Michael D. Mandel

Is Current smoking still an important environmental factor in inflammatory bowel diseases? Results from a population-based incident cohort

Background:Previous studies suggest that smoking is an important environmental factor in inflammatory bowel diseases (IBDs), with dichotomous effects in ulcerative colitis (UC) and Crohns disease (CD). The aim of this study was to analyze the relationship between smoking and IBD risk in a population-based database from Veszprem Province, which included incident cases diagnosed between January 1, 1977, and December 31, 2008. Methods:Data from 1420 incident patients were analyzed (UC: 914, age at diagnosis: 38.9 years; CD: 506, age at diagnosis: 31.5 years). Both inpatient and outpatient records were collected and comprehensively reviewed. Overall, smoking frequency in the adult general population was 36.1%. Results:Of patients with CD, 47.2% were current smokers at diagnosis. Smoking was more frequent in male patients (P = 0.002) and was associated with an increased risk of CD (odds ratio, 1.96; 95% confidence interval, 1.63–2.37; P < 0.001). In contrast, current smoking was protective against UC (odds ratio, 0.33; 95% confidence interval, 0.27–0.41). The effect of smoking was linked to gender (in CD, more deleterious in male patients) and age at diagnosis and was most prominent in young adults, with a difference already being seen in 18- to 19-year-olds. In CD, a change in disease behavior (P = 0.02), location from ileal or colonic to ileocolonic (P = 0.003), arthritis/arthropathy (P = 0.002), need for steroids (P = 0.06), or AZA (P = 0.038) was more common in current smokers. Smoking in UC was associated with more extensive disease (P = 0.01) and a tendency for decreased need for colectomy (P = 0.06). Conclusions:Current smoking was associated with the risk of IBD. This effect was linked to gender and age at diagnosis and was most prominent in young adults. No association was observed in pediatric or elderly patients. The deleterious and protective effects of smoking on the course in CD and UC were partially confirmed.

Evolution of disease phenotype in adult and pediatric onset Crohn’s disease in a population-based cohort

AIM To investigate the evolution of disease phenotype in adult and pediatric onset Crohns disease (CD) populations, diagnosed between 1977 and 2008. METHODS Data of 506 incident CD patients were analyzed (age at diagnosis: 28.5 years, interquartile range: 22-38 years). Both in- and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database, which included incident patients diagnosed between January 1, 1977 and December 31, 2008 in adult and pediatric onset CD populations. Disease phenotype according to the Montreal classification and long-term disease course was analysed according to the age at onset in time-dependent univariate and multivariate analysis. RESULTS Among this population-based cohort, seventy-four (12.8%) pediatric-onset CD patients were identified (diagnosed ≤ 17 years of age). There was no significant difference in the distribution of disease behavior between pediatric (B1: 62%, B2: 15%, B3: 23%) and adult-onset CD patients (B1: 56%, B2: 21%, B3: 23%) at diagnosis, or during follow-up. Overall, the probability of developing complicated disease behaviour was 49.7% and 61.3% in the pediatric and 55.1% and 62.4% in the adult onset patients after 5- and 10-years of follow-up. Similarly, time to change in disease behaviour from non stricturing, non penetrating (B1) to complicated, stricturing or penetrating (B2/B3) disease was not significantly different between pediatric and adult onset CD in a Kaplan-Meier analysis. Calendar year of diagnosis (P = 0.04), ileal location (P < 0.001), perianal disease (P < 0.001), smoking (P = 0.038) and need for steroids (P < 0.001) were associated with presence of, or progression to, complicated disease behavior at diagnosis and during follow-up. A change in disease location was observed in 8.9% of patients and it was associated with smoking status (P = 0.01), but not with age at diagnosis. CONCLUSION Long-term evolution of disease behavior was not different in pediatric- and adult-onset CD patients in this population-based cohort but was associated to location, perianal disease and smoking status.

Have Biologics Changed the Natural History of Crohn's Disease?

Crohns disease (CD) is a progressive condition, with most patients developing a penetrating or stricturing phenotype over time. The introduction of anti-tumor necrosis factor (TNF) therapies over the past 10-15 years, which was supported by accumulating evidence both from trials and clinical practice, has led to a significant change in patient management, monitoring, and treatment algorithms. Anti-TNF therapy was demonstrated to be effective for both luminal and fistulizing disease. Regular therapy with both infliximab and adalimumab was shown to increase the likelihood of clinical remission and mucosal healing, as well as to reduce the need for surgery and hospitalization in both clinical trials and clinical practice, especially in patients with pediatric-onset CD, shorter disease duration, and when used in combination with immunosuppressives. This has led to new treatment goals and to the use of early aggressive medical therapy in a selected group of patients with a worse prognosis. Exploratory clinical trials are underway to determine if further optimization of therapies and treatment beyond clinical remission leads to superior disease outcomes. However, more long-term clinical data are needed to assess whether an early, aggressive therapeutic strategy employing anti-TNF, alone or in combination with biologicals, can further improve long-term disease outcomes in both pediatric patients and young adults.

