Corrigendum to "Low Body Mass Index Can Identify Majority of Osteoporotic Inflammatory Bowel Disease Patients Missed by Current Guidelines".

[This corrects the article DOI: 10.1100/2012/807438.].

Impact of Low Immunoglobulin G Levels on Disease Outcomes in Patients with Inflammatory Bowel Diseases.

BACKGROUND: Inflammatory bowel diseases (IBDs) are considered immune-mediated disorders with dysregulated innate and adaptive immunities. Secondary immunogloblin deficiency can occur in IBD and its impact on the disease course of IBD is not clear. AIMS: We sought to determine associations between low IgG/G1 levels and poor clinical outcomes in IBD patients. METHODS: This historic cohort study was performed on IBD patients with obtained IgG/IgG1 levels. The primary outcome was defined as any IBD-related bowel resection surgery and/or hospitalization. Subgroup analyses assessed particular surgical outcomes in Crohn's disease (CD), ulcerative colitis (UC) or indeterminate colitis (IC), and ileal pouch-anal anastomosis (IPAA). The secondary outcomes included IBD drug escalations and C. difficile or cytomegalovirus infections. RESULTS: A total of 136 IBD patients had IgG/G1 levels checked and adequate follow-up, 58 (42.6 %) with normal IgG/G1 levels and 78 (57.4 %) having low levels. A total of 49 patients (62.8 %) with low immunoglobulin levels had IBD-related surgeries or hospitalizations, compared to 33 patients (56.9 %) with normal levels [odds ratio (OR) 1.28, 95 % confidence interval (CI) 0.64-2.56; p = 0.49]. Low IgG/G1 levels were associated with IBD-related surgery in CD in univariate analysis [hazard ratio (HR) 4.42, 95 % CI 1.02-19.23; p = 0.048] and in Kaplan-Meier survival curve analysis (p = 0.03), with a trend toward significance on multivariate analysis (HR 3.07, 95 % CI 0.67-14.31; p = 0.15). IBD patients with low IgG/G1 levels required more small bowel resections (12.8 vs. 1.7 %, p = 0.024) and 5-aminosalicylate initiations (28.2 vs. 13.8 %, p = 0.045). CONCLUSIONS: Our study demonstrated a possible association between low IgG/G1 levels and poor outcomes in CD including surgery. Future implications include using immunoglobulin levels in IBD patients as a prognostic indicator or boosting humoral immunity as a treatment in this subset.

Implementation of Clinical Pharmacogenomics within a Large Health System: From Electronic Health Record Decision Support to Consultation Services.

The number of clinically relevant gene-based guidelines and recommendations pertaining to drug prescribing continues to grow. Incorporating gene-drug interaction information into the drug-prescribing process can help optimize pharmacotherapy outcomes and improve patient safety. However, pharmacogenomic implementation barriers exist such as integration of pharmacogenomic results into electronic health records (EHRs), development and deployment of pharmacogenomic decision support tools to EHRs, and feasible models for establishing ambulatory pharmacogenomic clinics. We describe the development of pharmacist-managed pharmacogenomic services within a large health system. The Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B*57:01-abacavir, HLA-B*15:02-carbamazepine, and TPMT-thiopurines (i.e., azathioprine, mercaptopurine, and thioguanine) were systematically integrated into patient care. Sixty-three custom rules and alerts (20 for TPMT-thiopurines, 8 for HLA-B*57:01-abacavir, and 35 for HLA-B*15:02-anticonvulsants) were developed and deployed to the EHR for the purpose of providing point-of-care pharmacogenomic decision support. In addition, a pharmacist and physician-geneticist collaboration established a pharmacogenomics ambulatory clinic. This clinic provides genetic testing when warranted, result interpretation along with pharmacotherapy recommendations, and patient education. Our processes for developing these pharmacogenomic services and solutions for addressing implementation barriers are presented.

Autoimmune features are associated with chronic antibiotic-refractory pouchitis.

