Altered mRNA expression of telomere binding proteins (TPP1, POT1, RAP1, TRF1 and TRF2) in ulcerative colitis and Crohn's disease

AimsTo determine mRNA expression of telomeric binding proteins in inflammatory bowel disease (IBD), and to note any effects of pharmacotherapy on telomere binding protein expression.MethodsPeripheral blood mononuclear cells (PBMC) obtained from 31 IBD patients and 13 controls were activated with phytohaemagglutinin and purified to yield activated (CD25+) T lymphocytes. TPP1, POT1, RAP1, TRF1 and TRF2 mRNA expression in PBMC and activated T lymphocytes was measured with RT-PCR.ResultsIn activated (CD25+) T lymphocytes, mean TRF2 mRNA levels were lower in both UC (6.6 vs 10, p = 0.004) and CD subjects (6.9 vs 10; p = 0.004). Similarly. in activated (CD25+) T lymphocytes mean RAP1 mRNA expression was significantly lower in UC subjects (4.5 vs 9.8, p = 0.029) but not in CD subjects. In resting PBMC, mean TRF1 mRNA levels were lower in both UC (2.6 vs 3.5; p = 0.008) and CD subjects (1.0 vs 3.5; p = 0.04). No difference in PBMC and activated (CD25+) T lymphocytes mRNA levels of TPP1 and POT1 were noted in either UC or CD subjects. An association with 5-aminosalicylate therapy (R² = 0.4) was only detected with RAP1 mRNA expression. TRF2 mRNA expression was inversely associated with disease duration only in UC subjects (p = 0.05; R² = −0.6).ConclusionsThe downregulation of TRF2 and RAP1 mRNA expression in CD25+ T-lymphocytes in IBD suggests that these telomere binding proteins play a role in telomere regulation and may contribute to the telomeric fusions and chromosomal abnormalities observed in UC. These findings may also indicate a systemic process of telomere uncapping which could represent a biomarker for IBD associated cancer risk.     

Prevalence of Inflammatory Bowel Disease in the Canton of Vaud (Switzerland): A population-based cohort study

Background and aimsBecause of the changing epidemiology of Inflammatory Bowel Diseases (IBD), we set out to characterize the population-based prevalence of Crohn's Disease (CD) and Ulcerative Colitis (UC) in a defined population of Switzerland.MethodsAdult IBD patients were identified by a cross-matched review of histological, hospital and gastroenterologist files throughout a geographical defined population (Canton of Vaud). Demographic factors statistically significantly associated with prevalence were evaluated using a stepwise Poisson regression analysis. Results were compared to IBD prevalence rates in other population-based studies and time trends were performed, based on a systematic literature review.ResultsAge and sex-adjusted prevalence rates were 205.7 IBD (100.7 CD and 105.0 UC) cases per 10⁵ inhabitants. Among 1016 IBD patients (519 CD and 497 UC), females outnumbered males in CD (p < 0.001), but males were more represented in elderly UC patients (p = 0.008). Thus, being a male was statistically associated with UC (Relative Risk (RR) 1.25; p = 0.013), whereas being a female was associated with CD (RR 1.27; p = 0.007). Living in an urban zone was associated with both CD and UC (RR 1.49; p < 0.001, 1.63; p < 0.001, respectively). From 1960 to 2005, increases in UC and CD prevalences of 2.4% (95%CI, 2.1%–2.8%; p < 0.001) and 3.6% (95%CI, 3.1%–4.1%; p < 0.001) per annum were found in industrialised countries.ConclusionsExtrapolating our data to all of Switzerland yields an estimate of 12,000 IBD cases for the country, or 1 in 500 inhabitants. Our study gives support to an increase in IBD prevalence in Europe.     

