Early clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn's disease.

BACKGROUND: Adalimumab is a fully human monoclonal antibody targeting tumour necrosis factor with proven efficacy in the treatment of Crohn's disease (CD). AIM: To investigate the predictors of medium-term clinical efficacy and mucosal healing during adalimumab therapy, in patients with CD, in specialised centres approved for biological therapy in Hungary. METHODS: Data capture of the 201 CD patients was standardised and prospective (male/female: 112/89, median age: 33.0 years, duration: 8 years). Previous infliximab therapy had been administered in 48% of patients, concomitant steroids in 41%, azathioprine in 69% and combined therapy in 27% of patients. RESULTS: Overall clinical response and remission rates at 24 weeks were 78% and 52%, respectively; at 52 weeks were 69% and 44%, respectively. Endoscopic improvement and healing were achieved in 43% and 24% of patients. In a logistic regression model, clinical efficacy and CRP at week 12, need for combined immunosuppression at induction, shorter disease duration and smoking were identified as independent predictors for 12-month clinical outcome, whereas CRP at week 12, clinical remission at week 24, inflammatory parameters and nonsmoking were associated to endoscopic improvement/healing. Intensification to weekly dosing was needed in 16% of patients. Parallel azathioprine therapy and clinical remission at week 12 were inversely associated with dose escalation. CONCLUSIONS: Clinical efficacy and normalised CRP at week 12 (early deep clinical remission) are associated with medium-term clinical efficacy and mucosal healing during adalimumab therapy, whereas need for combined immunosuppression at induction and smoking status are predictors for non-response. Parallel azathioprine therapy may decrease the probability for dose escalation.

ATG16L1 and IL23 receptor (IL23R) genes are associated with disease susceptibility in Hungarian CD patients.

BACKGROUND: North American and European genome-wide association scans have identified ATG16L1 and IL23R as novel inflammatory bowel disease (IBD) susceptibility genes and subsequent reports confirmed these findings in large independent populations. The aims of this study were to investigate the association and examine genotype-phenotype relationships in a Hungarian IBD cohort. METHODS: 415 unrelated IBD patients (CD: 266, age: 35.2+/-12.1 years, duration: 8.7+/-7.5 years and UC: 149, age: 44.4+/-15.4 years, duration: 10.7+/-8.9 years) and 149 healthy subjects were investigated. IL23R Arg381Gln (R381Q, rs11209026) and ATG16L1 Thr300Ala (T300A, rs2241880) polymorphisms were tested using LightCycler allele discrimination method. Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: The association between IL23R rs11209026, ATG16L1 rs2241880 and CD was confirmed (OR(IL23R381Q): 0.38, 95% CI: 0.16-0.87; OR(ATG16L1300AA): 1.86, 95% CI: 1.04-3.40). No difference was found between patients with UC and either controls or CD. In CD, IL23R 381Gln heterozygosity was associated with inflammatory disease (70% vs. 34%, p=0.037), while disease restricted to the colon was more prevalent in patients with the ATG16L1 300Ala/Ala homozygosity (33.3% vs. 21.1%, p=0.036). In addition, carriage of the variant alleles did not predict response to steroids, infliximab or need for surgery. CONCLUSIONS: We confirmed that ATG16L1 and IL23R are susceptibility loci for CD in Hungarian CD patients. Further studies are needed to confirm the reported phenotype-genotype associations found in this study.

Interaction between seroreactivity to microbial antigens and genetics in Crohn's disease: is there a role for defensins?

Antibodies against different microbial epitopes are associated with disease phenotype, may be of diagnostic importance and may reflect a loss of tolerance in Crohn's disease (CD). Recently, an association was reported between the presence of these antibodies and mutations in pattern receptor genes. Our aim was to investigate whether mutations in various genes other than NOD2/CARD15 or TLR4 associated with CD (NOD1/CARD4, DLG5 and DEFB1) may influence the presence of antibodies against bacterial proteins and carbohydrates in a Hungarian cohort of CD patients. Three hundred and seventy-six well-characterized, unrelated, consecutive CD patients (male/female: 191/185, age at onset: 29.1 +/- 12.9 years, duration: 7.9 +/- 11.7 years) were investigated. Sera were assayed for anti-Omp, anti-Saccharomyces cerevisiae antibodies (ASCAs) immunoglobulin (Ig) A and IgG, and antibodies against a mannan epitope of S. cerevisiae (gASCA), laminaribioside (ALCA), chitobioside (ACCA), and mannobioside (AMCA). NOD1/CARD4, DLG5 and DEFB1 variants were tested by polymerase chain reaction-restriction fragment length polymorphism, and DEFB1 was genotyped in a subgroup of 160 patients. Detailed clinical phenotypes were determined by reviewing the patients' medical charts. The carriage of DEFB1 20A variant alleles less frequently led to antiglycan positivity compared with patients without (29.6% vs 46.2%, OR: 0.49, 95% CI: 0.25-0.97), regardless of disease location or behavior. Similar tendency was observed for DEFB1 44G (present: 21.6% vs absent: 10.2%, P = 0.06) and ALCA. A gene or serology dosage effect was not observed. However, no association was found between the DEFB1 G52A, DLG5 R30Q, and NOD1/CARD4 E266K variants and any of the serology markers. We found that variants in human beta-defensin 1 gene are inversely associated with antiglycan antibodies, further confirming an important role for innate immunity in the pathogenesis of CD.

