Predictive Biomarkers for Checkpoint Inhibitor Immune-Related Adverse Events.

Immune-checkpoint inhibitors (ICIs) are antagonists of inhibitory receptors in the immune system, such as the cytotoxic T-lymphocyte-associated antigen-4, the programmed cell death protein-1 and its ligand PD-L1, and they are increasingly used in cancer treatment. By blocking certain suppressive pathways, ICIs promote T-cell activation and antitumor activity but may induce so-called immune-related adverse events (irAEs), which mimic traditional autoimmune disorders. With the approval of more ICIs, irAE prediction has become a key factor in improving patient survival and quality of life. Several biomarkers have been described as potential irAE predictors, some of them are already available for clinical use and others are under development; examples include circulating blood cell counts and ratios, T-cell expansion and diversification, cytokines, autoantibodies and autoantigens, serum and other biological fluid proteins, human leucocyte antigen genotypes, genetic variations and gene profiles, microRNAs, and the gastrointestinal microbiome. Nevertheless, it is difficult to generalize the application of irAE biomarkers based on the current evidence because most studies have been retrospective, time-limited and restricted to a specific type of cancer, irAE or ICI. Long-term prospective cohorts and real-life studies are needed to assess the predictive capacity of different potential irAE biomarkers, regardless of the ICI type, organ involved or cancer site.

Baseline Circulating Blood Cell Counts and Ratios and Changes Therein for Predicting Immune-Related Adverse Events during Immune Checkpoint Inhibitor Therapy: A Multicenter, Prospective, Observational, Pan-Cancer Cohort Study with a Gender Perspective.

Several factors have been associated with the occurrence of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) therapy. Despite their availability, the predictive value of circulating blood cell parameters remains underexplored. Our aim was to investigate whether baseline values of and early changes in absolute neutrophil count (ANC), absolute lymphocyte count (ALC), other blood cell counts, and lymphocyte-related ratios can predict irAEs and whether sex may differentially influence this potential predictive ability. Of the 145 patients included, 52 patients (35.8%) experienced at least one irAE, with a 1-year cumulative incidence of 41.6%. Using Fine and Gray competing risk models, we identified female sex (hazard ratio (HR) = 2.17, 95% confidence interval (CI) = 1.20-3.85), high ALC before ICI initiation (HR = 1.63, 95% CI = 1.09-2.45), and low ANC after ICI initiation (HR = 0.81, 95% CI = 0.69-0.96) as predictors of irAEs. However, ALC and ANC may only have an impact on the risk of irAEs in women (stratified for female sex, ALC-related HR = 2.61, 95% CI = 1.40-4.86 and ANC-related HR = 0.57, 95% CI = 0.41-0.81). Priority should be given to developing models to predict ICI-related toxicity and their validation in various settings, and such models should assess the impact of patient sex on the risk of toxicity.

Prediction of Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors With a Panel of Autoantibodies: Protocol of a Multicenter, Prospective, Observational Cohort Study.

Introduction: Immune checkpoint inhibitor (ICI) therapy is markedly improving the prognosis of patients with several types of cancer. On the other hand, the growth in the use of these drugs in oncology is associated with an increase in multiple immune-related adverse events (irAEs), whose optimal prevention and management remain unclear. In this context, there is a need for reliable and validated biomarkers to predict the occurrence of irAEs in patients treated with ICIs. Thus, the main objective of this study is to evaluate the diagnostic performance of a sensitive routinely available panel of autoantibodies consisting of antinuclear antibodies, rheumatoid factor, and antineutrophil cytoplasmic antibodies to identify patients at risk of developing irAEs. Methods and Analysis: A multicenter, prospective, observational, cohort study has been designed to be conducted in patients diagnosed with cancer amenable to ICI therapy. Considering the percentage of ICI-induced irAEs to be 25% and a loss to follow-up of 5%, it has been estimated that a sample size of 294 patients is required to detect an expected sensitivity of the autoantibody panel under study of 0.90 with a confidence interval (95%) of no less than 0.75. For 48 weeks, patients will be monitored through the oncology outpatient clinics of five hospitals in Spain. Immune-related adverse events will be defined and categorized according to CTCAE v. 5.0. All the patients will undergo ordinary blood tests at specific moments predefined per protocol and extraordinary blood tests at the time of any irAE being detected. Ordinary and extraordinary samples will be frozen and stored in the biobank until analysis in the same autoimmunity laboratory when the whole cohort reaches week 48. A predictive model of irAEs will be constructed with potential risk factors of immune-related toxicity including the autoantibody panel under study. Ethics and Dissemination: This protocol was reviewed and approved by the Ethical Committee of the Basque Country and the Spanish Agency of Medicines and Medical Devices. Informed consent will be obtained from all participants before their enrollment. The authors declare that the results will be submitted to an international peer-reviewed journal for their prompt dissemination.

