Tamas Szamosi

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

Aliment Pharmacol Ther 2011; 34: 911–922

Efficacy and Safety of the Biosimilar Infliximab CT-P13 Treatment in Inflammatory Bowel Diseases: A Prospective, Multicentre, Nationwide Cohort

BACKGROUND AND AIMS Biosimilar infliximab CT-P13 is approved for all indications of the originator product in Europe. Prospective data on its efficacy, safety, and immunogenicity in inflammatory bowel diseases are lacking. METHODS A prospective, nationwide, multicentre, observational cohort was designed to examine the efficacy, safety, and immunogenicity of CT-P13 infliximab biosimilar in the induction treatment of Crohns disease [CD] and ulcerative colitis [UC]. Demographic data were collected and a harmonised monitoring strategy was applied. Early clinical remission, response, and early biochemical response were evaluated at Week 14, steroid-free clinical remission was evaluated at Week 30. Therapeutic drug level was monitored using a conventional enzyme-linked immunosorbent assay. RESULTS In all, 210 consecutive inflammatory bowel disease [126 CD and 84 UC] patients were included in the present cohort. At Week 14, 81.4% of CD and 77.6% of UC patients showed clinical response and 53.6% of CD and 58.6% of UC patients were in clinical remission. Clinical remission rates at Week 14 were significantly higher in CD and UC patients who were infliximab naïve, compared with those with previous exposure to the originator compound [p < 0.05]. Until Week 30, adverse events were experienced in 17.1% of all patients. Infusion reactions and infectious adverse events occurred in 6.6% and 5.7% of all patients, respectively. CONCLUSIONS This prospective multicentre cohort shows that CT-P13 is safe and effective in the induction of clinical remission and response in both CD and UC. Patients with previous infliximab exposure exhibited decreased response rates and were more likely to develop allergic reactions.

Association of beta-defensin 1 single nucleotide polymorphisms with Crohn's disease

Objective. It has been suggested that deficient defensin expression is associated with the chronic inflammation of Crohns disease. The regional localization of Crohns disease, ileal or colonic disease can be linked to different defensin profiles. As constitutive β-defensin 1 has a colonic expression, we considered it of interest to investigate single nucleotide polymorphisms (SNPs) of the β-defensin 1 gene (DEFB1) in Crohns disease. Material and methods. Three SNPs of the DEFB1 gene, DEFB1 G-20A (rs11362), DEFB1 C-44G (rs1800972) and DEFB1 G-52A (rs1799946), were genotyped either by Custom TaqMan® SNP genotyping assays or by restriction fragment length polymorphisms (RFLP) in 190 patients with Crohns disease and 95 Hungarian controls. Results. It was found that the G-20A and C-44G SNPs had a strong association with the colonic and ileocolonic localizations of the disease, respectively, but no association was detected for the ileal localization. A significantly higher frequency of the GA genotype of G-20A was observed among patients with colonic localization (60%) as compared with healthy controls (39%), with an odds ratio (OR) of 2.39. The GG genotype of C-44G SNP, which is regarded as a protective genotype, was much less frequent (4%) among patients than among controls (12%), OR 3.367. Conclusions. These results indicate that genetic variations in the DEFB1 gene encoding constitutive human β-defensin 1 may be associated with the risk for Crohns disease and may determine disease phenotype, e.g. colonic localization.

Early azathioprine/biological therapy is associated with decreased risk for first surgery and delays time to surgery but not reoperation in both smokers and nonsmokers with Crohn's disease, while smoking decreases the risk of colectomy in ulcerative colitis.

Background/aims Smoking may alter the natural course of Crohns disease (CD). Smokers are more likely to develop complications, relapses and have a greater risk for surgery. In contrast, in ulcerative colitis (UC), smoking might improve the disease course. Our aim was to assess the combined effect of disease phenotype, smoking, and immunomodulator [azathioprine (AZA), AZA/biological] treatment on the risk of intestinal resection/reoperation in CD and colectomy in UC. Patients/methods Six hundred and eighty-one inflammatory bowel disease patients were analyzed (CD: 340, male/female: 155/185, duration: 9.4±7.5 years; UC: 341, male/female: 174/164, duration: 11.5±9.7 years). Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. Medical records were retrospectively analyzed. Results Smoking was present in 45.5% in CD and 15.8% in UC. CD patients who underwent at least one bowel resection comprised 46.5%. In an univariate analysis, disease location, behavior, AZA, or AZA/biological use before surgery [odds ratio (OR): 0.26 and 0.22, P<0.001] and smoking (OR: 1.61, P = 0.03) were associated with risk for first surgery. Smoking, AZA, or AZA/biological (P<0.001) use before first surgery and disease behavior were independently associated with risk for surgery in a proportional Cox-regression analysis. Perianal disease (OR: 3.2, P = 0.001) and frequent relapses (OR: 4.8, P<0.001) but not smoking, AZA, or AZA/biological use after first surgery were predictive for reoperation. In UC, the rate of colectomy was 5.6%. Disease location (P = 0.001) and smoking status (P = 0.02) were independently associated with risk for colectomy in a proportional Cox-regression analysis. Conclusion Our data suggest that early AZA/biological therapy reduces the risk for first operation but not reoperation in CD, in both smokers and nonsmokers. In contrast, smoking was associated with a decreased need for colectomy in UC.

