Joachim Schweizer

Infliximab therapy in 30 patients with refractory pediatric Crohn disease with and without fistulas in the Netherlands

Objective: The purpose of this study was to describe the clinical experience with the anti–tumor necrosis factor chimeric monoclonal antibody, infliximab, in pediatric patients with Crohn disease in The Netherlands. Design: Descriptive. Methods: Clinical response and adverse effects of infliximab were recorded for pediatric patients with Crohn disease treated from October 1992 to January 2003. Results: Thirty patients (aged 7–18 years) with refractory Crohn disease (with or without severe fistulas) were treated with infliximab. Patients were treated with up to 30 infusions. Mean follow-up was 25.3 months. A total of 212 infusions were administered. Thirteen patients had refractory Crohn disease without fistulas. Six patients showed good long-term response to infliximab treatment (defined as clinical index ≤10 points). Sixteen patients had refractory Crohn disease with draining fistulas. Nine showed good long-term response (closure or nonproductiveness of fistulas). One patient with metastatic Crohn disease in the skin had a good long-term response. Six patients developed an allergic reaction during infusion. In one patient, the allergic reaction occurred after an infliximab-free interval of 9 years. One patient died of sepsis. Conclusions: Infliximab was an effective therapy in 53% of patients with refractory pediatric Crohn disease, with or without fistulas. Approximately half of the patients become unresponsive to infliximab therapy. Randomized controlled studies are mandatory to assess long-term efficacy and safety to define the optimal therapeutic strategy of infliximab therapy in children with Crohn disease.

Gluten-Specific T Cells Cross-React between HLA-DQ8 and the HLA-DQ2α/DQ8β Transdimer

Because susceptibility to celiac disease is associated strongly with HLA-DQ2 (DQA1*05/DQB1*02) and weakly with HLA-DQ8 (DQA1*03/DQB1*03), a subset of patients carries both HLA-DQ2 and HLA-DQ8. As a result, these patients may express two types of mixed HLA-DQ2/8 transdimers (encoded by DQA1*05/DQB1*03 and DQA1*03/DQB1*02) in addition to HLA-DQ2 and HLA-DQ8. Using T cells from a celiac disease patient expressing HLA-DQ8trans (encoded by DQA*0501/DQB*0302), but neither HLA-DQ2 nor HLA-DQ8, we demonstrate that this transdimer is expressed on the cell surface and can present multiple gluten peptides to T cell clones isolated from the duodenum of this patient. Furthermore, T cell clones derived from this patient and HLA-DQ2/8 heterozygous celiac disease patients respond to gluten peptides presented by HLA-DQ8trans, as well as HLA-DQ8, in a similar fashion. Finally, one gluten peptide is recognized better when presented by HLA-DQ8trans, which correlates with preferential binding of this peptide to HLA-DQ8trans. These results implicate HLA-DQ8trans in celiac disease pathogenesis and demonstrate extensive T cell cross-reactivity between HLA-DQ8 and HLA-DQ8trans. Because type 1 diabetes is strongly associated with the presence of HLA-DQ8trans, our findings may bear relevance to this disease as well.

Tef in the diet of celiac patients in The Netherlands

Objective. Celiac disease (CD) is a multifactorial disease with a strong genetic association. It is caused by a T-cell-mediated immune response to wheat gluten. The treatment is a strict gluten-free diet (GFD). The purpose of this study was to investigate whether the naturally gluten-free cereal Eragrostis tef (tef) is associated with health problems when used by CD patients. Material and methods. In March 2006, all 7990 members of the Dutch Celiac Disease Society were invited to complete a questionnaire on tef use and the development of symptoms after tef consumption. Respondents and their family members willing to participate were sent an extended questionnaire on the use of commercially available tef products and on the character of their subsequent symptoms. Results. Thirty-six percent responded to the first questionnaire of whom 53% consumed tef and 15% reported complaints. For the second questionnaire, out of the 1828 participants willing to complete it, 1545 had biopsy-proven CD (median duration GFD: 6.5 years (range: 0–66.5 years)). Of these, 66% used tef (median duration 1.4 years (range: 0.1–5 years)) and 17% reported symptoms after consumption. The percentage for symptoms was significantly lower than that in patients without tef consumption reporting on their regular GFD (17% versus 61%; p=0.0001). Conclusions. Tef is frequently used by Dutch CD patients and a wide majority can consume tef without experiencing any clinical symptoms. CD patients using tef reported a significant reduction in symptoms, possibly related to a reduction in gluten intake or to an increase in fiber intake. Hence, tef can be a valuable addition to the GFD of CD patients.

