Tuire Ilus

Incidence of Malignancies in Diagnosed Celiac Patients: A Population-based Estimate

OBJECTIVES:The association between celiac disease and malignancies is well recognized. In Finland, the prevalence of clinically diagnosed adult celiac disease is 0.6%. In this large, population-based cohort, we aimed at a realistic projection of the cancer risk.METHODS:In the period 2002–2011, the register comprised 32,439 adult celiac patients. This was linked with the Finnish Cancer Registry, which covers over 98% of diagnosed malignancies. The standardized incidence ratio (SIR) was calculated for the malignancies, on the basis of incidence figures for the whole population. A time-stratified analysis was made in celiac patients diagnosed after 2004 (n=11,991). Lifestyle factors, including smoking habits and obesity, were not obtainable.RESULTS:The overall incidence ratio of malignant diseases was not increased (SIR 0.94; 95% confidence intervals 0.89–0.98), but it was ≥5 years from the diagnosis of celiac disease (1.31, 1.04–1.63). The SIRs for non-Hodgkin lymphoma (NHL; 1.94; 1.62–2.29), small-intestinal cancer (4.29; 2.83–6.24), colon cancer (1.35; 1.13–1.58), and basal cell carcinoma of the skin (1.13; 1.03–1.22) were increased, whereas those for lung cancer (0.60; 0.48–0.74), pancreatic cancer (0.73; 0.53–0.97), bladder cancer (0.53; 0.35–0.77), renal cancer (0.72; 0.51–0.99), and breast cancer (0.70; 0.62–0.79) were decreased. SIR for NHL immediately after the diagnosis of celiac disease was 2.56 (1.37–4.38).CONCLUSIONS:There was no increased SIR of cancer in the whole series, but SIR was increased after 5 years from the diagnosis of celiac disease. The risk of breast and lung cancers was decreased. The risk of small-intestinal cancer and NHL was increased, but to a lesser extent than previously described.

Refractory coeliac disease in a country with a high prevalence of clinically‐diagnosed coeliac disease

Refractory coeliac disease (RCD) is thought to be a rare disorder, but the accurate prevalence is unknown.

Performing routine follow-up biopsy 1 year after diagnosis does not affect long-term outcomes in coeliac disease.

A repeat biopsy is recommended, but often omitted in coeliac disease patients on a gluten‐free diet. The effect of performing or not performing repeat biopsies is currently unknown.

Disappearance of epidermal transglutaminase and IgA deposits from the papillary dermis of dermatitis herpetiformis patients after a long‐term gluten‐free diet

Dermatitis herpetiformis (DH) is an itchy, blistering skin disease characterised by the deposition of granular immunoglobulin A (IgA) in the papillary dermis. It is regarded as the cutaneous manifestation of coeliac disease, an autoimmune-mediated condition affecting the small intestine. In addition to skin symptoms, DH patients have mostly subclinical small-intestinal villous atrophy and crypt hyperplasia or at least coeliac-type inflammatory changes. Moreover, DH patients have specific antibodies targeting epidermal transglutaminase (a.k.a. transglutaminase 3, TG3), the dominant autoantigen in DH 1. This article is protected by copyright. All rights reserved.

Ex vivo Culture of Duodenal Biopsies from Patients with Dermatitis Herpetiformis Indicates that Transglutaminase 3 Antibody Production Occurs in the Gut

Coeliac disease and dermatitis herpetiformis (DH) are characterized by autoantibodies targeting transglutaminase (TG)2 and TG3, respectively. Previous studies show that TG2 antibodies are produced in the gut and can be assessed in organ culture of small-intestinal biopsies from patients with coeliac disease. Thus far, no studies have investigated TG3 antibodies in organ culture of biopsies from patients with DH, or exploited the method in DH. The aim of this study was to investigate TG3 and TG2 antibody responses in serum and small-intestinal biopsies from patients with DH with active disease, and from those in remission. The majority of patients with DH were negative for both serum and organ culture medium TG2-targeting antibodies. Surprisingly, patients with active DH secreted TG3 antibodies into the culture medium despite seronegativity. In patients secreting high levels of TG3 antibodies into the culture medium, we also detected TG3-antibody-positive cells in the small-intestinal mucosa. These findings suggest that TG3 antibodies can be investigated in the organ culture system and that their secretion occurs in the small intestine, especially in active DH.

Dermatitis Herpetiformis Refractory to Gluten-free Dietary Treatment

Dermatitis herpetiformis (DH) is a blistering skin disease, which is regarded as an extra-intestinal manifestation of coeliac disease. Refractory cases of coeliac disease, that do not respond to a gluten-free diet and which carry an increased risk of lymphoma, are well-known in coeliac disease. To determine whether refractory cases of DH with active rash and persistent small bowel atrophy occur we analysed our series of 403 patients with DH. Seven (1.7%) patients, who had been on a gluten-free diet for a mean of 16 years, but who still required dapsone to treat the symptoms of DH, were identified. Of these, one patient died from mucinous adenocarcinoma before re-examination. At re-examination skin immunoglobulin A (IgA) deposits were found in 5/6 refractory and 3/16 control DH patients with good dietary response. Small bowel mucosa was studied at re-examination from 5 refractory and 8 control DH patients and was normal in all 5 refractory and 7/8 control DH patients. One refractory DH patient died from adenocarcinoma, but no lymphoma developed in any of the patients. This study documents for the first time refractory DH, in which the rash is non-responsive to a gluten-free diet, but the small bowel mucosa heals. This differs from refractory coeliac disease, in which the small bowel mucosa does not heal on a gluten-free diet.