Pancreatic autoantibodies are associated with reactivity to microbial antibodies, penetrating disease behavior, perianal disease, and extraintestinal manifestations, but not with NOD2/CARD15 or TLR4 genotype in a hungarian IBD cohort†

Background: Pancreatic autoantibodies (PAB) and goblet cell autoantibodies (GAB) are specific for Crohns disease (CD) and ulcerative colitis (UC), but the sensitivity alone is low. Conventional antibodies and carbohydrates (glycans) are associated with disease phenotype and may be of diagnostic importance in inflammatory bowel disease (IBD). Our aim was to determine the accuracy of PAB and GAB autoantibodies as well as to study relevant phenotype–serotype associations. Methods: A Hungarian study cohort of 1092 subjects, including 689 well‐characterized, unrelated IBD patients (CD: 579, m/f ratio: 274/305, duration: 7.9 ± 11.2 years; UC: 110, m/f ratio: 53/57, duration: 8.9 ± 9.8 years), 139 celiac patients, 100 healthy, and 64 non‐IBD gastrointestinal controls were investigated. Sera were assayed for PAB‐GAB IgA/IgG, anti‐Omp, anti‐Saccharomyces cerevisiae antibodies (ASCA), and anti‐glycans. TLR4 and NOD2/CARD15 was tested by polymerase chain reaction / restriction fragment length polymorphism (PCR‐RFLP). Detailed clinical phenotypes were determined. Results: The prevalence of PAB was significantly more frequent in CD (41.1%) versus UC (22.7%), celiac (22.3%), and controls (8% and 4.6%, P < 0.01 for each), while GAB detection was poor in all groups except UC (15.4%). In CD the combination of PAB and/or anti‐glycans/ASCA increased the sensitivity to 72% and 59%, respectively, for isolated colonic disease. PAB was associated to gylcans (odds ratio [OR] 1.74,P = 0.002), ASCA IgG/IgA (OR 1.75, P = 0.002), Omp (OR 1.86, P = 0.001) as well as perforating, perianal disease, arthritis, ocular, and cutaneous manifestations (P = 0.002–0.032). In contrast, PAB and GAB antibodies were not associated with NOD2/CARD15 or TLR4, response to medical therapy, or need for surgery. No associations were found in UC. Conclusions: PAB autoantibodies in combination with ASCA or anti‐glycan antibodies increase the sensitivity for detecting CD, especially isolated colonic CD. Antibody response to PAB was associated with complicated disease phenotype and extraintestinal manifestations in this Eastern European IBD cohort.

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.

Colesevelam Hydrochloride: Efficacy and Safety in Pediatric Subjects with Heterozygous Familial Hypercholesterolemia

OBJECTIVE Evaluate the efficacy and safety of colesevelam hydrochloride in children with heterozygous familial hypercholesterolemia (heFH). STUDY DESIGN This was a randomized, double-blind, 41-site study in 194 children aged 10 to 17 years (inclusive) with heFH (statin-naïve or on a stable statin regimen). After a 4-week stabilization period (period I), subjects were randomized 1:1:1 to placebo, colesevelam 1.875 g/d, or colesevelam 3.75 g/d for 8 weeks (period II). All then received open-label colesevelam 3.75 g/d for 18 weeks (period III), with follow-up 2 weeks later. The primary endpoint was percent change in low-density lipoprotein (LDL)-cholesterol from baseline to week 8. Secondary endpoints included percent change in other lipoprotein variables, including non-high-density lipoprotein (non-HDL)-cholesterol. Adverse events were also evaluated. RESULTS At week 8, a significant difference from baseline in LDL-cholesterol was reported with colesevelam 1.875 g/d (-6.3%; P = .031) and colesevelam 3.75 g/d (-12.5%; P < .001) compared with placebo. Significant treatment effects were also reported for total cholesterol (-7.4%), non-HDL-cholesterol (-10.9%), HDL-cholesterol (+6.1%), apolipoprotein A-I (+6.9%), and apolipoprotein B (-8.3%) and a nonsignificant effect for triglycerides (+5.1%) with colesevelam 3.75 g/d compared with placebo at week 8. These treatment effects were maintained during period III. CONCLUSIONS Colesevelam significantly lowered LDL-cholesterol levels in children with heFH.

Association of adherence to therapy and complementary and alternative medicine use with demographic factors and disease phenotype in patients with inflammatory bowel disease.

