Body composition, physical activity, and quality of life in pediatric patients with inflammatory bowel disease on anti-TNF therapy-an observational follow-up study.

BACKGROUND: Poor outcome of inflammatory bowel disease (IBD) is associated with malnutrition. Our aim was to compare body composition (BC) and physical activity (PA) between patients with IBD and healthy controls, and to assess the changes in BC, PA and health related quality of life (HRQoL) in children with IBD during anti-TNF therapy. METHODS: 32 children with IBD (21 with Crohn's disease (CD), (age: 15.2 ± 2.6 years, 9 male) and 11 with ulcerative colitis (UC), (age: 16.4 ± 2.2 years, 5 male) participated in this prospective, observational follow up study conducted at Semmelweis University, Hungary. As control population, 307 children (age: 14.3 ± 2.1) (mean ± SD) were included. We assessed BC via bioelectric impedance, PA and HRQoL by questionnaires at initiation of anti-TNF therapy, and at two and six months later. The general linear model and Friedman test were applied to track changes in each variable. RESULTS: During follow-up, the fat-free mass Z score of children with CD increased significantly (-0.3 vs 0.1, p = 0.04), while the BC of patients with UC did not change. PA of CD patients was lower at baseline compared to healthy controls (1.1 vs. 2.4), but by the end of the follow up the difference disappeared. CONCLUSIONS: The fat-free mass as well as PA of CD patients increased during the first six months of anti-TNF treatment. As malnutrition and inactivity affects children with IBD during an important physical and mental developmental period, encouraging them to engage in more physical activity, and monitoring nutritional status should be an important goal in patient care.

Disease Activity Is Associated with Obesity in Newly Diagnosed Pediatric Patients with Ulcerative Colitis.

Malnutrition and inflammatory bowel disease (IBD) are interrelated conditions. Our aim was to assess the prevalence of malnutrition, to compare anthropometric parameters in the evaluation of nutritional status in pediatric IBD, and to investigate the association between anthropometric parameters and disease activity indices (AI). Pediatric patients with newly diagnosed IBD recorded between 2010 and 2016 in the Hungarian Pediatric IBD Registry were included in this cross-sectional study. Body weight, body mass index (BMI), weight-for-height, and ideal body weight percent (IBW%) were analyzed. Pearson linear and non-linear correlations and polynomial regression analyses were performed to assess correlation between nutritional status and AI. p-values < 0.05 were considered significant. Anthropometric data of 1027 children with IBD (Crohn's disease (CD): 699; ulcerative colitis (UC): 328; mean age 13.7 years) were analyzed. IBW% identified more obese patients than BMI both in CD (7.02% vs. 2.28%) and UC (12.17% vs. 5.48%). Significant negative correlation was found among anthropometric parameters and AI in CD. In contrast, polynomial regression analysis revealed a U-shaped correlation curve between IBW% and AI in UC. Our findings show that obesity has a bimodal association with disease activity in pediatric UC. Furthermore, IBW% was more useful to identify obese pediatric patients with IBD.

The gastrointestinal effects of COVID­19 infection during childhood and among the children affected with inflammatory bowel disease / A COVID-19-fertozés gastrointestinalis hatásai gyermekkorban és a gyulladásos bélbeteg gyermekekben.

