Kaija-Leena Kolho

The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations.

Principal changes with respect to the 2004 ECCO guidelines Ileocolonoscopy is recommended within the first year after surgery where treatment decisions may be affected (Statement 8C). Thiopurines are more effective than mesalazine or imidazole antibiotics alone in post-operative prophylaxis (Statement 8F). ### 8.1 Epidemiology of post-operative Crohns disease In the natural history of CD, intestinal resection is almost unavoidable since about 80% of patients require surgery at some stage. Surgery is unfortunately not curative as the disease inexorably recurs in many patients. The post-operative recurrence rate varies according to the definition used: clinical, endoscopic, radiological, or surgical. It is lowest when the repeat resection rate is considered, intermediate when clinical indices are used and highest when endoscopy is employed as the diagnostic tool.1–10 Data from endoscopic follow-up of patients after resection of ileo-caecal disease have shown that in the absence of treatment, the post-operative recurrence rate is around 65–90% within 12 months and 80–100% within 3 years of the operation. The clinical recurrence without therapy is about 20–25%/year.1,10 It has been demonstrated that the post-operative clinical course of CD is best predicted by the severity of endoscopic lesions. Symptoms, in fact, appear only when severe lesions are present and it is not uncommon to observe patients with fairly advanced recurrent lesions at endoscopy who remain asymptomatic.1 For these reasons, clinical indices such as the CDAI have low sensitivity at discriminating between patients with or without post-operative recurrence.11 These data mandate strategies aimed at interrupting or delaying the natural course of post-operative recurrence. Several medications have been tried in an attempt to prevent post-operative recurrence, mostly with disappointing results. The aim of this Consensus was therefore critically to evaluate the optimal strategies for the management of post-operative recurrence in CD. Most, if not all, of the evidence available deals with …

Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting celiac disease

BACKGROUND & AIMS Tissue transglutaminase has been reported to be the target for endomysial antibodies in celiac disease. We sought to establish whether immunoglobulin (Ig) A class tissue transglutaminase autoantibodies can be considered specific for celiac disease. METHODS Serum samples from 136 patients with untreated celiac disease (diagnosed according to the criteria of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition) and 207 disease controls were studied. Enzyme-linked immunosorbent assay (ELISA) and Western blots were performed using calcium-treated and untreated tissue transglutaminase as antigen. Reticulin, endomysial, and mouse monoclonal tissue transglutaminase antibodies were studied by an indirect immunofluorescence method and gliadin antibodies with ELISA. RESULTS The calcium-activated tissue transglutaminase autoantibody ELISA was highly sensitive (129 of 136) and specific (194 of 207) in detecting celiac disease. The new autoantibody ELISA test correlated well with the endomysial antibody test. Tissue transglutaminase autoantibody ELISA showed a clearly better predictive potential than the IgA class gliadin antibody ELISA. Immunoblots and ELISA blocking studies showed that calcium is needed for the specific antigen-antibody reaction to occur. Double immunofluorescence staining in human umbilical cord with sera from patients with celiac disease and with monoclonal tissue transglutaminase antibodies showed complete overlap. CONCLUSIONS Calcium-activated tissue transglutaminase autoantibody ELISA is highly accurate in detecting untreated celiac disease. Tissue transglutaminase seems to be the target self-antigen for endomysial antibodies.

Crohn's Disease Activity Assessed by Fecal Calprotectin and Lactoferrin : Correlation with Crohn's Disease Activity Index and Endoscopic Findings

Background: Correlation of endoscopic Crohns disease activity with fecal calprotectin and lactoferrin is insufficiently studied. We evaluated the clinical significance of these neutrofil‐derived proteins in assessment of Crohns disease activity by comparing them with endoscopic disease activity and with Crohns disease activity index (CDAI) and serum CRP. Methods: A total of 77 CD patients underwent one or more ileocolonoscopies (n = 106) with scoring of Crohns disease index of severity (CDEIS). Patients provided stool samples for calprotectin and lactoferrin measurements and blood samples for CRP. Clinical activity was based on the CDAI. Results: Both fecal calprotectin and lactoferrin correlated significantly with CDEIS (Spearmans r 0.729 and 0.773, P < 0.001). With a cutoff level of 200 &mgr;g/g for a raised fecal calprotectin concentration, sensitivity was 70%, specificity 92%, positive predictive value (PPV) 94%, and negative predictive value (NPV) 61% in predicting endoscopically active disease (CDEIS ≥ 3). A fecal lactoferrin concentration of 10 &mgr;g/g as the cutoff value gave a sensitivity, specificity, PPV, and NPV of 66%, 92%, 94%, and 59%. Sensitivity of CDAI ≥ 150 to detect endoscopically active disease was only 27%, specificity 94%, PPV 91%, and NPV 40%. A raised serum CRP (> 5 mg/l) gave a sensitivity, specificity, PPV, and NPV of 48%, 91%, 91%, and 48%. Conclusions: For evaluation of Crohns disease activity, based on endoscopic findings, more sensitive surrogate markers than is CDAI or CRP are fecal calprotectin and lactoferrin. These prove to be useful tools for estimation of disease activity in Crohns disease.

