Impact of Functional Polymorphisms on Drug Survival of Biological Therapies in Patients with Moderate-to-Severe Psoriasis.

Biological therapies (BTs) indicated for psoriasis are highly effective; however, not all patients obtain good results, and loss of effectiveness is the main reason for switching. Genetic factors may be involved. The objective of this study was to evaluate the influence of single-nucleotide polymorphisms (SNPs) on the drug survival of tumor necrosis factor inhibitors (anti-TNF) medications and ustekinumab (UTK) in patients diagnosed with moderate-to-severe psoriasis. We conducted an ambispective observational cohort study that included 379 lines of treatment with anti-TNF (n = 247) and UTK (132) in 206 white patients from southern Spain and Italy. The genotyping of the 29 functional SNPs was carried out using real-time polymerase chain reaction (PCR) with TaqMan probes. Drug survival was evaluated with Cox regression and Kaplan-Meier curves. The multivariate analysis showed that the HLA-C rs12191877-T (hazard ratio [HR] = 0.560; 95% CI = 0.40-0.78; p = 0.0006) and TNF-1031 (rs1799964-C) (HR = 0.707; 95% CI = 0.50-0.99; p = 0.048) polymorphisms are associated with anti-TNF drug survival, while TLR5 rs5744174-G (HR = 0.589; 95% CI = 0.37-0.92; p = 0.02), CD84 rs6427528-GG (HR = 0.557; 95% CI = 0.35-0.88; p = 0.013) and PDE3A rs11045392-T together with SLCO1C1 rs3794271-T (HR = 0.508; 95% CI = 0.32-0.79; p = 0.002) are related to UTK survival. The limitations are the sample size and the clustering of anti-TNF drugs; we used a homogeneous cohort of patients from 2 hospitals only. In conclusion, SNPs in the HLA-C, TNF, TLR5, CD84, PDE3A, and SLCO1C1 genes may be useful as biomarkers of drug survival of BTs indicated for psoriasis, making it possible to implement personalized medicine that will reduce financial healthcare costs, facilitate medical decision-making and improve patient quality of life. However, further pharmacogenetic studies need to be conducted to confirm these associations.

Antibody-guided proteases enable selective and catalytic degradation of challenging therapeutic targets.

The exquisite specificity, natural biological functions, and favorable development properties of antibodies make them highly effective agents as drugs. Monoclonal antibodies are particularly strong as inhibitors of systemically accessible targets where trough-level concentrations can sustain full target occupancy. Yet beyond this pharmacologic wheelhouse, antibodies perform suboptimally for targets of high abundance and those not easily accessible from circulation. Fundamentally, this restraint on broader application is due largely to the stoichiometric nature of their activity-one drug molecule is generally able to inhibit a maximum of two target molecules at a time. Enzymes in contrast are able to catalytically turnover multiple substrates, making them a natural sub-stoichiometric solution for targets of high abundance or in poorly accessible sites of action. However, enzymes have their own limitations as drugs, including, in particular, the polypharmacology and broad specificity often seen with native enzymes. In this study, we introduce antibody-guided proteolytic enzymes to enable selective sub-stoichiometric turnover of therapeutic targets. We demonstrate that antibody-mediated substrate targeting can enhance enzyme activity and specificity, with proof of concept for two challenging target proteins, amyloid-ß and immunoglobulin G. This work advances a new biotherapeutic platform that combines the favorable properties of antibodies and proteolytic enzymes to more effectively suppress high-bar therapeutic targets.

What drives the decision to optimise biological treatment in children and youngsters with juvenile idiopathic arthritis? A discrete-choice experiment.