Összefoglaló. A SARS-CoV-2-infekció változatos kórlefolyású, a gyermekpopulációban növekvo incidenciát mutató fertozés. Ebben a korcsoportban a felnottekkel szemben sokkal gyakrabban tapasztalhatók gasztroenterológiai tünetek a betegség során, 18-32%-ban jelentkezik legalább egy szimptóma. Ezek nem specifikusak, gyakran megegyezhetnek a virális enteritisek, a gyulladásos bélbetegségek vagy a vakbélgyulladás tüneteivel. A gyermekkori SARS-CoV-2-infekciónak egy viszonylag ritkán megjeleno, de súlyos, akár életveszélyes szövodménye a gyermekkori sokszervi gyulladásos szindróma (multisystem inflammatory syndrome in children, MIS-C). Ilyenkor a gastrointestinalis tünetek gyakorisága 60-100%-ra no, sok esetben akut has benyomását keltve. A jelenlegi kutatások eredményei alapján a gyulladásos bélbeteg gyerekek az alapbetegségük miatt nincsenek nagyobb veszélynek kitéve az átlagpopulációhoz képest a COVID-19-fertozés szempontjából. A terápiájukban alkalmazott gyógyszereik közül a nagy dózisú szteroidkezelés okoz nagyobb kockázatot a megfertozodésre, illetve ebben az esetben a súlyosabb kórlefolyásra. Az éppen remisszióban lévo gyulladásos bélbetegek fenntartó terápiájának módosítások nélküli folytatása javasolt, kiemelt figyelmet fordítva a biológiai terápiák idoben történo, megszakítás nélküli alkalmazására. Törekedni kell a személyes vizitek számának csökkentésére a pandémia idején, ezek telemedicinával történo helyettesítése javasolt. A halasztható endoszkópos vizsgálatok noninvazív vizsgálómódszerekkel történo átmeneti kiváltása részesítendo elonyben a betegség aktivitásának, a terápia hatékonyságának megítélésére. A gyulladásos bélbetegségben szenvedo gyermekek COVID-19 elleni védooltása javasolt, jelenleg minden elérheto oltóanyag alkalmazható náluk (az élo ágenst tartalmazó vakcinák ellenjavalltak). Immunmoduláns, szteroid- vagy anti-tumornekrózisfaktor (TNF)-alfa-terápia esetén az oltás lehetséges csökkent hatékonyságával kell számolni. Orv Hetil. 2022; 163(6): 214-221. Summary. The SARS-CoV-2 infection is showing high variety in the disease course, with a constantly increasing incidence among the pediatric population. In this age group, at least one gastrointestinal symptom appears in 18-32% of the cases, showing a significant difference compared to the adult population. The gastrointestinal signs of COVID-19 are not specific, can mimic the symptoms of viral enteritis, inflammatory bowel diseases or acute appendicitis. The multisystem inflammatory syndrome in children (MIS-C) is a rather rare, but serious complication of the pediatric COVID-19 disease: in these cases, the incidence of the gastrointestinal symptoms is increased up to 60-100%, often observed as acute abdomen. Based on recent researches, patients with inflammatory bowel diseases (IBD) are shown to have the same risk in developing COVID-19 infection compared to the normal population: in their medications, the high dose steroid treatment is proved to increase the risk of infection or to make the disease course more serious. The treatment of patients with IBD should be continued without any changes (when the disease is in remission). The use of biologics should be done with special care, with more attention keeping the schedule and the continuity. It is advised to minimise the number of personal visits during the pandemic, they should be substituted with telemedicine. The postponable endoscopic examinations should be temporarily redeemed by non-invasive methods for screening the disease activity and the efficacy of the treatment. The vaccination against COVID-19 is advised in the population with IBD. All vaccines currently available are usable in this patient group (the use of vaccines containing live agents are contraindicated). In the case of patients treated with immunmodulators, steroids or anti-tumor necrosis factor (TNF) alpha, a possible lower efficacy can be expected after the vaccination. Orv Hetil. 2022; 163(6): 214-221.

Joint involvement, disease activity and quality of life in pediatric Crohn's disease - a cross-sectional study.

BACKGROUND: Few published data describe how joint involvement, the most prevalent extraintestinal manifestation, affects quality of life (QoL) of children with Crohn's disease (CD). Arthritis and arthralgia rates in pediatric CD patients are reportedly 3-24% and 17-22%, respectively, but studies on pre-emptive and systematic screening of joint involvement with detailed musculoskeletal rheumatological exam are lacking. More detailed data collection on joint involvement improves our understanding of how arthropathy relates to disease activity and QoL measured by the Pediatric CD Activity Index (PCDAI) and IMPACT-III questionnaire. Our study aims were to assess joint involvement in pediatric CD and correlate it with the PCDAI and IMPACT-III. METHODS: In this cross-sectional, observational study, a pediatric gastroenterologist assessed consecutively-seen pediatric CD patients at a tertiary care center. Patients were screened for prevalence of current and previous arthropathy, including arthritis, enthesitis and arthralgia. A single experienced pediatric rheumatologist evaluated detailed musculoskeletal history, joint status, and modified Juvenile Arthritis Multidimensional Assessment Reports (JAMAR). PCDAI, IMPACT-III, sacroiliac MRI, and HLA-B27 genetic testing were also completed. RESULTS: A total of 82 (male:female, 1.2:1; age, 13.7 ± 3.2 years) patients were involved in this study. Mean disease duration at time of study was 21.6 ± 21 months; eight of the patients were newly-diagnosed. Of the 82 patients, 29 (35%) had evidence of arthritis; for 24 of those, this was revealed by physical exam during cross-sectional screening, and by prior documentation for the remaining five patients. Joint examination confirmed active arthritis in 8/24 (33%), active enthesitis in 1/24 (4%), and evidence of previous arthritis in 15/24 (62.5%) patients. Hip (41%) and knee (38%) joints were most commonly affected. Cumulative incidence of arthralgia was 48% (39/82), and 46% (18/39) of those patients had only arthralgia without arthritis, usually affecting the knee. Axial involvement was present in 10/82 (12%) patients. Joint involvement correlated with more severe CD disease activity, specifically higher PCDAI and lower IMPACT-III scores, and increased requirement for infliximab treatment. Sacroiliitis and HLA-B27 positivity were insignificant factors in this cohort. CONCLUSIONS: When a rheumatologist performed the assessment, joint involvement in pediatric CD was more prevalent than previously reported, in this cross-sectional study. Arthritis was associated with more severe CD disease activity and lower QoL.