Abnormal liver enzymes 2 years after haematopoietic stem cell transplantation in children: prevalence and risk factors

To establish the prevalence of elevated liver enzymes in children transplanted in a Dutch haematopoietic stem cell transplantation (HSCT) centre, we retrospectively assessed AST and ALT values at 2 years after HSCT. Age, sex, diagnosis, type of transplant, conditioning regimen and early post-transplant complications involving the liver (veno-occlusive disease, acute GVHD, viral reactivation) were analysed as risk factors. AST and ALT values were available at 2 years after HSCT in 216 of 290 patients (75%) alive at that time and were above normal in 53 (25%) and at least twice normal in 17 (8%) patients. Older age at HSCT and a diagnosis of benign haematological disease are risk factors for abnormal liver enzymes late after HSCT. In half of the patients with benign haematological disease, iron overload is the most likely aetiological factor. Chronic hepatitis B or C is uncommon in our centre. In conclusion, the prevalence of abnormal liver enzymes late after HSCT in our centre is lower than reported in previous studies. Abnormal liver enzymes occur more often in children who are older at HSCT and transplanted for benign haematological disease. Long-term follow-up is crucial to establish if elevated liver enzymes precede clinical liver disease.

Screening for unrecognized coeliac disease in subfertile couples

Abstract Objective. Subfertility has been reported as a long-term complication of unrecognized and/or untreated coeliac disease (CD); however, the results from studies on this topic are ambiguous. We aimed to determine the prevalence of unrecognized CD in subfertile male–female couples visiting a fertility clinic compared with the general population. Methods. Subjects included 1038 male–female couples (n = 2076) who visited the fertility clinic of the Leiden University Medical Center in the Netherlands between 2003 and 2009. All consecutive patients were routinely, serologically screened, and those with positive test results for antibodies against IgA anti-tissue transglutaminase type 2 and IgA endomysial antibodies were considered to have unrecognized CD. Clinical data on gender, age, height, weight, diagnosis of subfertility, and previously diagnosed CD were collected from the clinical files. Subsequently, after serological screening, all patients were anonymized. The prevalence of unrecognized CD was compared with the one in the general adult population in the Netherlands (0.35%). Results. The prevalence of unrecognized CD in subfertile male–female couples was 0.48% (10/2076; 6 females and 4 males) and was not significantly more frequent compared with the general population. Compared with the control group, similar CD prevalences were found within the different subfertility categories separately: unexplained subfertility, anovulation, tubal pathology, and male factor (p = NS). Conclusion. In our large study cohort of subfertile male–female couples, the prevalence of unrecognized CD is comparable to the general population in the Netherlands. No association was observed between CD and subfertility in the different subfertility categories and genders.

Gastrointestinal Acute Graft-versus-Host Disease in Children: Histology for Diagnosis, Mesenchymal Stromal Cells for Treatment, and Biomarkers for Prediction of Response

Steroid-nonresponsive acute graft-versus-host disease (aGVHD) after hematopoietic stem cell transplantation carries a poor prognosis. Various groups have reported beneficial effects of mesenchymal stromal cell (MSC) infusion as salvage treatment. Response to treatment is typically evaluated using the diagnostic clinical criteria for aGVHD. In this study, we evaluated the usefulness of additional gastrointestinal biopsy specimens paired with serum biomarkers. In a cohort of 22 pediatric patients, persistent or recurrent diarrhea was seen in 18 children treated with MSC infusion for steroid-refractory aGVHD. To exclude other causes of gastrointestinal pathology, patients were biopsied for histological analysis. Eight of 12 patients exhibited residual tissue damage and villous atrophy, but no active aGVHD. Serum biomarkers have been identified as an alternative tool for monitoring the response to aGVHD treatment. The value of biomarkers for inflammation, tissue, and endothelial cell damage was evaluated in our cohort. Although predictive of response to treatment and survival, these markers lack the necessary specificity and sensitivity to predict response to MSC therapy. Objective endpoints for clinical trials on the treatment of steroid-refractory aGVHD remain to be defined. Thus, we recommend including biopsies and biomarkers to discriminate between ongoing aGVHD and postinflammatory malabsorption.