Methylprednisolone Pulses in Hospitalized COVID-19 Patients Without Respiratory Failure: A Randomized Controlled Trial.

Background: Corticosteroids are the cornerstone of the treatment of patients with COVID-19 admitted to hospital. However, whether corticosteroids can prevent respiratory worsening in hospitalized COVID-19 patients without oxygen requirements is currently unknown. Aims: To assess the efficacy of methylprednisolone pulses (MPP) in hospitalized COVID-19 patients with increased levels of inflammatory markers not requiring oxygen at baseline. Methods: Multicenter, parallel, randomized, double-blind, placebo-controlled trial conducted in Spain. Patients admitted for confirmed SARS-CoV-2 pneumonia with raised inflammatory markers (C-reactive protein >60 mg/L, interleukin-6 >40 pg/ml, or ferritin >1,000 µg/L) but without respiratory failure after the first week of symptom onset were randomized to receive a 3-day course of intravenous MPP (120 mg/day) or placebo. The primary outcome was treatment failure at 14 days, a composite variable including mortality, the need for ICU admission or mechanical ventilation, and clinical worsening, this last parameter defined as a PaO2/FiO2 ratio below 300; or a 15% decrease in the PaO2 from baseline, together with an increase in inflammatory markers or radiological progression. If clinical worsening occurred, patients received tocilizumab and unmasked corticosteroids. The secondary outcomes were 28-day mortality, adverse events, need for ICU admission or high-flow oxygen, length of hospital stay, SARS-CoV-2 clearance, and changes in laboratory parameters. Results: A total of 72 patients were randomized and 71 patients were analyzed (34 in the MPP group and 37 in the placebo group). Twenty patients presented with treatment failure (29.4 in the MPP group vs. 27.0% in the placebo group, p = 0.82), with no differences regarding the time to treatment failure between groups. There were no cases of death or mechanical ventilation requirements at 14 days post-randomization. The secondary outcomes were similar in MPP and placebo groups. Conclusions: A 3-day course of MPP after the first week of disease onset did not prevent respiratory deterioration in hospitalized COVID-19 patients with an inflammatory phenotype who did not require oxygen.

Association of immune-related adverse events induced by nivolumab with a battery of autoantibodies.

BACKGROUND: The aim of this study was to assess the diagnostic performance of an autoantibody battery in patients receiving immune checkpoint inhibitors who experienced immune-related adverse events (irAEs). METHODS: We retrospectively analyzed several variables potentially related to irAEs, namely, demographic, clinical, and laboratory characteristics, including an autoantibody battery (antinuclear, anti-neutrophil cytoplasmic, anti-thyroid antibodies and rheumatoid factor). RESULTS: Sixty-nine patients (48 men; 61.8 ± 10.9 years at baseline) diagnosed with stage-4 solid-organ cancer and treated with nivolumab were followed up for 12 ± 10.3 months. Thirty-two irAEs were detected in 26 patients (37.5%). Adverse events occurred more commonly in women (62% vs. 27%, p = .006), and younger patients (irAEs: 58.1 ± 9.8, no irAEs: 64.1 ± 10.9 years, p = .024). Autoantibody battery results were available for 26 patients and were more frequently positive in patients with irAEs (87% vs. 30%, p = .009). The positive predictive value, negative predictive value, and diagnostic accuracy of the battery were 82.3%, 77.8%, and 80.8%, respectively. Among the 64 patients with an evaluable response, 23 (38.5%) experienced tumour progression, this being less frequent in patients with irAEs (19% vs. 48.5%, p = .03). Overall survival was higher in patients developing irAEs (HR = 1.88, p = .05). CONCLUSION: Positivity in a readily available autoantibody battery may be associated with the occurrence of irAEs.KEY MESSAGESPositivity in an accessible and inexpensive autoantibody battery including antinuclear, anti-neutrophil cytoplasmic, anti-thyroid antibodies and rheumatoid factor may be associated with the occurrence of immune-related adverse events.Patients with cancer on immune checkpoint inhibitors experiencing immune-related adverse events showed a lower risk of progression and better overall survival than patients not experiencing this type of adverse effect.