Incidencia e historia natural de la enfermedad inflamatoria intestinal en Castilla y León: estudio prospectivo,multicéntrico y poblacional

IntroductionThe incidence of inflammatory bowel disease (IBD) is increasing worldwide.ObjectivesTo evaluate the incidence of IBD in Castilla y León describing clinical characteristics of the patients at diagnosis, the type of treatment received and their clinical course during the first year.Materials and methodsProspective, multicenter and population-based incidence cohort study. Patients aged >18 years diagnosed during 2017 with IBD (Crohn's disease [CD], ulcerative colitis [UC] and indeterminate colitis [IC]) were included from 8 hospitals in Castilla y León. Epidemiological, clinical, and therapeutic variables were registered. The global incidence and disease incidence were calculated.Results290 patients were diagnosed with IBD (54.5% UC, 45.2% CD, and 0.3% IC), with a median follow-up of 9 months (range 8?11). The incidence rate of IBD in Castilla y Leon in 2017 was 16.6 cases per 10,000 inhabitants-year (9/10⁵ UC cases and 7.5/10⁵ CD cases), with a UC/CD ratio of 1.2:1. Use of systemic corticosteroids (47% vs 30%; P = .002), immunomodulatory therapy (81% vs 19%; P = .000), biological therapy (29% vs 8%; P = .000), and surgery (11% vs 2%; p = .000) were significatively higher among patients with CD comparing with those with UC.ConclusionsThe incidence of patients with UC in our population increases while the incidence of patients with CD remains stable. Patients with CD present a worse natural history of the disease (use of corticosteroids, immunomodulatory therapy, biological therapy and surgery) compared to patients with UC in the first year of follow-up.     

Serum vitamin B12 and folate status in patients with inflammatory bowel diseases

BackgroundThe aims of this study were to investigate the prevalence of serum vitamin B₁₂ and folate abnormalities in patients with inflammatory bowel diseases (IBD) and to identify risk factors associated with B₁₂ and folate abnormalities in this entity.Methods138 patients with IBD (45 Crohn's disease and 93 ulcerative colitis) and 53 healthy subjects were enrolled into the study. Fasting serum B₁₂ and folic acid levels were measured and clinical data regarding inflammatory bowel diseases were gathered.ResultsWhile the mean serum B₁₂ concentration in CD patients was 281 ± 166 pg/ml, the mean serum vitamin B₁₂ concentration in UC patients was 348 ± 218 pg/ml (p = 0.224). The number of patients with vitamin B₁₂ deficiency in the CD group was greater than the number of patients with UC [n = 10 (22%) vs. n = 4 (7.5%), p = 0.014]. The number of patients (n = 10, 22%) with B₁₂ deficiency in the CD group was also greater than controls (n = 4, 7.5%) (p = 0.039). With regard to folate levels, the median serum folate level was 7.7 ± 5.3 ng/ml in CD patients, 8.6 ± 8.3 ng/ml in UC patients and 9.9 ± 3.3 ng/ml in the control group (p = n.s.). Patients with a prior ileocolonic resection had an abnormal B₁₂ concentration compared to patients without surgery (p = 0.008). In CD patients, ileal involvement was the only independent risk factor for having a low folate level.ConclusionSerum vitamin B₁₂ and folate deficiencies are common in patients with CD compared to UC patients and controls. In CD patients, prior small intestinal surgery is an independent risk factor for having a low serum vitamin B₁₂ level.     

Fistulizing pattern in Crohn's disease and pancolitis in ulcerative colitis are independent risk factors for cancer: A single-center cohort study

Background & AimsThe combined role of immunomodulators (IMM) and clinical characteristics of Inflammatory Bowel Disease (IBD) in determining the cancer risk is undefined. The aim was to assess whether clinical characteristics of IBD are independent risk factors for cancer, when considering thiopurines and anti-TNFs use.MethodsIn a single-center cohort study, clinical characteristics of IBD patients with IBD duration ≥ 1 year and ≥ 2 visits from 2000 to 2009 were considered. Tests for crude rates and survival analysis methods were used to assess differences of incidence of cancer between groups. The methods were adjusted for the time interval between diagnosis and immunomodulatory treatments.ResultsIBD population included 1222 patients :615 Crohn's disease (CD), 607 ulcerative colitis (UC). Cancer was diagnosed in 51 patients (34 CD,17 UC), with an incidence rate of 4.3/1000 pt/year. The incidence rate of cancer was comparable between CD and UC (4.6/1000 pt/year vs 2.9/1000 pt/year ;p = n.s.). Cancer most frequently involved the breast, the GI tract, the skin. Lymphoma was diagnosed in CD (1HL,1NHL,0 HSTCL). Risk factors for cancer included older age at diagnosis of IBD (CD: HR 1.25;95%CI 1.08–1.45; UC:HR 1.33;95%CI 1.15–1.55 for an increase by 5 years; p = 0.0023; p = 0.0002), fistulizing pattern in CD (HR 2.55; 95%CI 1.11–5.86,p = 0.0275), pancolitis in UC (HR 2.79;95%CI 1.05–7.40 p = 0.0396 vs distal). IMM and anti-TNFs did not increase the cancer risk in CD, neither IMM in UC (anti-TNFs risk in UC not feasible as no cases observed).ConclusionsFistulizing pattern in CD, pancolitis in UC and older age at diagnosis of IBD are independent risk factors for cancer.     

