Tibor Hlavaty

The impact of major depressive disorder on the short- and long-term outcome of Crohn's disease treatment with infliximab

Background:  Major depressive disorder is the most common psychiatric diagnosis in Crohns disease. In other chronic diseases, evidence suggests that depression influences the course of the disease. Strong evidence of such a mediating role of major depressive disorder in Crohns disease has never been found.

Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn's disease

Background : Infliximab treatment is effective in 70–80% of patients with refractory luminal and fistulizing Crohns disease. The effect of infliximab is ascribed to induction of apoptosis.

Colorectal cancer screening in patients with ulcerative and Crohn's colitis with use of colonoscopy, chromoendoscopy and confocal endomicroscopy.

Background Patients with ulcerative colitis and Crohns colitis have increased risk of colorectal cancer. Current screening endoscopy protocols based on white light endoscopy (WLE) and random biopsies are laborious and of uncertain sensitivity. Novel endoscopic techniques include chromoendoscopy (CE) and confocal laser endomicroscopy (CLE). Aim The aim was to compare WLE and CE for the detection of intraepithelial neoplasia (IEN). Furthermore, we analysed the sensitivity and specificity of CE and CLE for the diagnosis of IEN. Methods The cohort consisted of 30 patients examined by WLE, CE with 0.4% indigocarmine, and by a CLE system Pentax EC-3870CIFK during one examination. Additional 15 patients were examined by conventional protocol only. Random biopsies and biopsies from all suspicious lesions were taken. We compared the number of IENs detected by WLE and CE and analysed the predictive values of CE and CLE for the histology diagnosis. Results There were 1584 random biopsies (35.2 per patient) taken. There were 78 targeted biopsies (1.7 per patient) taken in 24 of 45 patients examined by WLE and an additional 36 biopsies in 16 of 30 patients examined by CE (1.17 additional per patient). There were no IENs found on random biopsies versus six low-grade or high-grade IENs in four patients (two detected by WLE, four additional by CE) from targeted biopsies, P=0.02. A total of 100 suspicious lesions were detected and analysed by CE and histology. CLE could not examine 32 of 100 lesions (two of 30 flat vs. 30 of 70 pedunculated lesions, P=0.0002, odds ratio 10.5). The sensitivity of CE/CLE for low-grade or high-grade IEN was 100/100%, the specificity 96.8/98.4%, positive predictive value was 62.5/66.7% and negative predictive value was 100/100%. Conclusion Targeted biopsies are superior to random biopsies in the screening of IEN in patients with inflammatory bowel disease. CE increases the diagnostic yield of WLE. In our study CLE did not provide additional clinical benefits.

Predictive model for the outcome of infliximab therapy in Crohn's disease based on apoptotic pharmacogenetic index and clinical predictors

Background: Infliximab (IFX) is an effective therapy for refractory luminal and fistulizing Crohns disease (CD). Predictors of response could improve selection of patients with a higher probability of favorable outcomes and could improve the safety profile. We aimed to develop a predictive model for the response to infliximab in CD. Methods: Genetic and clinical data collected in a previous pharmacogenetic study of apoptosis genes were analyzed using SAS Enterprise miner modeling software and SPSS 12.0. We proposed a novel apoptotic pharmacogenetic index (API) with a score ranging from 0 (low apoptotic response) to 3 (high apoptotic response) and subsequently developed a decision tree model. Results: Response and remission rates significantly increased with API score (P = 0.005 in the group of patients with luminal CD, P = 0.02 in the group of patients with fistulizing CD). Patients with an API ≤ 1 (n = 59) had the lowest response and remission rates in both the luminal CD (50% and 39.5%, respectively) and fistulizing CD (61.9% and 28.6%, respectively) groups, compared to those with an API of 2 (n = 158), whose response and remission rates were 73.8% and 56.1%, respectively, in the luminal CD group and 85.7% and 44.9%, respectively, in the fistulizing CD group; and those with an API of 3 (n = 10), whose response and remission rates were 100% and 85.7%, respectively, in the luminal CD group and 100% and 0% in the fistulizing CD group. Response in patients with an API ≤ 1 was significantly influenced by concurrent azathioprine therapy in the luminal CD (21.4% versus 78.9%, P < 0.001) and in the fistulizing CD (46.6% versus 100%, P = 0.04) groups. In patients with an API of 2, we saw an interaction with age older than 40 years and location of disease (response 52.2% versus 83.9%, P = 0.008) in the luminal CD group and with baseline CRP greater than 5 mg/L (73.9% versus 93.9%, P = 0.04) in the fistulizing CD group. Conclusions: From our newly proposed apoptotic pharmacogenetic index and clinical predictors, we developed a model for prediction of low, medium, and high responses to the first infusion of IFX in patients with CD. Further studies are needed to confirm the hypothesis generated by our study.

