MLH1 Promotor Hypermethylation in Colorectal and Endometrial Carcinomas from Patients with Lynch Syndrome.

Screening for Lynch syndrome (LS) in colorectal cancer (CRC) and endometrial cancer patients generally involves immunohistochemical staining of the mismatch repair (MMR) proteins. In case of MLH1 protein loss, MLH1 promotor hypermethylation (MLH1-PM) testing is performed to indirectly distinguish the constitutional MLH1 variants from somatic epimutations. Recently, multiple studies have reported that MLH1-PM and pathogenic constitutional MMR variants are not mutually exclusive. This study describes 6 new and 86 previously reported MLH1-PM CRCs or endometrial cancers in LS patients. Of these, methylation of the MLH1 gene promotor C region was reported in 30 MLH1, 6 MSH2, 6 MSH6, and 3 PMS2 variant carriers at a median age at diagnosis of 48.5 years [interquartile range (IQR), 39-56.75 years], 39 years (IQR, 29-51 years), 58 years (IQR, 53.5-67 years), and 68 years (IQR, 65.6-68.5 years), respectively. For 31 MLH1-PM CRCs in LS patients from the literature, only the B region of the MLH1 gene promotor was tested, whereas for 13 cases in the literature the tested region was not specified. Collectively, these data indicate that a diagnosis of LS should not be excluded when MLH1-PM is detected. Clinicians should carefully consider whether follow-up genetic MMR gene testing should be offered, with age <60 to 70 years and/or a positive family history among other factors being suggestive for a potential constitutional MMR gene defect.

Prenatal identification of an inverted duplicated 13q marker chromosome with a neocentromere.

In this case report, we describe a rare prenatal finding of a small marker chromosome. This marker chromosome corresponds to an inverted duplication of the 13q region 13q31.1q34 (or 13q31.1 → qter) with a neocentromere, detected during genetic analysis of a chorionic villus sample in a fetus with multiple congenital anomalies after a normal prenatal screening result by noninvasive prenatal testing.

A large family with MSH3-related polyposis.

Biallelic MSH3 germline variants are a rare cause of adenomatous polyposis as yet reported in two small families only. We describe the phenotype of a third family, the largest thus far, with adenomatous polyposis related to compound heterozygous MSH3 pathogenic variants. The index patient was a 55-years old male diagnosed with rectal cancer and adenomatous polyposis (cumulatively 52 polyps), with a family history of colorectal polyposis with unknown cause. Next-generation sequencing and copy number variation analysis of a panel of genes associated with colorectal cancer and polyposis revealed compound heterozygous germline pathogenic variants in the MSH3 gene. Nine out of 11 siblings were genotyped. Three siblings carried the same compound heterozygous MSH3 variants. Colonoscopy screening showed predominantly right-sided adenomatous polyposis in all compound heterozygous siblings, with a cumulative number of adenomas ranging from 18 to 54 in an average of four colonoscopies, and age at first adenoma detection ranging from 46 to 59. Microsatellite analysis demonstrated alterations at selected tetranucleotide repeats (EMAST) in DNA retrieved from the rectal adenocarcinoma, colorectal adenomas as well as of normal colonic mucosa. Gastro-duodenoscopy did not reveal adenomas in any of the four patients. Extra-intestinal findings included a ductal adenocarcinoma in ectopic breast tissue in one female sibling at the age of 46, and liver cysts in three affected siblings. None of the three heterozygous or wild type siblings who previously underwent colonoscopy had adenomatous polyposis. We conclude that biallelic variants in MSH3 are a rare cause of attenuated adenomatous polyposis with an onset in middle age.

Hypnotherapy for Irritable Bowel Syndrome-Type Symptoms in Patients with Quiescent Inflammatory Bowel Disease: A Randomized, Controlled Trial.