Long-term follow-up in adults with coeliac disease: Predictors and effect on health outcomes

INTRODUCTION Guidelines recommend regular follow-up in coeliac disease, but effect of this on long-term outcomes remains unclear. AIMS To evaluate predictors and significance of long-term follow-up. METHODS 677 previously diagnosed coeliac patients were recruited for a nationwide health survey. Medical data were gathered through interviews and patient records. Current symptoms and quality of life were assessed by validated questionnaires and blood samples were drawn for serology. All variables were compared between patients with and without long-term (>2 years) follow-up. RESULTS 15% had long-term follow-up, median duration 10 years. Predictors (p < 0.05) for the follow-up were immunological (35% vs. 24%) and circulatory (20% vs. 12%) comorbidities, whereas it was less common in subjects with musculoskeletal (23% vs. 34%) comorbidity and those not belonging to any at-risk group (16% vs. 27%). Patients with or without follow-up had comparable age, adherence and ability to manage a gluten-free diet and frequency of seropositivity. Also questionnaire scores paralleled, but those without follow-up reported more overall symptoms (16% vs. 26%). Most patients wished for follow-up. CONCLUSION Only a minority of patients had regular follow-up. However, patients with and without the follow-up were comparable in most long-term outcomes, indicating that it might not be always necessary. The results call for more personalized follow-up policies in coeliac disease.

Microbial Biomarkers in Patients with Nonresponsive Celiac Disease

Background and AimsIn nonresponsive celiac disease (NRCD), the symptoms and duodenal damage persist despite a gluten-free diet. Celiac disease patients with persistent symptoms are found to have a dysbiotic microbiota. We thus hypothesized that increased seroreactivity to the serum gluten-sensitive microbial antibodies Saccharomyces cerevisiae (ASCA), Pseudomonas fluorescens-associated sequence (I2), and Bacteroides caccae TonB-linked outer membrane protein (OmpW) is associated with NRCD.MethodsASCA, I2 and OmpW were measured in 20 seronegative CD patients with persistent villous damage despite strict dietary treatment (NRCD group). Fifty-eight responsive patients served as CD controls (55 on gluten-free treatment) and 80 blood donors as non-CD controls.ResultsAt least one microbial marker was positive in 80% of NRCD patients, in 97% of untreated CD and 87% of treated CD patients, and in 44% of controls. NRCD patients had the highest frequency of ASCA positivity (65% vs 52, 20, and 0%, respectively) and also significantly higher ASCA IgA (median 14.5 U/ml) and IgG (32.5 U/ml) titers than treated CD patients (7.0 U/ml, 13.0 U/ml) and non-CD controls (4.5 U/ml, 5.8 U/ml). The frequencies of I2 and OmpW were lower in NRCD than in untreated CD (65% and 45% vs 86% and 59%, respectively), and I2 titers were higher in NRCD (median absorbance 0.76) and untreated (1.0) and treated (0.83) CD than controls (0.32). OmpW was elevated in untreated (1.1) and treated (0.94) CD patients compared with controls (0.79).ConclusionsSeropositivity and high titers of ASCA are associated with NRCD and might serve as an additional follow-up tool in CD.

Commentary: refractory coeliac disease - rigorous management revealing, or resulting in, rarity? Authors' reply.

We appreciate the comments of Dr. Woodward: rigorous management of coeliac disease may indeed prevent the development of refractory coeliac disease (RCD). Successful management of RCD requires that we discover incomplete mucosal recovery while the patient is maintaining a gluten-free diet. In RCD, the differentiation between types I and II should be done. Regardless of symptoms, coeliac patients with poor mucosal recovery may be at increased risk of subsequent RCD and malignant complications. Symptom relief may thus not prevent later complications, nor does the normalisation of serology: subtotal villous atrophy may even be present in patients with negative anti-tissue transglutaminase antibodies. On the other hand, positive serology does not necessarily mean dietary transgressions, albeit this being the most common explanation. Given the high specificity of serology, coeliac disease is often evident even before verification through biopsy. However, the biopsy sample shows the extent of mucosal damage, thereby providing the reference for subsequent follow-up. Control biopsy on gluten-free diet is rarely necessary for the diagnosis; instead, it is the only method to detect incomplete mucosal recovery or RCD. When present, a meticulous dietetic review and repeated biopsies should be considered to identify slow responders, and to detect further mucosal deterioration. We agree with Dr Woodward that control biopsy is essential, that it should be carried out at least in adults over 40 years of age, and even in younger patients with persistent symptoms.