Duration of the acute hepatic encephalopathy episode determines survival in cirrhotic patients.

BACKGROUND: Episodes of hepatic encephalopathy (HE) have been related to low survival rate. However, the relation between its clinical evolution and mortality has not been assessed. METHODS: A retrospective analysis of 245 cirrhotic patients admitted for an acute episode of HE (⩾grade 2) or who developed an HE episode after an upper gastrointestinal bleeding (UGIB) event was performed to assess the relation between time in HE and transplant-free survival. RESULTS: Median (IQR25-75) time in HE was 48 h (24-96 h) in the whole cohort. Patients who presented a longer time in HE (>48 h; n = 89) exhibited a lower transplant-free survival at 28 days (67.2% versus 88.9%, p < 0.001), 90 days (48.7% versus 73.8%, p < 0.001) and 365 days (30.3% versus 53.2%, p < 0.001), as compared to those with less time in HE (⩽48 h; n = 156). Survival rates remained significantly different, with lower percentages in the group with time in HE >48 h, when comparing patients according to baseline HE grade (2 versus ⩾3) or model for end-stage liver disease (MELD) function (⩽15 versus >15). Time in HE was also an independent risk factor for mortality at each time point, hazard ratio (HR) (95 CI%) 28 days 2.59 (1.39-4.84); 90 days 1.98 (1.28-3.1) and 365 days 1.5 (1.08-2.19). CONCLUSIONS: The duration of the acute HE episode determines survival in cirrhotic patients independently of liver function and baseline HE grade.

Length of exposure to antiphospholipid antibodies, rather than age, is a risk factor for thrombosis: a retrospective single-centre observational study.

To investigate the association of age and other factors with thrombosis risk in antiphospholipid antibody (aPL) carriers, a retrospective observational study was conducted in a cohort of patients with medium-high aPL titres recruited in a tertiary care hospital. Assuming an age difference of 9.8 years between patients with and without thrombosis, we estimated that a sample size of 70 participants was required. Several variables besides age including gender, vascular risk factors, inherited thrombophilias, non-thrombotic clinical manifestations, laboratory parameters, aPL profile, length of aPL exposure, antithrombotic drugs and partial aPL score were assessed by univariate analysis followed by multivariate logistic regression. Outcomes were analysed by whether thromboses occurred before (model 1) or after (model 2) aPL detection. Seventy patients [50 females; median (interquartile range) baseline age: 46.99 (39.39-66.20) years] were followed for 2.59 (0.67-5.86) years. Overall, 18 and 5 thromboses were diagnosed applying models 1 and 2, respectively. Time to thrombosis after aPL detection was 2.10 (1.03-8.24) years. Age did not differ between patients with and without thrombosis using models 1 (p = 0.92) or 2 (p = 0.67). Instead, we identified other predictors of thrombosis, namely, lack of thromboprophylaxis [odds ratio (OR) 13.50, 95%  confidence interval (95% CI) 1.02-178.05, p = 0.048] and length of aPL exposure (OR 1.41, 95% CI 1.04-1.92, p = 0.026) in model 2, while lupus anticoagulant showed a tendency to increase the risk (OR 7.10, 95% CI 0.86-58.78, p = 0.069) in model 1. Unlike age, lack of thromboprophylaxis, prolonged aPL exposure and lupus anticoagulant may increase the risk of thrombosis in aPL carriers.