BACKGROUND AND AIMS: Many inflammatory bowel disease [IBD] patients in remission have persisting symptoms, compatible with irritable bowel syndrome [IBS-type symptoms]. We aimed to compare the effectiveness of gut-directed hypnotherapy vs standard medical treatment [SMT] for IBS-type symptoms in IBD patients. METHODS: In this multicentre, randomized, controlled, open-label trial, patients aged 12-65 years with IBD in clinical remission [global assessment] and biochemical remission [faecal calprotectin ≤100 µg/g, or ≤200 µg/g without inflammation at endoscopy] with IBS according to Rome III criteria were randomized to hypnotherapy or SMT. Primary outcome was the proportion with ≥50% reduction on a visual analog scale for symptom severity, as measured with the Irritable Bowel Syndrome Severity Scoring System [IBS-SSS] at week 40 [i.e. 6 months after finishing the intervention], compared to baseline. Secondary outcomes included total IBS-SSS score, quality of life, adequate relief, IBS-related cognitions, and depression and anxiety scores. RESULTS: Eighty patients were included, of whom 70 received at least one session of the allocated treatment and were included in the modified intention-to-treat-population. Seven patients were excluded because of missing baseline data required for the primary outcome. The primary outcome was met in nine [27%] of 33 patients randomized to SMT and nine [30%] of 30 patients randomized to hypnotherapy [p = 0.81]. Adequate relief was reported in 60% and 40% of subjects, respectively. Exploratory analyses of secondary outcomes revealed no apparent differences between the two treatment groups. CONCLUSIONS: Hypnotherapy was not superior to SMT in the treatment of IBS-type symptoms in IBD patients. Both treatment strategies are reasonable options from a clinical perspective.

Efficacy of dashboard driven dosing of infliximab in inflammatory bowel disease patients; a randomized controlled trial.

OBJECTIVES: Loss of response (LOR) to infliximab (IFX) remains a challenge in the management of inflammatory bowel diseases (IBD). Proactive dosing strategies to achieve and maintain predefined IFX trough levels (TL) may prevent LOR. We aimed to investigate the efficacy of dashboard driven IFX dosing compared to standard dosing in a prospective trial in IBD patients. METHODS: In this multicentre 1:1 'PRECISION' trial, we randomized IBD patients in clinical remission (Harvey Bradshaw Index ≤4 for Crohn's disease (CD) or a partial Mayo score ≤2 for ulcerative colitis (UC)) receiving IFX maintenance treatment. The precision group (PG) received IFX dosing guided by a Bayesian pharmacokinetic model, aiming to achieve and maintain a TL of 3 µg/ml by treatment (de)escalation as indicated by the dashboard. Patients in the control group (CG) continued treatment without dose adaptations. The primary endpoint was the proportion of patients in sustained clinical remission after 1 year. RESULTS: Eighty patients were enrolled (66 CD, 14 UC), and the median [interquartile range] age was 37 years [27-51]). After one year, 28/32 (88%) of patients in the PG were in sustained clinical remission versus 25/39 (64%) in the CG (p = .017). PG patients had lower median faecal calprotectin levels after 1 year (p = .031), whereas no significant differences in median CRP levels were found. CONCLUSION: We demonstrated that the use of a Bayesian dashboard for IFX dosing in maintenance treatment for IBD reduced the incidence of LOR compared to standard dosing. Precision dosing also resulted in lower FCP levels. CLINICALTRIALS.GOV NUMBER: NCT02453776.

A prospective study comparing patient-reported outcomes in Crohn's disease.

BACKGROUND: Patient reported outcomes are important in Crohn's disease. In this prospective cohort, we investigated the performance of the Bristol Stool Form Scale (BSFS) and a visual analog scale (VAS) for abdominal pain as outcome measures in Crohn's disease. METHODS: Patients with active Crohn's disease starting glucocorticoids or anti-tumor necrosis factor were included. Before treatment and 10 weeks later we collected: clinical activity [Harvey Bradshaw Index (HBI) and Crohn's-Disease-Activity-Index (CDAI)], serum C-reactive protein (CRP) and fecal calprotectin, and BSFS (1-7) and a 100-mm VAS based on a 7-day diary. Clinical response was defined as a reduction by at least 3 and at least 100 of HBI and CDAI, respectively. Fecal calprotectin-response and CRP-response were defined as reduction of at least 50%. RESULTS: Thirty-eight patients completed follow-up. At baseline, BSFS-parameters correlated more strongly with clinical activity (range: rs: 0.31-0.74) than with CRP (rs: -0.01 to 0.16) and fecal calprotectin (rs: 0.14-0.26). VAS scores correlated very weakly to moderately with clinical activity (rs: 0.18-0.45), and weakly to moderately with CRP (rs: 0.24-0.34) and fecal calprotectin (rs: 0.35-0.43). Changes in VAS scores correlated moderately to strongly (rs: 0.55-0.71) with changes in clinical activity, and weakly with changes in CRP and fecal calprotectin (rs: 0.21-0.35). Changes in BSFS parameters correlated weakly to moderately (rs: 0.23-0.53) with changes in clinical activity, and very weakly to weakly (rs: 0.01-0.35) with changes in CRP and fecal calprotectin. Responsiveness of VAS and BSFS was moderate to high (Guyatt's statistic 0.41-2.17) and highly dependent on the definition of response. CONCLUSIONS: The BSFS and a VAS appear to be responsive with moderate-to-strong construct validity to monitor patients with Crohn's disease.