OBJECTIVE: To analyse factors involved in the decision to optimise biologics in juvenile idiopathic arthritis. METHODS: A "discrete-choice" methodology was used. In a nominal group meeting, factors which may influence physicians' decisions to optimise biological dose were identified, together with decision nodes. 1000Minds® was used to create multiple fictitious clinical scenarios based on the factors identified, and to deploy surveys that were sent to a panel of experts. These experts decided for each item which of two clinical scenarios prompted them to optimise the dose of biologic. A conjoint analysis was carried out, and the partial-value functions and the weights of relative importance calculated. RESULTS: In the nominal group, three decision nodes were identified: (1) time to decide; (2) to maintain/reduce or prolong interval; (3) what drug to reduce. The factors elicited were different for each node and included patient and drug attributes. The presence of macrophage activation syndrome (MAS), systemic involvement, or subclinical inflammation made the decision easier (highest weights). The presence of joints of difficult control and year of debut influenced the decision in some but not all, and in different directions. Immunogenicity, adherence, and concomitant treatments were also aspects taken into account. CONCLUSIONS: The decision to optimise the dose of biological therapy in children and youngster can be divided into several nodes, and the factors, both patient and therapy-related, leading to the decision can be detailed. These decisions taken by experts may be transported to practice, study designs, and guidelines.

Surface programmed bacteria as photo-controlled NO generator for tumor immunological and gas therapy.

The use of bacteria as living vehicles has attracted increasing attentions in tumor therapy field. The combination of functional materials with bacteria dramatically facilitates the antitumor effect. Here, we presented a rationally designed living system formed by programmed Escherichia Coli MG1655 cells (Ec) and black phosphorus (BP) nanoparticles (NPs). The bacteria were genetically engineered to express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), via an outer membrane YiaT protein (Ec-T). The Ec-T cells were associated with BP NPs on their surface to acquire BP@Ec-T. The designed living system could transfer the photoelectrons produced by BP NPs after laser irradiation and triggered the reductive metabolism of nitrate to nitric oxide for the in situ release at tumor sites, facilitating the therapeutic efficacy and the polarization of tumor associated macrophages to M1 phenotype. Meanwhile, the generation of reactive oxygen species induced the immunogenic cell death to further improve the antitumor efficacy. Additionally, the living system enhanced the immunological effect by promoting the apoptosis of tumor cells, activating the effect of T lymphocytes and releasing the pro-inflammatory cytokines. The integration of BP NPs, MG1655 cells and TRAIL led to an effective tumor therapy. Our work established an approach for the multifunctional antitumor living therapy.

Biologic Therapy Carries a Very Low Risk of Reactivation in Hepatitis B Surface Antigen-Negative Phase of Hepatitis B.

BACKGROUND: The risk of hepatitis B reactivation in hepatitis B surface antigen-negative phase of hepatitis B virus-infected patients exposed to biologic agents is not clear. We aimed to investigate the reactivation rate in hepatitis B surface antigen-negative phase of hepatitis B virus-infected patients after biologic therapy. METHODS: Patients followed at gastroenterology, rheumatology, and dermatology clinics with a diagnosis of immune-mediated inflam matory diseases were screened. Immune-mediated inflammatory diseases patients exposed to biologic agents with a negative hepatitis B surface antigen and positive hepatitis B core immunoglobulin G antibody were included in the study. RESULTS: We screened 8266 immune-mediated inflammatory disease patients, and 2484 patients were identified as exposed to biologic agents. Two hundred twenty-one patients were included in the study. The mean age was 54.08 ± 11.69 years, and 115 (52.0%) patients were female. The median number of different biologic subtype use was 1 (range: 1-6). The mean biologic agent exposure time was 55 (range: 2-179) months. One hundred and fifty-two (68.8%) patients used a concomitant immunomodulatory agent, and 84 (38.0%) patients were exposed to corticosteroids during biologic use. No hepatitis B reactivation with a reverse seroconversion of hepatitis B surface antigen positivity was seen. Antiviral prophylaxis for hepatitis B was applied to 48 (21.7%) patients. Hepatitis B virus-DNA was screened in 56 (25.3%) patients prior to the biologic exposure. Two patients without antiviral prophylaxis had hepatitis B virus-DNA reactivation with a negative hepatitis B surface antigen during exposure to the biologic agent. CONCLUSION: We found 2 reactivations and no hepatitis B surface antigen seroconversion in our cohort. Antiviral prophylaxis for patients exposed to biologic agents may need to be discussed in more detail.

