Estimating tissue-specific TNF mRNA levels prior to anti-TNFα treatment may support therapeutic optimisation in IBD patients.

BACKGROUND AND AIMS: Tumour necrosis factor-α (TNF) antagonists have improved the management of inflammatory bowel disease (IBD), however, their usage and administration persist to be suboptimal. Here, we examined the relationship between tissue-specific TNF mRNA expression in mucosal biopsies from IBD patients and anti-TNF treatment response. METHODS: Archived tissue samples from patients with luminal IBD that had all been or were in treatment with anti-TNF were included (18 adults and 24 paediatric patients). Patients were stratified into three groups according to anti-TNF response: responders, primary non-responders (PNR) and secondary loss of response (SLOR). TNF mRNA was detected using RNAscope in situ hybridisation (ISH) and the expression was quantified using image analysis. RESULTS: The ISH analysis showed varying occurrence of TNF mRNA positive cells located in lamina propria and often with increased density in lymphoid follicles (LF). Consequently, expression estimates were obtained in whole tissue areas with and without LF. Significantly higher TNF mRNA expression levels were measured in adults compared to paediatric patients in both the analyses with and without LF (p = .015 and p = .016, respectively). Considering the relation to response, the adult and paediatric patients were evaluated separately. In adults, the TNF expression estimates were higher in PNRs compared to responders with and without LF (p = .017 and p = .024, respectively). CONCLUSION: Our data indicate that adult PNR have significantly higher TNF mRNA levels than responders. This suggests that higher anti-TNF dose may be considered for IBD patients with high TNF mRNA expression estimates from the start of treatment.

Renal involvement in paediatric inflammatory bowel disease.

Inflammatory bowel disease (IBD), which includes Crohn's disease, ulcerative colitis and inflammatory bowel disease unclassified, is a chronic inflammatory disorder that predominantly affects the gastrointestinal (GI) tract and has a rising incidence in both children and adults. Symptoms are caused by inappropriate inflammatory response triggered by interaction between the environment, gut microbiome and host immune system in a genetically susceptible individual. Extranintestinal manifestations of IBD are common and can affect any body system outside the gut; they can precede or run parallel to GI inflammation. Renal involvement in IBD is uncommon and can be part of extraintestinal manifestation or metabolic complications of IBD. Many medications used to treat IBD can cause renal damage. Renal manifestation in children with IBD can range from asymptomatic biochemical abnormalities to variable stages of renal impairment with significant morbidity and even mortality burden.

C4B gene influences intestinal microbiota through complement activation in patients with paediatric-onset inflammatory bowel disease.

Complement C4 genes are linked to paediatric inflammatory bowel disease (PIBD), but the mechanisms have remained unclear. We examined the influence of C4B gene number on intestinal microbiota and in-vitro serum complement activation by intestinal microbes in PIBD patients. Complement C4A and C4B gene numbers were determined by genomic reverse transcription-polymerase chain reaction (RT-PCR) from 64 patients with PIBD (Crohn's disease or ulcerative colitis). The severity of the disease course was determined from faecal calprotectin levels. Intestinal microbiota was assessed using the HITChip microarray. Complement reactivity in patients was analysed by incubating their sera with Yersinia pseudotuberculosis and Akkermansia muciniphila and determining the levels of C3a and soluble terminal complement complex (SC5b-9) using enzyme immunoassays. The microbiota diversity was wider in patients with no C4B genes than in those with one or two C4B genes, irrespective of intestinal inflammation. C4B and total C4 gene numbers correlated positively with soluble terminal complement complex (TCC, SC5b-9) levels when patient serum samples were stimulated with bacteria. Our results suggest that the C4B gene number associates positively with inflammation in patients with PIBD. Multiple copies of the C4B gene may thus aggravate the IBD-associated dysbiosis through escalated complement reactivity towards the microbiota.

IgE-Dependent Food Sensitisation and Its Role in Clinical and Laboratory Presentation of Paediatric Inflammatory Bowel Disease.

The rising prevalence of inflammatory bowel disease (IBD) and food allergies and their partially overlapping mechanisms such as microbiome diversity reduction raise questions about the role of allergies in IBD. While data on their comorbidity are available, analysis of IgE-sensitization's influence on the clinical presentation of IBD is lacking and is the aim of this study. Histories of 292 children with newly diagnosed IBD (173 cases of ulcerative colitis, 119 cases of Crohn's disease) were analyzed. Disease age of onset, activity, location, behaviour, and anthropometric and laboratory parameters were tested for its dependence on the presence of chosen IgE sensitization markers. A.o. Chi2, OR and phi coefficient were assessed. In Crohn's disease (CD), elevated total IgE (tIgE) correlated with weight loss, rectal bleeding, ASCA IgG positivity (φ = 0.19 for all) and negatively correlated with complicated disease behaviour (φ = -0.19). TIgE > 5 × reference range correlated with being underweight (φ = 0.2), ASCA IgG positivity (φ = 0.3), ASCA double (IgA and IgG) positivity (φ = 0.25) and elevated total IgG (φ = 0.18). The presence of specific IgEs (sIgE) correlated with extraintestinal manifestations of IBD (φ = 0.19): Egg white sIgE correlated with upper GI involvement (L4b) (φ = 0.26), severe growth impairment (φ = 0.23) and colonic mucosal eosinophilia (φ = 0.19). In ulcerative colitis, decreased IgA correlated with egg white sIgE (φ = 0.3), as well as the presence of any (φ = 0.25) or multiple sIgEs (φ = 0.2); the latter correlated also with elevated IgG (φ = 0.22), fever (φ = 0.18), abdominal pain (φ = 0.16) and being underweight (φ = 0.15). Cow's milk sIgE correlated positively with growth impairment (φ = 0.15) and elevated IgG (φ = 0.17) and negatively with extensive colitis (φ = -0.15). Pancolitis correlated negatively with sIgE presence (φ = -0.15). In summary, single moderate and numerous weak but interesting relationships were observed.

Ferric carboxymaltose treatment for iron deficiency anemia in children with inflammatory bowel disease: Efficacy and risk of hypophosphatemia.

BACKGROUND: Although intravenous ferric carboxymaltose (FCM) is effective in treating iron deficiency anemia (IDA) in paediatric inflammatory bowel disease (pIBD), no data are available on its post-infusion related risks. AIMS: We assessed the efficacy of FCM and the rate of post-infusion hypophosphatemia in a large cohort of children with IBD and IDA. METHODS: All children with IBD with IDA treated with FCM over 5-year period were reviewed. Disease activity, biohumoral assessment and treatments were evaluated at baseline, 4-6 and 12 weeks after each infusion. RESULTS: 128 patients [median age at first infusion: 13 years] were identified, 81 (63.3%) were <14 years, 10 (7.8%) <6 years. Eighty-three children (64.8%) received one infusion, whilst 45 (35.2%) repeated infusions. A significant increase in Hb (p<0.001), iron (p<0.001) and ferritin (p<0.001) was observed 4-6 and 12 weeks post-infusion. Hb gain was unrelated to disease severity. Low baseline iron was the main predicting factor for repeated infusions (p<0.05). Three patients reported infusion reactions, none <6 years. Twenty-five children had low post-infusion serum phosphate (11 were <14 years, 3 <6 years). Two children developed severe hypophosphatemia. CONCLUSIONS: FCM administration is effective for IDA management in pIBD, including children <6 years. Due to the high prevalence of post-infusion hypophosphatemia, serum phosphate monitoring should be mandatory.