ESPGHAN Revised Porto Criteria for the Diagnosis of Inflammatory Bowel Disease in Children and Adolescents

Background: The diagnosis of pediatric-onset inflammatory bowel disease (PIBD) can be challenging in choosing the most informative diagnostic tests and correctly classifying PIBD into its different subtypes. Recent advances in our understanding of the natural history and phenotype of PIBD, increasing availability of serological and fecal biomarkers, and the emergence of novel endoscopic and imaging technologies taken together have made the previous Porto criteria for the diagnosis of PIBD obsolete. Methods: We aimed to revise the original Porto criteria using an evidence-based approach and consensus process to yield specific practice recommendations for the diagnosis of PIBD. These revised criteria are based on the Paris classification of PIBD and the original Porto criteria while incorporating novel data, such as for serum and fecal biomarkers. A consensus of at least 80% of participants was achieved for all recommendations and the summary algorithm. Results: The revised criteria depart from existing criteria by defining 2 categories of ulcerative colitis (UC, typical and atypical); atypical phenotypes of UC should be treated as UC. A novel approach based on multiple criteria for diagnosing IBD-unclassified (IBD-U) is proposed. Specifically, these revised criteria recommend upper gastrointestinal endoscopy and ileocolonscopy for all suspected patients with PIBD, with small bowel imaging (unless typical UC after endoscopy and histology) by magnetic resonance enterography or wireless capsule endoscopy. Conclusions: These revised Porto criteria for the diagnosis of PIBD have been developed to meet present challenges and developments in PIBD and provide up-to-date guidelines for the definition and diagnosis of the IBD spectrum.

Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease

Children and adolescents with Crohns disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohns and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.

Correlation of faecal calprotectin and lactoferrin with an endoscopic score for Crohn's disease and histological findings

Background  Faecal calprotectin and lactoferrin increasingly serve as surrogate markers of disease activity in IBD. Data on the correlation of these markers with simple endoscopic score for Crohn’s disease (SES‐CD) and with histological findings are as yet limited.

Management of Pediatric Ulcerative Colitis: Joint ECCO and ESPGHAN Evidence-based Consensus Guidelines

Background and Aims: Pediatric ulcerative colitis (UC) shares many features with adult-onset disease but there are some unique considerations; therefore, therapeutic approaches have to be adapted to these particular needs. We aimed to formulate guidelines for managing UC in children based on a systematic review (SR) of the literature and a robust consensus process. The present article is a product of a joint effort of the European Crohns and Colitis Organization (ECCO) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). Methods: A group of 27 experts in pediatric IBD participated in an iterative consensus process including 2 face-to-face meetings, following an open call to ESPGHAN and ECCO members. A list of 23 predefined questions were addressed by working subgroups based on a SR of the literature. Results: A total of 40 formal recommendations and 68 practice points were endorsed with a consensus rate of at least 89% regarding initial evaluation, how to monitor disease activity, the role of endoscopic evaluation, medical and surgical therapy, timing and choice of each medication, the role of combined therapy, and when to stop medications. A management flowchart, based on the Pediatric Ulcerative Colitis Activity Index (PUCAI), is presented. Conclusions: These guidelines provide clinically useful points to guide the management of UC in children. Taken together, the recommendations offer a standardized protocol that allows effective, timely management and monitoring of the disease course, while acknowledging that each patient is unique.

