TM6SF2 rs58542926 is not associated with steatosis and fibrosis in large cohort of patients with genotype 1 chronic hepatitis C.

BACKGROUND & AIMS: We tested the putative association of the rs58542926 variant of TM6SF2, a recently described genetic determinant of nonalcoholic fatty liver disease, with steatosis and fibrosis in genotype 1(G1) chronic hepatitis C(CHC) patients. METHODS: A total of 694 consecutively biopsied Caucasian G1 CHC patients were genotyped for TM6SF2 rs58542926, IL28B rs12979860 and PNPLA3 rs738409. Steatosis was classified as absent (<5%), mild-moderate(5-29%) and severe(≥30%), Fibrosis was considered severe if=F3-F4. RESULTS: Carriers of TM6SF2 rs58542926 (6.3% of patients) exhibited lower serum levels of cholesterol (P = 0.04) and triglycerides (P = 0.01), but a similar distribution of steatosis severity (P = 0.63), compared to noncarriers. Prevalence and severity of steatosis were reduced in IL28B C allele carriers (P = 0.005) and elevated in PNPLA3 G allele carriers (P < 0.001). After adjustment for age, gender, body mass index and homoeostasis model assessment score, steatosis severity was independently associated with IL28B rs12979860 (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.55-0.86, P = 0.001) and PNPLA3 rs738409 (OR 1.84, 95% CI 1.46-2.83, P < 0.001), but not TM6SF2 rs58542926 (OR 1.48, 95% CI 0.82-2.69, P = 0.19). Variants of TM6SF2 (30.9% vs. 25%, P = 0.40), IL28B and PNPLA3 were not directly associated with fibrosis severity, although variants of IL28B and PNPLA3 promoted steatosis (OR 1.36, 95% CI 1.06-1.75, P = 0.01) that in turn is associated with severe fibrosis. CONCLUSIONS: In G1 CHC patients, TM6SF2 rs58542926 does not affect the histological severity of liver damage. However, IL28B rs12979860 and PNPLA3 rs738409 modify steatosis.

Immune-Mediated Inflammatory Diseases Awareness and Management among Physicians Treating Patients with Inflammatory Bowel Disease: An IG-IBD Survey.

(1) Background: Inflammatory bowel disease (IBD) is frequently associated to other immune-mediated inflammatory diseases (IMIDs). This study aims at assessing physicians' awareness of the issue and the current status of IMID management. (2) Methods: A web-based survey was distributed to all 567 physicians affiliated to IG-IBD. (3) Results: A total of 249 (43.9%) physicians completed the survey. Over 90% of the responding physicians were gastroenterology specialists, primarily working in public hospitals. About 51.0% of the physicians had access to an integrated outpatient clinic, where gastroenterologists collaborated with rheumatologists and 28.5% with dermatologists. However, for 36.5% of physicians, integrated ambulatory care was not feasible. Designated appointment slots for rheumatologists and dermatologists were accessible to 72.2% and 58.2% of physicians, respectively, while 20.1% had no access to designated slots. About 5.2% of physicians report investigating signs or symptoms of IMIDs only during the initial patient assessment. However, 87.9% inquired about the presence of concomitant IMIDs at the initial assessment and actively investigated any signs or symptoms during subsequent clinical examination. (4) Conclusions: While Italian physicians recognize the importance of IMIDs associated with IBD, organizational challenges impede the attainment of optimal multidisciplinary collaboration. Efforts should be directed toward enhancing practical frameworks to improve the overall management of these complex conditions.

Hyperuricaemia: another metabolic feature affecting the severity of chronic hepatitis because of HCV infection.

