Prevalence, significance and predictive value of antiphospholipid antibodies in Crohn's disease

AIM To assess the prevalence and stability of different antiphospholipid antibodies (APLAs) and their association with disease phenotype and progression in inflammatory bowel diseases (IBD) patients. METHODS About 458 consecutive patients [Crohn's disease (CD): 271 and ulcerative colitis (UC): 187] were enrolled into a follow-up cohort study in a tertiary IBD referral center in Hungary. Detailed clinical phenotypes were determined at enrollment by reviewing the patients' medical charts. Disease activity, medical treatment and data about evolvement of complications or surgical interventions were determined prospectively during the follow-up. Disease course (development f complicated disease phenotype and need for surgery), occurrence of thrombotic events, actual state of disease activity according to clinical, laboratory and endoscopic scores and accurate treatment regime were recorded during the follow-up, (median, 57.4 and 61.6 mo for CD and UC). Sera of IBD patients and 103 healthy controls (HC) were tested on individual anti-β2-Glycoprotein-I (anti-β2-GPI IgA/M/G), anti-cardiolipin (ACA IgA/M/G) and anti-phosphatidylserine/prothrombin (anti-PS/PT IgA/M/G) antibodies and also anti-Saccharomyces cerevisiae antibodies (ASCA IgA/G) by enzyme-linked immunosorbent assay (ELISA). In a subgroup of CD (n = 198) and UC patients (n = 103), obtaining consecutive samples over various arbitrary time-points during the disease course, we evaluated the intraindividual stability of the APLA status. Additionally, we provide an overview of studies, performed so far, in which significance of APLAs in IBD were assessed. RESULTS Patients with CD had significantly higher prevalence of both ACA (23.4%) and anti-PS/PT (20.4%) antibodies than UC (4.8%, P < 0.0001 and 10.2%, P = 0.004) and HC (2.9%, P < 0.0001 and 15.5%, P = NS). No difference was found for the prevalence of anti-β2-GPI between different groups (7.2%-9.7%). In CD, no association was found between APLA and ASCA status of the patients. Occurrence of anti-β2-GPI, ACA and anti-PS/PT was not different between the group of patients with active vs inactive disease state according to appropriate clinical, laboratory and endoscopic scores in CD as well as in UC patients. All subtypes of anti-β2-GPI and ACA IgM status were found to be very stable over time, in contrast ACA IgG and even more ACA IgA status showed significant intraindividual changes. Changes in antibody status were more remarkable in CD than UC (ACA IgA: 49.9% vs 23.3% and ACA IgG: 21.2% vs 5.8%). Interestingly, 59.1% and 30.1% of CD patients who received anti-TNF therapy showed significant negative to positive changes in ACA IgA and IgG antibody status respectively. APLA status was not associated with the clinical phenotype at diagnosis or during follow-up, medical therapy, or thrombotic events and it was not associated with the probability of developing complicated disease phenotype or surgery in a Kaplan-Meier analysis. CONCLUSION The present study demonstrated enhanced formation of APLAs in CD patients. However, presence of different APLAs were not associated with the clinical phenotype or disease course

Rediscovery of the Anti-Pancreatic Antibodies and Evaluation of their Prognostic Value in a Prospective Clinical Cohort of Crohn's Patients: The Importance of Specific Target Antigens [GP2 and CUZD1].

BACKGROUNDS Glycoprotein 2[GP2] and CUB zona pellucida-like domain 1[CUZD1] belong to protein families involved in gut innate immunity processes and have recently been identified as specific targets of anti-pancreatic autoantibodies [PAbs] in Crohn's disease[CD]. We aimed to determine the prognostic potential of novel target-specific PAbs regarding long-term disease course of an adult CD patient cohort. METHODS Sera of 458 consecutive well-characterised IBD patients from a single referral IBD centre were tested by enzyme-linked immunosorbent assay [ELISA] with isoform 4 of recombinant GP2 [anti-MZGP2 and anti-GP2 IgA/IgG] and indirect immunofluorescence test [IIFT] system with GP2 and CUZD1 expressing transfected HEK 293 cells [anti-rPAg2 and rPAg1 IgA/IgG]. Clinical data were available on complicated disease or surgical interventions as well as disease activity and medical treatment during the prospective follow-up [median, 108 months]. RESULTS Totals of 12.4% and 20.8% of CD patients were positive for IgA/IgG type of anti-GP2 and anti-CUZD1, respectively, with a significant difference compared with UC [p < 0.01]. Antibody status was stable over time. Agreement among three different anti-GP2 assays was good. Positivity for PAbs, mainly IgA subtypes, predicted a faster progression towards complicated disease course. In Kaplan-Meier analysis, time to surgery or development of perianal disease was associated with anti-GP2 IgA [pLogRank < 0.01] or anti-CUZD1 IgA [pLogRank < 0.001] positivity, respectively. Anti-CUZD1 IgA remained an independent predictor in the multivariate Cox-regression model (hazard ratio [HR]: 3.43, 95% confidence interval [CI]: 1.68-7.02, p < 0.001). CONCLUSIONS The present study has shown that specific PAbs [especially IgA subtype] predict complicated disease course including the development of perianal disease in CD

Presence of Anti-Microbial Antibodies in Liver Cirrhosis – A Tell-Tale Sign of Compromised Immunity?

