Guilherme Macedo

Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED)

Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter Study Group (EHSG), the European Society of Pathology (ESP) and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach (termed MAPS). A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia, and the need for adequate staging in the case of high grade dysplasia, and they focus on treatment and surveillance indications and methods.

Is it Possible to Change Phenotype Progression in Crohn's Disease in the Era of Immunomodulators? Predictive Factors of Phenotype Progression

OBJECTIVES:Crohns disease (CD) induces cumulative structural damage, initially characterized by a non-stenosing non-penetrating behavior (B1) with progression over time to a fibro-stenosing (B2) and/or penetrating phenotype (B3). Our aim was to assess the long-term evolution of disease behavior of CD and determine what factors predict phenotype progression.METHODS:This was a study based on prospectively collected data from a CD database in an inflammatory bowel disease outpatient clinic. B1 corresponds to a non-stenosing non-penetrating disease, B2 to a stenosing behavior, and B3 to a penetrating one.RESULTS:Seven hundred and thirty-six patients with CD (368 female) were followed up for 12.3 years (±8.4), with 87.0% of them exhibiting B1 phenotype at diagnosis. Of these patients, 28.5% progressed to B2 phenotype and 23.5% to B3. Fifty percent of the patients started azathioprine treatment before phenotype change and 13.9% started anti-tumor necrosis factor-α (anti-TNFα) treatment before phenotype change. Monotherapy with azathioprine before phenotype change as well as combination therapy with azathioprine/anti-TNFα before phenotype change delayed disease progression (B1–B2 or B3) in comparison with patients who did not receive treatment (P<0.001). The hazard ratio (HR) for disease progression was lower for both monotherapy with azathioprine (HR: 0.15, P<0.001) or combination therapy with anti-TNFα (HR: 0.33, P<0.001). Upper gastrointestinal tract involvement, male gender, and steroid use were associated with an early progression of phenotype from B1 to B2 or B3 (P<0.001). The HR for disease progression was higher in patients who used steroids without criteria of dependence or resistance (HR: 2.67, P<0.001) and was even higher in patients with criteria of dependence or resistance (HR: 6.44, P<0.001). Longer delays between CD diagnosis and beginning of therapy with azathioprine and/or anti-TNFα were associated with disease progression. The longer the duration of treatment, the less likely the disease progression.CONCLUSIONS:Monotherapy with azathioprine before behavior change as well as combination therapy with azathioprine and anti-TNFα before behavior change delays phenotype progression of CD, whereas upper gastrointestinal tract involvement, male gender, and steroid use with or without criteria of steroid dependence are associated with a higher risk for disease progression.

High C-reactive protein in Crohn's disease patients predicts nonresponse to infliximab treatment.

BACKGROUND Infliximab (IFX) is effective in treating Crohns disease (CD) and C-reactive protein (CRP) is a useful biomarker in assessing inflammatory activity. AIM Correlate CRP levels before beginning of IFX, at week 14 and CRP delta within the first year of IFX treatment. METHODS Retrospective study of CD patients undergoing treatment with IFX. Primary nonresponse (PNR) was defined as no symptomatic improvement and CRP persistently elevated; sustained response (SR) as symptomatic improvement for at least 1 year without therapeutic adjustment; response after therapeutic adjustment (RTA) as analytic and clinical response but requiring IFX dose/frequency adjustment or association with another drug. RESULTS Baseline CRP levels were higher in PNR compared with SR (26.2mg/L vs 9.6 mg/L, p=0.015) and RTA (26.2mg/L vs 7.6 mg/L, p=0.007). CRP levels greater than 15 mg/L at baseline predict PNR with 67% sensitivity and 65% specificity. Lower CRP levels at week 14 were more likely to predict SR relative to RTA (3.1mg/L vs 7.6 mg/L p=0.019) and PNR (3.1mg/L vs 9.1mg/L; p=0.013). CRP levels greater than 4.6 mg/L at week 14 predict PNR with 67% sensitivity and 62% specificity. A higher CRP delta between beginning of treatment and week 14 is more likely to predict SR relative to RTA (5.2mg/L vs 0.6 mg/L p=0.027). CONCLUSION CRP levels at week 14 were associated with SR in patients treated with IFX, independently of baseline CRP serum levels. High inflammatory burden at beginning of IFX treatment was correlated with a worse response.

