Therapeutic Drug Monitoring in Pediatric IBD: Current Application and Future Perspectives.

BACKGROUND: as the paradigm for IBD management is evolving from symptom control to the more ambitious goal of complete deep remission, the concept of personalized medicine, as a mean to deliver individualized treatment with the best effectiveness and safety profile, is becoming paramount. Therapeutic drug monitoring (TDM) is an essential part of personalized medicine and its role in the management of IBD patients is rapidly expanding. OBJECTIVE: to review the current knowledge that poses the rationale for the use of TDM, and the present and future role of TDM-based approaches in the management of pediatric IBD. METHOD: literature review. RESULTS: the concept of TDM has been introduced in the field of IBD along with thiopurines, over a decade ago, and evolved around anti-TNF therapies. TDM-based strategies proved to be costeffective in the management of patients with loss of response to biologics and, more recently, proactive TDM to optimize drug exposure has been shown to reduce treatment failure and drug adverse events. The role of TDM with new biologics and the usefulness of software-systems support tools to guide drug dosing are now under investigation. CONCLUSION: Therapeutic drug monitoring has the potential to maximize the cost-benefit profile of therapies and is becoming an essential part of IBD management.

A validated web-based tool to display individualised Crohn's disease predicted outcomes based on clinical, serologic and genetic variables.

BACKGROUND: Early treatment for Crohn's disease (CD) with immunomodulators and/or anti-TNF agents improves outcomes in comparison to a slower 'step up' algorithm. However, there remains a limited ability to identify those who would benefit most from early intensive therapy. AIM: To develop a validated, individualised, web-based tool for patients and clinicians to visualise individualised risks for developing Crohn's disease complications. METHODS: A well-characterised cohort of adult patients with CD was analysed. Available data included: demographics; clinical characteristics; serologic immune responses; NOD2 status; time from diagnosis to complication; and medication exposure. Cox proportional analyses were performed to model the probability of developing a CD complication over time. The Cox model was validated externally in two independent CD cohorts. Using system dynamics analysis (SDA), these results were transformed into a simple graphical web-based display to show patients their individualised probability of developing a complication over a 3-year period. RESULTS: Two hundered and forty three CD patients were included in the final model of which 142 experienced a complication. Significant variables in the multivariate Cox model included small bowel disease (HR 2.12, CI 1.05-4.29), left colonic disease (HR 0.73, CI 0.49-1.09), perianal disease (HR 4.12, CI 1.01-16.88), ASCA (HR 1.35, CI 1.16-1.58), Cbir (HR 1.29, CI 1.07-1.55), ANCA (HR 0.77, CI 0.62-0.95), and the NOD2 frameshift mutation/SNP13 (HR 2.13, CI 1.33-3.40). The Harrell's C (concordance index for predictive accuracy of the model) = 0.73. When applied to the two external validation cohorts (adult n = 109, pediatric n = 392), the concordance index was 0.73 and 0.75, respectively, for adult and pediatric patients. CONCLUSIONS: A validated, web-based tool has been developed to display an individualised predicted outcome for adult patients with Crohn's disease based on clinical, serologic and genetic variables. This tool can be used to help providers and patients make personalised decisions about treatment options.

Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn's disease.

BACKGROUND: Azathioprine (AZA), a pro-drug metabolised to the active metabolites 6-tioguanine nucleotides (6TGN), is a steroid-sparing therapy for Crohn's disease (CD). AIM: To investigate whether AZA therapy is optimised by individualised dosing based on thiopurine methyltransferase (TPMT) activity and 6TGN concentrations. METHODS: This multicentre, double-blind, randomised controlled trial compared the efficacy and safety of weight-based vs. individualised AZA dosing in inducing and maintaining remission in adults and children with steroid-treated CD. The primary outcome was clinical remission (CR) at 16 weeks. In the weight-based arm, subjects received 2.5 mg/kg/day. In the individualised dosing arm, the initial AZA dose was 1.0 mg/kg/day (if intermediate TPMT) or 2.5 mg/kg/day (if normal TPMT). Starting at week 5, the dose was adjusted to target 6TGN concentrations of 250-400 pmol/8 × 10(8) red blood cells (RBC), or to a maximal dose of 4 mg/kg/day. RESULTS: After randomising 50 subjects, the trial was stopped prematurely due to insufficient enrolment. In intention-to-treat analysis, CR rates at week 16 were 40% in the individualised arm vs. 16% in the weight-based arm (P = 0.11). In per-protocol (PP) analysis, week 16 CR rates were 60% in the individualised arm and 25% in the weight-based arm (P = 0.12). At week 16, median 6TGN concentrations in PP remitters and nonremitters were 216 and 149 pmol/8 × 10(8) RBC respectively (P = 0.07). CONCLUSIONS: Despite trends favouring individualised over weight-based AZA dosing, there were no statistically significant differences in efficacy, likely due to low statistical power and inability to achieve the target 6TGN concentrations in the individualised arm. [Clinicaltrials.Gov Identifier Nct00113503].