Tratamientos y bioterapias para COVID-19 / Therapeutics and biotherapies for covid-19

INTRODUCCIÓN: Un nuevo brote de coronavirus surgió en 2019 en Wuhan, China, causando conmoción en el sistema sanitario de todo el mundo; el Comité Internacional de Taxonomía de Virus lo denominó SARS-CoV-2, agente causante de la enfermedad COVID-19.El espectro de gravedad de la enfermedad es muy amplio: la mayoría de los pacientes no presentan gravedad, pero otros pueden desarrollar neumonías, y la insuficiencia respiratoria aguda es la causa más frecuente de mortalidad. Objetivo: analizar y desarrollar las distintas alternativas terapéuticas aportadas por la Biotecnología para tratar los síntomas de aquellos pacientes con COVID-19. Metodología: se realizó una revisión de la bibliografía disponible, a partir de enero de 2020 en PubMed, acerca de los tratamientos que se encuentran aún en ensayos clínicos y aquellos que cuentan con aprobación bajo uso de emergencia para la enfermedad COVID-19. También se realizaron búsquedas a través de Google y Google Académico para publicaciones de organismos de Salud en referencia a políticas de salud establecidas para la terapéutica durante dicha pandemia. Resultados: este trabajo aborda las nuevas alternativas terapéuticas para COVID-19 derivadas de la Biotecnología, que se encuentran tanto en uso como en etapas de ensayos clínicos comprendidos dentro del segmento de los biofármacos y las bioterapias. Se incluye un breve resumen del estatus regulatorio de entidades de salud, el mecanismo de acción de dichas terapias y características generales de cada uno. Se incluyen novedosas bioterapias que se empezaron a implementar para afrontar la pandemia. Conclusiones: la pandemia de coronavirus está poniendo a prueba el sistema sanitario internacional, para brindar soluciones tanto desde el diagnóstico y prevención como para el tratamiento de la población a fin de disminuir la mortalidad. Esto incluyó, obviamente también, al área de la Biotecnología aplicada a la salud, que ha aportado en los tres aspectos mencionados; el presente trabajo se centra en las respuestas de tipo terapéutico que ha brindado y que están comercializadas o en fases clínicas. (AU)

INTRODUCTION: A new coronavirus outbreak emerged in 2019 in Wuhan, China, causing a shock to the healthcare system around the world; the International Committee on Taxonomy of Viruses named it SARS-CoV- 2, the infectious agent of the COVID-19 disease. The spectrum of severity of the disease is very wide, most patients are not serious, but others can develop pneumonia, with acute respiratory failure being the most frequent cause of mortality. Objective: to analyze and develop the different therapeutic alternatives provided by Biotechnology dedicated to Health, to treat the symptoms of those COVID-19 patients who require it, and thus reduce mortality.Methodology: a review of the available literature from January 2020 in PubMed of the treatments that are still in clinical trials and those that have been approved under emergency use for the disease COVID-19 was performed. Searches were also carried out through Google and Google Scholar for publications of Health organizations in reference to health policies established for therapeutics during the mentioned pandemic. Results: this work addresses the new therapeutic alternatives derived from Biotechnology, which are both in use and in stages of clinical trials, to treat patients who developed COVID-19 included within the segment of biopharmaceuticals and biotherapies. A brief summary of the regulatory status of health entities, the mechanism of action of said therapies and general characteristics of each one is included. Innovative biotherapies that began to be implemented to face the pandemic are included. Conclusions: The coronavirus pandemic has driven the international health system to the test, to provide solutions both from the diagnosis, prevention and treatment of the population to reduce the mortality of patients. This obviously also included the area of Biotechnology applied to health, which has contributed in the three aspects mentioned. The present work focuses on the therapeutic responses that it has provided and that are commercialized or in clinical phases. (AU)

Extended Follow-up of Microbiome Therapeutic SER-109 Through 24 Weeks for Recurrent Clostridioides difficile Infection in a Randomized Clinical Trial.

This study examines adverse events and durability of response of SER-109, an investigational microbiome therapeutic comprised of purified Firmicutes spores, compared with placebo for Clostridioides difficile infection.

Cellular cross-talk in heart repair.

The cytokine meteorin-like (METRNL) improves cardiac function after heart attack in mice.

Safety of sequential biological therapy in inflammatory bowel disease: results from a tertiary referral centre.