Genetic and environmental factors as predictors of disease severity and extent at time of diagnosis in an inception cohort of inflammatory bowel disease,Copenhagen County and City 2003–2005

Background and aimsThe etiology of the inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) remains unknown. We aimed to investigate the influence of genetic, serological, and environmental factors on phenotypic presentation of IBD at diagnosis in a population-based Danish inception cohort from 2003–2005.MethodsThree-hundred-forty-seven (62%) of 562 cohort patients were genotyped. ASCA and p/c-ANCA were determined and patients answered a questionnaire concerning environmental factors with possible influence on IBD.ResultsFourteen percent of CD patients vs. 11% of controls were positive for common CARD15 mutation (ns), whereas more CD patients than healthy controls were homozygous for the OCTN-TC haplotype (p = 0.03). ASCA was more common in CD (22%) than UC (14%) (p = 0.045) and was related to age and localization of CD. p-ANCA was more frequent in UC (p = 0.00001) but was related to pure colonic CD (p = 0.0001). Sugar consumption was significantly higher in CD patients than in UC patients (p = 0.0001) and more CD patients than UC patients had undergone appendectomy prior to IBD diagnosis (p = 0.03). A possible relation between tonsillectomy and disease severity in CD, and a relation between use of oral contraception and disease localization of UC to rectum/left-sided colon were found.ConclusionsIn this cohort of unselected IBD patients we found a very low frequency of mutations in IBD susceptibility genes and observed a greater impact of ASCA and ANCA than of genetic factors on disease phenotypes. In addition, several environmental factors seemed to influence disease occurrence and disease presentation in both UC and especially CD.     

Familial aggregation in Crohn's disease and ulcerative colitis in a Norwegian population-based cohort followed for ten years

Background and aimsTo explore the change in risk among 1st degree relatives of ulcerative colitis (UC) and Crohn's disease (CD) for development of concordant disease in an incidence cohort followed for ten years. Furthermore, we wanted to compare familial and sporadic cases regarding clinical characteristics and the course of the disease.MethodsThis population-based study included 421 patients with UC and 197 with CD enrolled from 1990 to 1994. Clinical characteristics and the number of 1st degree relatives of the patients were recorded continuously during ten years.ResultsAge at diagnosis in CD patients (OR = 0.95, 95% CI: 0.93–0.98) and cumulative relapse rate in UC patients (OR = 4.91, 95% CI = 1.16, 20.75) were significantly associated to familial clustering. Based on the calculated population prevalence of CD (262/100 000) and UC (505/100 000), the age-adjusted risk for development of concordant disease was 25.9 and 8.6 among siblings and parents of CD, respectively. In UC, the corresponding risks were 8.6 and 1.5. In the course of ten years the increase in risk was observed only among siblings (28%) and parents (97%) of UC, in contrast to no increase in CD. Moreover, the concordance for UC was high in three generations.ConclusionsOur study confirmed the importance of genetic influence on the development of CD. Within an observation period of ten years, the increased concordance and relapse rate in familial UC, might point to a larger genetic component in UC than previously suggested.     