Long-term Outcome of Early Combined Immunosuppression Versus Conventional Management in Newly Diagnosed Crohn's Disease.

BACKGROUND AND AIMS: Long-term outcomes of early combined immunosuppression [top-down] compared to conventional management [step-up] in recently diagnosed Crohn's disease [CD] are unknown. We aimed to investigate long-term outcomes of participants of the Step-up/Top-down-trial. METHODS: Trial participants' medical records were reviewed retrospectively. For 16 semesters following the 2-year trial, we recorded: clinical activity, medication use, flares, hospitalization, surgery and fistulas. Colonoscopy reports were scored as: endoscopic remission, aphthous/small ulcers or large ulcers. The primary endpoint was the proportion of semesters in remission. RESULTS: Data were available from 119/133 patients [step-up n = 60]. During a median follow-up of 8 years, clinical remission rates were similar (70% vs 73% [p = 0.85] in step-up and top-down patients, respectively). A shorter time to flare was observed in step-up patients [median five vs nine semesters, p = 0.01]. Cumulatively, 62% of step-up patients used corticosteroids compared to 41% of top-down patients [p = 0.02]. Anti-tumour necrosis factor [anti-TNF] use was higher in the step-up group [73% vs 54%, p = 0.04]. No differences were found in to time to CD hospitalization [respectively 13 vs 14 semesters, p = 0.30], new fistula [14 vs 15 semesters, p = 0.20] or CD surgery [14 vs 15 semesters, p = 0.25]. Mucosal healing 2 years after treatment was associated with a reduced anti-TNF use, but not with differences in other long-term outcomes. Endoscopic remission occurred at similar rates between groups. CONCLUSIONS: Top-down treatment did not result in increased clinical remission during long-term follow-up, compared to step-up treatment. However, lower relapse rates and a reduced use of anti-TNF agents and corticosteroids were observed. No difference was found in rates of endoscopic remission, hospitalization, surgery or new fistulas.

Polyethylene Glycol 3350 With Electrolytes Versus Polyethylene Glycol 4000 for Constipation: A Randomized, Controlled Trial.

OBJECTIVE: The long-term efficacy and safety of polyethylene glycol (PEG) in constipated children are unknown, and a head-to-head comparison of the different PEG formulations is lacking. We aimed to investigate noninferiority of PEG3350 with electrolytes (PEG3350 + E) compared to PEG4000 without electrolytes (PEG4000). METHODS: In this double-blind trial, children aged 0.5 to 16 years with constipation, defined as a defecation frequency of <3 times per week, were randomized to receive either PEG3350 + E or PEG4000. Primary outcomes were change in total sum score (TSS) at week 52 compared to baseline, and dose range determination. TSS was the sum of the severity of 5 constipation symptoms rated on a 4-point scale (0-3). Noninferiority margin was a difference in TSS of ≤1.5 based on a 95%-confidence interval [CI]. Treatment success was defined as a defecation frequency of ≥3 per week with <1 episode of fecal incontinence. RESULTS: Ninety-seven subjects were included, of whom 82 completed the study. Mean reduction in TSS was -3.81 (95% CI: -4.96 to -2.65) and -3.74 (95%CI: -5.08 to -2.40), for PEG3350 + E and PEG4000, respectively. Noninferiority criteria were not met (maximum difference between groups: -1.81 to 1.68). Daily sachet use was: 0 to 2 years: 0.4 to 2.3 and 0.9 to 2.1; 2 to 4 years: 0.1 to 3.5 and 1.2 to 3.2; 4 to 8 years: 1.1 to 2.8 and 0.7 to 3.8; 8 to 16 years 0.6 to 3.7 and 1.0 to 3.7, in PEG3350 + E and PEG4000, respectively. Treatment success after 52 weeks was achieved in 50% and 45% of children, respectively (P = 0.69). Rates of adverse events were similar between groups, and no drug-related serious adverse events occurred. CONCLUSIONS: Noninferiority regarding long-term constipation-related symptoms of PEG3350 + E compared to PEG4000 was not demonstrated. However, analysis of secondary outcomes suggests similar efficacy and safety of these agents.

Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis.

BACKGROUND: It is important to minimize placebo rates in randomised controlled trials (RCTs) to efficiently detect treatment differences between interventions. Historically, high placebo rates have been observed in clinical trials of ulcerative colitis (UC). A better understanding of factors influencing placebo rates may lead to more informed clinical trial design. OBJECTIVES: A systematic review and meta-analysis was conducted to evaluate placebo response and remission rates in RCTs evaluating UC treatments in adult patients. SEARCH METHODS: Electronic databases (i.e. MEDLINE, EMBASE, and CENTRAL) were searched from inception to 1 March 2017 with no language restrictions applied. Reference lists and conference proceedings of major gastroenterology meetings were also handsearched to identify additional studies. SELECTION CRITERIA: Placebo-controlled RCTs of adult patients with UC treated with corticosteroids, aminosalicylates, immunosuppressives or biologics were eligible, provided enrolment and outcome assessment was conducted using the Ulcerative Colitis Disease Activity Index (UCDAI) or the Mayo Clinic Score. The minimum trial duration was two weeks for induction trials and four months maintenance trials. DATA COLLECTION AND ANALYSIS: Pairs of authors independently determined study eligibility and extracted data with any disagreements resolved through consensus. Outcomes of interest included the proportion of patients with clinical response and remission. Trial characteristics such as the design, participant demographics and disease history, interventions, and enrolment and assessment criteria were also recorded. The methodological quality of the included studies was evaluated using the Cochrane risk of bias tool. Pooled placebo response and remission rates and 95% confidence intervals (95% CI) were calculated using a binomial normal model for proportions. Induction of remission and maintenance studies were pooled separately. The impact of study-level characteristics on placebo response and remission rates was investigated using mixed-effects meta-regression analyses with logits of event rates as the outcome variables. An assessment of pooled placebo rates over time was conducted using a cumulative meta-analysis based on date of publication. Publication bias was examined using funnel plots. MAIN RESULTS: The screening process identified 61 included studies which encompass 58 induction phases (5111 patients randomised to placebo) and 12 maintenance phases (1579 patients randomised to placebo). For induction trials, the pooled estimate of placebo response was 33% (95% CI 30% to 36%) while the pooled estimate of placebo remission was 12% (95% CI 9% to 15%). For maintenance trials, the pooled estimate of placebo response was 23% (95% CI 19% to 28%) while the pooled estimate of placebo remission was 17% (95% CI 10% to 27%).Studies enrolling patients with more active disease confirmed objectively by endoscopy were associated with significantly lower placebo remission and response rates than trials enrolling patients with less active disease (27% versus 4%, OR 2.60, 95% CI 1.25 to 5.42, P = 0.01 for UCDAI endoscopy sub score ≥1 versus ≥ 2 for remission; and 27% versus 4%, OR 1.70, 95% CI 1.02 to 2.82, P = 0.02 for UCDAI endoscopy sub score greater than or equal to one versus greater than or equal to two for response). With respect to drug class, the lowest placebo response and remission rates were observed in trials evaluating corticosteroids (23%; 95% CI 19 to 29%, and 5%; 95% CI 2 to 11%, respectively). Trials of biologics had the highest placebo response rate (35%; 95% CI 30 to 41%), while trials evaluating aminosalicylates had the highest placebo remission rate (18%; 95% CI 12 to 24%). Disease duration of greater than five years prior to enrolment was associated with a significantly lower placebo response rate compared to disease duration of less than or equal to five years (29% versus 47%, respectively; OR 0.54, 95% CI 0.32 to 0.92, P = 0.02). The requirement of a minimum rectal bleeding score for study eligibility was associated with an increased placebo response rate compared to studies that did not use rectal bleeding for trial eligibility (37% versus 32%, respectively; OR 1.70, 95% CI 1.02 to 2.82, P = 0.02). Finally, the time point of primary outcome assessment was found to be significantly associated with placebo remission rates such that every one week increment in endpoint assessment was associated with a 6% increase in the placebo remission rate (OR 1.06, 95% CI 1.02 to 1.10, P = 0.01).Cumulative meta-analysis indicated a consistent increase in the placebo response rate from 1987 to 2007 (from 13% to 33%), although rates have remained constant from 2008 to 2015 (32% to 34%). Similarly, placebo remission rates increased from 1987 to 2007 (5% to 14%) but have remained constant from 2008 to 2015 (12 to 14%). On meta-regression, there were no statistically significant differences between the 1987-2007 and 2008-2015 point estimates for both response (P = 0.81) and remission (P = 0.32). AUTHORS' CONCLUSIONS: Placebo response and remission rates vary according to endoscopic disease severity and rectal bleeding score at trial entry, class of agent, disease duration, and the time point at which the primary outcome was measured. These observations have important implications for the design and conduct of future clinical trials in UC and will help researchers design trials, determine required sample sizes and also provide useful information about trial design features which should be considered when planning new trials.