BACKGROUND: Several works observed a link between uric acid serum levels and clinical and histological features of nonalcoholic fatty liver disease. An association between chronic hepatitis C (CHC) and uric acid levels has been poorly investigated. AIMS: To assess the potential association between uric acid serum levels and both histological features of liver damage and sustained virological response (SVR) in a homogeneous cohort of CHC patients. METHODS: Consecutive biopsy-proven CHC patients were included. Hyperuricaemia was diagnosed with uric acid serum levels >7 mg/dl in men, and >6 mg/dl in women. Patients underwent therapy with pegylated interferon plus ribavirin. RESULTS: Hyperuricaemia, observed in 7.5% of patients, was associated with low density lipoprotein cholesterol (OR 1.015, 95% CI 1.004-1.026, P = 0.008), arterial hypertension (OR 3.024, 95% CI 1.290-7.088, P = 0.01), estimated glomerular filtration rate (OR 0.942, 95% CI 0.919-0.965, P < 0.001) and severity of steatosis (OR 3.176, 95% CI 1.828-5.517, P < 0.001) by multivariate logistic regression analysis. The following features were independently linked to the severity of liver steatosis (<5% vs. ≥5% to <30% vs. ≥30%) using ordinal regression analysis: age (OR 1.027, 95% CI 1.011-1.044, P = 0.01), body mass index (OR 1.088, 95% CI 1.039-1.138, P < 0.001), triglycerides (OR 1.005, 95% CI 1.001-1.009, P = 0.02), homeostasis model assessment (OR 1.095, 95% CI 1.014-1.184, P = 0.02), hyperuricaemia (OR 2.751, 95% CI 1.423-5.322, P = 0.003), hepatitis C virus genotype 3 (OR 4.567, 95% CI 1.515-13.763, P = 0.007) and severe necroinflammatory activity (OR 1.584, 95% CI 1.067-2.349, P = 0.02). No independent association was found among uric acid levels and necroinflammatory activity, fibrosis and SVR. CONCLUSIONS: In CHC patients, hyperuricaemia was independently associated with severity of steatosis, representing, in this setting, via steatosis induction, an indirect factor affecting both liver damage and poor response to therapy, and thus a novel potential therapeutic target in CHC management.

Safety and potential interaction of immunosuppressive drugs for the treatment of inflammatory bowel disease in elderly patients.

Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are chronic diseases associated with increased morbidity and reduced quality of life. Age may represent a risk factor for adverse events, due to the multimorbidity and polypharmacy, common in elderly patients. Elderly are often not included in clinical trials evaluating efficacy and safety of study drugs for the treatment of inflammatory bowel diseases. Several drugs, such as aminosalicylates, systemic corticosteroids, immunosuppressant drugs, biological drugs and Janus Kinase inhibitors, are available for the management of inflammatory bowel diseases. With the increasing spectrum of therapeutic options, it is therefore important to analyze the evidence regarding the safety of the use of these agents in elderly patients. Selection of immunosuppressive therapy is a challenge in the management of elderly patients with inflammatory bowel diseases, for whom biologics with a lower risk of infection or cancer, such as vedolizumab and ustekinumab, may be preferred in elderly patients. Concomitant therapies and comorbidities must be thoroughly investigated before initiating any immunosuppressive or biological therapy in order to minimize the risk of drug-drug interactions. This review aims to provide an overview of the safety of thiopurines, methotrexate and target therapies as well as their drug-drug interactions in patients with inflammatory bowel diseases.

Ustekinumab in Crohn's disease: Real-world outcomes from the Sicilian network for inflammatory bowel diseases.

BACKGROUND AND AIM: Ustekinumab is approved in Europe for the treatment of moderate to severe Crohn's disease (CD). Italian real-life data are scarce, so the aim of this study was to assess the effectiveness and safety of ustekinumab in an Italian cohort of CD patients. METHODS: Data of patients with CD who started using ustekinumab were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Disease. Primary end-points were steroid-free clinical remission at 8, 24, and 52 weeks of therapy and reduction of C-reactive protein. Secondary end-points were treatment response, treatment persistence at 12 months, and safety. RESULTS: A total of 131 patients (males 56%; mean age 46 years ±15) were included. All patients were biologics experienced except for one. At 24 and 52 weeks, 40% and 43% of patients achieved steroid-free clinical remission, and 64% and 62% had clinical response, respectively. At the end of follow-up, there was a significant reduction of steroid use (P = 0.012) and of the Harvey-Bradshaw Index (P = 0.001). The probability of persistence in therapy with ustekinumab after 12 months of treatment was 89%. The only factor associated with discontinuation was older age. CONCLUSIONS: Data from our real-life cohort of treatment-refractory CD patients suggest the satisfactory effectiveness and safety profile of ustekinumab.