Disease severity in familial cases of IBD

BackgroundPhenotypic traits of familial IBD relative to sporadic cases are controversial, probably related to limited statistical power of published evidence.AimTo know if there are phenotype differences between familial and sporadic IBD, evaluating the prospective Spanish registry (ENEIDA) with 11,983 cases.Methods5783 patients (48.3%) had ulcerative colitis (UC) and 6200 (51.7%) Crohn's disease (CD). Cases with one or more 1st, 2nd or 3rd degree relatives affected by UC/CD were defined as familial case.ResultsIn UC and CD, familial cases compared with sporadic cases had an earlier disease onset (UC: 33 years [IQR 25–44] vs 37 years [IQR 27–49]; p < 0.0001); (CD: 27 years [IQR 21–35] vs 29 years [IQR 22–40]; p < 0.0001), higher prevalence of extraintestinal immune-related manifestations (EIMs) (UC: 17.2% vs 14%; p = 0.04); (CD: 30.1% vs 23.6%; p < 0.0001). Familial CD had higher percentage of ileocolic location (42.7% vs 51.8%; p = 0.0001), penetrating behavior (21% vs 17.6%; p = 0.01) and perianal disease (32% vs 27.1%; p = 0.003). Differences are not influenced by degree of consanguinity.ConclusionWhen a sufficiently powered cohort is evaluated, familial aggregation in IBD is associated to an earlier disease onset, more EIMs and more severe phenotype in CD. This feature should be taken into account at establishing predictors of disease course.     

Gas Exchange and Ventilatory Efficiency During Exercise in Pulmonary Vascular Diseases

Background and ObjectiveVentilatory inefficiency (high V′_E/V′CO₂) and resting hypocapnia are common in pulmonary vascular disease and are associated with poor prognosis. Low resting PaCO₂ suggests increased chemosensitivity or an altered PaCO₂ set-point. We aimed to determine the relationships between exercise gas exchange variables reflecting the PaCO₂ set-point, exercise capacity, hemodynamics and V′_E/V′CO₂.MethodsPulmonary arterial hypertension (n = 34), chronic thromboembolic pulmonary hypertension (CTEPH, n = 19) and pulmonary veno-occlusive disease (PVOD, n = 6) patients underwent rest and peak exercise arterial blood gas measurements during cardiopulmonary exercise testing. Patients were grouped according to resting PaCO₂: hypocapnic (PaCO₂ ≤34 mmHg) or normocapnic (PaCO₂ 35–45 mmHg). The PaCO₂ set-point was estimated by the maximal value of end-tidal PCO₂ (maximal P_ETCO₂) between the anaerobic threshold and respiratory compensation point.ResultsThe hypocapnic group (n = 39) had lower resting cardiac index (3.1 ±0.8 vs. 3.7 ±0.7 L/min/m², p < 0.01), lower peak V′O₂ (15.8 ± 3.5 vs. 20.7 ± 4.3 mL/kg/min, p < 0.01), and higher V′_E/V′CO₂ slope (60.6 ± 17.6 vs. 38.2 ± 8.0, p < 0.01). At peak exercise, hypocapic patients had lower PaO₂, higher V_D/V_T and higher P_(a-ET)CO₂. Maximal P_ETCO₂ (r = 0.59) and V_D/V_T (r = −0.59) were more related to cardiac index than PaO₂ or PaCO₂ at rest or peak exercise. Maximal P_ETCO₂ was the strongest correlate of V′_E/V′CO₂ slope (r = −0.86), peak V′O₂ (r = 0.64) and peak work rate (r = 0.49).ConclusionsResting hypocapnia is associated with worse cardiac function, more ventilatory inefficiency and reduced exercise capacity. This could be explained by elevated chemosensitivity and lower PaCO₂ set-point. Maximal P_ETCO₂ may be a useful non-invasive marker of PaCO₂ setpoint and disease severity even with submaximal effort.     

Low mannose-binding lectin (MBL) is associated with paediatric inflammatory bowel diseases and ileal involvement in patients with Crohn disease