BACKGROUND: Biologicals represent the cornerstone of treatment for moderate-to-severe inflammatory bowel diseases (IBD). Many patients cycle between biologicals when encountering loss of response or adverse events. AIM: To assess the occurrence of serious infections and malignancies with exposure to several (classes of) biologicals. METHODS: We performed a retrospective cohort study in a tertiary referral centre including consecutive IBD patients exposed to adalimumab, infliximab, ustekinumab or vedolizumab between 1996 and 2019. All serious infections and malignancies, as well as potential confounders, were accounted for. RESULTS: In total, 1575 patients were included with a median (interquartile range) follow-up of 10 (6-16) years and a duration of biological therapy of 71 (39-112) months. Incidence rates of serious infections were 3.4 per 100 patients' years (PY) in the post-biological setting. Serious infections after biological exposure were associated with systemic steroids in monotherapy (hazard ratio 2.96 [95% confidence interval 1.78-4.93], p < 0.0001), combination therapy of systemic steroids and a biological (2.44 [1.37-4.34], p = 0.002), female gender (1.25 [1.04-1.51], p = 0.02), and prior serious infections in the pre-biological setting (1.42 [1.03-1.96], p = 0.03). Malignancy rates were 1.06 per 100PY in the post-biological setting and increased with older age at biological initiation (1.04 [1.02-1.05], p < 0.0001). The risk for serious infections or malignancies was independent of type and number of biologicals to which the patient was exposed. CONCLUSION: This study shows that the sequential use of biological therapy in IBD does not seem to convey an overall higher risk of serious infections or malignancies, but that underlying more refractory disease seems to increase this risk.

Actualización práctica de las recomendaciones del Grupo de Psoriasis de la Academia Española de Dermatología y Venereología (GPS) para el tratamiento de la psoriasis con terapia biológica. Parte 1. «Conceptos y manejo general de la psoriasis con terapia biológica» / Practical update of the Recommendations Published by the Psoriasis Group of the Spanish Academy of Dermatology and Venereology (GPS) on the Treatment of Psoriasis with Biologic Therapy. Part 1. Concepts and General Management of Psoriasis with Biologic Therapy

Justificación y objetivos: La aprobación de un gran número de nuevos fármacos en los últimos años y los cambios en el paradigma de tratamiento de la psoriasis hacen recomendable un nuevo documento de recomendaciones del GPS para el tratamiento de la psoriasis moderada-grave. Metodología: Para la elaboración del consenso se siguió la metodología de grupos nominales, con ayuda de una scoping review. Tras designar a un coordinador, se seleccionó un grupo de integrantes del GPS. El coordinador definió los objetivos y puntos clave del documento y, con ayuda de un documentalista, se realizó una scoping review incluyendo datos de Medline, Embase y Cochrane Library (hasta enero del 2021). Se seleccionaron revisiones sistemáticas, metaanálisis y ensayos clínicos no incluidos en las mismas, así como estudios de calidad en vida real. Se revisaron otras guías de práctica clínica y documentos de consenso nacionales e internacionales sobre el manejo de la psoriasis moderada-grave. El coordinador generó una serie de recomendaciones preliminares que fueron evaluadas y modificadas en una reunión de grupo nominal. Tras varios procesos de revisión, que incluyeron la revisión externa por parte de los miembros del GPS, se redactó el documento definitivo. Resultados: En el documento se incluyen principios generales sobre el tratamiento de los pacientes con psoriasis moderada-grave, la definición de objetivos terapéuticos y los criterios de indicación y selección de tratamiento tanto en primera como en sucesivas líneas terapéuticas de fármacos biológicos. Se abordan asimismo cuestiones prácticas como el fracaso terapéutico o el mantenimiento de la respuesta (AU)

Background and objectives: A new, updated AEDV Psoriasis Group consensus document on the treatment of moderate to severe psoriasis was needed owing to the approval, in recent years, of a large number of new drugs and changes in the treatment paradigm. Methodology: The consensus document was developed using the nominal group technique and a scoping review. First, a designated coordinator selected a group of Psoriasis Group members for the panel. The coordinator defined the objectives and key points for the document and, with the help of a documentalist, conducted a scoping review of articles in Medline, Embase, and the Cochrane Library up to January 2021. The review included systematic reviews and meta-analyses as well as clinical trials not included in those studies and high-quality real-world studies. National and international clinical practice guidelines and consensus documents on the management of moderate to severe psoriasis were also reviewed. Based on these reviews, the coordinator drew up a set of proposed recommendations, which were then discussed and modified in a nominal group meeting. After several review processes, including external review by other GPs members, the final document was drafted. Results: The present guidelines include general principles for the treatment of patients with moderate to severe psoriasis and also define treatment goals and criteria for the indication of biologic therapy and the selection of initial and subsequent therapies. Practical issues, such as treatment failure and maintenance of response, are also addressed (AU)