Evaluation of short-term responsiveness and cutoff values of inflammatory bowel disease questionnaire in Crohn's disease.

Background: The inflammatory bowel disease questionnaire (IBDQ) is a frequently used outcome parameter in clinical trials. Whereas the validity and reproducibility of the IBDQ have been extensively studied, there are limited data on its short‐term responsiveness and cutoff values for remission and partial clinical response. Methods: The IBDQ score and its bowel (BD), systemic (SysD), emotional (ED), and social (SocD) dimensions were tested for responsiveness in a cohort of 224 patients with Crohns disease (CD) treated with infliximab for refractory luminal disease. Changes in the IBDQ score and its dimensions 4 weeks after therapy were analyzed and correlated with changes in the Crohns Disease Activity Index (CDAI). The responsiveness ratios of the IBDQ and its dimensions were analyzed. Using regression line with &Dgr;CDAI, the cutoff values for the IBDQ remission and response were calculated. Results: Overall, there was a good correlation between the CDAI and IBDQ at week 0 (correlation coefficient, 0.69; P < .001) and week 4 (−0.76; P < .001) and change after 4 weeks (0.74; P < .001). The correlation coefficients for &Dgr;CDAI and changes in BD, SysD, ED, and SocD were 0.753, 0.552, 0.620, and 0.631, respectively; all P < 0.001. The responsiveness ratios for &Dgr;IBDQ, BD, SysD, ED, and SocD were 2.6, 2.1, 1.9, 1.7, and 1.9, respectively. Regression line for the IBDQ (r = −0.76, P < .001) resulted in a cutoff value for remission of 168 points and for &Dgr;IBDQ resulted in a cutoff value of 22 and 27 points for clinical improvement based on &Dgr;CDAI ≥−70 and ≥−100 points. Conclusions: The IBDQ is a responsive instrument for reflecting quick change in the quality of life of patients with CD. Cutoff values for the IBDQ remission and partial response were 168 and ≥27 points.

Biological therapy in inflammatory bowel diseases: access in Central and Eastern Europe.

Biological drugs opened up new horizons in the management of inflammatory bowel diseases (IBD). This study focuses on access to biological therapy in IBD patients across 9 selected Central and Eastern European (CEE) countries, namely Bulgaria, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania and Slovakia. Literature data on the epidemiology and disease burden of IBD in CEE countries was systematically reviewed. Moreover, we provide an estimation on prevalence of IBD as well as biological treatment rates. In all countries with the exception of Romania, lower biological treatment rates were observed in ulcerative colitis (UC) compared to Crohns disease despite the higher prevalence of UC. Great heterogeneity (up to 96-fold) was found in access to biologicals across the CEE countries. Poland, Bulgaria, Romania and the Baltic States are lagging behind Hungary, Slovakia and the Czech Republic in their access to biologicals. Variations of reimbursement policy may be one of the factors explaining the differences to a certain extent in Bulgaria, Latvia, Lithuania, and Poland, but association with other possible determinants (differences in prevalence and incidence, price of biologicals, total expenditure on health, geographical access, and cost-effectiveness results) was not proven. We assume, nevertheless, that health deterioration linked to IBD might be valued differently against other systemic inflammatory conditions in distinct countries and which may contribute to the immense diversity in the utilization of biological drugs for IBD. In conclusion, access to biologicals varies widely among CEE countries and this difference cannot be explained by epidemiological factors, drug prices or total health expenditure. Changes in reimbursement policy could contribute to better access to biologicals in some countries.