Adherence to the Porto Criteria Based on the Hungarian Nationwide Pediatric Inflammatory Bowel Disease Registry (HUPIR).

Objectives: According to the Porto criteria, upper endoscopy and ileocolonoscopy with histology for patients with pediatric inflammatory bowel disease (pIBD) are recommended with small bowel imaging (SBI). We aimed to evaluate the adherence to the Porto criteria and biopsy sampling practice and to evaluate the diagnostic yield of magnetic resonance enterography (MRE) first time in a nationwide pIBD inception cohort. Methods: Newly diagnosed pIBD cases (ages 0-18 years) are registered in the prospective, nationwide Hungarian Paediatric IBD Registry (HUPIR). We analyzed the diagnostic workup of patients recorded between the 1st of January 2007 and the 31st of December 2016. Results: Data for diagnostic workup was available in 1,523 cases. Forty percent of the cases had complied with the Porto criteria. Adherence to the Porto criteria increased significantly from 20 to 57% (p < 0.0001) between 2007 and 2016. The most frequent reason for the incomplete diagnostic work-up was the lack of small bowel imaging (59%). In 2007, 8% of cases had a biopsy from all segments, and this rate reached 51% by 2016 (p < 0.0001). We analyzed the diagnostic yield of MRE in 113 patients (10.1%), who did not have any characteristic lesion for Crohn's disease. The MRE was positive for the small bowel in 44 cases (39%). Conclusions: Adherence to the Porto criteria increased significantly during the 10-year period. This is the first study that reports multiple biopsy sampling as the less accepted recommendation. The diagnostic yield of MRE in patients without characteristic lesion for Crohn's disease is 39%.

Immunomodulatory role of Parkinson's disease 7 in inflammatory bowel disease.

Recently the role of Parkinson's disease 7 (PARK7) was studied in gastrointestinal diseases, however, the complex role of PARK7 in the intestinal inflammation is still not completely clear. Expression and localization of PARK7 were determined in the colon biopsies of children with inflammatory bowel disease (IBD), in the colon of dextran sodium sulphate (DSS) treated mice and in HT-29 colonic epithelial cells treated with interleukin (IL)-17, hydrogen peroxide (H2O2), tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß or lipopolysaccharide (LPS). Effect of PARK7 on the synthesis of IBD related cytokines was determined using PARK7 gene silenced HT-29 cells and 3,4,5-trimethoxy-N-(4-(8-methylimidazo(1,2-a)pyridine-2-yl)phenyl)benzamide (Comp23)-compound increasing PARK7 activity-treated mice with DSS-colitis. PARK7 expression was higher in the mucosa of children with Crohn's disease compared to that of controls. While H2O2 and IL-17 treatment increased, LPS, TNF-α or TGF-ß treatment decreased the PARK7 synthesis of HT-29 cells. PARK7 gene silencing influenced the synthesis of IL1B, IL6, TNFA and TGFB1 in vitro. Comp23 treatment attenuated the ex vivo permeability of colonic sacs, the clinical symptoms, and mucosal expression of Tgfb1, Il1b, Il6 and Il10 of DSS-treated mice. Our study revealed the role of PARK7 in the regulation of IBD-related inflammation in vitro and in vivo, suggesting its importance as a future therapeutic target.

Foreign body type reaction causing differential diagnostic difficulty after appendectomy / Differenciáldiagnosztikai nehézséget okozó fonálgranuloma appendectomia után.