Branched-chain amino acids for people with hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy is a brain dysfunction with neurological and psychiatric changes associated with liver insufficiency or portal-systemic shunting. The severity ranges from minor symptoms to coma. A Cochrane systematic review including 11 randomised clinical trials on branched-chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy. SEARCH METHODS: We identified trials through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded and Conference Proceedings Citation Index - Science, and LILACS (May 2017). SELECTION CRITERIA: We included randomised clinical trials, irrespective of the bias control, language, or publication status. DATA COLLECTION AND ANALYSIS: The authors independently extracted data based on published reports and collected data from the primary investigators. We changed our primary outcomes in this update of the review to include mortality (all cause), hepatic encephalopathy (number of people without improved manifestations of hepatic encephalopathy), and adverse events. The analyses included random-effects and fixed-effect meta-analyses. We performed subgroup, sensitivity, regression, and trial sequential analyses to evaluate sources of heterogeneity (including intervention, and participant and trial characteristics), bias (using The Cochrane Hepato-Biliary Group method), small-study effects, and the robustness of the results after adjusting for sparse data and multiplicity. We graded the quality of the evidence using the GRADE approach. MAIN RESULTS: We found 16 randomised clinical trials including 827 participants with hepatic encephalopathy classed as overt (12 trials) or minimal (four trials). Eight trials assessed oral BCAA supplements and seven trials assessed intravenous BCAA. The control groups received placebo/no intervention (two trials), diets (10 trials), lactulose (two trials), or neomycin (two trials). In 15 trials, all participants had cirrhosis. We classed seven trials as low risk of bias and nine trials as high risk of bias (mainly due to lack of blinding or for-profit funding). In a random-effects meta-analysis of mortality, we found no difference between BCAA and controls (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.69 to 1.11; 760 participants; 15 trials; moderate quality of evidence). We found no evidence of small-study effects. Sensitivity analyses of trials with a low risk of bias found no beneficial or detrimental effect of BCAA on mortality. Trial sequential analysis showed that the required information size was not reached, suggesting that additional evidence was needed. BCAA had a beneficial effect on hepatic encephalopathy (RR 0.73, 95% CI 0.61 to 0.88; 827 participants; 16 trials; high quality of evidence). We found no small-study effects and confirmed the beneficial effect of BCAA in a sensitivity analysis that only included trials with a low risk of bias (RR 0.71, 95% CI 0.52 to 0.96). The trial sequential analysis showed that firm evidence was reached. In a fixed-effect meta-analysis, we found that BCAA increased the risk of nausea and vomiting (RR 5.56; 2.93 to 10.55; moderate quality of evidence). We found no beneficial or detrimental effects of BCAA on nausea or vomiting in a random-effects meta-analysis or on quality of life or nutritional parameters. We did not identify predictors of the intervention effect in the subgroup, sensitivity, or meta-regression analyses. In sensitivity analyses that excluded trials with a lactulose or neomycin control, BCAA had a beneficial effect on hepatic encephalopathy (RR 0.76, 95% CI 0.63 to 0.92). Additional sensitivity analyses found no difference between BCAA and lactulose or neomycin (RR 0.66, 95% CI 0.34 to 1.30). AUTHORS' CONCLUSIONS: In this updated review, we included five additional trials. The analyses showed that BCAA had a beneficial effect on hepatic encephalopathy. We found no effect on mortality, quality of life, or nutritional parameters, but we need additional trials to evaluate these outcomes. Likewise, we need additional randomised clinical trials to determine the effect of BCAA compared with interventions such as non-absorbable disaccharides, rifaximin, or other antibiotics.