The risk of lymphoma and immunomodulators in patients with inflammatory bowel diseases: Results from a population-based cohort in Eastern Europe

BACKGROUND AND AIMS Prior studies suggest a small but significantly increased risk of lymphoma in adults with inflammatory bowel disease (IBD), especially in patients treated with thiopurines. No data was available from Eastern Europe. The aim of this study was to analyze the incidence of lymphomas as related to drug exposure, in a population-based Veszprem province database, which included incident cases diagnosed between January 1, 1977 and December 31, 2008. METHODS Data from 1420 incident patients were analyzed (UC: 914, age at diagnosis: 36.5 years; CD: 506, age at diagnosis: 28.5.5 years). Both in- and outpatient records were collected and comprehensively reviewed. The rate of lymphoma was calculated as patient-years of exposure per medication class, of medications utilized in IBD. RESULTS Of the 1420 patients, we identified three patients who developed lymphoma (one CLL, two low-grade B-cell NHL including one rectal case), during 19,293 patient-years of follow-up (median follow-up: 13 years). All three patients were male. None had received azathioprine or biologicals. The absolute incidence rate of lymphoma was 1.55 per 10,000 patient-years, with 3 cases observed vs. 2.18 expected, with a standardized incidence ratio (SIR) of 1.37 (95% confidence interval [CI]: 0.44-4.26). No cases have been exposed to either azathioprine or biologicals. CONCLUSIONS The overall risk of lymphoma in IBD was not increased; only three cases were seen in this population-based incident cohort over a 30-year period. An association with thiopurine exposure was not found.

Incidence rates and disease course of paediatric inflammatory bowel diseases in Western Hungary between 1977 and 2011.

BACKGROUND Limited data are available on paediatric inflammatory bowel diseases in Eastern Europe. Our aim was to analyse disease characteristics in the population-based Veszprem province database between 1977 and 2011. METHODS 187 (10.5%, ulcerative colitis/Crohns disease/undetermined colitis: 88/95/4) out of 1565 incident patients were diagnosed with a paediatric onset in this population-based prospective inception cohort. RESULTS The incidence of Crohns disease and ulcerative colitis increased from 0 and 0.7 in 1977-1981 to 7.2 and 5.2 in 2007-2011 per 100,000 person years. Ileocolonic location (45%) and inflammatory disease behaviour (61%) were most frequent in Crohns disease, while azathioprine use was frequent (66%) and surgical resection rates were high (33% at 5 years) in cases with paediatric onset. In ulcerative colitis, 34% of patients were diagnosed with extensive disease, with high rates of disease extension (26% and 41% at 5 and 10 years), fulminant episodes (19.3%) and systemic steroid use (52.3%). The cumulative rate of colectomy was low (6.9%). CONCLUSIONS The incidence of paediatric inflammatory bowel diseases has rapidly increased in the last three decades in Western Hungary. Ileocolonic disease and a need for azathioprine were characteristic in paediatric Crohns disease, while paediatric onset ulcerative colitis was characterised by extensive disease and disease extension, while the need for colectomy was low.

Inflammatory bowel disease course in Crohn’s disease:Is the natural history changing?

Crohns disease (CD) is a multifactorial potentially debilitating disease. It has a variable disease course, but the majority of patients eventually develop penetrating or stricturing complications leading to repeated surgeries and disability. Studies on the natural history of CD provide invaluable data on its course and clinical predictors, and may help to identify patient subsets based on clinical phenotype. Most data are available from referral centers, however these outcomes may be different from those in population-based cohorts. New data suggest the possibility of a change in the natural history in Crohns disease, with an increasing percentage of patients diagnosed with inflammatory disease behavior. Hospitalization rates remain high, while surgery rates seem to have decreased in the last decade. In addition, mortality rates still exceed that of the general population. The impact of changes in treatment strategy, including increased, earlier use of immunosuppressives, biological therapy, and patient monitoring on the natural history of the disease are still conflictive. In this review article, the authors summarize the available evidence on the natural history, current trends, and predictive factors for evaluating the disease course of CD.

Recommendations for identifying Crohn’s disease patients with poor prognosis

Clinical presentation at diagnosis and the disease course of Crohn’s disease is heterogeneous and variable over time. The majority of patients with Crohn’s disease will develop at least one stricturing or perforating complication requiring surgery during follow-up. New data support a change in the natural history of the disease associated with the advent of biologicals and tailored treatment strategy. Therefore, it is important to identify patients at risk for disease progression as soon as possible. In recent years, much emphasis has been placed on determining important predictive factors. Complex evaluation of factors such as clinical and endoscopic presentation, fecal, serological and routine laboratory tests, and genetic factors is needed. This review summarizes the available evidence and will hopefully assist clinicians when choosing a treatment strategy in everyday practice.