Differences in the management of Crohn's disease among experts and community providers, based on a national survey of sample case vignettes.

BACKGROUND: When faced with the same set of facts, healthcare providers often make different diagnoses, employ different tests and prescribe disparate therapies. AIM: To perform a national survey to measure process of care and variations in decision-making in Crohn's disease, and the compared results between experts and community providers. METHODS: We constructed a survey with five vignettes to elicit provider beliefs regarding the appropriateness of diagnostic tests and therapies in Crohn's disease. We measured agreement between community gastroenterologists and Crohn's disease experts, and measured variation within each group using the RAND Disagreement Index (DI), which is a validated measure of provider variation. RESULTS: We received 186 responses (42% response rate). Experts and community providers generally agreed on diagnostic testing decisions in Crohn's disease. However, there was a significant disagreement between groups for several decisions (use of 5-aminosalicylate in particular), and there was evidence of 'extreme variation' (defined as DI > 1.0) within groups across a range of decisions. CONCLUSIONS: Although experts and community providers are in general consensus about diagnostic decision-making in Crohn's disease, extreme variation exists both between and within groups for key therapeutic decisions in Crohn's disease. We must understand and decrease this variation prior to future efforts of creating explicit quality indicators in Crohn's disease.

New patients: should children be treated differently?

Inflammatory bowel disease (IBD) in childhood is often diagnosed at a vulnerable time of growth and development, and is recognized as one of the most significant chronic gastrointestinal diseases to affect children. Children and adolescents with IBD are at increased risk of complications as a result of malnutrition secondary to reduced appetite, increased metabolism and decreased absorptive capacity. The most common and serious complications are growth failure, bone demineralization and impaired psychosocial development. These issues add to the complexity of childhood IBD management and it is essential that adequate medical management is in place to prevent these long-term complications. Current treatment options include 5-aminosalicylic acid, antibiotics, corticosteroids, nutritional therapy and immunomodulators used to induce and maintain remission; some are specifically employed to maintain a steroid free long-term remission. As a general rule, long-term corticosteroid use should be avoided to reduce the risk of bone demineralization and growth failure. Newer treatment options such as infliximab have been shown to be effective for inducing and prolonging remission of Crohn's disease in children and paediatric use of infliximab is likely to increase in the near future. A recent case report, involving a 15-year old boy presenting with abdominal pain and bloody diarrhoea, illustrates the difficulty in correctly diagnosing IBD in children and the need for optimizing therapy to achieve treatment success.

An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy.

BACKGROUND AND AIMS: A substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy. METHODS: Ten CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities. RESULTS: Seventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity. CONCLUSIONS: 6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short- and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.

Clinical utility of serodiagnostic testing in suspected pediatric inflammatory bowel disease.