BACKGROUND: Chronic antibiotic-refractory pouchitis (CARP) occurs more frequently in patients with ileal pouch-anal anastomosis (IPAA) with concomitant autoimmune disorders. The aim of this study was to assess the overlap between dysregulated immune features in patients with IPAA and their association with CARP. METHODS: We identified 150 symptomatic patients with IPAA who met inclusion criteria, including measurement of select autoimmune serology. Demographic and clinical variables were compared between patients with and without CARP. RESULTS: Autoimmune thyroid disease was more frequent among patients with CARP. The frequency of primary sclerosing cholangitis (16.7% versus 5.3%; P = 0.04) and serum positivity for microsomal antibody (25% versus 6.1%, P = 0.003) were significantly greater in patients with CARP compared with non-CARP patients, respectively. Increased tissue infiltration by IgG4-expressing plasma cells was detected in 17 of 31 patients (54.8%) in the CARP group as compared with 10/67 (14.9%) in the non-CARP group (P = 0.0001). Forty-seven percent of patients in the CARP group versus 22.8% in the non-CARP group had at least 2 immune features (P = 0.019). Among patients with IgG4 histology, 87% of patients in the CARP group versus 60% in the non-CARP group had at least 1 immune marker (P = 0.004). On multivariate analysis, microsomal antibody expression (odds ratio, 6.8; 95% confidence interval, 1.3-42.6; P = 0.02) and increased IgG4-expressing plasma cells tissue infiltration (odds ratio, 9.6; 95% confidence interval, 3.2-32.6, P = 0.0001) were risk factors for CARP. CONCLUSIONS: There is marked overlap of certain immune markers in patients with pouch dysfunction, especially those with CARP. Microsomal antibody expression and elevated IgG4-positive plasma cell infiltration were independent risk factors for CARP.

Safety and efficacy of endoscopic dilation for primary and anastomotic Crohn's disease strictures.

BACKGROUND: Literature on endoscopic dilation of Crohn's disease (CD) strictures, especially for primary (non-anastomotic) strictures is limited. METHODS: A historical cohort study was performed on patients who underwent endoscopic stricture dilations for CD in our IBD center. Primary endpoint was the efficacy of first endoscopic dilation in preventing the need for surgery in primary strictures compared to anastomotic strictures. Cox proportional hazards models using robust sandwich covariance matrix estimate were used to evaluate the need for surgery and any further endoscopic intervention. RESULTS: In our study cohort (mean age 42.2 ± 13.1 years, 57% females, 16.4% current smokers, and median follow-up 1.8 years), 128 patients underwent a total of 430 endoscopic stricture dilations for 169 strictures (88 primary, 81 secondary). Forty-two patients (32.8%) required surgery in the follow-up period, with a mean interval period between first dilation and surgery of 33 months. There was no difference between primary or anastomotic strictures with respect to the need for surgery (34.1% vs. 29.6%, p=0.53), redilation (59.1% vs. 58%, p=0.89) or total interventions (surgery+redilations, 71.6% vs. 72.8%, p=0.86). Multivariable analysis did not show any significant difference between patients who received and did not receive intralesional steroid injections, biologics or immunomodulators with respect to the need for repeat intervention or surgery. CONCLUSION: Efficacy and safety of endoscopic dilation are similar between primary and anastomotic CD strictures. Intralesional steroid injection or use of biologics did not decrease the need for re-intervention or surgery for either primary or anastomotic strictures.

Similar outcomes of IBD inpatients with Clostridium difficile infection detected by ELISA or PCR assay.