Összefoglaló. Az appendectomia szövodményei a leggyakrabban a korai posztoperatív idoszakban jelentkeznek. A mutét után évekkel megjeleno szövodmény ritka. Egy 11 éves kislányt vizsgáltunk 2 hete fennálló hasi panaszok miatt. Anamnézisében 8 évvel ezelott hagyományos módon elvégzett appendectomia szerepel. Az Ausztriában készült elso hasi ultrahangvizsgálat eltérést nem talált. Az intézetünkben elvégzett képalkotó vizsgálatok - hasi ultrahang, MR-vizsgálat - ileocoecalisan elhelyezkedo szolid terimét igazoltak, és felvetették a folyamat gyulladásos eredetét. A szerteágazó klinikai tünetek, a laboratóriumi és a képalkotó diagnosztikai eltérések kapcsán differenciáldiagnosztikai szempontból a gyulladásos bélbetegség lehetosége is felmerült, és biztonsággal a tumoros folyamatot sem sikerült kizárni. A rosszabbodó status miatt mutét történt. Ennek során a colon ascendenssel összefüggo, makroszkóposan tumoros megjelenésu elváltozást távolítottak el. A szövettani vizsgálat malignitást nem igazolt, a folyamat idegen test okozta - varróanyag-granuloma - krónikus gyulladásos jellegét erosítette meg. A vizsgálatok kapcsán coeliakia is igazolódott. A hasi mutétek ritka szövodménye a Schloffer-tumor, melyet idegen test típusú - gyakran sebészi varróanyag-maradvány körüli - granulomatosus gyulladásos folyamat jellemez. Az entitás ismerete differenciáldiagnosztikai szempontból fontos. Nehezítette a diagnózist az elso hasi ultrahangvizsgálat negatív eredménye és az egyidejuleg manifesztálódó coeliakia. Orv Hetil. 2021; 162(3): 112-115. Summary. Generally, complications with appendectomy occur during the early postoperative stage and are quite rare years after the operation. In case of late manifestation of complications, the clinical signs are generally unspecific. We report a case of an 11-year-old girl - who underwent an appendectomy 8 years ago - with abdominal pain during the last 2 weeks. The first ultrasound examinations were carried out in Austria with normal results. In our department, the ultrasonography and the MR examinations showed an inhomogeneous abdominal mass which was connected to the abdominal wall and with the suspicion of inflammation. Because of the diversified results of radiology imaging and laboratory test, inflammatory bowel disease and tumor were considered in the differential diagnosis. During the operation, a tumor-like lesion related to the ascending colon was found. The histopathological examination revealed a foreign body type suture granuloma with a central abscess. Malignancy was not found. The clinical investigation proved celiac disease, too. The Schloffer tumor is a rare complication after abdominal surgery. This is a foreign body type inflammatory granuloma mainly around a surgical thread. The knowledge of the entity is important in differential diagnostic aspect. The presence of celiac disease in combination with the negative result of the first ultrasound examination made the exact diagnosis more difficult. Orv Hetil. 2021; 162(3): 112-115.

PARK7 Diminishes Oxidative Stress-Induced Mucosal Damage in Celiac Disease.

Coeliac disease (CD) is a chronic, immune-mediated small intestinal enteropathy, accompanied with gluten-triggered oxidative damage of duodenal mucosa. Previously, our research group reported an increased mucosal level of the antioxidant protein Parkinson's disease 7 (PARK7) in children with CD. In the present study, we investigated the role of increased PARK7 level on the epithelial cell and mucosal integrity of the small intestine. The presence of PARK7 was investigated using immunofluorescent staining on duodenal mucosa of children with CD and on FHs74Int duodenal epithelial cells. To investigate the role of oxidative stress, FHs74Int cells were treated with H2O2 in the absence or presence of Comp23, a PARK7-binding compound. Intracellular accumulation of reactive oxygen species (ROS) was determined by DCFDA-based assay. Cell viability was measured by MTT, LDH, and Annexin V apoptosis assays. Disruption of cytoskeleton and cell adhesion was investigated by immunofluorescence staining and by real-time RT PCR. Effect of PARK7 on mucosal permeability was investigated ex vivo using intestinal sacs derived from control and Comp-23-pretreated mice. Comp23 treatment reduced the H2O2-induced intracellular accumulation of ROS, thus preserving the integrity of the cytoskeleton and also the viability of the FHs74Int cells. Accordingly, Comp23 treatment increased the expression of antioxidants (NRF2, TRX1, GCLC, HMOX1, NQO1), cell-cycle regulators (TP53, CDKN1A, PCNA, BCL2, BAX), and cell adhesion molecules (ZO1, CDH1, VCL, ITGB5) of H2O2-treated cells. Pretreatment with Comp23 considerably decreased the small intestinal permeability. In this study, we demonstrate that PARK7-binding Comp23 reduces the oxidative damage of duodenal epithelial cells, via increased expression of NRF2- and P53-regulated genes. Our results suggest that PARK7 plays a significant role in the maintenance of mucosal integrity in CD.

Role of microRNA-223 in the regulation of poly(ADP-ribose) polymerase in pediatric patients with Crohn's disease.