Burden of Clostridium difficile infection between 2010 and 2013: Trends and outcomes from an academic center in Eastern Europe

AIM To analyze the incidence and possible risk factors in hospitalized patients treated with Clostridium difficile infection (CDI). METHODS A total of 11751 patients were admitted to our clinic between 1 January 2010 and 1 May 2013. Two hundred and forty-seven inpatients were prospectively diagnosed with CDI. For the risk analysis a 1:3 matching was used. Data of 732 patients matched for age, sex, and inpatient care period and unit were compared to those of the CDI population. Inpatient records were collected from an electronic hospital database and comprehensively reviewed. RESULTS Incidence of CDI was 21.0/1000 admissions (2.1% of all-cause hospitalizations and 4.45% of total inpatient days). The incidence of severe CDI was 12.6% (2.63/1000 of all-cause hospitalizations). Distribution of CDI cases was different according to the unit type, with highest incidence rates in hematology, gastroenterology and nephrology units (32.9, 25 and 24.6/1000 admissions, respectively) and lowest rates in 1.4% (33/2312) in endocrinology and general internal medicine (14.2 and 16.9/1000 admissions) units. Recurrence of CDI was 11.3% within 12 wk after discharge. Duration of hospital stay was longer in patients with CDI compared to controls (17.6 ± 10.8 d vs 12.4 ± 7.71 d). CDI accounted for 6.3% of all-inpatient deaths, and 30-d mortality rate was 21.9% (54/247 cases). Risk factors for CDI were antibiotic therapy [including third-generation cephalosporins or fluoroquinolones, odds ratio (OR) = 4.559; P < 0.001], use of proton pump inhibitors (OR = 2.082, P < 0.001), previous hospitalization within 12 mo (OR = 3.167, P < 0.001), previous CDI (OR = 15.32; P < 0.001), while presence of diabetes mellitus was associated with a decreased risk for CDI (OR = 0.484; P < 0.001). Treatment of recurrent cases was significantly different from primary infections with more frequent use of vancomycin alone or in combination (P < 0.001), and antibiotic therapy duration was longer (P < 0.02). Severity, mortality and outcome of primary infections and relapsing cases did not significantly differ. CONCLUSION CDI was accounted for significant burden with longer hospitalization and adverse outcomes. Antibiotic, PPI therapy and previous hospitalization or CDI were risk factors for CDI.

Is early limited surgery associated with a more benign disease course in Crohn’s disease?

AIM To analyze the difference in disease course and need for surgery in patients with Crohns disease (CD). METHODS Data of 506 patients with incident CD were analyzed (age at diagnosis: 31.5 ± 13.8 years). Both hospital and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database, which includes incident CD patients diagnosed between January 1, 1977 and December 31, 2008. Follow-up data were collected until December 31, 2009. All patients included had at least 1 year of follow-up available. Patients with indeterminate colitis at diagnosis were excluded from the analysis. RESULTS Overall, 73 patients (14.4%) required resective surgery within 1 year of diagnosis. Steroid exposure and need for biological therapy were lower in patients with early limited surgery (P < 0.001 and P = 0.09). In addition, surgery rates during follow-up in patients with and without early surgery differed significantly after matching on propensity scores (P < 0.001, HR = 0.23). The need for reoperation was also lower in patients with early limited resective surgery (P = 0.038, HR = 0.42) in a Kaplan-Meier and multivariate Cox regression (P = 0.04) analysis. However, this advantage was not observed after matching on propensity scores (P(Logrank) = 0.656, P(Breslow) = 0.498). CONCLUSION Long-term surgery rates and overall exposure to steroids and biological agents were lower in patients with early limited resective surgery, but reoperation rates did not differ.

Prevalence and predictors of hospitalization in Crohn’s disease in a prospective population-based inception cohort from 2000-2012

AIM To analyze the prevalence, length and predictors of hospitalization in the biological era in the population-based inception cohort from Veszprem province. METHODS Data of 331 incident Crohns disease (CD) patients diagnosed between January 1, 2000 and December 31, 2010 were analyzed (median age at diagnosis: 28; IQR: 21-40 years). Both in- and outpatient records were collected and comprehensively reviewed. RESULTS Probabilities of first CD-related hospitalization and re-hospitalization were 32.3%, 45.5%, 53.7% and 13.6%, 23.9%, 29.8%, respectively after one, three and five years of follow-up in Kaplan-Meier analysis. First-year hospitalizations were related to diagnostic procedures (37%), surgery or disease activity (27% and 21%). Non-inflammatory disease behavior at diagnosis (HR = 1.32, P = 0.001) and perianal disease (HR = 1.47, P = 0.04) were associated with time to first CD-related hospitalization, while disease behavior change (HR = 2.38, P = 0.002) and need for steroids (HR = 3.14, P = 0.003) were associated with time to first re-hospitalization in multivariate analyses. Early CD-related hospitalization (within the year of diagnosis) was independently associated with need for immunosuppressives (OR = 2.08, P = 0.001) and need for surgeries (OR = 7.25, P < 0.001) during the disease course. CONCLUSION Hospitalization and re-hospitalization rates are still high in this cohort, especially during the first-year after the diagnosis. Non-inflammatory disease behavior at diagnosis was identified as the pivotal predictive factor of both hospitalization and re-hospitalization.