BACKGROUND AND AIMS Previous studies have suggested an increasing use of complementary and alternative medicine (CAM) in patients with inflammatory bowel disease (IBD). Furthermore, a significant number of IBD patients fail to comply with treatment. The aim of our study was to evaluate the prevalence of non-adherence and the use of CAM in Hungarian patients with IBD. METHODS A total of 655 consecutive IBD patients (CD: 344, age: 38.2 [SD 12.9]years; UC: 311, age: 44.9 [15.3]years) were interviewed during the specialist visit by self-administered questionnaire including demographic and disease-related data as well as items analyzing the extent of non-adherence and CAM use. Patients taking more than 80% of each prescribed medication were classified as adherent. RESULTS The overall rate of self-reported non-adherence (CD: 20.9%, UC: 20.6%) and CAM (CD: 31.7%, UC: 30.9%) use did not differ between Crohns disease (CD) and ulcerative colitis (UC). The most common causes of non-adherence were: forgetfulness (47.8%), too many/unnecessary pills (39.7%), being afraid of side effects (27.9%) and too frequent dosing. Most common forms of CAM were herbal tea (47.3%), homeopathy (14.6%), special diet (12.2%), and acupuncture (5.8%). In CD, disease duration, date of last follow-up visit, educational level and previous surgeries were predicting factors for non-adherence. Alternative medicine use was associated in both diseases with younger age, higher educational level, and immunosuppressant use. In addition, CAM use in UC was more common in females and in patients with supportive psychiatric/psychological therapy. CONCLUSIONS Non-adherence and CAM use is common in patients with IBD. Special attention should be paid to explore the identified predictive factors during follow-up visits to improve adherence to therapy and improving patient-doctor relationship.

Efficacy and safety of infliximab induction therapy in Crohn's Disease in Central Europe - A Hungarian nationwide observational study

BackgroundInfliximab (IFX) has proven to be an effective addition to the therapeutic arsenal for refractory, fistulizing, and steroid dependent Crohns disease (CD), with efficacy in the induction and maintenance of clinical remission of CD. Our objective in this study is to report the nationwide, multicenter experience with IFX induction therapy for CD in Hungary.MethodsDuring a 6-year-period, beginning in 2000, a total of 363 CD patients were treated with IFX as induction therapy (5 mg/kg IFX infusions given at week 0, 2 and 6) at eleven centers in Hungary in this observational study. Data analysis included patient demographics, important disease parameters and the outcome of IFX induction therapy.ResultsThree hundred and sixty three patients (183 women and 180 men) were treated with IFX since 2000. Mean age was 33.5 ± 11.2 years and the mean duration of disease was 6.7 ± 6.1 years. The population included 114 patients (31.4%) with therapy-refractory CD, 195 patients (53.7%) with fistulas, 16 patients (4.4%) with both therapy-refractory CD and fistulas, and 26 patients (7.2%) with steroid dependent CD. Overall response rate was 86.2% (313/363). A higher response rate was observed in patients with shorter disease duration (p = 0.05, OR:0.54, 95%CI:0.29-0.99) and concomitant immunosuppressant therapy (p = 0.05, OR: 2.03, 95%CI:0.165-0.596). Concomitant steroid treatment did not enhance the efficacy of IFX induction therapy. Adverse events included 34 allergic reactions (9.4%), 17 delayed type hypersensitivity (4.7%), 16 infections (4.4%), and 3 malignancies (0.8%).ConclusionIFX was safe and effective treatment in this cohort of Hungarian CD patients. Based on our experience co-administration of immunosuppressant therapy is suggested in patients receiving IFX induction therapy. However, concomitant steroid treatment did not enhanced the efficacy of IFX induction therapy.

Effect of Diet and Physical Exercise Treatment on Insulin Resistance Syndrome of Schoolchildren

Background: Insulin resistance syndrome (IRS) of schoolchildren may contribute to cardiovascular diseases (CVD) of young adults. The investigation of different steps, baseline screening parameters and treatment of IRS may help the prevention. Methods: Schoolchildren (53 boys and 61 girls age 5–17 years) because of adverse family history of CVD, hypertension, and obesity were investigated. Patients were divided into 3 groups according to baseline plasma glucose level (PGL) 120 and 180 min. after glucose consumption (GC): (1) PGL ≤ 5.5 mmol/L 180 min. after GC, (2) PGL ≥ 5.5 mmol/L 180 min. but ≤ 7.8 mmol/L 120 min. after GC (3) PGL ≥ 7.8 mmol/L 120 min. after GC. Body mass index (BMI), blood pressure (BP) and parameters of glucose and lipid metabolism were measured at baseline and after two years lifestyle modification. Results: No significant diference was found in the prevalence of cardiovascular risk factors (CRF) between groups 2 and 3. Fasting PGL > 5.5 mmol/L was found in 1, 2, and 6 cases; HOMA index > 4.4 in 7 (24%), 21 (37%), and 9 (35%) subjects; OGIS index < 400 in 3(10%), 29(51%) and 11 (42%) schoolchildren of groups 1, 2, 3, respectively. Lifestyle modification significantly improved BMI, systolic BP, serum triglyceride and HDL-cholesterol levels and insulin sensitivity. Conclusions: PGL measured 180 minutes after GC may define an important subgroup of pre-diabetic children. The similar prevalance of CRF in both praediabetic groups underlines the importance of this subgroup. Lifestyle modification for two years improves CRF in this population.