Branched-chain amino acids for people with hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy is a brain dysfunction with neurological and psychiatric changes associated with liver insufficiency or portal-systemic shunting. The severity ranges from minor symptoms to coma. A Cochrane systematic review including 11 randomised clinical trials on branched-chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy. SEARCH METHODS: We identified trials through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index (August 2015). SELECTION CRITERIA: We included randomised clinical trials, irrespective of the bias control, language, or publication status. DATA COLLECTION AND ANALYSIS: The authors independently extracted data based on published reports and collected data from the primary investigators. We changed our primary outcomes in this update of the review to include mortality (all cause), hepatic encephalopathy (number of people without improved manifestations of hepatic encephalopathy), and adverse events. The analyses included random-effects and fixed-effect meta-analyses. We performed subgroup, sensitivity, regression, and trial sequential analyses to evaluate sources of heterogeneity (including intervention, and participant and trial characteristics), bias (using The Cochrane Hepato-Biliary Group method), small-study effects, and the robustness of the results after adjusting for sparse data and multiplicity. We graded the quality of the evidence using the GRADE approach. MAIN RESULTS: We found 16 randomised clinical trials including 827 participants with hepatic encephalopathy classed as overt (12 trials) or minimal (four trials). Eight trials assessed oral BCAA supplements and seven trials assessed intravenous BCAA. The control groups received placebo/no intervention (two trials), diets (10 trials), lactulose (two trials), or neomycin (two trials). In 15 trials, all participants had cirrhosis. We classed seven trials as low risk of bias and nine trials as high risk of bias (mainly due to lack of blinding or for-profit funding). In a random-effects meta-analysis of mortality, we found no difference between BCAA and controls (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.69 to 1.11; 760 participants; 15 trials; moderate quality of evidence). We found no evidence of small-study effects. Sensitivity analyses of trials with a low risk of bias found no beneficial or detrimental effect of BCAA on mortality. Trial sequential analysis showed that the required information size was not reached, suggesting that additional evidence was needed. BCAA had a beneficial effect on hepatic encephalopathy (RR 0.73, 95% CI 0.61 to 0.88; 827 participants; 16 trials; high quality of evidence). We found no small-study effects and confirmed the beneficial effect of BCAA in a sensitivity analysis that only included trials with a low risk of bias (RR 0.71, 95% CI 0.52 to 0.96). The trial sequential analysis showed that firm evidence was reached. In a fixed-effect meta-analysis, we found that BCAA increased the risk of nausea and vomiting (RR 5.56; 2.93 to 10.55; moderate quality of evidence). We found no beneficial or detrimental effects of BCAA on nausea or vomiting in a random-effects meta-analysis or on quality of life or nutritional parameters. We did not identify predictors of the intervention effect in the subgroup, sensitivity, or meta-regression analyses. In sensitivity analyses that excluded trials with a lactulose or neomycin control, BCAA had a beneficial effect on hepatic encephalopathy (RR 0.76, 95% CI 0.63 to 0.92). Additional sensitivity analyses found no difference between BCAA and lactulose or neomycin (RR 0.66, 95% CI 0.34 to 1.30). AUTHORS' CONCLUSIONS: In this updated review, we included five additional trials. The analyses showed that BCAA had a beneficial effect on hepatic encephalopathy. We found no effect on mortality, quality of life, or nutritional parameters, but we need additional trials to evaluate these outcomes. Likewise, we need additional randomised clinical trials to determine the effect of BCAA compared with interventions such as non-absorbable disaccharides, rifaximin, or other antibiotics.