BACKGROUND: Clostridium difficile infection (CDI) is known as a risk factor for exacerbation of inflammatory bowel disease (IBD). CDI has been most commonly tested with enzyme-linked immunosorbent assay for toxins, but with a suboptimal sensitivity. Compared with conventional ELISA, the polymerase chain reaction-based assay (PCR) is a highly sensitive detection technique for C. difficile. However, its pure detection of only the DNA of toxin B may lead to over-treatment. AIMS: The purpose of this study was to compare the frequency and clinical outcomes of IBD inpatients with CDI between the PCR and ELISA assays and to assess the factors associated with CDI. METHODS: The retrospective study was performed with the IBD inpatients at Cleveland Clinic from 2009 to 2011, who were tested by either ELISA or PCR or both. Outcomes under comparison included intensive care unit transfer, length of hospital stay, requirement for gastrointestinal surgeries and all cause re-hospitalization. Multivariable analysis was performed to assess the associated factors for the combined cohorts. RESULTS: A total of 255 patients were included, among them 222 had ELISA test, and 103 had PCR test. Thirteen (5.9 %) patients were ELISA positive, versus 14 (13.5 %) patients who were PCR positive (P = 0.02). With comparable demographic and clinical background, clinical outcomes of the ELISA and PCR positive groups showed no significant difference. Instead, the overall percentage of C. difficile positive patients had a much higher rehospitalization rate than C. difficile negative patients (P < 0.01). Multivariable analysis identified comorbidities (P = 0.03), extra-intestinal manifestations (P = 0.03) and PPI use (P < 0.01) as the associated factors for CDI. CONCLUSION: There was a greater percentage of patients tested positive by PCR compared to ELISA. The outcomes of CDI diagnosed by PCR or ELISA, however, appeared comparable. The presence of comorbidities, extra-intestinal manifestations, and the use of PPI were found to be associated with CDI.

Manometric evaluation of evacuatory difficulty (dyschezia) in ileal pouch patients.

BACKGROUND: Dyschezia occurs in patients with ileal pouch-anal anastomosis. There are limited data on the mechanisms of this condition. We hypothesized that paradoxical contractions may contribute to dyschezia in those patients with mechanical or inflammatory pouch conditions. This study was aimed to evaluate the underlying manometric abnormalities in this population. METHODS: In this retrospective analysis, we screened our Pouchitis Registry for patients with dyschezia and underlying inflammatory bowel disease. Patients having undergone anopouch manometry were considered eligible and included. Patients without inflammatory or structural diseases of the pouch (the functional pouch disorder [FPD] group) were compared with those with inflammatory or structural diseases (the inflammatory/structural pouch disorder [ISPD] group). Demographic, clinical, manometric, and laboratory variables were analyzed. RESULTS: A total of 45 patients were included; of which, 21 (46.7%) were female. The median age of patients in the FPD group (n = 10) and ISPD group (n = 35) were 41 (interquartile range =32.5-56) years and 40 (interquartile range = 28-49) years, respectively (P = 0.469). There were no differences in the demographic, clinical, and laboratory variables between the 2 groups, with the exception of the modified Pouch Disease Activity Index. For manometric evaluations, paradoxical contractions and failure of balloon expulsion occurred in 50.0% and 60.0%, respectively, of the FPD group and in 17.1% and 20.0%, respectively, of the ISPD group (P = 0.048 and 0.043, respectively). CONCLUSIONS: In this cohort, manometric evaluation demonstrated that paradoxical contractions occurred more frequently in patients with FPD than in those with inflammatory/structural conditions. This suggests that the underlying physiologic mechanisms of dyschezia in these patients differ.

Risk factors for nephrolithiasis in patients with ileal pouches.