Biosimilars in the therapy of inflammatory bowel diseases.

A biosimilar is a copy of an approved biological medicine whose patent protections have expired. Biosimilars of antibodies to tumour necrosis factor &agr; (TNF&agr;) are becoming important in the treatment of inflammatory bowel diseases (IBD). The first one introduced commercially is an infliximab biosimilar. The aim of this study was to provide an overview of anti-TNF&agr; biosimilars. The literature on biosimilars of monoclonal anti-TNF&agr; antibodies was reviewed, including their manufacture and approval pathways, concerns about efficacy, safety, immunogenicity, extrapolation, switching and labelling. Previous experience with biosimilars of epoetin and other growth factors was also reviewed. The infliximab biosimilar CT-P13 was the first biosimilar monoclonal antibody registered for the treatment of IBD. The major advantage of biosimilars is the reduced cost of therapy. Concerns have arisen, however, about the efficacy and safety of CT-P13 in IBD, the extrapolation of results from rheumatologic trials to IBD and the free interchangeability of CT-P13 with infliximab. Experience with simple peptide biosimilars, such as epoetins and growth factors, has generally been positive, with these biosimilars having similar efficacy and safety as the original products, although immunogenicity remains a major concern. Upcoming postregistration studies will address concerns on biosimilars in IBD, including their efficacy, safety, immunogenicity, switching and interchangeability. Biosimilars active against the same epitopes, but with improved pharmacokinetic properties that enhance their efficacy and/or safety, may be the next stage in the development of biosimilars. Anti-TNF&agr; biosimilars represent promising new treatment options for patients with IBD. However, data on their efficacy and safety in IBD are needed.

Cholelithiasis and markers of nonalcoholic fatty liver disease in patients with metabolic risk factors

Abstract Cholelithiasis and nonalcoholic fatty liver disease (NAFLD) share the same risk factors. The aim of our study was to explore the relationship between these two conditions and to indentify independent predictors of both diseases in a cohort of patients with metabolic risk factors. Consecutive patients with metabolic risk factors referred to the outpatient clinic during a one-year period were included. Cholelithiasis was defined by the presence of gallstones on abdominal ultrasound examination at inclusion or previously performed cholecystectomy. NAFLD was defined by the presence of at least one surrogate marker such as elevated alanine aminotransferase and/or gamma-glutamyl transpeptidase and/or ultrasound signs of fatty liver. Other common liver diseases were thoroughly excluded. The prevalence of cholelithiasis among patients with and without NAFLD was determined and clinical and laboratory parameters were identified as predictors of NAFLD by multivariate logistic regression. In total, 482 consecutive patients were included: mean age 61 years; 61% were women; 52% of patients had more than 2 metabolic risk factors (obesity, type 2 diabetes, hypertension, hypertriglyceridemia, or low HDL cholesterol). NAFLD and cholelithiasis were present in 41% and 34% of all patients, respectively. Significantly higher prevalence of cholelithiasis was found among patients with NAFLD compared with patients without NAFLD (47% vs. 26%, respectively; p < 0.0001). In multivariate logistic regression model, type 2 diabetes (odds ratio (OR) = 1.99), BMI above 25 kg/m2 (OR = 1.78), and cholelithiasis (OR = 1.77) were identified as independent predictors of NAFLD. Fifty six percent of patients with cholelithiasis had NAFLD compared with 33% of patients without cholelithiasis (p < 0.0001). Multivariate logistic regression identified age above 50 years (OR = 3.46), NAFLD (OR = 1.92), triglycerides above 1.7 mmol/l (OR = 1.91), BMI above 25 kg/m2 (OR = 1.84), and total cholesterol concentration (OR = 0.711) as independent predictors of cholelithiasis. In conclusion, patients with metabolic risk factors and cholelithiasis suffer significantly more often from NAFLD compared with the reference group. Cholelithiasis represents an independent risk factor of NAFLD in addition to metabolic risk factors and could be regarded as an additional risk factor of liver damage in patients with NAFLD. Furthermore, NAFLD is an independent risk factor for cholelithiasis and might represent a pathogenetic link between the metabolic syndrome and cholelithiasis.

