Emil Chuang

Combination of genetic and quantitative serological immune markers are associated with complicated Crohn's disease behavior

Background: Treatment of Crohns disease (CD) with biologics may alter disease progression, leading to fewer disease‐related complications, but cost and adverse event profiles often limit their effective use. Tools identifying patients at high risk of complications, who would benefit the most from biologics, would be valuable. Previous studies suggest that biomarkers may aid in determining the course of CD. We aimed to determine if combined serologic immune responses and NOD2 genetic markers are associated with CD complications. Methods: In this cross‐sectional study, banked blood from well‐characterized CD patients (n = 593; mean follow‐up: 12 years) from tertiary and community centers was analyzed for six serological biomarkers (ASCA‐IgA, ASCA‐IgG, anti‐OmpC, anti‐CBir1, anti‐I2, pANCA). In a patient subset (n = 385), NOD2 (SNP8, SNP12, SNP13) genotyping was performed. Complications included stricturing and penetrating disease behaviors. A logistic regression model for the risk of complications over time was constructed and evaluated by cross‐validation. Results: For each serologic marker, complication rates were stratified by quartile. Complication frequency was significantly different across quartiles for each marker (P trend ≤ 0.001). Patients with SNP13 NOD2 risk alleles experienced increased complications versus patients without NOD2 mutations (P ≤ 0.001). A calibration plot of modeled versus observed complication rates demonstrated good agreement (R = 0.973). Performance of the model integrating serologic and genetic markers was demonstrated by area under the receiver operating characteristic curve (AUC = 0.801; 95% confidence interval: 0.757–0.846). Conclusions: This model combining serologic and NOD2 genetic markers may provide physicians with a tool to assess the probability of patients developing a complication over the course of CD.

Combined Serological, Genetic, and Inflammatory Markers Differentiate Non-IBD, Crohn’s Disease, and Ulcerative Colitis Patients

Background:Previous studies have demonstrated that serological markers can assist in diagnosing inflammatory bowel disease (IBD). In this study, we aim to build a diagnostic tool incorporating serological markers, genetic variants, and markers of inflammation into a computational algorithm to examine patterns of combinations of markers to (1) identify patients with IBD and (2) differentiate patients with Crohns disease (CD) from ulcerative colitis (UC). Methods:In this cross-sectional study, patient blood samples from 572 CD, 328 UC, 437 non-IBD controls, and 183 healthy controls from academic and community centers were analyzed for 17 markers: 8 serological markers (ASCA-IgA, ASCA-IgG, ANCA, pANCA, OmpC, CBir1, A4-Fla2, and FlaX), 4 genetic markers (ATG16L1, NKX2-3, ECM1, and STAT3), and 5 inflammatory markers (CRP, SAA, ICAM-1, VCAM-1, and VEGF). A diagnostic Random Forest algorithm was constructed to classify IBD, CD, and UC. Results:Receiver operating characteristic analysis compared the diagnostic accuracy of using a panel of serological markers only (ASCA-IgA, ASCA-IgG, ANCA, pANCA, OmpC, and CBir1) versus using a marker panel that in addition to the serological markers mentioned above also included gene variants, inflammatory markers, and 2 additional serological markers (A4-Fla2 and FlaX). The extended marker panel increased the IBD versus non-IBD discrimination area under the curve from 0.80 (95% confidence interval [CI], ±0.05) to 0.87 (95% CI, ±0.04; P < 0.001). The CD versus UC discrimination increased from 0.78 (95% CI, ±0.06) to 0.93 (95% CI, ±0.04; P < 0.001). Conclusions:Incorporating a combination of serological, genetic, and inflammation markers into a diagnostic algorithm improved the accuracy of identifying IBD and differentiating CD from UC versus using serological markers alone.

Monitoring of adalimumab and antibodies-to-adalimumab levels in patient serum by the homogeneous mobility shift assay

This report describes the analytical validation and application of the homogeneous mobility shift assay (HMSA) method for the measurement of adalimumab and human antibodies-to-adalimumab (ATA) in serum samples from patients who have lost response to adalimumab treatment. Validation of the ATA- and the adalimumab-HMSA revealed a lower limit of detection to be 0.026 U/mL for ATA and 0.018 μg/mL for adalimumab in serum samples. Intra-assay and inter-assay precision determination yielded a coefficient of variation of less than 15%, and the accuracy of both assays was within 20%. Adalimumab drug tolerance in the ATA-HMSA was up to 20 μg/mL in the test serum. Serum samples from 100 drug-naïve healthy subjects were tested to set-up the cut point of 0.55 U/mL for ATA and 0.68 μg/mL for adalimumab. Analysis of 100 serum samples from patients who were losing response to adalimumab showed that 26% had an adalimumab level below the cut point, of these 68% were ATA positive. Overall, 44% of the patients (44/100) were positive for ATA. This study presents evidence that drug and anti-drug antibody levels are important determinants of patient response to therapy.