The prevalence of irritable bowel syndrome-type symptoms in inflammatory bowel disease patients in remission.

OBJECTIVE: Symptoms of irritable bowel syndrome (IBS) are common in inflammatory bowel disease (IBD) and are believed to reflect ongoing inflammation. Consequently, a low prevalence of IBS-type symptoms in IBD patients with normal inflammatory markers is expected. We aimed to investigate the prevalence of IBS-type symptoms in IBD patients in biochemical remission (evidenced by low fecal calprotectin levels) and the relationship of these symptoms with fecal calprotectin levels. PATIENTS AND METHODS: In this observational, cross-sectional study, we included all adults with a history of IBD who had calprotectin levels less than 200 µg/g during routine follow-up between August 2014 and May 2015 at our hospital. Patients were excluded if calprotectin was measured because of gastrointestinal complaints. All patients were approached by telephone to evaluate the presence of IBS-type symptoms using Rome III questionnaires. Patients fulfilling IBS criteria were subclassified according to bowel habits. RESULTS: In total, 74 patients were included; 33 (45%, 95% confidence interval: 34-56%) fulfilled the IBS criteria. A larger proportion of Crohn's disease patients with IBS-type symptoms had ileal disease compared with Crohn's disease patients without IBS symptoms (55 vs. 24%; P=0.03). Other characteristics were similar between groups. No difference was found in calprotectin levels between patients with and without IBS-type symptoms (P=0.91). The majority of patients with IBS-type symptoms had diarrhea-predominant or mixed-type IBS (64 and 27% of patients with IBS-type symptoms, respectively). CONCLUSION: The prevalence of IBS-type symptoms in IBD patients in biochemical remission is high. A significant proportion of IBS-type symptoms is unrelated to ongoing inflammation and probably reflects 'true IBS'.

Application of Population Pharmacokinetic Modeling for Individualized Infliximab Dosing Strategies in Crohn Disease.

OBJECTIVES: The pharmacokinetics of infliximab (IFX) is highly variable in children with Crohn disease (CD), and a one-size-fits-all approach to dosing is inadequate. Model-based drug dosing can help individualize dosing strategies. We evaluated the predictive performance and clinical utility of a published population pharmacokinetic model of IFX in children with CD. METHODS: Within a cohort of 34 children with CD who had IFX trough concentrations measured, the pharmacokinetics of each patient was estimated in NONMEM using a published population pharmacokinetic model. Infliximab concentrations were then predicted based on each patient's dosing history and compared with actual measured concentrations (n = 59). In addition, doses 5 to 10 mg/kg and dosing intervals every 4 to 8 weeks were simulated in each patient to examine dose-trough relationships. RESULTS: Predicted concentrations were within ±1.0 µg/mL of actual measured concentrations for 88% of measurements. The median prediction error (ie, measure of bias) was -0.15 µg/mL (95% confidence interval -0.37 to -0.05 µg/mL) and absolute prediction error (ie, measure of precision) was 0.26 µg/mL (95% confidence interval 0.15 to 0.40 µg/mL). At standard maintenance dosing of 5 mg/kg every 8 weeks, a trough >3 µg/mL was predicted to be achieved in 32% of patients. To achieve a trough >3 µg/mL, a dosing interval ≤every 6 weeks was predicted to be required in 29% of patients. CONCLUSIONS: A published IFX population pharmacokinetic model demonstrated accurate predictive performance in a pediatric CD population. Individualized IFX dosing strategies in children with CD will be critical to consistently achieve trough concentrations associated with optimal outcomes.