Fecal calprotectin, lactoferrin, and endoscopic disease activity in monitoring anti‐TNF‐alpha therapy for Crohn's disease

Background: Fecal calprotectin and lactoferrin are promising noninvasive biomarkers for intestinal inflammation. In Crohns disease (CD), during anti‐TNF‐alpha (TNF‐&agr;) treatment, the clinical significance of these markers has, however, been insufficiently explored. Methods: Among CD patients receiving anti‐TNF‐&agr; therapy we assessed the role of fecal calprotectin and lactoferrin as surrogate markers for mucosal healing. Before and 3 months after the beginning of anti‐TNF‐&agr; induction, 15 patients underwent ileocolonoscopy with scoring of the Crohns Disease Index of Severity (CDEIS). Fecal samples for calprotectin and for lactoferrin measurements were collected and the Crohns Disease Activity Index (CDAI) was calculated at the time of the endoscopies and 2 and 8 weeks after the first treatment. Results: The median CDEIS fell from 13.0 to 4.8 (P = 0.002) and CDAI from 158 to 68 (P = 0.005). Accordingly, the median fecal calprotectin concentration fell from 1173 &mgr;g/g to 130 &mgr;g/g (P = 0.001) and fecal lactoferrin from 105.0 &mgr;g/g to 2.7 &mgr;g/g (P = 0.001). Of the 15 patients, 11 (73%) showed an endoscopic response to treatment and 5 of these achieved endoscopic remission (CDEIS < 3). In those 5 patients the fecal calprotectin concentration declined from 1891 &mgr;g/g (range 813–2434) to 27 &mgr;g/g (13–130) and lactoferrin from 92.4 &mgr;g/g (35.5–235.6) to 1.9 &mgr;g/g (0.0–2.1). Conclusions: Compared to pretreatment values, concentrations of fecal calprotectin and lactoferrin after the anti‐TNF‐&agr; treatment were significantly lower. During anti‐TNF‐&agr; therapy these fecal neutrophil‐derived proteins may thus be useful surrogate markers for mucosal healing.

IL-23/IL-17 Immunity as a Hallmark of Crohn's Disease

Background: We studied the balance between ileal T‐effector cells versus T‐regulatory cells in active and inactive Crohns disease (CD). Methods: We compared effector and regulatory T‐cell‐related markers such as interleukin (IL)–17, interferon (IFN)‐&ggr;, IL‐4, and Foxp3 transforming growth factor (TGF)–&bgr; CTLA‐4 and markers for innate immune activation such as IL‐6, IL‐10, IL‐18, IL‐23, tumor necrosis factor (TNF)–&agr;, and IL‐12p70, studied with immunohistochemistry and RT‐PCR in ileal biopsies from patients with active or inactive CD and from control subjects. IL‐17 in fecal samples was detected by ELISA. The effect of IL‐17 on IL‐8 and TNF‐&agr; mRNA expression in epithelial cell line Caco‐2 was studied. Results: The numbers of IL‐4‐, IL‐17‐, and IL‐23(p19)‐positive cells in the lamina propria were higher in patients with CD, both active and inactive, than in the controls. mRNA expression of IL‐17A, IL‐6, and Foxp3 was increased in the biopsies both from patients with active disease and those in remission, whereas mRNA expression of IL‐23 was increased only in active disease. Fecal IL‐17 concentration was increased in patients with active disease. IL‐17 enhanced the IL‐8 and TNF‐&agr; response of the epithelial cell line to lipopolysaccharide (LPS) in vitro. Conclusions: Our findings suggest that activation of the IL‐23/IL‐17 axis is fundamentally connected to the etiology of CD and may represent the basis for the relapsing nature of the disease by increasing the sensitivity of epithelium to microbial LPS.

A genetic test which can be used to diagnose adult-type hypolactasia in children

Background/Aims: Adult-type hypolactasia (primary lactose malabsorption) affects most of world’s human population and limits the use of fresh milk due to lactose intolerance. The diagnosis of adult-type hypolactasia has been difficult to establish because of unsatisfactory diagnostic methods. C/T-13910 single nucleotide polymorphism residing 13910 base pairs from the 5′ end of the lactase gene has been shown to be associated with lactase persistence. The aim of the study was to assess the applicability of the C/T-13910 variant as a diagnostic test for adult-type hypolactasia during childhood. Methods: Intestinal biopsies were obtained from 329 children and adolescents of African, Finnish, and other White origins aged 0.1–20 years undergoing upper gastrointestinal endoscopy because of abdominal complaints. The biopsies were assayed for lactase, sucrase, and maltase activity and genotyped for the C/T-13910 variant using polymerase chain reaction minisequencing. Results: The frequency of the C/C-13910 genotype defining lactase non-persistence was well in agreement in this study with published figures for the prevalences of adult-type hypolactasia in Africans and Whites. The C/C-13910 genotype was associated with very low lactase activity (<10 U/g protein) in the majority of children tested at 8 years of age and in every child older than 12 years of age giving a specificity of 100% and sensitivity of 93% for the genetic test. The decline of lactase activity was somewhat earlier in African compared with Finnish children with C/C-13910 genotype (p<0.03). Conclusions: Genetic test of C/T-13910 polymorphism can be used as a first stage screening test for adult-type hypolactasia.