Endoscopic surveillance of colorectal cancer in inflammatory bowel diseases: a review of the literature.

INTRODUCTION: The risk of colorectal cancer (CRC) in patients with inflammatory bowel diseases (IBD) is higher compared to the general population and it is related to the type, severity, duration, and extension of the disease. AREAS COVERED: This review aims to highlight current evidence from the literature supporting the role of endoscopic surveillance of CRC in patients with IBD. EXPERT OPINION: Even in the absence of randomized controlled trials (RCTs), evidence from the literature supports the effectiveness of endoscopic surveillance in reducing IBD-related CRC incidence and mortality. As a consequence, current guidelines recommend colonoscopy 8-10 years after disease or symptom onset in all patients with ulcerative colitis (UC) and Crohn's disease (CD) involving at least one-third of the colon and agree on the necessity of annual surveillance in high-risk patients. Nevertheless, an overall agreement on the optimal intervals for surveillance of low-intermediate risk patients is absent and 2-5 year intervals have been proposed. In the near future, further studies are needed to assess the most effective intervals and tailor the surveillance based on the personal risk profile. Additionally, further efforts should be made to evaluate the role of noninvasive tests as primary screening, thus avoiding unnecessary colonoscopies.

Anti-TNF combination therapy in inflammatory bowel disease: de novo or selective?

Anti-TNFs still remain the backbone of advanced therapies in inflammatory bowel diseases, but their efficacy is not universal and tends to diminish over time. As a consequence, there is the need for optimization of these treatments, and the use of combination therapy - i.e. an anti-TNF plus an immunosuppressant - is one of the main strategies. The rationale for this approach lies in the evidence that the immunosuppressant reduces the formation of antibodies directed against the anti-TNF, thus avoiding the reduction or elimination of circulating drug levels, and in the combination of the therapeutic effect of two drugs. Nowadays, two different combination therapies should be distinguished. In the "de novo" combination therapy, the anti-TNF is used in combination with an immunosuppressant from the beginning of the treatment, in order to prevent the formation of anti-drug antibodies. In the "selective" combination therapy, the immunosuppressant is added at a later time in patients who experience a loss of response during anti-TNF monotherapy due to the development of anti-drug antibodies. The purpose of this review is to summarize the available evidence on both de novo and selective combination therapy. In addition, we will express our point of view on the choice between these two different treatment modalities.

Clinical features and outcomes of patients with drug-induced autoimmune hepatitis: a retrospective cohort study.

BACKGROUND: Drugs and herbal products can induce autoimmune hepatitis. We assessed frequency and clinical outcomes of patients suffering from drug-induced autoimmune hepatitis. METHODS: All patients with drug-induced liver injury admitted between 2000 and 2011 were retrospectively studied. Diagnoses of drug-induced autoimmune hepatitis and idiopathic autoimmune hepatitis were made according to simplified criteria. After discharge, all patients had regular follow-up and were contacted to update outcomes. RESULTS: Among 10,270 in-hospital patients, 136 (1.3%) were diagnosed with drug-induced liver injury. Among them, 12 (8.8%) were diagnosed as drug-induced autoimmune hepatitis (41.7% males, age range 17-73); 8 (66.7%) were with jaundice at admission. Liver biopsies showed a pattern compatible with drug-induced autoimmune hepatitis, featured by severe portal inflammation and lymphoplasmacytic infiltrate. Drug-induced autoimmune hepatitis group had a shorter duration of drug intake, and higher values of transaminases and gamma globulins. All patients received immunosuppressive therapy with subsequent clinical remission, and five achieved a steroid-free long-term remission. CONCLUSIONS: A diagnosis of drug-induced autoimmune hepatitis was quite rare in our cohort, and clinical pattern was similar to idiopathic autoimmune hepatitis. Severe portal inflammation, prominent portal-plasma cells, rosette formation and severe focal necrosis were significantly more frequent in drug-induced autoimmune hepatitis as compared to drug-induced liver injury.