[Translated article] Practical Update of the Recommendations Published by the Psoriasis Group of the Spanish Academy of Dermatology and Venereology (GPs) on the Treatment of Psoriasis with Biologic Therapy. Part 1. Concepts and General Management of Psoriasis With Biologic Therapy / Actualización práctica de las recomendaciones del Grupo de Psoriasis de la Academia Española de Dermatología y Venereología (GPS) para el tratamiento de la psoriasis con terapia biológica. Parte 1. Conceptos y manejo general de la psoriasis con terapia biológica

Background and objectives: A new, updated AEDV Psoriasis Group consensus document on the treatment of moderate to severe psoriasis was needed owing to the approval, in recent years, of a large number of new drugs and changes in the treatment paradigm. Methodology: The consensus document was developed using the nominal group technique and a scoping review. First, a designated coordinator selected a group of Psoriasis Group members for the panel. The coordinator defined the objectives and key points for the document and, with the help of a documentalist, conducted a scoping review of articles in Medline, Embase, and the Cochrane Library up to January 2021. The review included systematic reviews and meta-analyses as well as clinical trials not included in those studies and high-quality real-world studies. National and international clinical practice guidelines and consensus documents on the management of moderate to severe psoriasis were also reviewed. Based on these reviews, the coordinator drew up a set of proposed recommendations, which were then discussed and modified in a nominal group meeting. After several review processes, including external review by other GPs members, the final document was drafted. Results: The present guidelines include general principles for the treatment of patients with moderate to severe psoriasis and also define treatment goals and criteria for the indication of biologic therapy and the selection of initial and subsequent therapies. Practical issues, such as treatment failure and maintenance of response, are also addressed (AU)

Justificación y objetivos: La aprobación de un gran número de nuevos fármacos en los últimos años y los cambios en el paradigma de tratamiento de la psoriasis hacen recomendable un nuevo documento de recomendaciones del GPS para el tratamiento de la psoriasis moderada-grave. Metodología: Para la elaboración del consenso se siguió la metodología de grupos nominales, con ayuda de una scoping review. Tras designar a un coordinador, se seleccionó un grupo de integrantes del GPS. El coordinador definió los objetivos y puntos clave del documento y, con ayuda de un documentalista, se realizó una scoping review incluyendo datos de Medline, Embase y Cochrane Library (hasta enero del 2021). Se seleccionaron revisiones sistemáticas, metaanálisis y ensayos clínicos no incluidos en las mismas, así como estudios de calidad en vida real. Se revisaron otras guías de práctica clínica y documentos de consenso nacionales e internacionales sobre el manejo de la psoriasis moderada-grave. El coordinador generó una serie de recomendaciones preliminares que fueron evaluadas y modificadas en una reunión de grupo nominal. Tras varios procesos de revisión, que incluyeron la revisión externa por parte de los miembros del GPS, se redactó el documento definitivo. Resultados: En el documento se incluyen principios generales sobre el tratamiento de los pacientes con psoriasis moderada-grave, la definición de objetivos terapéuticos y los criterios de indicación y selección de tratamiento tanto en primera como en sucesivas líneas terapéuticas de fármacos biológicos. Se abordan asimismo cuestiones prácticas como el fracaso terapéutico o el mantenimiento de la respuesta (AU)

Plant lectins as prospective antiviral biomolecules in the search for COVID-19 eradication strategies.