BACKGROUND AND AIMS: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become a standard of care in patients with ulcerative colitis (UC). Nephrolithiasis is common in patients with inflammatory bowel disease (IBD), but has never been studied as a complication of IPAA. We aimed to assess the risk factors for nephrolithiasis in patients with IPAA. METHODS: Using an IRB-approved, prospectively maintained pouch registry, we identified 1221 patients between 2000 and 2010. Those with post-IPAA nephrolithiasis served as the study group whereas IPAA patients without nephrolithiasis served as the controls. Demographic and clinical variables were analyzed using multivariable logistic regression to identify risk factors. RESULTS: There were a total of 218 IPAA patients: 81 with nephrolithiasis (37%) and 137 without (63%). Of the 81 patients in the study group, 17 were excluded due to limited clinical data. Three risk factors were found to be associated with nephrolithiasis: the presence of extra-intestinal manifestations (odd's ratio [OR]=2.9, 95% confidence interval [CI]: 1.4, 5.8, p=0.003), no use of antibiotics (OR=3.2, 95% CI: 1.5, 6.5, p=0.002) and low serum bicarbonate level (OR=0.87, 95% CI: 0.77, 0.99, p=0.038). CONCLUSION: Nephrolithiasis was a common finding in our patients with IPAA. As pouch patients with nephrolithiasis can develop adverse clinical complications, those with at least one of the risk factors we identified may need to be monitored more closely and possibly receive prophylactic treatment with oral bicarbonate.

Low body mass index can identify majority of osteoporotic inflammatory bowel disease patients missed by current guidelines.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at high risk of developing osteoporosis. Our objective was to determine the usefulness of IBD guidelines in identifying patients at risk for developing osteoporosis. METHODS: We utilized institutional repository to identify patients seen in IBD center and extracted data on demographics, disease history, conventional, and nonconventional risk factors for osteoporosis and Dual Energy X-ray Absorptiometry (DXA) findings. RESULTS: 59% of patients (1004/1703) in our IBD cohort had at least one risk factor for osteoporosis screening. DXA was documented in 263 patients with indication of screening (provider adherence, 26.2%), and of these, 196 patients had DXA completed ("at-risk" group). Ninety-five patients not meeting guidelines-based risk factors also had DXA completed ("not at-risk" group). 139 (70.9%) patients in "at-risk" group had low BMD, while 51 (53.7%) of "not-at-risk" patients had low BMD. Majority of the patients with osteoporosis (83.3%) missed by the current guidelines had low BMI. Multivariate logistic regression analysis showed that low BMI was the strongest risk factor for osteoporosis (OR 3.07; 95% CI, 1.47-6.42; P = 0.003). CONCLUSIONS: Provider adherence to current guidelines is suboptimal. Low BMI can identify majority of the patients with osteoporosis that are missed by current guidelines.

Duration and severity of primary sclerosing cholangitis is not associated with risk of neoplastic changes in the colon in patients with ulcerative colitis.

BACKGROUND: Annual surveillance colonoscopy to detect colon cancer is recommended for patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). Limited data currently support these recommendations. OBJECTIVE: To study whether a relationship exists between the severity and duration of PSC and the risk of colon cancer and dysplasia (colon neoplasia). DESIGN: Retrospective, longitudinal study. SETTING: Tertiary-care referral center. PATIENTS: Information pertaining to duration of PSC, UC, requirement for orthotopic liver transplantation, and time to diagnosis of colon neoplasia was obtained for patients with PSC and UC. Patients were evaluated and followed-up from 1985 to 2011 at a single institution. MAIN OUTCOME MEASUREMENTS: Association between the severity and duration of PSC-UC and the time of occurrence of colon neoplasia. RESULTS: Of 167 patients with a combined diagnosis of PSC-UC, 55 had colonic neoplasia on colonoscopy. Colonic neoplasia occurred more frequently within 2 years of a combined diagnosis of PSC-UC (6.6/100 patient-years of follow-up) than after 8 years from PSC-UC (2.7/100 patient-years of follow-up). On proportional hazards analysis, older age at PSC diagnosis (hazard ratio 1.23 for every 5 years; 95% confidence interval, 1.03-1.34; P = .014) increased the risk of colon neoplasia. LIMITATIONS: Retrospective study. CONCLUSION: In this study, the severity of PSC was not significantly associated with the risk of colon neoplasia. Patients with PSC and UC have a high risk of colon neoplasia soon after the coexistence of the two diseases is discovered. Older age at PSC diagnosis increases this risk.

Temporal trends in colon neoplasms in patients with primary sclerosing cholangitis and ulcerative colitis.