OBJECTIVES: Crohn's disease (CD) is a multifactorial disease, characterized by oxidant-induced tissue injury with a possible activation of poly(ADP-ribose) polymerase (PARP)-1. MicroRNAs (miRs) can offer a potential link between the genetic susceptibility, environmental and immunologic factors in the pathogenesis of CD. Previously, PARP-1 was identified as a direct target gene of miR-223 in an epithelial cell line. Our aim was to examine PARP activation and miR-223 expression in colonic biopsies of pediatric CD. To support our in vivo findings, the effect of lipopolysaccharide (LPS) on same parameters was examined in HT-29 colonic epithelial cell line. METHODS: Colonic biopsies were taken from patients with macroscopically inflamed and intact mucosa with CD and controls. LPS treated HT-29 cells served as our in vitro model. To analyze the PARP-1 expression real-time PCR, Western blot and immunohistochemical analyses were used. PARP-1 enzymatic activity was assessed on the basis of poly(ADP-ribosyl)ated proteins. Expression of miR-223 was examined by real-time PCR. RESULTS: PARP-1 mRNA and miR-223 expression was significantly elevated, however, the amount of PARP-1 protein and poly(ADP-ribose) was reduced in pediatric CD compared to controls. LPS incubation did not affect the expression of PARP-1 mRNA, however, decreased miR-223 expression, and enhanced PARP-1 activity. CONCLUSIONS: In our study, we showed that the expression of miR-223 is up-regulated and poly(ADP-ribosyl)ation is reduced in pediatric patients with CD. Moreover, we confirmed their opposite change in LPS treated epithelial cells, too. These data suggest that the hypofunctionality of PARP-1 may play a potential role in the pathomechanism of CD.

Long time enzyme replacement therapy stabilizes obstructive lung disease and alters peripheral immune cell subsets in Fabry patients.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder, causing accumulation of globotriaosylceramid in different organs. Glycolipids are activators of different immune cell subsets the resulting inflammation is responsible for organ damage. Pulmonary involvement leads to airway inflammation; however, data on severity, as well as the effect of enzyme replacement therapy on lung function parameters and changes in peripheral immune cell subsets on lung involvement are sparse. METHODS: Seven Fabry patients and four carriers underwent detailed clinical examinations screening for pulmonary manifestations. Repetitive measurements were performed on five patients on ERT (average follow-up 5 years). Patients with Fabry disease and control volunteers were included into peripheral blood cell measurements. RESULTS: Lung involvement was present in all patients. Symptoms suggestive for lung disease were mild, however, obstructive ventilatory disorder, dominantly affecting small airways accompanied by hyperinflation was demonstrated in all affected patients. ERT resulted in small improvement of FEV1 in most treated patients. Decreased ratio of myeloid DC, Th17 cells while increase in T helper (Th)1 cells, and no change in Th2 and regulatory T (Treg) cells were detected in Fabry patients. CONCLUSIONS: Fabry disease results mainly in mild symptoms related to lung involvement, characterized by moderate non-reversible obstructive ventilatory disorder. Stabilization of airway obstruction during follow-up was observed using ERT in most patients, emphasizing the importance of this treatment in respect of pulmonary manifestations. Changes of immune cell subsets in the peripheral blood might play a role in inflammatory process, including small airways in Fabry patient's lung.

The impact of DMARD and anti-TNF therapy on functional characterization of short-term T-cell activation in patients with rheumatoid arthritis--a follow-up study.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a systemic dysfunction of T-cells. In this study we tested the impact of DMARD and anti-TNF agents on short-term activation characteristics of T-cells. We enrolled 12 patients with newly diagnosed RA (naïve RA) who were treated with methothrexate (MTX) and glucocorticsteroid (GCS) and 22 patients with established RA non responding to conventional DMARD therapy who were treated with different anti-TNF agents. Nine healthy volunteers served as controls. Blood samples were taken at baseline, then at 4th and 8th week of therapy. The characteristics of several intracellular activation processes during short-term activation of T-cells including cytoplasmic Ca(2+) level, mitochondrial Ca(2+) level, reactive oxygen species (ROS) and nitric oxide (NO) generation were determined by a novel flow-cytometry technique. At baseline, the tested processes were comparable to controls in naïve RA. During GCS therapy, cytoplasmic Ca(2+) level and ROS generation decreased. After the addition of MTX to GCS cytoplasmic Ca(2+) level became comparable to controls, while ROS generation decreased further. In DMARD non responders, cytoplasmic Ca(2+) level was higher than controls at baseline. The cytoplasmic Ca(2+) level became comparable to controls and ROS generation decreased during each of the three anti-TNF-α agent therapies. Mitochondrial Ca(2+) level and NO generation were unaltered in all of the patient groups. These results indicate that intracellular machinery is affected in T-cells of RA patients. This may alter the behavior of T-cells during activation. Different therapeutic approaches may modulate the abnormal T-cell functions.

