Alimentary Pharmacology and Therapeutics

Refractory coeliac disease in a country with a high prevalence of clinically-diagnosed coeliac disease T. Ilus*, K. Kaukinen*,†, L. J. Virta‡, H. Huhtala§, M. M€aki¶, K. Kurppa¶, M. Heikkinen**, M. Heikura††, E. Hirsi‡‡, K. Jantunen§§, V. Moilanen¶¶, C. Nielsen***, M. Puhto†††, H. P€ olkki‡‡‡, I. Vihri€al€a§§§ & P. Collin*

*Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland. † Department of Medicine, Sein€ajoki Central Hospital, Sein€ajoki, Finland. ‡ Research Department, The Social Insurance Institution, Turku, Finland. § School of Health Sciences, University of Tampere, Tampere, Finland. ¶ Centre for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland. **Kuopio University Hospital, Kuopio, Finland. †† North Karelia Central Hospital, Joensuu, Finland. ‡‡ South Karelia Central Hospital, Lappeenranta, Finland. §§ Kymenlaakso Central Hospital, Kotka, Finland. ¶¶ Satakunta Central Hospital, Pori, Finland. ***Vaasa Central Hospital, Vaasa, Finland. ††† Mikkeli Central Hospital, Mikkeli, Finland. ‡‡‡ L€ansi-Pohja′s Central Hospital, Kemi, Finland. §§§ Keski-Pohjanmaa′s Central Hospital, Kokkola, Finland.

Correspondence to: Dr P. Collin, Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, FIN-33521 Tampere, Finland. E-mail: pekka.collin@uta.fi Publication data Submitted 17 September 2013 First decision 29 September 2013 Resubmitted 12 December 2013 Accepted 13 December 2013 EV Pub Online 6 January 2014

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SUMMARY Background Refractory coeliac disease (RCD) is thought to be a rare disorder, but the accurate prevalence is unknown. Aim We aimed to identify the prevalence of and the risk factors for developing RCD in a Finnish population where the clinical detection rate of coeliac disease is high. Methods The study involved 11 hospital districts in Finland where the number of treated RCD patients (n = 44), clinically diagnosed coeliac disease patients (n = 12 243) and adult inhabitants (n = 1.7 million) was known. Clinical characteristics at diagnosis of coeliac disease between the RCD patients and patients with uncomplicated disease were compared. Results The prevalence of RCD was 0.31% among diagnosed coeliac disease patients and 0.002% in the general population. Of the enrolled 44 RCD patients, 68% had type I and 23% type II; in 9% the type was undetermined. Comparing 886 patients with uncomplicated coeliac disease with these 44 patients that developed RCD later in life, the latter were significantly older (median 56 vs 44 years, P < 0.001), more often males (41% vs. 24%, P = 0.012) and seronegative (30% vs. 5%, P < 0.001) at the diagnosis of coeliac disease. Patients with evolving RCD had more severe symptoms at the diagnosis of coeliac disease, including weight loss in 36% (vs. 16%, P = 0.001) and diarrhoea in 54% (vs. 38%, P = 0.050). Conclusions Refractory coeliac disease is very rare in the general population. Patients of male gender, older age, severe symptoms or seronegativity at the diagnosis of coeliac disease are at risk of future refractory coeliac disease and should be followed up carefully. Aliment Pharmacol Ther 2014; 39: 418–425

ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12606

Refractory coeliac disease INTRODUCTION The majority of coeliac disease patients respond to a gluten-free diet with resolution of gastrointestinal symptoms and improvement in the small-bowel mucosal histology. In a subgroup of patients, however, the mucosal damage persists, the most common reason being ongoing gluten ingestion.1-3 Refractory coeliac disease (RCD) should be considered when there are continuous symptoms and signs of malabsorption and persistent or recurrent villous atrophy despite a strict gluten-free diet for a minimum of 6–12 months and where other aetiologies of villous atrophy and intestinal lymphoma have been excluded.4, 5 RCD can be further divided into two categories according to the immunophenotype of intra-epithelial lymphocytes (IELs) and the clonality of the T-cell receptor gene. Type I RCD has normal IELs indistinguishable from those in uncomplicated active coeliac disease, and the disease follows a relatively benign course with a 5-year survival of 80–96%. In contrast, type II RCD presents with abnormal, often monoclonal IELs and imposes a significant burden of morbidity and mortality. This condition is usually resistant to treatment and often progresses to an overt intestinal lymphoma and premature death.6–10 Although up to 79% of long-term treated coeliac disease patients evidence persistent small-bowel mucosal atrophy,11–17 genuine RCD is considered to be rare, probably presenting in 1.5–10% of diagnosed coeliac disease patients.4, 13, 18–21 Nevertheless, the relevant literature is sparse and limited to small case series from tertiary centres. The accurate prevalence of RCD in the general population is obscure and there is no realistic projection of the refractory state among patients with coeliac disease. In Finland, we have reached a high prevalence (0.6%) of clinically diagnosed coeliac disease as a result of an active case-finding policy by educating the health staff and advocating serological screening in at-risk groups.22 We hypothesised that due to early diagnosis and treatment of coeliac disease, RCD would prove to be less common in here than in countries with a lower detection rate of coeliac disease. We therefore investigated the prevalence of RCD in 11 hospital districts in Finland, where the number of adult inhabitants and diagnosed coeliac disease patients was known. Furthermore, to identify particular risk factors for forthcoming RCD, we compared clinical characteristics between the enrolled RCD patients and a cohort of patients with uncomplicated coeliac disease at the primary diagnosis of coeliac disease.

Aliment Pharmacol Ther 2014; 39: 418-425 ª 2014 John Wiley & Sons Ltd

MATERIAL AND METHODS Epidemiological data We gathered information on the prevalence of RCD in a survey involving 11 of 21 hospital districts in Finland covering 1.7 million (39%) of the adult population (Figure 1). Our national guidelines advocate control biopsies taken from all coeliac disease patients diagnosed as adults after 1 year on gluten-free diet and subjects with ongoing symptoms and persistent villous atrophy to be evaluated for complications. RCD was defined according to the international diagnostic criteria4: persistent or recurrent symptoms and villous atrophy despite a strict gluten-free diet. Other aetiologies of villous atrophy such as hypogammaglobulinaemia and intestinal lymphomas

Lapin shp

Länsi-Pohjan shp

Pohjois-Pohjanmaan shp Kainuun shp Keski-Pohjanmaan shp Pohjois-Savon shp Pohjois-Karjalan shp Etelä-Pohjanmaan shp

Vaasan shp

Keski-Suomen shp Pirkanmaan shp Satakunnan shp

Itä-Savon shp Etelä-Savon shp

Etelä-Karjalan shp Kanta-Hämeen shp Kymenlaakson shp Varsinais-Suomen shp HUS Kuntarajat © Tilastokeskus Karttakuva © Kuntaliitto

Figure 1 | The map of Finland showing the catchment areas of the participating centres (indicated by the brown colour).

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T. Ilus et al. are to be excluded before a diagnosis of RCD can be made. Exclusion of dietary transgressions by a thorough dietetic interview had to be done in each centre before making the diagnosis of RCD. There is also recent evidence that olmesartan can cause severe enteropathy with villous atrophy resembling RCD and this was taken into consideration retrospectively while analysing the data.5 In Finnish health-care system, the clinical investigations for potent RCD patients are made exclusively in central and university hospitals, where skilled dietitians are trained to evaluate the diet even for hidden gluten traces. Data for the present study were collected from these tertiary centres. RCD is an uncommon condition, and the cases were carefully followed up in each participating centre. Centres with no reliable data on their cases were not included in the study. Therefore, it is unlikely that there would be many missing cases in this register. The number of adult (aged 16 years or more) coeliac patients living in the above-mentioned hospital districts in December 2012 was obtained from the Social Insurance Institution of Finland, which has run a register of all Finnish coeliac patients receiving compensation for the additional costs of a gluten-free diet since 2002. The prerequisite for this payment is that the diagnosis of coeliac disease is demonstrated by duodenal biopsy showing typical villous atrophy.22, 23 Altogether 99% of these diagnoses of coeliac disease have been shown to be correct.23 Including all RCD patients alive in December 2012, we calculated the prevalence of RCD among adult coeliac patients and in the adult general population.

