Exit strategies in inflammatory bowel disease: Looking beyond anti-tumor necrosis factors.

The long-term management of patients with inflammatory bowel disease (IBD) is still a matter of debate, and no clear guidelines have been issued. In clinical practice, gastroenterologists often have to deal with patients in prolonged remission after immunomodulatory or immunosuppressive therapies. When planning an exit strategy for drug withdrawal, the risk of disease relapse must be balanced against the risk of drug-related adverse events and healthcare costs. Furthermore, there is still a dearth of data on the withdrawal of novel biologics, such as the anti-α4ß7 integrin antibody (vedolizumab) and anti-IL12/23 antibody (ustekinumab), as well as the small molecule tofacitinib. Models for estimating the risk of disease relapse and the efficacy of retreatment should be evaluated according to the patient's age and IBD phenotype. These models should guide clinicians in programming a temporary drug withdrawal after discussing realistic outcomes with the patient. This would shift the paradigm from an exit strategy to a holiday strategy.

National production of certified reference fungal cultures / Producción nacional de cultivos fúngicos de referencia certificados

Reference fungal cultures (RFCs) are essential for the internal quality control of laboratories. The production of these cultures requires standardized procedures (IRAM 14950:2016 and ISO 17034:2016 standards) carried out by a recognized and accredited laboratory. The aim of this work was to produce RFC in paper disks of autochthonous strains, characterized by two, homogeneous and stable reference methods traceable at species level. RFC were produced using 14 regional species (7 yeasts and 7 filamentous fungi) from the fungal culture collection (DMic). Paper disks were impregnated with a culture suspension, dried and packed. Homogeneity, viability, identity and purity were verified. Short-and long-term stability at different temperatures and storage times were studied. Characterization of each strain allowed to confirm its identity and to ensure its traceability at international level. Produced batches were homogeneous and stable at -20 ±5 °C for 30 months. This method of production was adequate to produce homogeneous and stable RFC with phenotypic and genotypic characteristics correctly defined and internationally traceable. Standardized procedures were developed for the production of certified RFC that could be transferred to other microorganisms. Providing RFC that represent regional strains allows laboratories to produce more reliable results with a favorable impact on medical diagnosis, the environment or the food industry.

Los cultivos microbianos de referencia (CR) son imprescindibles para el control de calidad interno de los laboratorios. Asegurar su producción requiere de procedimientos estandarizados (IRAM 14950:2016 e ISO 17034:2016) realizados en un laboratorio reconocido y acreditado. El objetivo de este estudio fue producir cultivos fúngicos de referencia en discos de papel, a partir de un panel de cultivos autóctonos caracterizados por dos métodos de referencia, trazables a nivel taxonómico de especie, homogéneos y estables. Se produjeron CR de 14 especies circulantes en Argentina (7 de levaduras y 7 de hongos miceliales), depositadas en la colección de hongos de interés médico (DMic). Los discos de papel fueron embebidos con una suspensión del cultivo por producir, secados y envasados. Se verificó la homogeneidad, viabilidad, identidad y pureza de cada lote. Se evaluó la estabilidad a corto y largo plazo a distintas temperaturas y tiempos de almacenamiento. La caracterización de cada CR nos permitió confirmar su identidad y asegurar su trazabilidad a nivel internacional. Los lotes producidos fueron homogéneos y estables durante 30 meses conservados a -20 ±5 °C. Este método resultó adecuado para producir CR homogéneos y estables, con características fenotípicas y genotípicas correctamente definidas y trazables a nivel internacional. Los procedimientos estandarizados desarrollados en este trabajo pueden ser transferidos para producir CR certificados de otros microorganismos. La provisión de CR que represente cepas regionales permite a los laboratorios producir resultados más confiables con un impacto favorable en el diagnóstico médico, los estudios ambientales y la industria alimenticia.

Risk factors and timing for colectomy in chronically active refractory ulcerative colitis: A systematic review.

