Danilo Di Bona

Effect of peginterferon alfa‐2a on liver histology in chronic hepatitis C: A meta‐analysis of individual patient data

Multicenter randomized trials have shown that once‐weekly pegylated interferon (peginterferon) alfa‐2a is more efficacious than conventional interferon alfa‐2a (IFN) in patients with chronic hepatitis C. We performed a meta‐analysis of 1,013 previously untreated patients (from 3 randomized trials) with pretreatment and post‐treatment liver biopsies to assess the differences between peginterferon alfa‐2a and IFN in terms of their effects on liver histology. Reported values were standardized mean differences (SMD) between patients receiving peginterferon alfa‐2a and those receiving IFN (post‐treatment value minus baseline value for each group). We used a random‐effects model to quantify the average effect of peginterferon alfa‐2a on liver histology. Peginterferon alfa‐2a significantly reduced fibrosis compared with IFN (SMD, −0.14; 95% CI: −0.27, −0.01; P = .04). A reduction in fibrosis was observed among sustained virologic responders (SMD, −0.59; 95% CI: −0.89, −0.30; P < .0001) and patients with recurrent disease (SMD, −0.34; 95% CI: −0.54, −0.14; P = .0007), whereas no significant reduction was observed among nonresponders (SMD, −0.13; 95% CI: −0.32, 0.05; P = .15). Logistic regression analysis indicated that patients with sustained virologic responses (SVRs) had an odds ratio (OR) of 1.61 (95% CI: 1.14, 2.29) for reduction in fibrosis compared with patients without SVRs, whereas obese patients (body mass index [BMI] > 30 kg/m2) had an OR of 0.56 (95% CI: 0.35, 0.90) compared with normal‐weight (BMI < 25 kg/m2) and overweight patients (BMI, 25–30 kg/m2). In conclusion, in patients with chronic hepatitis C with or without cirrhosis, peginterferon alfa‐2a (relative to IFN) significantly reduced fibrosis. The beneficial effects of peginterferon on liver histology are closely related to virologic response. (HEPATOLOGY 2004;39:333–342.)

Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C

Conflicting data exist regarding the relationship between hepatitis C virus genotype 1 and hepatic steatosis as well as the latters role in the progression of fibrosis and treatment response. We assessed factors associated with hepatic steatosis in genotype 1 chronic hepatitis C and the impact of hepatic fat on fibrosis development and interferon responsiveness. Two hundred ninety‐one non‐diabetic patients with genotype 1 chronic hepatitis C were examined for the presence of steatosis and its correlation with clinical, virological, and biochemical data, including insulin resistance (IR), evaluated by the homeostasis model assessment (HOMA) score. Steatosis was graded as mild (1%‐20% of hepatocytes involved), moderate (21%‐40% of hepatocytes involved), and severe (>40% of hepatocytes involved). Steatosis was mild in 110 of 291 (37.8%) and moderate/severe in 55 of 291 (18.9%) subjects. By logistic regression, moderate/severe steatosis was independently associated with the female sex (odds ratio [OR] 2.74; 95% CI 1.40‐5.35), high γ‐glutamyltransferase levels (OR 1.52; 95% CI 1.22‐1.91), and HOMA‐score (OR 1.076; 95% CI 1.001‐1.26). By logistic regression, moderate/severe steatosis (OR 2.78; 95% CI 1.21‐6.4), and platelet counts (OR 0.97; 95% CI 0.96‐0.98) were independent predictors of advanced fibrosis. Patients with moderate/severe steatosis had an OR of 0.52 (95% CI 0.30‐0.90) for sustained virological response compared with patients with mild/absent steatosis. In conclusion, in nondiabetic European patients with genotype 1 hepatitis C at low risk for the metabolic syndrome, the prevalence of steatosis was nearly 60%. IR is a risk factor for moderate/severe steatosis, especially in men. Moderate/severe steatosis has clinical relevance, being associated with advanced fibrosis and hyporesponsiveness to antiviral therapy. (HEPATOLOGY 2006;43:64–71.)

Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: A meta-analysis–based comparison

BACKGROUND Subcutaneous (SCIT) and sublingual (SLIT) immunotherapy are the 2 most prescribed routes for administering allergen-specific immunotherapy. They were shown to be effective in control of symptoms and in reducing rescue medication use in patients with allergic diseases, but their effectiveness has to be balanced against side effects. In recent years, SLIT has been increasingly prescribed, instead of SCIT, because of improved safety and easy administration. OBJECTIVE We assessed which route is the most effective in the treatment of patients with seasonal allergic rhinitis to grass pollen. METHODS An indirect meta-analysis-based comparison between SCIT and SLIT was performed. Treatment efficacy was determined as the standardized mean difference (SMD) in symptom and medication scores obtained with active treatment, SCIT or SLIT, compared with placebo. Studies were included if they were double-blind randomized controlled trials comparing SCIT or SLIT with placebo. Thirty-six randomized controlled trials (3014 patients; 2768 controls) were analyzed. RESULTS The overall effect size of SCIT for symptom score (SMD, -0.92; 95%CI, -1.26 to -0.58) was significantly higher than SLIT, both administered via drops (SMD, -0.25; 95% CI, -0.45 to -0.05) and tablets (SMD, -0.40; 95%CI, -0.54 to -0.27). Similar results were reported for medication score (SCIT: SMD, -0.58; 95% CI, -0.86 to -0.30. SLIT drops: SMD, -0.37; 95% CI, -0.74 to -0.00. SLIT tablets SMD, -0.30; 95% CI, -0.44 to -0.16). CONCLUSIONS Our results provide indirect but solid evidence that SCIT is more effective than SLIT in controlling symptoms and in reducing the use of antiallergic medications in seasonal allergic rhinoconjuntivitis to grass pollen.

When and how to treat acute hepatitis C

BACKGROUND Appropriate treatment of acute hepatitis C is still a matter of controversy due to the lack of large controlled trials. AIM To assess the effectiveness of interferon as treatment for acute hepatitis C by meta-analysis. METHODS MEDLINE search (1985-2002) was supplemented with manual searches of reference lists. Studies were included if they were controlled trials comparing interferon to no treatment and if they included patients with either post-transfusion or sporadic acute hepatitis C. Twelve trials were analyzed (414 patients). The outcome assessed was the sustained virological response (SVR) rate (undetectable hepatitis C virus RNA in serum at least 6 months after cessation of therapy). RESULTS Interferon significantly increased the SVR (risk difference 49%; 95% confidence interval 32.9-65%) in comparison to no treatment. The risk difference of SVR increased from 5 to 90% when trials were ordered by increasing interferon weekly dose. Delaying therapy by 8-12 weeks after the onset of disease does not compromise the SVR rate. CONCLUSIONS Current evidence is sufficient to recommend interferon treatment of patients with acute hepatitis C. A later initiation of therapy yields the same likelihood of response as early treatment. A daily induction dose during the 1st month is the best option of treatment.

Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: A systematic review and meta-analysis

BACKGROUND The benefit of sublingual immunotherapy (SLIT) with grass allergens for seasonal allergic rhinitis has been extensively studied, but data on efficacy are still equivocal. OBJECTIVE To assess the effectiveness of SLIT with grass allergens in the reduction of symptoms and medication in patients with seasonal allergic rhinitis to grass pollen. METHODS Computerized bibliographic searches of MEDLINE (1995-2010) were supplemented by hand searches of reference lists. Studies were included if they were double-blind randomized controlled trials (RCTs) comparing SLIT to placebo and if they included patients with history of allergy to grass pollen treated with natural grass pollen extracts. Nineteen RCTs with 2971 patients were analyzed. The outcomes assessed were symptom and medication scores. RESULTS Using a random-effects model, SLIT with grass allergens significantly reduces both symptoms (standardized mean difference, -0.32; 95% CI, -0.44 to -0.21) and medication use (standardized mean difference, -0.33; 95% CI, -0.50 to -0.16) compared with placebo. The treatment is more efficacious in adults than in children. Prolonging duration of preseasonal treatment for more than 12 weeks improves the treatment efficacy. CONCLUSION This meta-analysis found that SLIT with grass allergens is effective in patients with seasonal allergic rhinitis compared with placebo. The benefit is clinically modest, and criteria are needed to identify patients most likely to benefit from SLIT.