The Placebo Response in Pediatric Abdominal Pain-Related Functional Gastrointestinal Disorders: A Systematic Review and Meta-Analysis.

OBJECTIVE: To investigate the magnitude and determinants of the placebo response in studies with pediatric abdominal pain-related functional gastrointestinal disorders. STUDY DESIGN: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL were searched for systematic reviews and randomized placebo-controlled trials concerning children 4-18 years of age with an abdominal pain-related functional gastrointestinal disorder. The primary outcome was the pooled proportion of subjects assigned to placebo with improvement as defined by the authors. The effect of trial characteristics on the magnitude of the placebo response was investigated using univariate meta-regression analysis. RESULTS: Twenty-one trials were identified. The pooled proportion of subjects with improvement was 41% (95% CI, 34%-49%; 17 studies) and with no pain was 17% (95% CI, 8%-32%; 7 studies). The pooled standardized mean difference on the Faces Pain Scales compared with baseline was -0.73 (95% CI, -1.04 to -0.42; 8 studies). There was significant heterogeneity across studies with respect to both outcomes. Lower dosing frequency (P = .04), positive study (P = .03), longer duration of treatment (P < .001), and higher placebo dropout (P < .001) were associated with higher report of no pain. Response on Faces Pain Scales was greater in studies conducted in the Middle East (P = .002), in studies that did not report the randomization schedule (P = .02), and in studies with a higher percentage of females (P = .04). CONCLUSIONS: Approximately 41% of children with abdominal pain-related functional gastrointestinal disorders improve on placebo. Several trial characteristics are correlated significantly with the proportion of patients with no pain on placebo and with the magnitude of the placebo response on Faces Pain Scales. These data could be valuable for the design of future studies.

Relationship of clinical symptoms with biomarkers of inflammation in pediatric inflammatory bowel disease.

UNLABELLED: In adult inflammatory bowel disease (IBD) patients, there is a strong discrepancy between symptoms and biomarkers of inflammation. Data on pediatric IBD patients are conflicting. Therefore, we aimed to investigate the relationship between clinical symptoms and biomarkers of inflammation in pediatric IBD. Patients aged <18 years with previously diagnosed Crohn's disease (CD) or ulcerative colitis (UC) were included. Clinical disease activity was determined using the abbreviated Pediatric CD Activity Index (aPCDAI) or Pediatric UC Activity Index (PUCAI). Biochemical disease activity was assessed using fecal calprotectin (FC) and C-reactive protein (CRP). In total, 127 patients (62 male; median age 14.9 years) were included (82 CD, 45 UC). FC correlated weakly with total aPCDAI score (r s = 0.32; 95 % CI 0.12-0.51; p = 0.003) and total PUCAI score (r s = 0.36; 95 % CI 0.07-0.62; p = 0.015). Only aPCDAI components abdominal examination and perirectal disease and PUCAI component activity level had a significant correlation with levels of FC. CRP correlated weakly with total aPCDAI score (r s = 0.28; 95 % CI 0.05-0.46; p = 0.012) and aPCDAI components abdominal examination and activity level. No significant correlation was observed between CRP and total PUCAI score (r s = 0.01; 95 % CI -0.34-0.29; p = 0.961) or individual PUCAI components. CONCLUSION: There is a strong discrepancy between clinical symptoms and biomarkers of inflammation in children with IBD. WHAT IS KNOWN: • A substantial proportion of asymptomatic pediatric inflammatory bowel disease (IBD) patients have elevated biomarkers of inflammation. • There is a strong discrepancy between symptoms and biomarkers of inflammation in adults with IBD. What is New: • Clinical symptoms are only weakly associated with levels of fecal calprotectin and serum C-reactive protein in children and adolescents with previously diagnosed IBD. • Similarly to adult IBD patients, there is a strong discrepancy between clinical symptoms and biomarkers of inflammation in children with IBD.