Autoregressive cross-lagged models of IMPACT-III and Pediatric Crohn's Disease Activity Indexes during one year infliximab therapy in pediatric patients with Crohn's disease.

BACKGROUND: Quality of life (QoL) is an important outcome measure in the evaluation of therapies for inflammatory bowel disease. The primary aim of this study was to determine the effect of one year infliximab treatment on QoL and clinical parameters in pediatric patients with Crohn's diseases (CD). METHODS: Our prospective study involved 51 children with conventional therapy resistant, severe CD (mean age: 15.25years, range: 11-18years). Infliximab was given according to the protocol (5mg/kg, at weeks 0, 2, 6 and every 8weeks). During the infliximab courses QoL of patients was evaluated by IMPACT-III questionnaire at weeks 0, 6, 30 and 53. At the same time, the Pediatric Crohn's Disease Activity Index (PCDAI) score was calculated. Moreover, serum C-reactive protein (CRP), serum platelets and serum albumin were followed up. Auto-regressive, cross-lagged models were used to assess relation between QoL and the clinical parameters. RESULTS: The initial IMPACT-III scores [median, percentile 25-75 (pc 25-75) at week 0: 115, 102.5-130.25] increased significantly (p<0.001) following infliximab therapy at week 54 (median: 141.5, 124.5-153.75). Clinical and laboratory parameters also improved significantly (p<0.001). Auto-regressive regression coefficients (ß value) were significant between each variable over time. The strongest cross-lagged relations were observed between IMPACT-III and serum albumin, IMPACT-III and platelets. Reliability test of IMPACT-III revealed an excellent level of internal consistency (Cronbach's alpha=0.931). CONCLUSION: Infliximab treatment has beneficial clinical effect which is confirmed by decrease of PCDAI and increase of IMPACT-III. Autoregressive regression analysis showed regression relation between IMPACT-III and PCDAI and laboratory parameters.

The impact of conventional DMARD and biological therapies on CD4+ cell subsets in rheumatoid arthritis: a follow-up study.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by abnormal prevalence of Th1, Th2, Th17, and regulatory (Treg) subsets. Some data suggest that these subsets are influenced by anti-RA agents. Follow-up studies monitoring T cell phenotype in response to therapy are limited. We investigated the alteration of CD4+ T cell subset distribution after the initiation of disease-modifying antirheumatic drug (DMARD) (with glucocorticosteroid (GCS) and methotrexate (MTX)) and anti-TNFα therapy. We enrolled 19 treatment naive (early) RA patients and initiated GCS (in a dose of 16 mg/day for 4 weeks; then 8 mg/day). MTX, 10 mg/week, was started at week 4. We also enrolled 32 RA patients unresponsive to DMARD and initiated anti-TNFα therapy: adalimumab (ADA), 40 mg/2 weeks, n = 12; etanercept (ETA), 50 mg/weeks, n = 12; or infliximab (IFX) on week 0, 2, and 6, 3 mg/kg bw, n = 8. Blood was taken before and 4 and 8 weeks after the initiation of therapy. Ten volunteers served as controls. The T cell phenotype was assessed with flow cytometry. In early RA, Th1, Th2, and Th17 prevalence was higher, while Treg prevalence was lower than normal. GCS alone decreased Th2 prevalence. GCS + MTX decreased Th17 prevalence. Immune phenotype in unresponsive RA before anti-TNF therapy was as in early RA. Four and 8 weeks after initiating anti-TNF therapy, Th1 prevalence was higher than baseline in ETA or IFX, while it was stable in ADA groups. Th2 prevalence was higher than normal in ADA or IFX, while normalized in ETA group. In each group, Treg prevalence increased, while Th17 prevalence was at the baseline. The proinflammatory immune phenotype is normalized only under GCS + MTX combination in early RA. Anti-TNFα therapy exhibit marked effects on all the cell populations investigated (except Th17); some slight differences in this action exist between ADA, ETA, and IFX therapy.

Characteristics of allergic colitis in breast-fed infants in the absence of cow's milk allergy.