Inflammation, ageing and cancer

Cancer is generally recognized as an age-related disease. In fact, incidence and mortality rates of most human cancers increase consistently with age up to 90 years, but they plateau and decline thereafter. A low-grade systemic inflammation characterizes ageing and this pro-inflammatory status underlies biological mechanisms responsible for age-related inflammatory diseases. On the other hand, clinical and epidemiological studies show a strong association between chronic infection, inflammation and cancer and indicate that even in tumours not directly linked to pathogens, the microenvironment is characterized by the presence of a smouldering inflammation, fuelled primarily by stromal leukocytes. In this review, we have briefly mentioned inflammatory mediators involved in cancer although we decided to choose the ones which show a strict association with ageing and longevity. Inflammation is necessary to manage with damaging agents and is crucial for survival. But, in our opinion, the pro-inflammatory status of ageing might be one of the mechanisms which relate cancer to ageing. The most appropriate inflammatory genes have been selected to survive and to reproduce. Paradoxically, inflammatory age-related diseases (including cancer) are the marks of the same evolutionistic trait. Centenarians are characterized by a higher frequency of genetic markers associated with better control of inflammation. The reduced capacity of centenarians to mount inflammatory responses appears to exert a protective effect towards the development of those age-related pathologies having a strong inflammatory pathogenetic component, including cancer. All in all, centenarians seem to carry a genetic background with a peculiar resistance to cancer which is also an anti-inflammatory profile.

Inflammation, genes and zinc in Alzheimer's disease.

Alzheimers disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. AD has been linked to inflammation and metal biological pathway. Neuro-pathological hallmarks are senile plaques, resulting from the accumulation of several proteins and an inflammatory reaction around deposits of amyloid, a fibrillar protein, Abeta, product of cleavage of a much larger protein, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Amyloid deposition, due to the accumulation of Abeta peptide, is the main pathogenetic mechanism. Inflammation clearly occurs in pathologically vulnerable regions of AD and several inflammatory factors influencing AD development, i.e. environmental factors (pro-inflammatory phenotype) and/or genetic factors (pro-inflammatory genotype) have been described. At the biochemical level metals such as zinc are known to accelerate the aggregation of the amyloid peptide and play a role in the control of inflammatory responses. In particular, zinc availability may regulate mRNA cytokine expression, so influencing inflammatory network phenotypic expression.

Association between the interleukin-1β polymorphisms and Alzheimer's disease: A systematic review and meta-analysis

The pro-inflammatory cytokine interleukin(IL)-1beta is a main component in inflammatory pathways and is overexpressed in the brain of Alzheimers disease (AD) patients. Several studies report associations between IL-1beta polymorphisms and AD, but findings from different studies are controversial. Our aim was to verify the correlation between the single nucleotide polymorphisms (SNPs) of the IL-1beta, at sites -511 and +3953, and AD by meta-analysis. Computerized bibliographic searches of PUBMED and AlzGene database (http://www.alzgene.org) were supplemented with manual searches of reference lists. There is evidence for association between IL-1beta +3953 SNP and AD, with an OR=1.60 (95% C.I.: 1.16-2.22; Z=2.83 p=0.005) for TT genotype. No significant difference in genotype distribution of the IL-1beta -511 SNP in AD was obtained, but high between-study heterogeneity was found. To reduce heterogeneity, subgroup analyses were performed using, as stratifying variables, characteristics of the population under study (age, gender, type of AD diagnosis, Mini Mental State Examination of the controls) and characteristics related to the study design (statistical power of individual studies). The frequency of the IL-1beta -511 TT genotype resulted significantly higher than other genotypes only when the Caucasian studies with the highest statistical power were included in the subgroup analysis (OR=1.32; 95% C.I.: 1.03-1.69; p=0.03), with no evidence of between-study heterogeneity. Our data support an association between the TT genotype of IL-1beta +3953 SNP and AD, and suggest a possible association of the -511 TT genotype. Unreplicability of the results seems to be due mainly to the lack of statistical power of the individual studies.