BACKGROUND AND AIM: Surveillance for colon cancer is recommended in patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). It is unclear whether characteristics of colon neoplasia have changed over time. The aim of the study was to examine the temporal trends in colon neoplasia in patients with PSC and UC. METHODS: A total of 167 patients followed up at our institution between 1985 and 2011, 55 of these with neoplasia detected on colonoscopic biopsy were identified. Characteristics of patients with colon neoplasia in PSC-UC were studied for two different time periods: 1985-1998 (early cohort) compared to 1999-2011 (recent cohort). RESULTS: The median age at diagnosis of colon neoplasms was 53 years (median IQR, 43-63). The baseline characteristics were similar in both cohorts. The colonic neoplasms that developed in PSC-UC patients were spread throughout the colon on colonoscopy, while there was predominant right sided distribution on colectomy in both cohorts. (81.7% vs. 18.3%, p<0.001) Compared to the recent cohort, both the PSC (17 vs. 11 years, p=0.02) and UC duration (20 vs. 12 years, p=0.02) were longer in the early cohort. There were no differences in the grades and stages of cancer diagnosis. In addition, no differences in transplant-free survival or UC characteristics were revealed. CONCLUSIONS: With annual colonoscopic surveillance, dysplasia and cancer in patients with a combined diagnosis of PSC//UC is being diagnosed in patients with a shorter duration of these conditions. The nature and the location of neoplasia have, however, not changed.

Severity of primary sclerosing cholangitis and its impact on the clinical outcome of Crohn's disease.

BACKGROUND AND AIM: Crohn's disease (CD) is associated with primary sclerosing cholangitis (PSC). The aim of the study was to study the association between the severity of PSC and clinical outcome of CD, comparing the course of CD in patients with PSC not needing orthotopic liver transplantation (OLT) and those requiring OLT. METHODS: A total of 41 patients with PSC and CD seen at the Cleveland Clinic between 1985 and 2011 were included in this study. Clinical and demographic variables were obtained regarding the outcome of CD in patients with and without OLT. RESULTS: Patients with PSC-CD were divided into two groups: 20 without OLT (non-OLT) and 21 with OLT. 18 (85.7%) of patients in the OLT group had pancolitis in contrast to 14 (70%) in the non-OLT group. (p=0.22). There were no significant differences regarding duration of CD, but the duration of PSC was longer in the OLT group [16.0±7.8 vs. 10.3±6.4, p=0.01]. The OLT and non-OLT groups did not differ in the number of CD flares [0 (0, 0) vs. 0 (0, 5), p=0.28) and need for surgery for CD [(6 (28.6%) vs. 9 (45%), p=0.27]. Colon carcinoma and dysplasia were similar in the non-OLT and OLT groups [(4 (20%) vs. 3 (13.2%), p=0.52]. On Cox regression analysis, OLT for PSC [Hazards ratio (HR) 1.2 (95% confidence interval (C.I.): 0.38-3.7, p=0.79] did not impact the risk of colectomy. CONCLUSIONS: In contrast to UC, severe PSC requiring OLT does not appear to impact the clinical outcome of CD.

Progressive primary sclerosing cholangitis requiring liver transplantation is associated with reduced need for colectomy in patients with ulcerative colitis.

BACKGROUND & AIMS: We investigated the association between the severity of primary sclerosing cholangitis (PSC) and clinical outcomes of patients with ulcerative colitis (UC) on the basis of need for colectomy. METHODS: We analyzed data from 167 patients with PSC and UC who were followed from 1985 to 2011. Patients with PSC and UC were divided into groups that received orthotopic liver transplantation (OLT) (n = 86) or did not (non-OLT, n = 81). Clinical and demographic variables were obtained, and patients were followed until they received OLT or the date of their last clinical visit. RESULTS: The OLT group had significantly more subjects with less severe symptoms of UC (59, 68.6%) than the non-OLT group (12, 14.8%; P < .001). The subjects in the OLT group had a median of 0 UC flares compared with 3 in the non-OLT group (P < .001); fewer subjects in the OLT group required use of azathioprine or mercaptopurine (1, 1.2%), compared with the non-OLT group (14, 17.3%; P = .006). More subjects in the non-OLT group required colectomies (61, 75.3%) than in the OLT group (23, 26.7%; P < .001). On the basis of Cox regression analysis, OLT for PSC independently reduces the need for colectomy (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.25-0.75; P = .003), as does a high Mayo risk score at diagnosis (HR, 0.52; 95% CI, 0.37-0.72; P < .001). Development of colon neoplasia increased the risk for colectomy (HR, 2.47; 95% CI, 1.63-3.75; P < .001). CONCLUSIONS: Severe progressive PSC that requires liver transplantation appears to reduce the disease activity of UC and the need for colectomy.