Complement activating antibodies against the human 60 kDa heat shock protein as a new independent family risk factor of coronary heart disease.

BACKGROUND: Several groups have reported high levels of antibodies against 60 kDa heat shock proteins (hsp) associated with coronary heart disease. METHODS AND RESULTS: Complement activating (CA) antihsp60 autoantibodies were measured by the AtheroRisk kit (CardioPath Ltd, Alloa, UK), in parallel with IgG antibodies to human hsp60 and mycobacterial hsp65 by ELISA in 32 healthy children (18 boys, 14 girls, 11.8 +/- 4.0 years). At least one of the parents of these children had a history of myocardial infarction before 55 years of age (high family risk (HFR) group). The control group consisted of 63 healthy children (31 boys, 32 girls, 9.0 +/- 3.6 years) without known family history of coronary heart disease (CHD), hypertension, and diabetes mellitus. Concentrations of CA antihsp60 antibodies were significantly (P = 0.021) higher in the HFR group than in the control group. Also in the HFR group, significantly (P = 0.004) lower high-density lipoprotein cholesterol (HDL-C)-cholesterol (measured enzymatically) and significantly (P = 0.020) higher low-density lipoprotein cholesterol (LDL-C)-cholesterol levels (calculated by the Friedewald formula) were observed when compared with the controls. The difference in the CA antihsp60 antibody levels between the HFR and control groups remained significant even after adjustments for age, smoking, HDL-cholesterol, LDL-cholesterol levels, and white blood cell count. Children with high (in the highest quartile) CA antihsp60 antibody levels compared with those with normal levels of these antibodies also had adjusted odds ratios (OR) of 9.80 (2.15-44.58, P = 0.003), indicating high family risk. No significant difference in the IgG antihsp antibody levels was observed. CONCLUSIONS: These findings indicate that high levels of CA autoantibodies against hsp60 can be considered to be a novel family risk factor of CHD, independent of HDL- and LDL-cholesterol levels.

[The cumulative risk index in stroke prevention]. / Kumulatív kockázati index a stroke-prevencióban.

The screening and special management of high risk patient, is possible strategy to reduce the high morbidity and mortality of stroke. In the II. district of Budapest we examined high vascular risk patients cooperating with general practitioners. We let the severity of risk with arithmetic of the cumulative risk index. Significant relation was found between of high cumulative risk index and 50% or higher carotis stenosis, as well as the cumulative risk index and low Se HDL level. Increased blood pressure level has been found in among the treated hypertonic patient. Reduction of high blood pressure was documented in the 6 month control examination. Finally there was very low level of smoking in the high vascular risk patient group.

Atherosclerosis risk factors in children of high risk families.

UNLABELLED: The Objective of this study was to determine the frequency of care reactive atherosclerosis risk factors in children of parents with premature coronary heart disease observed before their 45 years of age for the promotion of the effectivity of the preventive work started in childhood and adolescent ages. METHODS: Height and weight was measured. Body mass index (BMI) was calculated. Fat analysis was performed in children with overweight. Blood pressure was measured and both 24 hour monitoring and fundoscopy were performed in cases with a blood pressure higher than 90 centile values. Fasting blood sugar (BS) level was measured. Oral glucose tolerance test was made in cases with a fasting BS level higher than 5 mmol/l. Serum total cholesterol (TC), HDL-cholesterol (HDLC) and total triglyceride (TT) levels were measured and LDL-cholesterol (LDLC) level was calculated. The plasma thiobarbituric acid reactive system (TBARS) was investigated. Statistical analyses were performed by chi2 and Student t-probes. Data of 1140 offsprings and 457 referents without any high atherosclerotic risk family history were analyzed. RESULTS: BMI of 87 offsprings was higher than the 90 centile value. The fat percent of the body of these children was higher than 40. The blood pressure of 311 children and adolescents was higher than the 90 centile value. Fasting BS level was higher than 5 mmol/l in 47 cases 17 of them showed a pathologic oral glucose tolerance test. High serum TC level was observed in 67 cases, high serum TT level was found in 8 cases. 245 offsprings had a low serum HDLC level. The plasma TBARS level was high in 241 cases. Data of referents differed significantly from those of offsprings. Their serum TC, LDLC levels and plasma TBARS level were lower, serum HDLC level was higher than that of children and adolescents with high risk atherosclerotic family history. CONCLUSION: Risk factors of atherosclerosis are detectable in children and adolescents of high risk families. The measurement of these factors may help the efficacy of the preventive work.

