; women who have received a solid organ transplant or hematopoietic stem cell transplantation aged 9-26 years; and patients diagnosed with recurrent respiratory papillomatosis. CONCLUSIONS: Data concerning non-routine HPV vaccination in populations with a high risk of HPV infection and associated lesions were scarce. We have developed a document to evaluate and establish evidence-based guidelines on HPV vaccination in high-risk populations in Spain, based on best available scientific evidence

Critical role of interleukin (IL)-17 in inflammatory and immune disorders: An updated review of the evidence focusing in controversies

Medicaments biològics; Inflamació; PsoriasiBiological drugs; Inflammation; PsoriasisMedicamentos biológicos; Inflamación; PsoriasisInterleukin 17 (IL-17) is a proinflammatory cytokine that has been the focus of intensive research because of its crucial role in the pathogenesis of different diseases across many medical specialties. In this context, the present review in which a panel of 13 experts in immunology, dermatology, rheumatology, neurology, hematology, infectious diseases, hepatology, cardiology, ophthalmology and oncology have been involved, puts in common the mechanisms through which IL-17 is considered a molecular target for the development of novel biological therapies in these different fields. A comprehensive review of the literature and analysis of the most outstanding evidence have provided the basis for discussing the most relevant data related to IL-17A blocking agents for the treatment of different disorders, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, cardiovascular disorders, non alcoholic fatty liver disease, multiple sclerosis, inflammatory bowel disease, uveitis, hematological and solid cancer. Current controversies are presented giving an opening line for future research.This work was supported by Novartis Pharmaceuticals Spain