Branched-chain amino acids for people with hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy is a brain dysfunction with neurological and psychiatric changes associated with liver insufficiency or portal-systemic shunting. The severity ranges from minor symptoms to coma. A Cochrane systematic review including 11 randomised clinical trials on branched-chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy. SEARCH METHODS: We identified trials through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index on 2 October 2014. SELECTION CRITERIA: We included randomised clinical trials, irrespective of the bias control, language, or publication status. DATA COLLECTION AND ANALYSIS: The authors independently extracted data based on published reports and collected data from the primary investigators. We changed our primary outcomes in this update of the review to include mortality (all cause), hepatic encephalopathy (number of people without improved manifestations of hepatic encephalopathy), and adverse events. The analyses included random-effects and fixed-effect meta-analyses. We performed subgroup, sensitivity, regression, and trial sequential analyses to evaluate sources of heterogeneity (including intervention, and participant and trial characteristics), bias (using The Cochrane Hepato-Biliary Group method), small-study effects, and the robustness of the results after adjusting for sparse data and multiplicity. We graded the quality of the evidence using the GRADE approach. MAIN RESULTS: We found 16 randomised clinical trials including 827 participants with hepatic encephalopathy classed as overt (12 trials) or minimal (four trials). Eight trials assessed oral BCAA supplements and seven trials assessed intravenous BCAA. The control groups received placebo/no intervention (two trials), diets (10 trials), lactulose (two trials), or neomycin (two trials). In 15 trials, all participants had cirrhosis. Based on the combined Cochrane Hepato-Biliary Group score, we classed seven trials as low risk of bias and nine trials as high risk of bias (mainly due to lack of blinding or for-profit funding). In a random-effects meta-analysis of mortality, we found no difference between BCAA and controls (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.69 to 1.11; 760 participants; 15 trials; moderate quality of evidence). We found no evidence of small-study effects. Sensitivity analyses of trials with a low risk of bias found no beneficial or detrimental effect of BCAA on mortality. Trial sequential analysis showed that the required information size was not reached, suggesting that additional evidence was needed. BCAA had a beneficial effect on hepatic encephalopathy (RR 0.73, 95% CI 0.61 to 0.88; 827 participants; 16 trials; high quality of evidence). We found no small-study effects and confirmed the beneficial effect of BCAA in a sensitivity analysis that only included trials with a low risk of bias (RR 0.71, 95% CI 0.52 to 0.96). The trial sequential analysis showed that firm evidence was reached. In a fixed-effect meta-analysis, we found that BCAA increased the risk of nausea and vomiting (RR 5.56; 2.93 to 10.55; moderate quality of evidence). We found no beneficial or detrimental effects of BCAA on nausea or vomiting in a random-effects meta-analysis or on quality of life or nutritional parameters. We did not identify predictors of the intervention effect in the subgroup, sensitivity, or meta-regression analyses. In sensitivity analyses that excluded trials with a lactulose or neomycin control, BCAA had a beneficial effect on hepatic encephalopathy (RR 0.76, 95% CI 0.63 to 0.92). Additional sensitivity analyses found no difference between BCAA and lactulose or neomycin (RR 0.66, 95% CI 0.34 to 1.30). AUTHORS' CONCLUSIONS: In this updated review, we included five additional trials. The analyses showed that BCAA had a beneficial effect on hepatic encephalopathy. We found no effect on mortality, quality of life, or nutritional parameters, but we need additional trials to evaluate these outcomes. Likewise, we need additional randomised clinical trials to determine the effect of BCAA compared with interventions such as non-absorbable disaccharides, rifaximin, or other antibiotics.

Oral branched-chain amino acids have a beneficial effect on manifestations of hepatic encephalopathy in a systematic review with meta-analyses of randomized controlled trials.

Supplements with branched-chain amino acid (BCAA) have cerebral, metabolic, and nutritional effects that may benefit patients with hepatic encephalopathy (HE). We therefore conducted a systematic review on the effects of oral BCAAs compared with control supplements or placebo for patients with cirrhosis and recurrent overt or minimal HE. The quantitative analyses included data from 8 trials (n = 382 patients). Individual patient data were retrieved from 4 trials to recalculate outcomes (n = 255 patients). The mean dose of the oral BCAA supplements was 0.25 g/(kg body weight · d). Random effects meta-analysis showed that improvements in HE manifestations were registered for 87 of 172 patients in the BCAA group compared with 56 of 210 controls [risk ratio = 1.71 (95% CI: 1.17, 2.51) number needed to treat = 5 patients]. The effect of BCAAs differed (P = 0.04) for patients with overt [risk ratio = 3.26 (95% CI: 1.47, 7.22)] and minimal HE [risk ratio = 1.32 (95% CI: 0.97, 1.79)]. Subgroup, sensitivity, regression, and sequential analyses found no other sources of heterogeneity or bias. BCAA supplements had no effect on mortality or markers of nutritional status and did not induce adverse events. In conclusion, oral BCAA supplements improve manifestations of HE but have no effect on survival.

Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: what is the evidence?

Hepatic encephalopathy (HE) is a serious complication of acute and chronic liver disease associated with severe morbidity and mortality. We performed updated random effects meta-analyses to evaluate the evidence for non-absorbable disaccharides (lactulose and lactitol), rifaximin and branched chain amino acids (BCAA). A meta-analysis of randomized trials showed that, compared with placebo or no intervention, non-absorbable disaccharides have beneficial effects on HE manifestations and prevention of HE episodes. The addition of rifaximin to non-absorbable disaccharides versus rifaximin alone was more beneficial than non-absorbable disaccharides used alone on both outcome measures. Likewise, a meta-analysis of randomised controlled trials found that oral BCAA supplements have beneficial effects on manifestations of HE compared with control supplements. The effect was found in a variety of clinical settings. No convincing effects of intravenous BCAA for episodic HE were identified. In conclusion, evidence-based treatment recommendations for patients with HE should include non-absorbable disaccharides combined with rifaximin or BCAA. Additional evidence is needed to evaluate the effect of combining all three interventions.

Intensity and duration of anticoagulation therapy in antiphospholipid syndrome.

Antithrombotic drugs are the therapeutic cornerstone for patients with antiphospholipid syndrome (APS) and thrombosis. Choosing the specific agent (vitamin K antagonists or antiplatelet drugs), the intensity of anticoagulation (e.g., international normalized ratio [INR] range 2.0 to 3.0 or 3.0 to 4.0), and the duration of treatment has been a recurrent matter of debate. A recent consensus document recommends warfarin to an INR range of 2.0 to 3.0 for patients with a first venous thromboembolic event. Higher anticoagulation intensity is recommended for patients presenting with arterial events. Combined therapy with warfarin and aspirin is another possibility, but some authors recommend standard intensity warfarin or aspirin, either as monotherapy. In general, a more intense regimen is warranted for high-risk patients. On the basis of an increased risk of recurrence during the first 6 months following warfarin withdrawal, long-term anticoagulation is considered the standard treatment. Nevertheless, anticoagulation regimes of shorter duration could be given in selected patients with venous thromboembolism who have transient risk factors and a low-risk profile.

Sarcoid intermediate uveitis following etanercept treatment: a case report and review of the literature.

PURPOSE: To describe a case of sarcoid uveitis subsequent to anti-TNFα therapy and review previously reported cases. METHODS: Review of the clinical records of the authors' patient and of the literature using the PubMed database. RESULTS: A 30-year-old woman presented with intermediate uveitis with snowballs in both eyes. She was on treatment with etanercept due to psoriatic arthritis. An ultrasound-guided biopsy of a mediastinal adenopathy showed non-necrotizing granulomas compatible with sarcoidosis. The clinical picture resolved after etanercept was withdrawn and treatment with immunosuppressants. In a literature search the authors identified six other cases of sarcoid uveitis induced by anti-TNFα therapy. The types of uveitis were anterior uveitis, posterior uveitis, or panuveitis. Management consisted of withdrawal of anti-TNFα therapy and administration of immunosuppressive agents in 5 cases. CONCLUSIONS: Sarcoid uveitis induced by TNFα antagonists is a rare complication. Appropriate management consists of withdrawing the TNFα antagonist and giving immunosuppressants.

Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study.