Iron Deficiency in Inflammatory Bowel Disease: The use of Zincprotoporphyrin and Red Blood Cell Distribution Width.

Objectives: Iron deficiency (ID) in children with inflammatory bowel disease (IBD) is either an absolute (depleted iron stores) or a functional deficiency (caused by chronic inflammation). Differentiating between these 2 types of ID is important because they require a different therapeutic approach. Zinc protoporphyrin (ZPP) and red blood cell distribution width (RDW) are parameters of functional ID. Studies using these parameters to differentiate are nonexistent. We aimed to evaluate the prevalence of and risk factors for absolute and functional ID in paediatric IBD patients while using ZPP and RDW. Methods: We evaluated the iron status and medical charts of 59 paediatric IBD patients in a secondary hospital in the Netherlands. Absolute ID was defined as serum ferritin <15u200a&mgr;g/L in the absence of infection and/or acute inflammation (C-reactive protein <10u200amg/L). Iron deficiency anaemia (IDA) was defined as absolute ID in combination with anaemia. Functional ID, in patients without absolute ID, was defined as ZPP >70u200a&mgr;mol/mol haem and/or an RDW >14%. Anaemia of chronic disease (ACD) was defined as functional ID in combination with anaemia. Results: Absolute and functional ID were found in 19/59 (32.2%) and 32/40 (80%) patients, respectively. The prevalence of IDA and ACD was 27.1% (16/59) and 20% (8/40), respectively. Multivariate analyses showed that absolute ID and IDA were both associated with a more recent IBD-diagnosis (both P < 0.05). Conclusions: Absolute and functional ID are common in paediatric IBD patients, and this differentiation is important because of therapeutic consequences. Furthermore, absolute ID and IDA are associated with a more recent IBD-diagnosis.

E-Healthcare for Celiac Disease-A Multicenter Randomized Controlled Trial

Objective To evaluate the (cost‐)effectiveness of online consultations in follow‐up of patients with celiac disease (CD). Study design Multicenter randomized, controlled trial involving 304 patients aged ≤25 years with CD for ≥1 year, randomized to an online (n = 156) or outpatient consultation (n = 148). An online consultation included questionnaires for symptom and growth measurement. Antitransglutaminase‐type‐2 antibodies were determined using a point‐of‐care (POC) test. Controls had a traditional consultation with antitransglutaminase‐type‐2 antibodies testing in laboratories. Both groups completed questionnaires concerning CD‐specific health‐related quality of life (HRQOL), gluten‐free diet adherence, and patient satisfaction. Six months later, participants repeated HRQOL and patient satisfaction questionnaires and the POC test. The primary outcome was anti‐transglutaminase‐type‐2 antibodies after 6 months, and the secondary outcomes were health problems, dietary adherence, HRQOL, patient satisfaction, and costs. Results The performance of the POC test was inferior to laboratory testing (2/156 positive POC tests vs 13/148 positive laboratory tests; P = .003). Health problems were detected significantly more frequently using online consultation. The detection of growth problems and dietary transgressions was similar. HRQOL (from 1 [good] to 5 [poor]) improved after online consultation (from 3.25 to 3.16 [P = .013] vs controls from 3.10 to 3.23; P = .810). Patient satisfaction (from 1 [low] to 10 [high]) was 7.6 (online) vs 8.0 (controls; P = .001); 58% wished to continue online consultations. Mean costs per participant during the studied period were &U20AC;202 less for the online group (P < .001). Conclusions The primary outcome could not be tested because the POC test was unreliable. Nevertheless, our results indicate that online consultations for children and young adults with CD are cost saving, increase CD‐specific HRQOL, and are satisfactory for the majority. Trial Registration Trialregister.nl: NTR3688.