Lectins or clusters of carbohydrate-binding proteins of non-immune origin are distributed chiefly in the Plantae. Lectins have potent anti-infectivity properties for several RNA viruses including SARS-CoV-2. The primary purpose of this review is to review the ability of lectins mediated potential biotherapeutic and bioprophylactic strategy against coronavirus causing COVID-19. Lectins have binding affinity to the glycans of SARS-COV-2 Spike glycoprotein that has N-glycosylation sites. Apart from this, the complement lectin pathway is a "first line host defense" against the viral infection that is activated by mannose-binding lectins. Mannose-binding lectins deficiency in serum influences innate immunity of the host and facilitates infectious diseases including COVID-19. Our accumulated evidence obtained from scientific databases particularly PubMed and Google Scholar databases indicate that mannose-specific/mannose-binding lectins (MBL) have potent efficacies like anti-infectivity, complement cascade induction, immunoadjuvants, DC-SIGN antagonists, or glycomimetic approach, which can prove useful in the strategy of COVID-19 combat along with the glycobiological aspects of SARS-CoV-2 infections and antiviral immunity. For example, plant-derived mannose-specific lectins BanLac, FRIL, Lentil, and GRFT from red algae can inhibit and neutralize SARS-CoV-2 infectivity, as confirmed with in-vitro, in-vivo, and in-silico assessments. Furthermore, Bangladesh has a noteworthy resource of antiviral medicinal plants as well as plant lectins. Intensifying research on the antiviral plant lectins, adopting a glyco-biotechnological approach, and with deeper insights into the "glycovirological" aspects may result in the designing of alternative and potent blueprints against the 21st century's biological pandemic of SARS-CoV-2 causing COVID-19.

Small Bowel Crohn's Disease Recurrence is Common After Total Proctocolectomy for Crohn's Colitis.

BACKGROUND: Surgical intervention for Crohn's disease involving the colon is often a total proctocolectomy with end ileostomy. There are limited data regarding postoperative small bowel recurrence rates in the recent era. OBJECTIVE: The purpose of this study was to determine the rate of small bowel Crohn's disease recurrence following total proctocolectomy and secondarily define risk factors for disease recurrence. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at four hospitals within a single healthcare system. PATIENTS: Patients were those with Crohn's disease undergoing total proctocolectomy with end ileostomy between 2009-2019. MAIN OUTCOME MEASURES: Main outcome measures were clinical, endoscopic, radiographic, and/or surgical Crohn's disease recurrence. RESULTS: In total, 193 patients were included with a median follow-up of 1.8 years (IQR 0.4-4.6). Overall, 74.6% (n = 144) of patients had been previously exposed to biologic therapy, and 51.3% (n = 99) had a history of small bowel Crohn's disease. Postoperatively, 14.5% (n = 28) of patients received biologic therapy. Crohn's disease recurrence occurred in 23.3% (n = 45) of patients with an estimated median 5-year recurrence rate of 40.8% (95% CI' 30.2-51.4). Surgical recurrence occurred in 8.8% (n = 17) of patients with an estimated median 5-year recurrence rate of 16.9% (95% CI' 8.5-25.3). On multivariable analysis, prior small bowel surgery for Crohn's disease (HR 2.61; 95% CI' 1.42-4.81) and Crohn's diagnosis at age <18 years (HR 2.56; 95% CI' 1.40-4.71) were associated with Crohn's recurrence. In patients without prior small bowel Crohn's disease, 14.9% (n = 14) had Crohn's recurrence with an estimated 5-year overall recurrence rate of 31.1% (95% CI' 13.3-45.3) and 5-year surgical recurrence rate of 5.7% (95% CI' 0.0-12.0). LIMITATIONS: The study was limited by its retrospective design and lack of consistent follow-up on all patients. CONCLUSIONS: Greater than one third of patients who underwent total proctocolectomy for Crohn's disease were estimated to have small bowel Crohn's recurrence at 5 years after surgery. Patients with a history of small bowel surgery for Crohn's and diagnosis at any early age may benefit from more intensive postoperative surveillance and consideration for early medical prophylaxis. See Video Abstract at http://links.lww.com/DCR/B762. RECURRENCIA FRECUENTE DE LA ENFERMEDAD DE CROHN DEL INTESTINO DELGADO DESPUS DE LA PROCTOCOLECTOMA TOTAL POR COLITIS DE CROHN: ANTECEDENTES:La cirugia para la enfermedad de Crohn que involucra el colon es a menudo una proctocolectomía total con ileostomía terminal. Hay datos limitados con respecto a las tasas de recurrencia posoperatoria de la enfermedad de Crohn del intestino delgado en la actualidad.OBJETIVO:Buscamos determinar la tasa de recurrencia de la enfermedad de Crohn del intestino delgado después de la proctocolectomía total y, en segundo lugar, definir los factores de riesgo de recurrencia de la enfermedad.DISEÑO:Estudio de cohorte retrospectivo.ENTORNO CLINICO:Cuatro hospitales de un mismo sistema sanitario.PACIENTES:Pacientes con enfermedad de Crohn sometidos a proctocolectomía total con ileostomía terminal entre 2009-2019.PRINCIPALES MEDIDAS DE VALORACIÓN:Recurrencia clínica, endoscópica, radiográfica y / o quirúrgica de la enfermedad de Crohn.RESULTADOS:Se incluyeron 193 pacientes con un seguimiento promedio de 1,8 años (IQR 0,4-4,6). El 74,6% (n = 144) de los pacientes habían recibido previamente terapia biológica y el 51,3% (n = 99) tenían antecedentes de enfermedad de Crohn del intestino delgado. Después de la operación, el 14,5% (n = 28) de los pacientes recibieron terapia biológica. La recurrencia de la enfermedad de Crohn ocurrió en el 23,3% (n = 45) de los pacientes con una tasa de recurrencia media estimada a los 5 años del 40,8% (IC del 95%: 30,2-51,4). La recidiva quirúrgica se produjo en el 8,8% (n = 17) de los pacientes con una tasa de recidiva media estimada a los 5 años del 16,9% (IC del 95%: 8,5-25,3). En el análisis multivariable, la cirugía previa del intestino delgado para la enfermedad de Crohn (HR 2,61, IC del 95%: 1,42-4,81) y el diagnóstico de Crohn a la edad <18 (HR 2,56, IC del 95%: 1,40-4,71) se asociaron con la recurrencia de Crohn. En pacientes sin enfermedad previa de Crohn del intestino delgado, el 14,9% (n = 14) tuvo recurrencia de Crohn con una tasa de recurrencia general estimada a 5 años del 31,1% (IC del 95%: 13,3-45,3) y una tasa de recurrencia quirúrgica a 5 años del 5,7% (IC del 95%: 0,0-12,0).LIMITACIONES:Diseño retrospectivo, falta de seguimiento constante de todos los pacientes.CONCLUSIONES:Se estimó que más de un tercio de los pacientes que se sometieron a proctocolectomía total tenían recurrencia de Crohn del intestino delgado a los 5 años después de la cirugía. Los pacientes con antecedentes de cirugía por enfermedad de Crohn del intestino delgado y diagnóstico a una edad temprana pueden beneficiarse de una vigilancia posoperatoria más intensiva y la consideración de una profilaxis médica temprana. Consulte Video Resumen en http://links.lww.com/DCR/B762. (Traducción- Dr. Ingrid Melo).