BACKGROUND: In patients with chronic refractory ulcerative colitis (UC) the precise timing for indication to colectomy is unclear. AIMS: We performed a systematic review of the literature on the risk factors for colectomy in patients with chronic refractory UC in the biologic era. METHODS: PubMed Central/Medline and Embase were systemically searched for records published between January 2000 and December 2017. Current evidence was summarized and filtered by expert opinion. RESULTS: 70 studies were included in the qualitative synthesis. Several factors were found to be associated with a higher or reduced risk for colectomy, including variables at baseline - such as progression from proctitis/left-sided to extensive colitis, extensive colitis at diagnosis, high baseline C Reactive Protein or erythrocyte sedimentation rate, male gender, and younger age at diagnosis - previous medical history, and factors arising during therapy with biologics, including the absence of clinical response after induction with infliximab or adalimumab, and the lack of mucosal healing during therapy with anti-TNFs. CONCLUSIONS: Two main points may help physicians to decide when the surgical option may be considered in patients with chronic refractory UC: (1) a first risk stratification can be obtained by analyzing factors at baseline and medical history, including the previous exposure to anti-TNFs; (2) during therapy with biologics, the early assessment (after 12-16 weeks of treatment) of clinical and endoscopic response is a strong predictor of the subsequent risk of colectomy.

National production of certified reference fungal cultures.

Reference fungal cultures (RFCs) are essential for the internal quality control of laboratories. The production of these cultures requires standardized procedures (IRAM 14950:2016 and ISO 17034:2016 standards) carried out by a recognized and accredited laboratory. The aim of this work was to produce RFC in paper disks of autochthonous strains, characterized by two, homogeneous and stable reference methods traceable at species level. RFC were produced using 14 regional species (7 yeasts and 7 filamentous fungi) from the fungal culture collection (DMic). Paper disks were impregnated with a culture suspension, dried and packed. Homogeneity, viability, identity and purity were verified. Short- and long-term stability at different temperatures and storage times were studied. Characterization of each strain allowed to confirm its identity and to ensure its traceability at international level. Produced batches were homogeneous and stable at -20±5°C for 30 months. This method of production was adequate to produce homogeneous and stable RFC with phenotypic and genotypic characteristics correctly defined and internationally traceable. Standardized procedures were developed for the production of certified RFC that could be transferred to other microorganisms. Providing RFC that represent regional strains allows laboratories to produce more reliable results with a favorable impact on medical diagnosis, the environment or the food industry.

The safety of beclomethasone dipropionate in the treatment of ulcerative colitis.

INTRODUCTION: Beclomethasone dipropionate (BDP) is a second-generation corticosteroid that uses novel drug technologies to ensure colonic targeting and potentially reducing systemic corticosteroid concentrations. It is approved for treatment of patients with mild-to-moderate ulcerative colitis (UC) who do not respond to mesalazine. The gut-selective mechanism of action has the potential to improve the safety profile of BDP compared with other conventional corticosteroids. Areas covered: We reviewed the mechanism of action, efficacy, and safety of BDP in the treatment of UC. The positioning of BDP in management algorithms is also discussed. Expert opinion: The highly selective mechanism of action of BDP restricts the steroid-related side effects. BDP is efficacious in the treatment of active UC. Topical formulation is the first choice in distal UC, while oral formulation is used in patients with an extensive involvement of the colon. The rates of adverse events (AE), serious AEs, and steroid-related side-effects are similar to placebo and mesalamine and slightly inferior to traditional corticosteroids.

Prognostic performance of MR-pro-adrenomedullin in patients with community acquired pneumonia in the Emergency Department compared to clinical severity scores PSI and CURB.