OBJECTIVES: Protein intake impacts on nutritional status and may determine the recurrence of hepatic encephalopathy (HE). A low-protein diet has been considered the standard treatment after an episode of HE, while branched-chain amino acids (BCAA) have been shown to improve minimal HE. We performed a study to investigate the long-term effects of supplementing a protein-controlled diet with BCAA. METHODS: A randomized, double-blind, multicenter study that included 116 patients with cirrhosis and a previous episode of HE was conducted in four tertiary care hospitals. All patients received a standard diet of 35 kcal/kg per day and 0.7 g of proteins/kg per day and a supplement of 30 g of BCAA (BCAA group) or maltodextrin (MDX group) during 56 weeks. RESULTS: The actuarial risk of remaining free of HE did not differ between groups (BCAA=47%, MDX=34%, P=0.274), but patients in the BCAA group exhibited a better outcome on two neuropsychological tests and an increase in the mid-arm muscle circumference. Recurrence was associated with low plasma albumin at baseline and a decrease in sodium and an increase in creatinine during follow-up. Patients with recurrence of HE exhibited a lack of improvement in global cognitive function. CONCLUSIONS: Diet supplementation with BCAA after an episode of HE does not decrease recurrence of HE. However, supplementation with BCAA improves minimal HE and muscle mass. Identification of risk factors for recurrence of HE may allow the development of new preventive therapies that could decrease the neuropsychological sequelae of repeated episodes of HE.

Quality of life in cirrhosis is related to potentially treatable factors.

OBJECTIVE: Improvement of prognosis and availability of diverse therapeutic options for complications of advanced liver disease highlight the importance of health-related quality of life (HRQOL) in cirrhosis. The aim of this study was to identify factors that influence HRQOL and may be potentially treatable in patients with cirrhosis. METHODS: HRQOL was measured in 212 outpatients with cirrhosis using a generic questionnaire (Medical Outcomes Study Form, SF-36) and a liver-specific questionnaire (Chronic Liver Disease Questionnaire, CLDQ). All patients underwent a systematic clinical and neuropsychological assessment. Independent factors associated with poor HRQOL were identified by multiple linear regression. RESULTS: HRQOL scores exhibited by patients were: global CLDQ: 4.8+/-1.2; Physical Component Score of SF-36: 38.5+/-10.7; Mental Component Score of SF-36: 45.3+/-14.3. The independent variables for global CLDQ were female sex, nonalcoholic etiology, current ascites, and a decrease in albumin (R = 0.22). For Physical Component Score of SF-36, the independent variables were prior hepatic encephalopathy, current ascites, and a decrease in hemoglobin (R = 0.22). For Mental Component Score of SF-36, the independent variables were nonalcoholic etiology, the Grooved Pegboard test, and a decrease in hemoglobin (R = 0.14). CONCLUSION: Several clinical variables, potentially treatable, may alter particular aspects of HRQOL. Correction of ascites, hypoalbuminemia, minimal hepatic encephalopathy, and anemia may cause a positive impact on HRQOL of patients with cirrhosis.

Current trends in chronic hepatitis B management: results of a questionnaire.

OBJECTIVE: Diagnosis and treatment of chronic hepatitis B (CHB) have improved in recent years with introduction of new oral antiviral drugs. Aim of this study was to analyze general knowledge, therapeutic and diagnostic trends of physicians treating CHB in Spain. METHODS: A questionnaire was distributed to 692 physicians of the Spanish Association for the Study of the Liver. The questionnaire assessed habits in CHB management and approach to a pair of hypothetical CHB cases: HBeAg positive and HBeAg negative. RESULTS: One hundred and nineteen (17%) physicians answered the questionnaire. Most of them correctly identified indications for CHB treatment (95%), and had experience with lamivudine (89%), adefovir dipivoxil (84%) and interferon (76%), but only 45% knew the efficacy rate of these drugs. Seventy-six percent recommended pegylated interferon as initial treatment for HBeAg-positive patients, and 86% would treat HBeAg-negative patients with oral antiviral drugs (42% with lamivudine, 36% with adefovir dipivoxil, and 8% with entecavir). Hepatitis B virus (HBV)-DNA determination was used to monitor therapy by 74%, and only 24% used HBV drug resistance test. The only independent factor associated with adequate use of drugs and correct monitoring was experience of treating more than five patients per year. Antiviral prophylaxis for HBV carriers receiving immunosuppression was indicated by 78% of physicians. Physicians working at university hospitals were significantly more likely to recommend antiviral prophylaxis than physicians working at nonuniversity hospitals (86 vs. 65%; P=0.009). CONCLUSION: CHB management decisions are not always based on scientific evidence. Continuous medical education could improve knowledge and management of CHB.