Potential markers of the atherosclerotic process in high-risk children.

Children whose parents had early coronary heart disease were investigated. In order to assess high-risk parameters serum total cholesterol (TC), total triglyceride (TT), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), lipid peroxide (LP), prostacyclin (PGI2), thromboxane (TX) levels, and the distribution of the complement 3 (C3), protein phenotypes were measured. Compared to a group of control children, the offspring of high-risk subjects had increased LDLC, LP, TC, and TX levels, a higher incidence of fast-slow heterozygotes, and decreased HDLC and PGI2 levels. The measurement of serum PGI2, TX levels and the distribution of C3 protein phenotypes may give further information about the true risk of atherosclerosis.

[Chronic recurrent abdominal pain and lactose malabsorption in childhood]. / Krónikus, visszatérö hasi fájdalom és laktóz malabszorpció gyermekkorban.

The Authors examined 515 children with abdominal pain in the outpatient clinics for a period of two years. The pain was frequently periumbilical or mid epigastric with a history of more than two months. Persistent lactose malabsorption was found in 252 children (48,9%), which justifies the use of Breath Hydrogen Test as a first diagnostic procedure for assessing recurrent abdominal pain. Putative pathogens were identified in the stool specimens of 21 patients. Oesophagitis was diagnosed in 18 children and duodenal ulcer in one. 91 patients (less than 6 years old) improved after successful treatment of the chronic upper respiratory inflammations. The authors did not find any causes in 18.1 per cent of the children examined and they think that the abdominal pain in these children may be psychogenic. The use of high-fiber diet is proposed for the later group.

Different cholesterol fractions, LCAT activity and lipid peroxides in the serum of children whose parents had early coronary heart disease.

Children whose parents had early coronary heart disease were investigated for lipid abnormalities. In order to assess high risk parameters and the efficacy of the applied care, serum total cholesterol (TC), total triglyceride (TT), total free cholesterol (FC) high density lipoprotein cholesterol (HDLC), high density lipoprotein free cholesterol (HDLFC), lipid peroxide (LP) levels, and lecithin: cholesterol acyl transferase (LCAT) activity were measured. Compared to a group of control children, the offspring of high risk subjects had increased TC, FC, and LP levels and decreased HDLC levels. After one year of preventative care all parameters normalized except the high FC level and elevated LCAT activity. The measurement of serum FC and LP levels seems to be a useful method for the determination of true high risk. The LCAT activity may show the efficacy of the dietary treatment.

Serum lipids, lipid peroxides and the care of children with high risk atherosclerotic family history.

Children of parents who had their first acute myocardial infarction (AMI) before the age of 45 years were investigated and divided into 2 groups. Group 1 consisted of 12 children: both their parents or one parent and grandparents suffered from AMI. Group 2 consisted of 55 children, each of whom had one parent with AMI. Serum levels of total cholesterol (TC) and lipid peroxide (LP) were higher in these children and HDL-cholesterol values were lower than those of 39 control children. The extent of serum TC and HDL-C differences was similar in both high risk groups but the serum LP level was significantly higher in group 1 than in group 2. The serum free cholesterol (FC) level was higher in group 1 than in controls. Children were treated according to a program giving advice on diet, physical exercise and health education for 1 year. At the end of this period the serum HDL-C level increased in both groups, while LP and TC levels decreased. The high serum FC level did not change.

Screening of children with high familial risk of arteriosclerosis.

Serum total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C) and total triglyceride levels were determined in children with high risk arteriosclerotic family history. Significantly higher TC and lower HDL-C levels were found in children whose parents' first arteriosclerotic sign had appeared before 40 years of age. There were no similar significant alterations observed in children whose parents' first arteriosclerotic symptom appeared after the forties. Screening therefore seems to be necessary in the offsprings of patients if the first sign of arteriosclerosis has been detected before 40 years of age.

Serum cholesterol and triglyceride levels in progeria as a model of ageing.

Hutchinson-Gilford progeria was observed in two brothers. Their parents, sister and other relatives did not show any signs of this illness. Serum total cholesterol and total triglyceride levels were normal in the whole family. The serum high density lipoprotein cholesterol (HDL-C) level of parents was low and that of boys was extremely low. The serum HDL-C level of the healthy sister and other relatives was normal. These findings in homozygous children and heterozygous parents may explain the development of the very early fatal arteriosclerosis described in this disease. The connection between the disorder of the lipid metabolism and progeria can serve as a useful model in the study of the role of lipid metabolism in normal ageing.