Real world use of biologic drug levels and anti-drug antibodies in patients with psoriasis - does therapeutic drug monitoring have a place in routine clinical practice?

Background: Psoriasis is a chronic disorder with increasing new treatments targeting the T-helper cell (Th)-1/Th17 axis. There remains a subset of patients who experience a primary or secondary failure to biologic treatments.Methods: We present ten patients with psoriasis who failed biologic therapy with measurement of serum drug levels and anti-drug antibody levels (ADAs) with review of the current literature. Our objective was to identify demographic factors, disease status, drug level and ADAs which might correlate with primary and secondary failure.Results: There are a number of factors affecting drug levels in patients with psoriasis on biologics including the presence of ADAs, patient adherence to treatment regimes, pharmacogenetics and the pharmacokinetic properties of the drug following subcutaneous injection. Our results demonstrate that biologic failure is related to low serum drug levels subtherapeutic in 80% of our cohort. Primary failure may correlate with the presence of ADAs but not with serum drug levels. All patients were ANA negative and there remains considerable debate on the utility of routine ANA testing.Conclusions: The role of therapeutic drug monitoring in dermatology remains uncertain and requires further study. We aim to promote debate in the dermatology community as to the utility of therapeutic drug monitoring in routine practice.

Del-1 enhances therapeutic efficacy of bacterial cancer immunotherapy by blocking recruitment of tumor-infiltrating neutrophils.