Antibodies to infliximab are associated with lower infliximab levels and increased likelihood of surgery in pediatric IBD.

Background:Adult studies suggest antibodies to infliximab (ATI) correlate with loss of response in inflammatory bowel disease but pediatric data are limited. Methods:We conducted a cross-sectional study of trough infliximab levels and ATI in 134 pediatric and young adult patients receiving infliximab. At the time serum was obtained demographics, disease phenotype, duration of infliximab therapy, use of combination therapy (methotrexate or 6-mercaptopurine with infliximab), and surgery were recorded. Results:Assays were performed on 134 subjects currently receiving infliximab (85 male; mean age, 17.3 ± 4.3 years; 114 Crohns disease and 20 ulcerative colitis). Infliximab use ranged from 12 days to 12 years: median 2.0 (interquartile range [1.1–4.3]) years. Twenty-seven of 134 (20%) patients had ATI ≥5 U/mL. Of patients with ATI ≥5 U/mL, 59% had infliximab levels <5 &mgr;g/mL, compared with 14% of patients with ATI <5 U/mL (P < 0.001). Ten (7%) patients (9 Crohns disease, 1 ulcerative colitis) underwent bowel resections after beginning infliximab infusions. Sixty percent who underwent surgery had ATI ≥12 U/mL; in contrast, only 8% of patients who did not undergo surgery had ATI ≥12 U/mL (P = 0.01). At the time of serum sampling, 50 (37%) patients were receiving combination therapy, compared with 84 (63%) on infliximab alone. Combination therapy at the time of serum sampling did not correlate with either increase infliximab levels or lower ATI compared with infliximab monotherapy. However, prior immunomodulator use was associated with lower antibody levels (P = 0.007). Conclusions:ATI correlates with reduction in infliximab level and a higher risk of surgery in patients with inflammatory bowel disease.

A 9-year evaluation of temporal trends in alosetron postmarketing safety under the risk management program

Objectives: Adverse events (AEs) of ischemic colitis (IC) and complications of constipation (CoC) associated with alosetron are rare and have been adjudicated during the first 5.5 years of the risk management program (RMP); however, changes in incidence rates relative to reductions in AE reports and increases in alosetron prescriptions over the 9-year RMP have not been evaluated. The authors aim to evaluate temporal trends in alosetron postmarketing safety over the 9-year RMP. Methods: The alosetron safety database was searched to identify cases of IC, CoC, and related AEs from 20 November 2002 to 31 December 2011. Adjudication of IC and CoC cases were based on US Food and Drug Administration-defined criteria. Incidence rates were calculated using the number of AEs and alosetron prescriptions (expressed as cases/1000 patient-years exposure). Results: A total of 29 cases were adjudicated as probable/possible IC and 7 cases were adjudicated as CoC. Cumulative adjudicated incidence rate of IC (1.03 cases/1000 patient-years) is low and stable, while that of CoC (0.25 cases/1000 patient-years) is low, declining progressively over time. Decreases in the incidence rates of potential symptoms of IC (abdominal pain with bloody diarrhea/hematochezia) and CoC (constipation) were also observed. Conclusions: Over the 9-year RMP period, incidence rates of IC and CoC remain rare. Substantial reductions over time were observed in the incidence of CoC and in symptoms suggestive of IC or CoC, while IC incidence has been stable at approximately 1.0 case/1000 patient-years. Decreases in AEs and serious outcomes associated with IC and CoC since the reintroduction of alosetron are likely attributable to the RMP.