AIM: To investigate the characteristics of mucosal lesions and their relation to laboratory data and long-term follow up in breast-fed infants with allergic colitis. METHODS: In this study 31 breast-fed infants were prospectively evaluated (mean age, 17.4 wk) whose rectal bleeding had not ceased after a maternal elimination diet for cow's milk. Thirty-four age-matched and breast-fed infants (mean age, 16.9 wk) with no rectal bleeding were enrolled for laboratory testing as controls. Laboratory findings, colonoscopic and histological characteristics were prospectively evaluated in infants with rectal bleeding. Long-term follow-up with different nutritional regimes (L-amino-acid based formula or breastfeeding) was also included. RESULTS: Iron deficiency, peripheral eosinophilia and thrombocytosis were significantly higher in patients with allergic colitis in comparison to controls (8.4 ± 3.2 µmol/L vs 13.7 ± 4.7 µmol/L, P < 0.001; 0.67 ± 0.49 G/L vs 0.33 ± 0.17 G/L, P < 0.001; 474 ± 123 G/L vs 376 ± 89 G/L, P < 0.001, respectively). At colonoscopy, lymphonodular hyperplasia or aphthous ulceration were present in 83% of patients. Twenty-two patients were given L-amino acid-based formula and 8 continued the previous feeding. Time to cessation of rectal bleeding was shorter in the special formula feeding group (mean, 1.4 wk; range, 0.5-3 wk) when compared with the breast-feeding group (mean, 5.3 wk; range, 2-9 wk). Nevertheless, none of the patients exhibited rectal bleeding at the 3-mo visit irrespective of the type of feeding. Peripheral eosinophilia and cessation of rectal bleeding after administration of elemental formula correlated with a higher density of mucosal eosinophils. CONCLUSION: Infant hematochezia, after cow's milk allergy exclusion, is generally a benign and probably self-limiting disorder despite marked mucosal abnormality. Formula feeding results in shorter time to cessation of rectal bleeding; however, breast-feeding should not be discouraged in long-lasting hematochezia.

Incidence, Paris classification, and follow-up in a nationwide incident cohort of pediatric patients with inflammatory bowel disease.

OBJECTIVES: The aim of the study was to evaluate the incidence, baseline disease characteristics, and disease location based on the Paris classification in pediatric inflammatory bowel disease (IBD) in the Hungarian nationwide inception cohort. In addition, 1-year follow-up with therapy was analyzed. METHODS: From January 1, 2007 to December 31, 2009, newly diagnosed pediatric patients with IBD were prospectively registered. Twenty-seven pediatric gastroenterology centers participated in the data collection ensuring the data from the whole country. Newly diagnosed patients with IBD younger than 18 years were reported. Disease location was classified according to the Paris classification. RESULTS: A total of 420 patients were identified. The incidence rate of pediatric IBD was 7.48/105 (95% confidence interval [CI] 6.34/105-8.83/105). The incidence for Crohn disease (CD) was 4.72/105 (95% CI 3.82-5.79), for ulcerative colitis (UC) 2.32/105 (95% CI 1.71-3.09), and for IBD-unclassified 0.45/105 (95% CI 0.22-0.84). Most common location in CD was L3 (58.7%); typical upper gastrointestinal abnormalities (ulcer, erosion and aphthous lesion) were observed in 29.9%. Extensive colitis in patients with UC (E4, proximal to hepatic flexure) was the most common disease phenotype (57%), whereas only 5% of children had proctitis. A total of 18.6% of patients had ever severe disease (S1). Frequency of azathioprine administration at diagnosis was 29.5% in patients with CD, and this rate increased to 54.6% (130/238) at 1-year follow-up. In UC, only 3.3% received azathioprine initially, and this rate elevated to 22.5% (25/111). Use of corticosteroid decreased from 50% to 15.3% in patients with UC. Rate of bowel resection in patients with CD during the first year of follow-up was 5%. CONCLUSIONS: The incidence of pediatric IBD in Hungary was among the higher range reported. This is the first large, nationwide incident cohort analyzed according to the Paris classification, which is a useful tool to determine the characteristic pediatric CD phenotype.

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

BACKGROUND: Mannose-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. METHODS: This 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. RESULTS: The 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. CONCLUSIONS: Our results suggest that low MBL associated with paediatric-onset IBD and ileal CD may be considered an additional marker of the IBD pathogenesis.

[The role of intestinal alkaline phosphatase in pediatric inflammatory bowel and celiac diseases]. / Az intestinalis alkalikus foszfatáz szerepe gyermekkori gyulladásos bélbetegségben és coeliakiában.