Bacterial translocation plays important role in the complications of liver cirrhosis. Antibody formation against various microbial antigens is common in Crohn's disease and considered to be caused by sustained exposure to gut microflora constituents. We hypothesized that anti-microbial antibodies are present in patients with liver cirrhosis and may be associated with the development of bacterial infections.<0.001, OR:2.02) by Cox-regression analysis.The present study suggests that systemic reactivity to microbial components reflects compromised mucosal immunity in patients with liver cirrhosis, further supporting the possible role of bacterial translocation in the formation of anti-microbial antibodies

norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis

Background & Aim: Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C-23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500 mg/d, 1,000 mg/d or 1,500 mg/d) compared with placebo in patients with PSC. Methods: One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit. Results: norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1,000, and 1,500 mg/d groups (p = 0.029, tively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary end-points, such as ALT, AST, gamma-GT, or the rate of patients achieving ALP levels <1.5 x ULN. Serious adverse events occurred in seven patients in the 500 mg/d, five patients in the 1,000 mg/d, two patients in the 1500 mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. Conclusions: norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V.Peer reviewe

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis

Background & Aims: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (ADNo ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. Methods: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. Results: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. Conclusions: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. Lay summary: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes. (c) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. ClinicalTrials.gov number: NCT03056612. Lay summary: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk

A Randomized, Open-Label, Non-Inferiority Study of Intravenous Iron Isomaltoside 1,000 (Monofer) Compared With Oral Iron for Treatment of Anemia in IBD (PROCEED)

OBJECTIVES: In the largest head-to-head comparison between an oral and an intravenous (IV) iron compound in patients with inflammatory bowel disease (IBD) so far, we strived to determine whether IV iron isomaltoside 1,000 is non-inferior to oral iron sulfate in the treatment of iron deficiency anemia (IDA). METHODS: This prospective, randomized, comparative, open-label, non-inferiority study was conducted at 36 sites in Europe and India. Patients with known intolerance to oral iron were excluded. A total of 338 IBD patients in clinical remission or with mild disease, a hemoglobin (Hb) <12 g/dl, and a transferrin saturation (TSAT) <20% were randomized 2:1 to receive either IV iron isomaltoside 1,000 according to the Ganzoni formula (225 patients) or oral iron sulfate 200 mg daily (equivalent to 200 mg elemental iron; 113 patients). An interactive web response system method was used to randomize the eligible patient to the treatment groups. The primary end point was change in Hb from baseline to week 8. Iron isomaltoside 1,000 and iron sulfate was compared by a non-inferiority assessment with a margin of −0.5 g/dl. The secondary end points, which tested for superiority, included change in Hb from baseline to weeks 2 and 4, change in s-ferritin, and TSAT to week 8, number of patients who discontinued study because of lack of response or intolerance of investigational drugs, change in total quality of life (QoL) score to weeks 4 and 8, and safety. Exploratory analyses included a responder analysis (proportion of patients with an increase in Hb ≥2 g/dl after 8 weeks), the effect of regional differences and total iron dose level, and other potential predictors of the treatment response. RESULTS: Non-inferiority in change of Hb to week 8 could not be demonstrated. There was a trend for oral iron sulfate being more effective in increasing Hb than iron isomaltoside 1,000. The estimated treatment effect was −0.37 (95% confidence interval (CI): −0.80, 0.06) with P=0.09 in the full analysis set (N=327) and −0.45 (95% CI: −0.88, −0.03) with P=0.04 in the per protocol analysis set (N=299). In patients treated with IV iron isomaltoside 1,000, the mean change in s-ferritin concentration was higher with an estimated treatment effect of 48.7 (95% CI: 18.6, 78.8) with P=0.002, whereas the mean change in TSAT was lower with an estimated treatment effect of −4.4 (95% CI: −7.4, −1.4) with P=0.005, compared with patients treated with oral iron. No differences in changes of QoL were observed. The safety profile was similar between the groups. The proportion of responders with Hb ≥2 g/dl (IV group: 67% oral group: 61%) were comparable between the groups (P=0.32). Iron isomaltoside 1,000 was more efficacious with higher cumulative doses of >1,000 mg IV. Significant predictors of Hb response to IV iron treatment were baseline Hb and C-reactive protein (CRP). CONCLUSIONS: We could not demonstrate non-inferiority of IV iron isomaltoside 1,000 compared with oral iron in this study. Based on the dose–response relationship observed with the IV iron compound, we suggest that the true iron demand of IV iron was underestimated by the Ganzoni formula in our study. Alternative calculations including Hb and CRP should be explored to gauge iron stores in patients with IBD