Risk of colonic neoplasia after liver transplantation for primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) confers an increased risk of colon cancer in patients with inflammatory bowel disease (IBD). However, there is a scarcity of data to determine whether the rate of colon cancer changes after liver transplantation (LT) in IBD patients with PSC. The aims were 1) to estimate the risk of colon neoplasia after LT in IBD patients with PSC; 2) to identify the factors associated with colon neoplasia after LT in IBD patients with PSC. METHODS: We identified patients with IBD/PSC who underwent LT from 1998-2005 (n = 43). Two control groups were identified. Control 1 was IBD/PSC who did not undergo LT, matched 1:1 for age, gender, and type of IBD. Control 2 was patients with chronic liver disease other than PSC who underwent LT, matched 1:1 for age, gender, and follow-up time since LT. All patients were monitored by serial colonoscopy. Logistic regression analysis was used. RESULTS: During a mean follow-up of 54.7 ± 47.7 months, patients with IBD/PSC who underwent LT had similar rate of colon neoplasia compared to those who did not have LT (34% versus 30%, P = 0.24). The rate of colon neoplasia in LT recipients was higher in PSC patients compared to those with other forms of chronic liver disease (34% versus 0%, P = 0.018). Post-LT cytomegalovirus infection was associated with higher likelihood of colon neoplasia post-LT in IBD/PSC patients (hazard ratio = 4.4, P = 0.024). There was no significant difference in survival outcome between the three study groups. CONCLUSIONS: IBD/PSC patients remain at an increased risk of colon neoplasia after LT.

The effects of an oral supplement enriched with fish oil, prebiotics, and antioxidants on nutrition status in Crohn's disease patients.

BACKGROUND: Research in the treatment of Crohn's disease (CD) supports anti-inflammatory benefits of n-3 fatty acids from fish oil, prebiotics, and antioxidants. A nutritionally balanced inflammatory bowel disease nutrition formula (IBDNF) enriched with these compounds has the potential to improve nutrition status and disease activity in CD. METHODS: This is an open-label pilot study investigating the effects of IBDNF on nutrition status in CD patients. Twenty-eight patients with active CD on stable medication were asked to consume 16 oz of IBDNF/d for 4 months. Nutrition status was assessed with dual-energy X-ray absorptiometry scans and serum micronutrient levels. Disease activity and quality of life were measured using the Crohn's Disease Activity Index (CDAI) and the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: Twenty patients completed the final visit. After 4 months, there was a significant decrease in plasma phospholipid levels of arachidonic acid with increases in eicosapentaenoic acid (EPA) and docosahexaenoic acid. Ten patients had a final EPA concentration of >2%. There was improvement in fat-free and fat mass in patients with final EPA >2% (P = .014 and P = .05). Vitamin D (25-OH) levels improved in all patients (18.5-25.9 ng/mL, P < .001). Those with EPA >2% had significantly lower CDAI (116 ± 94.5 vs 261.8 ± 86.5; P = .005) and higher IBDQ (179.1 ± 26.6 vs 114.6 ± 35.9, P < .001) compared to those with EPA <2%. CONCLUSIONS: IBDNF has the potential to deposit fat-free and fat mass, improve vitamin D status, and improve quality of life in CD patients.