Effect of interleukin-6 polymorphisms on human longevity: A systematic review and meta-analysis

Several studies have assessed changes in frequency of -174 interleukin (IL)-6 single nucleotide polymorphism (SNP) with age. If IL-6 tracks with disability and age-related diseases, then there should be reduction, in the oldest old, of the frequency of homozygous GG subjects, who produce higher IL-6 levels. However, discordant results have been obtained. To explore the relationship between this polymorphism and longevity, we analyzed individual data on long-living subjects and controls from eight case-control studies conducted in Europeans, using meta-analysis. There was no significant difference in the IL-6 genotype between the oldest old and controls (Odds Ratio [OR]=0.96; 95% C.I.: 0.77-1.20; p=0.71), but there was significant between-study heterogeneity (I2=55.5%). In a subgroup analyses when male centenarians from the three Italian studies were included, the frequency of the IL-6 -174 GG genotype was significantly lower than the other genotypes (OR=0.49; 95% C.I.: 0.31-0.80; p=0.004), with no evidence of heterogeneity (I2=0%). Our data supports a negative association between the GG genotype of IL-6 SNP and longevity in Italian centenarians, with males who carry the genotype being two times less likely to reach extreme old age compared with subjects carrying CC or CG genotypes. These findings were not replicated in other European groups suggesting a possible interaction between genetics, sex and environment in reaching longevity.

Systematic review by meta-analyses on the possible role of TNF-α polymorphisms in association with Alzheimer's disease

It has been hypothesized that polymorphisms of Tumor Necrosis Factor (TNF)-alpha gene affect the risk of developing Alzheimers disease (AD). However, results of different studies are often inconsistent. Our aim was to investigate by meta-analysis the association of the common polymorphisms comprehensively defining the genetic variability of the TNF-alpha gene with AD risk. Hence, the results being stated are of a meta-analysis across studies, and that this meta-analysis does not invalidate the results of the individual studies previously performed. Seventeen studies that investigated the association between 5 TNF-alpha polymorphisms (-850, -308, -863, -238, and -1031) and AD were retrieved and analyzed. The model-free approach was applied to meta-analyze these case-control genetic association studies. Available data suggested a significant association between -850 polymorphism and AD risk (TT vs. TC+CC: pooled odds ratio [OR], 1.61; 95% confidence interval [CI], 1.08-2.29; p=0.02) with no evidence of between-study heterogeneity (chi(2), p>0.1). Subgroup analysis suggested that the possession of T allele significantly increased the risk of AD associated with carriage of the apolipoprotein E epsilon 4 allele in Caucasian Australians and Northern Europeans (TT+TC vs. CC: OR, 1.95; 95% CI, 1.45-2.62; p=0.00001; p>0.1; chi(2) for heterogeneity, p>0.1). No significant difference in genotype distribution of -308 polymorphism in AD was found, with a high degree of between-study heterogeneity. For the -863 and -1031 polymorphisms we did not find an association with AD, but significant between-study heterogeneity discouraged genotype data pooling. Only four studies investigated the -238 variant and the results were not significant. Current findings support an association between -850 C>T polymorphism and the risk of developing AD; hence, they strengthen the suggestion of a potential role for anti-TNF therapy to maintain physiologic levels of TNF-alpha.