High incidence of hepatocellular carcinoma following successful interferon-free antiviral therapy for hepatitis C associated cirrhosis

Please cite this article as: Cardoso, H., Vale, A.M., Rodrigues, S., Gonçalves, R., Albuquerque, A., Pereira, P., Lopes, S., Silva, M., Andrade, P., Morais, R., Coelho, R., Macedo, G., High incidence of hepatocellular carcinoma following successful interferon-free antiviral therapy for hepatitis C associated cirrhosis, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.07.027

Tuberculosis in anti-TNF-α treated patients remains a problem in countries with an intermediate incidence: Analysis of 25 patients matched with a control population

BACKGROUND AND AIMS An increased incidence of tuberculosis (TB) in patients under anti-TNF-α therapy has been reported, but outcome compared with TB in the general population are unknown. METHODS Patients who had active tuberculosis while taking anti-TNF-α drugs were studied and compared with a control group of community-acquired TB matched for sex, age and data of TB. RESULTS Twenty-five cases of TB were reported from a cohort of 765 patients under anti-TNF-α from 2001 to 2012. The incidence of TB per 100,000 patient-years was estimated to be 1337, 792 and 405 respectively for those on infliximab, adalimumab and etanercept. Twelve patients had inflammatory bowel disease, ten had rheumatologic diseases and three had psoriasis. From the 17 patients screened for latent TB before anti-TNF-α, three were treated with isoniazid. TB was diagnosed 1-108 months after starting anti-TNF-α, being the median time six, seven and 89 months respectively for those on infliximab, adalimumab and etanercept. Sixty per cent of the cases had extra-pulmonary TB. No deaths occurred in the case groups, while two died in control TB patients. Patients on anti-TNF-α drugs had more frequent extra-pulmonary TB, fever on presentation, higher mean C-reactive protein and lower positive rate of acid-fast bacilli. CONCLUSIONS TB may still occur in those with negative testing, some of them probably representing new infections instead of reactivations. Three out of 25 patients had TB in spite of previously treated LTB, although, the outcome of TB was not worse than in the general population.

Increased hepatic expression of TLR2 and TLR4 in the hepatic inflammation-fibrosis-carcinoma sequence:

We evaluated expression of TLR2, TLR4 and proinflammatory genes [NF-κB, TNF-α, cyclooxygenase-2 (COX-2)] in liver samples of patients in different stages of liver disease. Fifteen patients with unexplained transaminases elevation (reference group), 22 with viral chronic hepatitis (hepatitis group), 14 with virus-induced severe fibrosis/cirrhosis (cirrhosis group) and 10 with hepatocarcinoma (hepatocarcinoma group) were consecutively included in the study. Quantification of TLR2, TLR4, NF-κB, TNF-α and COX-2 mRNA was done by real-time RT-PCR and TLR2 and TLR4 protein expression was evaluated by immunohistochemistry. Compared with reference, TLR2 and TLR4 mRNA was increased in hepatitis (TLR2: 2.66 ± 0.69; TLR4: 3.11 ± 0.79; P < 0.05) and cirrhosis (TLR2: 2.14 ± 0.5; TLR4: 1.74 ± 0.27; P < 0.05) and decreased in hepatocarcinoma (TLR2: 0.48 ± 0.15; TLR4: 0.54 ± 0.10; P < 0.05). This associated with increased TNF-α and COX-2 mRNA in hepatitis (TNF-α: 3.24 ± 0.79; COX-2: 2.47 ± 0.36; P < 0.05) and cirrhosis (TNF-α: 1.73 ± 0.28; COX-2: 1.8 ± 0.35, P < 0.05), whereas NF-κB mRNA was increased in hepatitis (2.42 ± 0.31; P < 0.05) and unchanged in cirrhosis (1.34 ± 0.17; P = 0.3). Hepatocarcinoma presented increased COX-2 mRNA (1.63 ± 0.15; P < 0.05) and maintained (at decreased levels) mRNA of NF-κB (0.52 ± 0.12) and TNF-α (0.52 ± 0.12; P < 0.05, all genes). Immunohistochemistry confirmed increased expression of TLR2 and TLR4 in hepatitis and cirrhosis and maintained expression in hepatocarcinoma. Upregulation of TLR2, TLR4 and their proinflammatory mediators is associated with virus-induced hepatic IFC sequence.

Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy: A single center report of 8 cases

This article describes cases of anti-tumor necrosis factor (TNF)-α-induced autoimmune hepatitis and evaluates the outcome of these patients in relation to their immunosuppressive strategy. A retrospective analysis of medical records was performed in our center, in order to detect cases of autoimmune hepatitis (AIH) associated with anti-TNF biologic agents. We describe and analyze eight cases of AIH following anti-TNF therapy, 7 with infliximab and 1 with adalimumab. A distinction should be made between induction of autoimmunity and clinically evident autoimmune disease. Liver biopsy is useful in detecting the role of the TNF-α antagonist in the development of AIH. The lack of relapse after discontinuing immunosuppressive therapy favors, as in this case series, an immune-mediated drug reaction as most patients with AIH have a relapse after treatment is suspended. Although AIH related to anti-TNF therapy is rare, a baseline immunological panel along with liver function tests should be performed in all patients with autoimmune disease before starting biologics.

Listeria infection in patients on anti-TNF treatment: Report of two cases and review of the literature

Listeria monocytogenes is an aerobic gram positive intracellular bacillus, predominantly affecting pregnant women, immunocompromised patients and old individuals. Invasive listeriosis, meningitis and meningoencephalitis, bacteraemia with or without joint, eye or heart focalization are clinical manifestations of the disease. Anti-TNF-α drugs blocking the hosts response against various microorganisms, particularly intracellular agents like Listeria monocytogenes, increase the risk of disease. We report two cases of L. monocytogenes meningitis in ulcerative colitis patients under infliximab plus steroids. One patient is HIV-1 infected. A review of reported invasive listeriosis cases under anti-TNF drugs is also showed.

Attenuation of toll-like receptor 2-mediated innate immune response in patients with alcoholic chronic liver disease.

Background: Alcoholic chronic liver disease (ACLD) is a common form of acquired immunodeficiency.

Epstein-Barr virus in inflammatory bowel disease-correlation with different therapeutic regimens.

Background: Inflammatory bowel disease (IBD) is associated with a higher prevalence of opportunistic infections. Epstein–Barr virus (EBV) is a ubiquitous virus related to several malignancies, namely lymphoma; its prevalence in patients with IBD and its relation with different therapeutic regimens are not well studied. Methods: Patients followed in our IBD outpatient clinic were consecutively enrolled for participation in a prospective study, and healthy volunteers were recruited as controls. EBV DNA was measured at least 1 time in each patient. Results: Three hundred and seventy-nine individuals were enrolled in the study (93 treated with 5-aminosalicylates, 91 with azathioprine, 70 with infliximab, 43 with combined treatment with infliximab and azathioprine, and 82 controls). More than 90% of the patients had previous EBV exposure. EBV DNA was found in 132 samples (35%); its prevalence was significantly higher in every group of patients with IBD, comparing to controls. Among patients with IBD, infliximab with or without azathioprine was related to higher prevalence of EBV comparing to azathioprine alone or 5-aminosalicylates (P < 0.05). Age above 60 years was related to EBV DNA positivity with a specificity of 92%. Concerning treated groups, ulcerative colitis was the only risk factor identified for high levels of EBV DNA (>1000 and 2500 copies per milliliter). No relationship was found between EBV and C-reactive protein. Conclusions: IBD is a risk factor for the presence of EBV DNA in blood, particularly in older patients and in those taking infliximab. C-reactive protein was not related to EBV DNA prevalence.