BACKGROUND: Bacterial-mediated cancer immunotherapy (BCI) elicits a more robust initial immune response than conventional immunotherapy, but does not prevent tumor recurrence and metastasis. BCI is associated with recruitment of tumor-infiltrating neutrophils, which could suppress the therapeutic efficacy of this modality. Development endothelial locus 1 (Del-1), a potent inhibitor of neutrophil recruitment, antagonizes lymphocyte function-associated antigen-1 on the vascular endothelium. Here, we aimed to determine the effect of Del-1-secreting S.t△ppGpp on anti-tumor activity and tumor-infiltrating neutrophil recruitment in a mouse model of colon cancer. METHODS: We investigated the anti-cancer activity of Del-1-secreting engineered Salmonella (△ppGpp S. Typhimurium) in the mice colon cancer models. RESULTS: In the present study, we identified that Del-1-secreting engineered Salmonella had more potent anti-cancer activity compared with normal S.t△ppGpp without Del-1 secretion. We postulated that Del-1 expression increased M1 macrophage recruitment to tumors by decreasing tumor-infiltrating neutrophils. This approach could enhance the anti-cancer effects of S.t△ppGpp. CONCLUSIONS: Collectively, the approach of using engineered bacteria that deliver Del-1 to block tumor-infiltrating neutrophil recruitment is a potential therapeutic approach.

Evaluation of the Anti-Aging Effects of a Probiotic Combination Isolated From Centenarians in a SAMP8 Mouse Model.

Population aging is a prominent global problem in today's society. However, there are currently no good methods to treat or prevent aging, so anti-aging research has crucial implications. In this research, we screened bacteria from centenarians, and finally selected four probiotics (Lactobacillus fermentum SX-0718, L. casei SX-1107, Bifidobacterium longum SX-1326, and B. animalis SX-0582) to form a probiotic combination. By using the senescence accelerated mouse prone 8 (SAMP8) model, the anti-aging effects of the probiotic combination were evaluated by using behavioural testing, neuroinflammation, intestinal inflammation, and intestinal microbiota. The results showed that probiotic combination improved the impaired spatial memory, motor dysfunction, and decreased exploratory behavior in aging mice. The probiotic combination inhibited Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NFκB)-induced neuroinflammation and up-regulated the expression of Sirt 1 to protect hippocampal neurons. At the same time, the probiotic combination regulated the intestinal microbiota, reduced the relative abundance of Alistipes and Prevotella in SAMP8 mice, inhibited TLR4/NFκB-induced intestinal inflammation, and increased the expression of intestinal permeability related proteins zonula occludens-1 (ZO-1) and Occuldin. The anti-aging effects of the probiotic combination may be through the regulating intestinal microbiota and inhibiting TLR4/NFκB-induced inflammation. This research provides the basis and technical support for the future production and application of the probiotic combination.

New developments in Sjogren's syndrome.

SS is a chronic, autoimmune condition characterized by lymphocytic infiltration of the exocrine glands and B-cell dysfunction. Current treatment strategies are largely empirical and offer only symptomatic relief for patients. There are no proven treatments that alter disease progression or treat the systemic manifestations of disease. B-cell depletion is used in patients with systemic disease but its overall clinical efficacy has not been demonstrated in two large randomized controlled trials. Studies are now focussing on alternative strategies to target B-cells, including co-stimulation targets, with promising data. It is increasingly clear that clinical trials in SS will require patient stratification and relevant and sensitive outcome measures to identify successful treatment modalities.

New developments in systemic lupus erythematosus.

In this review, the results of recent and ongoing clinical trials in patients with SLE are discussed. After many unsuccessful trials in the past decade, belimumab was the first biologic specifically designed for SLE that met its primary end point. At the same time, studies on the pathophysiology of SLE have further elucidated the pathways involved in the disease, which has led to the identification of new possible therapeutics and has encouraged the initiation of new trials. These new drugs include biologics that target B cells, T cells and type 1 interferons, and small molecules that inhibit kinases. Other therapeutics aim to restore immunological balance by restoring tolerance. Results from phase II and even phase III trials are promising and it is likely that some of the therapeutics discussed will receive approval in the following years. Hopefully, this will allow for more tailor-made medicine for SLE patients in the future.