BackgroundMannose-binding lectin (MBL) is a pattern-recognition molecule of the innate immune system and may be involved in the pathogenesis of inflammatory bowel disease (IBD). Our aim was to assess the prevalence of MBL deficiency in a cohort of patients with paediatric-onset IBD and study whether it is associated with the clinical manifestations, serum antibody formation, or genetic factors.MethodsThis prospective study included 159 paediatric patients (mean age: 14.0 years) with IBD [107 patients with Crohn disease (CD) and 52 patients with ulcerative colitis (UC)]. Furthermore, 95 controls were investigated. Serum samples were determined for MBL by enzyme-linked immunosorbent assay (ELISA) and for serologic markers [autoantibodies against Saccharomyces cerevisiae (ASCA) and perinuclear components of neutrophils (pANCA)] by indirect immunofluorescent assay. NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism.ResultsThe MBL serum concentration was significantly lower in IBD patients(both with CD and UC) compared to controls (IBD, p = 0.007, CD, p = 0.04, UC p = 0.004). Prevalence of low MBL level (< 500 ng/mL) was significantly higher in both CD and UC groups compared to controls (p = 0.002 and p = 0.006). Furthermore, low MBL level was associated with isolated ileal involvement (p = 0.01) and MBL deficiency (< 100 ng/mL) with male gender (p = 0.004) in patients with CD. We failed to confirm any correlation between MBL deficiency and serum autoantibodies or NOD2/CARD15 variants.ConclusionsOur results suggest that low MBL associated with paediatric-onset IBD and ileal CD may be considered an additional marker of the IBD pathogenesis.     

Total soluble and endogenous secretory receptor for advanced glycation endproducts (RAGE) in IBD

Background and aimsRecruitment and activation of neutrophils, with release of specific proteins such as S100 proteins, is a feature of inflammatory bowel disease (IBD). Soluble forms of the receptor for advanced glycation endproducts (sRAGE), and variants such as endogenous secretory (esRAGE), can act as decoy receptors by binding ligands, including S100A12. The aims of this study were to determine total sRAGE and esRAGE concentrations in patients with IBD and correlate these with C-reactive protein (CRP), endoscopic scores and clinical disease activity scores.MethodsEDTA-plasma was collected from patients undergoing colonoscopy including those with Crohn's disease (CD: n = 125), ulcerative colitis (UC: n = 79) and control patients without endoscopic signs of inflammation (non-IBD: n = 156). Concentrations of sRAGE and esRAGE were determined by enzyme-linked immunosorbent assay and plasma CRP concentrations measured. Standard clinical disease activity and endoscopic severity scores were defined for all subjects.ResultsPlasma sRAGE concentrations were lower in UC (but not CD) than non-IBD subjects (p < 0.01). Whilst sRAGE concentrations correlated negatively with endoscopic activity in UC (p < 0.05), this was not seen in CD. In contrast, esRAGE correlated negatively with disease activity in both UC (p = 0.002) and CD (p = 0.0001). Furthermore, sRAGE and esRAGE concentrations correlated inversely with CRP values (p < 0.0001).ConclusionsAlthough total sRAGE varied with activity in UC, esRAGE concentrations correlated inversely with endoscopic disease activity and CRP levels in both UC and CD. Additional studies are required to further define the significance of sRAGE and esRAGE in IBD.     

A unique clinical phenotype of primary sclerosing cholangitis associated with Crohn's disease

Background and aimsA distinct clinical phenotype has been demonstrated for ulcerative colitis with concomitant primary sclerosing cholangitis (PSC). The course and behaviour of Crohn's disease (CD) with PSC has, in contrast, never been defined. We aimed to define the characteristics of patients with concomitant PSC and CD.MethodsThe Oxford PSC and IBD databases were abstracted for: PSC subtype, date of diagnosis, symptom onset, smoking history, Mayo Clinic PSC score and outcomes (hepatic failure, liver transplantation, Montréal CD classification, treatment, cancer and death). Patients with PSC/CD were matched 1:2 to two control groups: one with PSC/UC and one with isolated CD.Results240 patients with PSC were identified; 32 (13%) with CD, 129 (54%) with co-existing UC, and 79 had PSC without IBD. For PSC/CD vs. CD controls, isolated ileal CD was less common (6% vs. 31%, p = 0.03). Smoking was less common in PSC/CD (13% vs. 34%, p = 0.045). No difference in the distribution of CD, or treatment required was observed. For PSC/CD vs. PSC/UC controls, more patients with PSC/CD were female (50% vs. 28%, p = 0.021). 22% of PSC/CD patients had small duct PSC compared with 6% with PSC/UC, (p = 0.038). Major event-free survival was prolonged in the PSC/CD group compared with PSC/UC, (Cox regression p = 0.04).ConclusionUnlike PSC/UC, patients with PSC/CD were as likely to be female as male, more commonly had small duct PSC and less commonly progressed to cancer, liver transplantation, or death. Compared to patients with isolated CD, patients with PSC/CD were less likely to smoke or have ileal disease.     