AIM: (i) evaluate the performance of MR-pro-ADM in reflecting the outcome and risk for CAP patients in the emergency department, and (ii) compare the prognostic performance of MR-pro-ADM with that of clinical scores PSI and CURB65. METHODS: Observational prospective, single-center study in patients with suspected community acquired pneumonia (CAP). Eighty one patients underwent full clinical and laboratory assessment as by protocol, and were followed up a 28 days. Primary endpoints measured were: death, death at 14 days, non-invasive mechanical ventilation (NIMV), endotracheal intubation (EI), ICU admission, overall hospital stay >10 days, emergency department stay >4 days. The discriminative performance of MR-pro-ADM and clinical scores was assessed by AUROC analysis. RESULTS: The distribution for MR-pro-ADM followed an upward trend, increasing with the increase of both PSI (p<0.001) and CURB65 (p<0.001) classes. However, the difference between MRproADM values and score classes was significant only in the case of CURB65 classes 0 and 1 (p = 0.046), 2 (p = 0.013), and 3 (p = 0.011); and with PSI classes 5, 3 (p = 0.044), and 1 (p = 0.020). As to the differences among variables for the six end-points, MR-pro-ADM values in the two groups selected for each considered end-point differed in a statistically significant manner for all endpoints. Both PSI and CURB65 differed significantly for all end-points, except for stay in the ED longer than 4 days and the hospital stay longer than 10 days and endotracheal intubation (only PSI classes differed with statistical significance). ROC analyses evidenced that MR-pro-ADM values gave the greatest AUC for the prediction of death, endotracheal intubation, hospital stay >10 days and DE stay >4 days, compared to the PSI and CURB (though difference not statistically significant). For each endpoint measured, the best thresholds values for Mr-pro-ADM were: 1.6 (specificity 76.5%; sensitivity 77.8%) for death; 2.5 (specificity 88.9%; sensitivity 80.0%) for death at 14 days; 1.5 (specificity 77.0%; sensitivity 87.5%) for NIMV; 2.4 (specificity 88.7%; sensitivity 83.3%) for endotracheal intubation; 0.9 (specificity 53.5%; sensitivity 70.6%) for DE stay greater than 4 days; 1.9 (specificity 82.1%; sensitivity 55.3%) for hospital stay greater than 10 days. The AUC for the combination of MR-pro-ADM and PSI was 81.29% [63.41%-99.17%], but not in a statistically significant manner compared to the AUCs of the single predictors. Conversely, the AUC for the combination of MR-pro-ADM and CURB65 was 87.58% [75.54%-99.62%], which was significantly greater than the AUC of CURB65 (p = 0.047) or PSI (p = 0.017) alone. CONCLUSIONS: The present study confirms that assessment of MR-pro-ADM levels in CAP patients in addition to CURB scores increases the prognostic accuracy of CURB alone and may help rule out discrepancies arising from flawed clinical severity classification. With particular reference to patients scoring in the upper classes of CURB and PSI, MR-pro-ADM values provided additional information towards a better risk stratification of those patients. In particular, our results pointed towards two MR-pro-ADM threshold values that appear to predict with a good degree of accuracy the patient's need for non-invasive mechanical ventilation, endotracheal intubation, or intensive care. This aspect, however, deserves further investigation.

Six year adalimumab efficacy in steroid-dependent Crohn's disease patients: A prospective single-center real life study.

BACKGROUND: Adalimumab is effective in the treatment of Crohn's disease. We have already reported data on the efficacy of adalimumab in 110 steroid-dependent patients. At the end of the study 90 patients (64.5%) maintained clinical remission. AIMS: To assess efficacy and safety of adalimumab after 6 years in patients of the original cohort who responded to treatment. METHODS: The present study is an extension of the published paper on 90/110 patients. We report results on clinical remission and safety of 6 year maintenance therapy with adalimumab. RESULTS: Of the original cohort 90 patients completed the study, 17 were lost to follow-up and 3 died. At the end of follow-up (74.16±10.3 months) 37/90 patients (41%) maintained clinical remission. Of these, 32 (86%) continued adalimumab and 5 (13%) discontinued treatment due to clinical remission and mucosal healing. Of the remaining 53/90 patients, 47 (52%) discontinued adalimumab due to clinical failure and 6 (7%) to adverse events. We obtained endoscopy data in 31/32 patients in clinical remission continuing adalimumab: 11 (36%) did not improve, 6 (19%) worsened, 14 (45%) improved. At univariable analysis no variables were related to treatment outcome. CONCLUSIONS: This "real life" prospective study shows that adalimumab is a long-term effective and safe maintenance treatment in steroid-dependent Crohn's disease patients.

Active Tuberculosis Case Finding Interventions Among Immigrants, Refugees and Asylum Seekers in Italy.