Systems Biology Approaches for Inflammatory Bowel Disease: Emphasis on Gut Microbial Metabolism

Abstract:Although the prevalence of main idiopathic forms of inflammatory bowel disease (IBD) has risen considerably over the last decades, their clinical features do not allow accurate prediction of prognosis, likelihood of disease progression, or response to specific therapy. Through a better understanding of the molecular pathways involved in IBD and the promise of more targeted therapies, the personalized approach to the management of IBD shows potential. To achieve this, there remains a significant need to better understand the disease process at cellular and molecular levels for any given individual with IBD. The complexity of biological functional networks behind the etiology of IBD highlights the need for their comprehensive analysis. In this, omics technologies can generate a systemic view of IBD pathogenesis on which to base novel, multiple pathway-integrated therapies. Omics sciences have just started to contribute here by generating gene, protein expression, metabolite data at global level and large scale, and more recently by offering new opportunities to explore gut functional ecology. In particular, there is much expectation regarding the putative role of the gut microbiome in IBD. No doubt it will provide additional insights and lead to the development of alternative, hopefully better, diagnostic, prognostic, and monitoring tools in the management of IBD. This review discusses perspectives of relevance to clinical translation with emphasis on gut microbial metabolic activities.

Serum Infliximab, Antidrug Antibodies, and Tumor Necrosis Factor Predict Sustained Response in Pediatric Crohn's Disease.

Background:Serum infliximab (s-IFX) levels, antibodies to IFX (ATI), and inflammatory markers are important in predicting clinical outcomes in adults, but their roles in pediatric Crohns disease (CD) require further study. The primary aim of this study was to determine the association between serologic parameters during induction and ongoing IFX therapy at 12 months in pediatric CD. Methods:S-IFX, ATI, serum tumor necrosis factor alpha (s-TNF-&agr;), and C-reactive protein were measured at IFX initiation, 10 weeks, 6 months, and 12 months in a prospective cohort study of children with CD at a single tertiary care center. Results:At 12 months, 60 of 77 participants (78%) remained on IFX. Participants who completed 12 months of IFX had higher 10-week median s-IFX levels (20.40 &mgr;g/mL; interquartile range [IQR], 11.20–35.00] versus 8.70 &mgr;g/mL; IQR 0.90–16.90; P = 0.01), a greater proportion with undetectable 10-week ATI (P = 0.008), and a greater median change in s-TNF-&agr; between baseline and week 10 (−5.96 pg/mL; IQR, −8.73 to −4.17 versus −1.76 pg/mL; IQR, −5.60 to 0.30; P = 0.006). Receiver operating characteristic analysis to predict ongoing IFX at 12 months showed area under the curve (95% confidence interval) for 10-week s-IFX and change in s-TNF-&agr; from baseline to 10 weeks to be 0.71 (0.54–0.88) and 0.74 (0.58–0.91), respectively. C-reactive protein was not associated with ongoing therapy. Conclusions:ATI, s-IFX, and s-TNF-&agr; during IFX induction are associated with 12-month clinical outcomes in pediatric CD. Future studies are needed to further define the clinical role of s-TNF-&agr; measurement and to compare the clinical utility of 10 and 14-week ATI and s-IFX levels.

Evaluation of treatment continuation with alosetron by IBS-D severity criteria

Abstract Objectives: This article evaluates the characteristics and treatment patterns of female patients with severe diarrhea-predominant irritable bowel syndrome (IBS-D) who were treated with alosetron under a risk management program. Methods: Patients prescribed alosetron (2002–2009) and who voluntarily enrolled in the follow-up study were evaluated. Questionnaires were administered at baseline, Wk 5, Wk 10, and quarterly thereafter for ≤1 year. Subgroup analyses were conducted in female patients with IBS-D ≥6 months, stratified by IBS-D severity criteria met (1–3) from the alosetron prescribing information (treatment recommended in female patients meeting ≥1 severity criterion). The voluntary and observational nature of the study are potential limitations, such that eligible patients in the clinical practice setting may have had more severe IBS-D, possibly representing a more motivated and homogeneous subpopulation of patients than the broader IBS-D population. Results: A total of 7841 patients enrolled in the study; 92.4% were adult females; 79.4% (n = 6229) met label criteria. Mean follow-up time was ∼10.3 months; 50.3% completed 1 year. Of the 6229 female patients, 76.9% met 3/3 severity criteria; 21.5% met 2/3 severity criteria; 1.4% met 1/3 severity criteria. The most common complaint was restriction of daily activities, followed by accidents/fecal incontinence, and stomach cramps/bloating. One-year treatment continuation was ≥64% across IBS-D severity groups. Conclusions: One-year treatment continuation with alosetron was high, irrespective of the number of IBS-D severity criteria met. Restriction of daily activities was the primary indicator of disease severity. These findings demonstrate that alosetron continues to be safely and effectively used under the risk management program, and appears to provide long-term benefit in appropriate patients with IBS-D.