OCTN1 variant L503F is associated with familial and sporadic inflammatory bowel disease

PurposeA two-allele haplotype of TC (OCTN1 rs1050152 and OCTN2 -207G→C) is associated with Crohn's disease (CD). The association has been replicated in different populations, but also failed in some studies. The present study is to replicate the association of OCTN1 rs1050152 and examine another variant rs272879 with familial and sporadic inflammatory bowel disease (IBD) in a cohort from central Pennsylvania, USA.MethodsThe study samples (n = 465) included 212 inflammatory bowel disease patients (CD = 115, UC = 97), including 103 familial (CD = 55, UC = 46) and 111 sporadic (CD = 60, UC = 51) IBD, 139 non-IBD family members from a familial IBD registry, and 114 unrelated healthy controls. A total of 12 OCTN1 variants within exonic sequences were examined. Two nonsynonymous SNPs, rs1050152 (L503F) and rs272879 (L395V) were genotyped by a PCR-based RFLP/cRFLP method and statistically analyzed. These samples with an additional 141 unrelated healthy samples were also genotyped for rs1050152 using the SNPlex? Genotyping System.ResultsThe OCTN1 rs1050152 is associated with CD (OR = 1.745, 95% CI = 1.019–2.990, χ² = 4.129, p = 0.042) and with IBD (OR = 1.68, 95% CI = 1.052–2.676, χ² = 4.732, p = 0.030); while the variant rs272879 is not associated with IBD, CD or ulcerative colitis (UC). The distribution of the rs1050152 variant showed a high level of the T allele in male UC (OR = 2.585, 95% CI = 1.139–5.869, p = 0.023) and IBD (OR = 2.039, 95% CI = 1.024–4.059, p = 0.042) patients, and in female CD patients (OR = 2.329, 95% CI = 1.038–5.226, ρ value = 0.039).ConclusionThe present results replicated the association of the OCTN1 rs1050152 (L503F) variant with CD and IBD overall. A weak gender-specific effect of rs1050152 (L503F) on male UC and female CD was observed.     

IFN-γ stimulation of dental follicle mesenchymal stem cells modulates immune response of CD4+ T lymphocytes in Der p1+ asthmatic patients in vitro

BackgroundHouse dust mite (Dermataphagoides pteronyssinus) is a widespread risk factor in the development of asthma. CD4⁺ T lymphocytes have an important role in the pathogenesis of allergic asthma by polarizing to Th2 cells.ObjectiveWe aimed to evaluate the immunoregulatory effects of dental follicle mesenchymal stem cells with and without IFN-γ stimulation on peripheral blood mononuclear cells of house dust mite sensitive asthmatic patients, and compared those with Dexamethasone as a systemic steroid.Material and methodsPBMC of asthmatic patients and healthy individuals separately cultured with or without DF-MSCs in the presence and absence of IFN-γ or Der p1 or Dexamethasone for 72 h. CD4⁺ T proliferation, cell viability, CD4⁺CD25⁺FoxP3⁺ Treg cell frequency and cytokine profiles of PBMC were evaluated via flow cytometry.ResultsDF-MSCs suppressed proliferation of CD4⁺ T lymphocytes (p_CDmix < 0.01, p_Derp1 < 0.01, p_IFN < 0.005) by increasing the number of FoxP3 expressing CD4⁺CD25⁺ T regulatory cells (p_CDmix < 0.005, p_Derp1 < 0.01, p_IFN < 0.001) and suppressed lymphocyte apoptosis (p_CDmix < 0.05, p_Derp1 < 0.05, p_IFN < 0.05), while Dexamethasone increased the apoptosis and decreased Treg cell frequency in asthmatic patients. IFN-γ stimulation increased the suppressive effect of DF-MSCs and also enhanced the frequency of FoxP3 expressing CD4⁺CD25⁺ T regulatory cells. The cytokine levels were regulated by DF-MSCs by reducing IL-4 cytokine levels (p_CDmix < 0.01, p_Derp1 < 0.05, p_IFN < 0.05) and upregulating IFN-γ levels (p_CDmix < 0.01, p_Derp1 < 0.05, p_IFN < 0.005) in asthmatic patients.ConclusionIFN-γ stimulated DF-MSCs were found to have a high modulatory effect on CD4⁺ T cell responses, while Dexamethasone had an apoptotic effect on CD4⁺ T cells in asthmatic patients. DF-MSCs may be a new cell-based therapy option for allergic diseases including asthma.     