In Italy tuberculosis (TB) is largely concentrated in vulnerable groups such as migrants and in urban settings. We analyzed three TB case finding interventions conducted at primary centers and mobile clinics for regular/irregular immigrants and refugees/asylum seekers performed over a four-year period (November 2009-March 2014) at five different sites in Rome and one site in Milan, Italy. TB history and presence of symptoms suggestive of active TB were investigated by verbal screening through a structured questionnaire in migrants presenting for any medical condition to out-patient and mobile clinics. Individuals reporting TB history or symptoms were referred to a TB clinic for diagnostic workup. Among 6347 migrants enrolled, 891 (14.0%) reported TB history or symptoms suggestive of active TB and 546 (61.3%) were referred to the TB clinic. Of them, 254 (46.5%) did not present for diagnostic evaluation. TB was diagnosed in 11 individuals representing 0.17% of those screened and 3.76% of those evaluated. The overall yield of this intervention was in the range reported for other TB screening programs for migrants, although we recorded an unsatisfactory adherence to diagnostic workup. Possible advantages of this intervention include low cost and reduced burden of medical procedures for the screened population.

The impact of antiviral therapy and the influence of metabolic cofactors on the outcome of chronic HCV infection.

NATURAL HISTORY OF HCV RELATED CHRONIC HEPATITIS IS INFLUENCED AND MODIFIED BY MANY FACTORS: virus features, coinfections and host characteristics. In particular, a peculiar genetic background of the host by conditioning the occurrence of intracellular metabolic derangements (i.e., insulin resistance) might contribute to accelerate the rate of progression to cirrhosis and eventually the occurrence of hepatocellular carcinoma (HCC) and death. Likely, direct interplays between virus genotype and host genetic background might be hypothesized at this level. Morbidity and mortality in cirrhosis is primarily associated with complications of liver cirrhosis (ascites, hepatic encephalopathy, jaundice, and gastroesophageal bleeding) and HCC occurrence. Therefore the main goal of therapy is to clear viral infection and decrease liver necro-inflammation that directly relates to development of cirrhosis and HCC. Among patients treated with Interferon-based therapy, those with sustained viral response showed a significant reduction of progression to cirrhosis and development of HCC. However, a residual risk of hepatocellular carcinoma still remains indicating the need for careful follow-up using ultrasonography every six months in cirrhotic patients, even in those showing persistently normal ALT and undetectable HCV RNA levels after antiviral therapy.

The optimal dose of ribavirin for chronic hepatitis C: From literature evidence to clinical practice: The optimal dose of ribavirin for chronic hepatitis C.

Approximately 170 million people worldwide are chronically infected by hepatitis C virus (HCV), which can result in progressive hepatic injury and fibrosis, culminating in cirrhosis and end-stage liver disease. The benchmark therapy for untreated HCV patients is a combination of pegylated interferon-alpha (PEG-IFN) and ribavirin (RBV). Several studies have suggested several potential new approaches to improve HCV therapy-optimization of the dose and duration of RBV therapy, accompanied by careful clinical management, is crucial in ensuring the greatest likelihood of a long response to therapy. RBV causes serious side effects, but in clinical practice, there are no alternatives for the treatment of HCV infection. Based on our results, weight-based doses of RBV are advantageous for genotype 1-infected patients, but its success in genotype 2- and 3-infected patients is unknown, particularly for shorter treatment durations.

Pegylated-interferon-α(2a) in clinical practice: how to manage patients suffering from side effects.

INTRODUCTION: The goal of antiviral therapy in patients with chronic hepatitis C is to slow or halt the progression of fibrosis and prevent the development of cirrhosis. Accordingly, antiviral treatment is proposed for a large population of patients with chronic hepatitis. AREAS COVERED: The standard-of-care for chronic hepatitis C is the combination of pegylated IFN (PEG-IFN) and ribavirin. The use of these drugs has been correlated with a range of adverse effects, including influenza-like symptoms, hematological changes and neuropsychiatric disturbances. The effects of these adverse events associated with PEG-IFN therapy are manifold and are a major reason why patients decline or stop therapy. This review addresses the screening for adverse event risk factors and guides the patient to success with adherence strategies. EXPERT OPINION: Knowledge of the side effects correlated with PEG-IFN is very relevant for clinicians because it can allow them to arrange the best methods for treating these effects and avoid the discontinuation of antiviral treatment. Moreover, the use of new antiviral drugs will considerably shorten treatment periods reducing many of the above-described side effects and, thus, increase adherence to scheduled therapy.