Higher vitamin D serum concentration increases health related quality of life in patients with inflammatory bowel diseases.

AIM To investigate the effect of vitamin D (VD) concentrations and VD supplementation on health related quality of life in inflammatory bowel disease (IBD) patients. METHODS A cohort of 220 IBD patients including 141 Crohns disease (CD) and 79 ulcerative colitis (UC) patients was followed-up at a tertiary IBD center. A subgroup of the cohort (n = 26) took VD supplements for > 3 mo. Health related quality of life was assessed using the short IBD questionnaire (sIBDQ). VD serum concentration and sIBDQ score were assessed between August and October 2012 (summer/autumn period) and between February and April 2013 (winter/spring period). The mean VD serum concentration and its correlation with disease activity of CD were determined for each season separately. In a subgroup of patients, the effects of VD supplementation on winter VD serum concentration, change in VD serum concentration from summer to winter, and winter sIBDQ score were analyzed. RESULTS During the summer/autumn and the winter/spring period, 28% and 42% of IBD patients were VD-deficient (< 20 ng/mL), respectively. In the winter/spring period, there was a significant correlation between sIBDQ score and VD serum concentration in UC patients (r = 0.35, P = 0.02), with a trend towards significance in CD patients (r = 0.17, P = 0.06). In the winter/spring period, VD-insufficient patients (< 30 ng/mL) had a significantly lower mean sIBDQ score than VD-sufficient patients; this was true of both UC (48.3 ± 2.3 vs 56.7 ± 3.4, P = 0.04) and CD (55.7 ± 1.25 vs 60.8 ± 2.14, P = 0.04) patients. In all analyzed scenarios (UC/CD, the summer/autumn period and the winter/spring period), health related quality of life was the highest in patients with VD serum concentrations of 50-59 ng/mL. Supplementation with a median of 800 IU/d VD day did not influence VD serum concentration or the sIBDQ score. CONCLUSION VD serum concentration correlated with health related quality of life in UC and CD patients during the winter/spring period.

The prevalence and risk factors for osteoporosis in patients with inflammatory bowel disease.

AIM Osteoporosis is a known chronic complication of inflammatory bowel diseases (IBD). The aim of our study was to describe the prevalence of reduced bone mineral density (BMD) in IBD patients and to identify crucial risk factors for osteoporosis. METHODS The cohort consisted of 76 IBD patients, 40 with Crohns disease (CD) and 36 with ulcerative colitis (UC). Clinical characteristics of every patient were recorded, i.e. age, sex, duration of the disease, clinical behavior, location of disease according to Montreal classification, surgeries, steroid medication, sIBDQ, and smoking habits. We examined the serum 25-hydroxyl vitamin D3 (25-OHD3) in each patient. The BMD was determined by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and femoral neck. RESULTS Osteoporosis was documented in 10 IBD patients (13.2 %), while osteopenia in 35 of them (46.1 %). Patients with CD have significantly lower femoral Z score than patients with UC. Femoral Z score was strongly associated with disease duration, and in CD patients suffering from stricturing form, with ileic or ileocolic location and history of proctocolectomy or total colectomy. Patients with osteoporosis had a significantly lower level of 25-OHD3 than patients with normal BMD. CONCLUSION Patients with long disease duration and those suffering from stricturing form of CD with ileic/ileocolic location and history of proctocolectomy/total colectomy are at higher risk of developing osteoporosis than other IBD patients. The high proportion of osteopenia/osteoporosis in our study underlines the importance of BMD measurement in all IBD patients as a base for initiating the appropriate treatment (Tab. 1, Fig. 3, Ref. 63).