Case report of cheilitis granulomatosa and joint complaints as presentation of Crohn's disease.

Cheilitis granulomatosa is characterized by granulomatous lip swelling. We report a case of a 13-year-old girl who presented with orofacial swelling and arthralgia, who eventually was diagnosed with Crohn's disease, which was successfully treated with infliximab and azathioprine combination therapy. Recurrent or persistent orofacial swelling should prompt consideration of cheilitis granulomatosa, and further diagnostic evaluation to exclude the presence of Crohn's disease seems warranted.

Annual Costs of Care for Pediatric Irritable Bowel Syndrome, Functional Abdominal Pain, and Functional Abdominal Pain Syndrome.

OBJECTIVES: To estimate annual medical and nonmedical costs of care for children diagnosed with irritable bowel syndrome (IBS) or functional abdominal pain (syndrome; FAP/FAPS). STUDY DESIGN: Baseline data from children with IBS or FAP/FAPS who were included in a multicenter trial (NTR2725) in The Netherlands were analyzed. Patients' parents completed a questionnaire concerning usage of healthcare resources, travel costs, out-of-pocket expenses, productivity loss of parents, and supportive measures at school. Use of abdominal pain related prescription medication was derived from case reports forms. Total annual costs per patient were calculated as the sum of direct and indirect medical and nonmedical costs. Costs of initial diagnostic investigations were not included. RESULTS: A total of 258 children, mean age 13.4 years (±5.5), were included, and 183 (70.9%) were female. Total annual costs per patient were estimated to be €2512.31. Inpatient and outpatient healthcare use were major cost drivers, accounting for 22.5% and 35.2% of total annual costs, respectively. Parental productivity loss accounted for 22.2% of total annual costs. No difference was found in total costs between children with IBS or FAP/FAPS. CONCLUSIONS: Pediatric abdominal pain related functional gastrointestinal disorders impose a large economic burden on patients' families and healthcare systems. More than one-half of total annual costs of IBS and FAP/FAPS consist of inpatient and outpatient healthcare use. TRIAL REGISTRATION: Netherlands Trial Registry: NTR2725.

The association of infliximab trough levels with disease activity in pediatric inflammatory bowel disease.

OBJECTIVE: Low serum trough levels (TLs) of infliximab (IFX) and antibodies to IFX (ATIs) are associated with the loss of therapeutic response in adults with inflammatory bowel disease (IBD) receiving IFX. Until now, pediatric data are scarce. Therefore, we aimed to cross-sectionally investigate the association between ATIs and IFX TLs, and clinical and biochemical disease activity in children receiving IFX for IBD. MATERIAL AND METHODS: Children aged <18 years receiving IFX maintenance treatment for Crohn's disease (CD) or ulcerative colitis (UC) at three Dutch hospitals were included. Prior to two consecutive IFX infusions, IFX TLs and ATI levels were measured. Clinical disease activity was determined by Pediatric Crohn's Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI), for CD and UC, respectively. Biochemical disease activity was assessed by serum C-reactive protein (CRP) and fecal calprotectin (FC). Clinical remission was defined as a PUCAI or PCDAI score of <10. Therapeutic range of IFX was considered 3-7 µg/ml. RESULTS: Thirty-nine patients were included (31 CD; 16 females). Median age was 15 years. Median IFX TL was 3.5 µg/ml [IQR 2-7]. Subtherapeutic and supratherapeutic TLs were found in 38% and 23% of children, respectively. ATIs were detected in four patients. A correlation was found between IFX TL and CRP [rs = -0.51; p < 0.01] and FC [rs = -0.49; p < 0.01]. However, when only clinical disease activity was considered, no difference in median TL was found between remission and active disease (resp. 3.5 µg/ml [IQR 2-5] and 2.3 µg/ml [IQR 0.3-4.6]; p = 0.2). CONCLUSIONS: IFX TLs are related to biochemical markers of disease activity. This could provide a rationale for monitoring TLs in children receiving IFX for IBD.