Intestinal alkaline phosphatase enzyme plays a pivotal role in the maintenance of intestinal mucosal barrier integrity with the detoxification capacity of lipopolysaccharide, the ligand of Toll-like receptor 4. The inappropriate immune responses and the damage of the mucosal barrier may contribute to the initiation of inflammatory bowel and celiac diseases. In the inflamed colonic mucosa of children with inflammatory bowel disease and in the duodenal mucosa of newly diagnosed children with celiac disease, the decreased intestinal alkaline phosphatase and increased Toll-like receptor 4 protein expression may generate enhanced lipopolysaccharide activity, which may strengthen tissue damaging processes. The enhancement of intestinal alkaline phosphatase activity in an animal model of colitis and in therapy resistant, adult patients with ulcerative colitis reduced the symptoms of intestinal inflammation. In accordance with these results, the targeted intestinal administration of the enzyme in the two examined disorders may be a supplemental therapeutic option in the future.

Intestinal alkaline phosphatase in the colonic mucosa of children with inflammatory bowel disease.

AIM: To investigate intestinal alkaline phosphatase (iAP) in the intestinal mucosa of children with inflammatory bowel disease (IBD). METHODS: Colonic biopsy samples were taken from 15 newly diagnosed IBD patients and from 10 healthy controls. In IBD patients, specimens were obtained both from inflamed and non-inflamed areas. The iAP mRNA and protein expression was determined by reverse transcription-polymerase chain reaction and Western blotting analysis, respectively. Tissue localization of iAP and Toll-like receptor (TLR) 4 was investigated by immunofluorescent staining. RESULTS: The iAP protein level in the inflamed mucosa of children with Crohn's disease (CD) and ulcerative colitis (UC) was significantly decreased when compared with controls (both P < 0.05). Similarly, we found a significantly decreased level of iAP protein in the inflamed mucosa in CD compared with non-inflamed mucosa in CD (P < 0.05). In addition, the iAP protein level in inflamed colonic mucosa in patients with UC was decreased compared with non-inflamed mucosa in patients with CD (P < 0.05). iAP protein levels in the non-inflamed mucosa of patients with CD were similar to controls. iAP mRNA expression in inflamed colonic mucosa of children with CD and UC was not significantly different from that in non-inflamed colonic mucosa with CD. Expression of iAP mRNA in patients with non-inflamed mucosa and in controls were similar. Co-localization of iAP with TLR4 showed intense staining with a dotted-like pattern. iAP was present in the inflamed and non-inflamed mucosa of patients with CD, UC, and in control biopsy specimens, irrespective of whether it was present in the terminal ileum or in the colon. However, the fluorescent signal of TLR4 was more pronounced in the colon compared with the terminal ileum in all groups studied. CONCLUSION: Lower than normal iAP protein levels in inflamed mucosa of IBD patients may indicate a role for iAP in inflammatory lesions in IBD. Based on our results, administration of exogenous iAP enzyme to patients with the active form of IBD may be a therapeutic option.

Pancreatic autoantibodies and autoantibodies against goblet cells in pediatric patients with inflammatory bowel disease.

BACKGROUND: Significance of pancreatic autoantibodies determined by using exocrine pancreas (PAB) and antibodies against recombinant pancreas antigen (rPAB), as well as the importance of autoantibodies against goblet cells (GAB), is not known in pediatric patients with inflammatory bowel disease (IBD). Our aim was to determine the complex analysis of PAB, rPAB, GAB, antibodies against Saccharomyces cerevisiae, and perinuclear components of neutrophils in pediatric patients with IBD. Moreover, association with NOD2/CARD15 and disease phenotype was determined. METHODS: A total of 152 pediatric patients (median age 13.9 years) with IBD (103 patients with Crohn disease [CD] and 49 patients with ulcerative colitis [UC]) and 104 controls were included. Serum autoantibodies were determined by indirect immunofluorescence assay. NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism. RESULTS: The presence of PAB and rPAB was significantly higher in CD (34% and 35.9%) and in UC (20.4% and 24.5%) compared with pediatric control cohort (0% and 0%, P<0.0001). In addition, GAB positivity was significantly increased in patients with UC in comparison with CD and controls, respectively (UC, 12.2%; CD, 1.9%; controls, 1.9%; P=0.02). Specificity of PAB and rPAB was 100%; however, sensitivity was low. The combination of PAB and/or antibodies against Saccharomyces cerevisiae/perinuclear components of neutrophils improved the sensitivity of serological markers in CD (87.4%) and in UC (79.6%); specificities were 89.3% and 93.2%, respectively. Pancreatic autoantibodies (PAB, rPAB) and GAB were not related to clinical presentation, medical therapy, or need for surgery in CD or in UC. CONCLUSIONS: Pancreatic autoantibodies and GAB were specific for IBD, but the sensitivity was limited as well because there was lack of correlation with clinical phenotype. Combinations of these antibodies have shown increased sensitivity; therefore, it may be recommended in the diagnostic procedure of IBD.