Tu1392 Psychological Variables Add Incremental Value to Biological Markers in Differentiating IBS From Healthy Volunteers

Background: The development of a diagnostic test for irritable bowel syndrome (IBS) would aid physicians in the clinical management of patients presenting with gastrointestinal complaints without apparent organic cause. While no validated test yet exists there has been promising progress in the area of biological markers (Lembo et et, APT 2009). Given that IBS is thought to be a heterogeneous condition and the biopsychosocial model allows for the possibility of a bidirectional relationship between the central and enteric nervous systems we explored the possibility that psychological variables might provide additional discrimination of IBS from health over and above that provided by a panel of biological markers. Aim: To test the hypothesis that psychological variables provide incremental value in discriminating IBS from health but not IBS subtypes from each other. Method: n=244 individuals recruited from community gastroenterologists and hospital clinics. The sample was comprised of 76 healthy volunteers, 60 IBS-C, 57 IBS-D and 51 IBS-M (mixed). A panel of 34 biological markers was considered (including serum histamine, IL-6, IL-10, TNFalpha, PGE2, VIPr1, tTG) in addition to psychological measures of anxiety and depression (Hospital Anxiety and Depression Scale -HADS), perceived stress and Patient Health Questionnaire (PHQ-15) with items referring to GI complaints removed. Logistic regression was used to create diagnostic models and model performance was assessed through calculation of the area under the receiver-operator characteristic curve (AUC) and sensitivity and specificity with the Rome III criteria as the reference standard. Results: A panel of 34 biomarkers provides useful discrimination of IBS from health with AUC=0.81 and sensitivity 0.81 and specificity 0.64. The addition of four psychological measures increases performance to AUC=0.93 (Fig 1), sensitivity 0.85 and specificity 0.88. Discrimination of IBS-C from IBS-D is increased from AUC 0.92 to 0.94, IBS-C from IBS-M from 0.85 to 0.88 and IBS-D from IBS-M from 0.86 to 0.91. Conclusion: The results supported the hypothesis that psychological characteristics provide independent discrimination of IBS from health. The improvement in overall discriminatory performance appears to result improved specificity with little improvement in sensitivity. The results also supported the hypothesis that psychological characteristics provide little additional value in discriminating IBS subtypes from each other.

Alosetron use in clinical practice: significant improvement in irritable bowel syndrome symptoms evaluated using the US Food and Drug Administration composite endpoint:

Background: Alosetron is approved to treat women with severe IBS and diarrhea (IBS-D) who have failed standard therapy. In our study, we aimed to evaluate alosetron efficacy using new US Food and Drug Administration (FDA) endpoints and utilization in clinical practice. Methods: This prospective, open-label, multicenter, observational 12-week study evaluated women with severe IBS-D enrolled in the alosetron prescribing program. The coprimary FDA endpoints were changes from baseline in stool consistency and abdominal pain severity. Responders achieved a 30% decrease compared with baseline in weekly average of the worst abdominal pain in the past 24 h, and a 50% or greater reduction from baseline in the number of days/week with at least one stool of type 6 (mushy) or type 7 (watery) consistency. Secondary endpoints included changes from baseline in stool frequency, fecal urgency and fecal incontinence. Results: Enrolled patients (n = 192) were primarily White (90.6%), with a mean age of 44.5 years. Patient and physician rating of IBS severity was between moderate and severe (85.9% concordance, Spearman coefficient 0.429, p < 0.0001). Alosetron 0.5 mg twice daily (82.8%) was the most common dosing regimen. A total of 152 alosetron-treated patients completed the study. Of 105 fully evaluable patients, 45% met the FDA composite endpoint responder criteria for ⩾50% of the study period. Improvements in all individual symptoms were statistically significant compared with baseline. There were no serious adverse events, cases of colonic ischemia, or complications of constipation. Conclusion: In a clinical practice setting study, alosetron demonstrated treatment success using a rigorous FDA composite endpoint and also improved multiple other IBS symptoms, including fecal urgency and incontinence in women with severe IBS-D [ClinicalTrials.gov identifier: NCT01257477].