OBJECTIVES: Confronted with nonspecific symptoms, accurate screening tests would be useful to clinicians to distinguish between functional childhood disorders and inflammatory bowel disease (IBD), thus avoiding invasive diagnostic testing. Traditional ulcerative colitis-specific perinuclear antineutrophil cytoplasmic antibody (pANCA) and Crohn's disease-specific anti-Saccharomyces cerevisiae antibody (ASCA) serodiagnostic assays have recently been modified, with ELISA cut-off values recalculated to maximize sensitivity. The aim of this study was to determine whether the combination of these serodiagnostic tests could maximize diagnostic accuracy and minimize invasive investigations in pediatric patients presenting with nonspecific symptoms suggestive of IBD. METHODS: With investigators blinded to clinical diagnoses, ASCA, ANCA, and pANCA profiles were obtained prospectively from 128 patients undergoing complete diagnostic evaluation for IBD. In phase I, diagnostic accuracy and predictive values of the modified and traditional assays were compared for the IBD (n = 54) and non-IBD groups (n = 74). In phase II, the overall accuracy of a novel sequential diagnostic testing strategy was determined. Additionally, the potential number of invasive investigations avoided with the hypothetical application of this strategy to the cohort was determined. RESULTS: For phase I, the modified serodiagnostic assay was more sensitive (81 vs 69%), whereas the traditional assay had a higher specificity (96 vs 72%) for IBD (p < 0.05) For phase II, false-positive diagnoses would have been reduced by 81%, yielding an overall sequential testing strategy accuracy of 84%. CONCLUSIONS: The incorporation of sequential noninvasive testing into a diagnostic strategy may avoid unnecessary and costly evaluations and facilitate clinical decision making when the diagnosis of IBD in children is initially uncertain.

Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.

BACKGROUND & AIMS: The effects of 6-mercaptopurine (6-MP) are mediated via its intracellular conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) nucleotide metabolites, the latter genetically controlled by thiopurine methyltransferase (TPMT). We sought to determine optimal therapeutic 6-MP metabolite levels and their correlation with medication-induced toxicity and TPMT genotype. METHODS: Therapeutic response was determined in 92 pediatric patients with inflammatory bowel disease coincidentally with hematologic, pancreatic, and hepatic laboratory parameters, and compared with erythrocyte metabolite levels and TPMT genotype. RESULTS: Clinical response was highly correlated with 6-TG levels (P < 0.0001) but not with any other variable, including 6-MMP levels, drug dose, gender, and concurrent medications. The frequency of therapeutic response increased at 6-TG levels > 235 pmol/8 x 10(8) erythrocytes (P < 0.001). Hepatotoxicity correlated with elevated 6-MMP levels (>5700 pmol/8 x 10(8) erythrocytes; P < 0.05). Although leukopenia was associated with higher 6-TG levels (P < 0.03), it was observed in only 8% of responders. Patients heterozygous for TPMT (8/92) had higher 6-TG levels (P < 0.0001), and all responded to therapy. CONCLUSIONS: 6-MP metabolite levels and TPMT genotyping may assist clinicians in optimizing therapeutic response to 6-MP and identifying individuals at increased risk for drug-induced toxicity.

Diagnostic markers of inflammatory bowel disease.

The diagnosis of inflammatory bowel disease is usually straightforward, based on a detailed history and physical examination, along with standard radiographic and endoscopic investigations, biopsies, and laboratory parameters. More challenging is the search for clinically useful, noninvasive markers for Crohn disease and ulcerative colitis to accurately screen cases with nonspecific and indolent symptoms. Equally required are diagnostic markers that discriminate between these two disorders in cases with indeterminate colitis. Another dilemma for clinicians is that there are no simple measures to observe disease activity and predict relapses. This review describes the recent advances in diagnostic markers that afford the ability to screen for inflammatory bowel disease, discriminate between its types, and monitor disease activity. These include serological, fecal, and tissue markers; permeability tests; and diagnostic imaging using color Doppler ultrasonography.

Novel immunosuppressive therapies for intestinal and hepatic diseases.

Recent advances in the understanding of the pathogenesis of immune-mediated hepatic and intestinal diseases have led to major therapeutic advances. The introduction of genetically engineered biologic agents specifically designed to target inflammatory mediators responsible for the perpetuation of chronic inflammatory processes is a novel example. Although corticosteroids remain important as a first-line therapeutic option for active inflammatory bowel disease, approximately one third and one fifth of patients develop steroid dependence and resistance, respectively. From a pediatric perspective, a major advance has thus been the advocation of prolonged immunosuppressive therapy with 6-mercaptopurine or azathioprine for children with inflammatory bowel disease. The introduction of effective steroid-sparing agents for the induction and maintenance of remission is a key management issue. The past year has also witnessed the increased utilization of powerful immunosuppressive agents with rapid onset of action, such as cyclosporine and tacrolimus, in patients resistant to conventional therapies. This review will afford pediatricians a sense of what to expect for the management of hepatic and intestinal disorders with immunosuppression as we advance into the new millenium.