Bile acid malabsorption assessed by 7 alpha-hydroxy-4-cholesten-3-one in pediatric inflammatory bowel disease: Correlation to clinical and laboratory findings

Background and aimsMeasurement of 7 alpha-hydroxy-4-cholesten-3-one (C4) in serum is a semiquantitative test for bile acid malabsorption (BAM). We have previously established pediatric normal values for C4 with an upper limit of normal of 66.5 ng/mL, independent of age and sex. Here we performed the C4 test in 58 pediatric patients with Crohn's disease (CD) and ulcerative colitis (UC).MethodsC4 was measured using high performance liquid chromatography (HPLC) in fasting serum samples of 44 patients with CD (range 7–19 years) and 14 with UC (4–18 years). Disease activity was assessed by the pediatric CD and UC activity indices (PCDAI and PUCAI, respectively) plus serum (CRP, ESR) and fecal inflammatory markers (calprotectin).ResultsC4 concentrations were increased in 10 CD (23%) (range: 70.8–269.3 ng/mL) but only one UC patient (72.9 ng/mL). CD patients with diarrhea (n = 12) had higher C4-values compared to those without (76.9 vs. 30.4 ng/mL; p = 0.0043). Ileal resection in CD patients (n = 10) was associated with increased C4 concentrations (81.2 vs. 24.3 ng/mL, p = 0.0004). No correlation was found between C4 values and inflammatory markers. Six of 7 CD patients with persistent diarrhea but quiescent disease (PCDAI ≤ 12.5) had C4 values indicating BAM.ConclusionElevated C4 concentrations indicating BAM are common in children with CD. They are associated with ileal resection and non-bloody diarrhea in the absence of active disease or elevated inflammatory markers. The C4-test identifies a subgroup of CD patients with persistent diarrhea in spite of clinical remission which may benefit from bile acid binding therapy.     

Increased titers of anti-Saccharomyces cerevisiae antibodies in Crohn's disease patients with reduced H-ficolin levels but normal MASP-2 activity

Background and aimsMannan-binding lectin (MBL) and ficolins are microbial pattern recognition molecules that activate the lectin pathway of complement. We previously reported the association of MBL deficiency with anti-Saccharomyces cerevisiae antibodies (ASCA) in patients with Crohn's disease (CD). However, ASCA are also frequently found in MBL-proficient CD patients. Here we addressed expression/function of ficolins and MBL-associated serine protease-2 (MASP-2) regarding potential association with ASCA.MethodsASCA titers and MBL, ficolin and MASP-2 concentrations were determined by ELISA in the serum of patients with CD, ulcerative colitis (UC), and in healthy controls. MASP-2 activity was determined by measuring complement C4b-fixation. Anti-MBL autoantibodies were detected by ELISA.ResultsIn CD and UC patients, L-ficolin concentrations were significantly higher compared to healthy controls (p < 0.001 and p = 0.029). In contrast, H-ficolin concentrations were slightly reduced in CD and UC compared to healthy controls (p = 0.037 for UC vs. hc). CD patients with high ASCA titers had significantly lower H-ficolin concentrations compared to ASCA-low/negative CD patients (p = 0.009). However, MASP-2 activity was not different in ASCA-negative and ASCA-positive CD patients upon both, ficolin- or MBL-mediated MASP-2 activation. Finally, anti-MBL autoantibodies were not over-represented in MBL-proficient ASCA-positive CD patients.ConclusionsOur results suggest that low expression of H-ficolin may promote elevated ASCA titers in the ASCA-positive subgroup of CD patients. However, unlike MBL deficiency, we found no evidence for low expression of serum ficolins or reduced MASP-2 activity that may predispose to ASCA development.