Clinical characteristics of RCD patients For the enrolled RCD patients, we recorded gender, age at the primary diagnosis of coeliac disease, symptoms leading to the diagnosis, coeliac disease serology (endomysium- or transglutaminase antibodies), the presence of HLA DQ2 or DQ8 haplotypes, serum haemoglobin levels and histology in the first diagnostic small-bowel mucosal biopsy. Data on other diagnosed autoimmune diseases and adherence to the gluten-free diet were obtained from medical records. Regarding the diagnosis of RCD, patients’ age and symptoms at the time were recorded. Histology reports were obtained from the pathology departments concerning the diagnosis of RCD, including immunohistochemistry and immunogenetics. In fact, precise definition of RCD is lacking and the diagnostic criteria for RCD vary from centre to centre.4 As the classification between RCD types I and II was carried out by local pathologists, some variation in 420

diagnostic criteria is possible. A proportion of >50% of abnormal (monoclonal) CD3+ CD8- T-cells was recommended as a cut-off; the counts were done in separately stained sections. Gamma chain T-cell monoclonal rearrangement was investigated by TCR rearrangement molecular analysis (Master Diagnostica, Granada, Spain). We also recorded serum haemoglobin and albumin levels and coeliac antibody titres as well as body mass indices (BMIs, calculated by dividing the patients’ weight in kilograms by the square of height in metres) at the diagnosis of RCD. Clinical manifestations of RCD, including ulcerative jejunitis, hyposplenism and mesenterial lymph node cavitations were listed if found. Treatment of RCD was documented as duration of medication and clinical as well as histological response to it. Finally, we recorded intestinal lymphomas and other malignancies diagnosed and, if the patients had died, the causes of death.

Clinical characteristics of control subjects with uncomplicated coeliac disease To discover factors present at the primary diagnosis of coeliac disease, which might adumbrate RCD later in life, patients with uncomplicated disease were used as controls. This cohort comprised 886 biopsy-proven coeliac disease patients enrolled in a previous study investigating different clinical, pathogenic and genetic aspects of coeliac disease.24 These patients were recruited in a nationwide search using newspaper advertisements and via local coeliac societies. Only patients diagnosed with coeliac disease in adulthood were included, as none of our RCD patients had a childhood coeliac disease diagnosis. This control group and the enrolled RCD patients were diagnosed with coeliac disease during the same period of time and came from the same geographical regions. All patients in this control group responded well to a gluten-free diet. Age, presenting symptoms, coeliac serology and duodenal mucosal histology at the diagnosis of coeliac disease were collected from these patients’ medical records and also by structured interviews. The presence of other autoimmune diseases and strictness of gluten-free diet were also listed. Statistics Results were summarised using means and percentages. Fisher’s exact test was used for categorical variables and t-test for continuous variables to compare patients with uncomplicated disease with RCD patients. SPSS version 19 was used for statistical analysis. Aliment Pharmacol Ther 2014; 39: 418-425 ª 2014 John Wiley & Sons Ltd

Refractory coeliac disease Ethical considerations The study protocol was approved by the Ethical Committee of Tampere University Hospital and the National Institute for Health and Welfare. Patients with uncomplicated coeliac disease also gave their written informed consent. RESULTS Prevalence of RCD in coeliac disease and in the general population Altogether 44 RCD patients were eligible for the study and 38 of them were alive in December 2012. At that time, 12 243 adult coeliac disease patients and 1 730 555 adult inhabitants lived in the same hospital districts, giving a point prevalence of 0.31% of RCD among the diagnosed coeliac disease patients and 0.002% (2 per 100 000) in the general population. The figures also showed the prevalence of diagnosed coeliac disease in this population to be at that time-point 0.7%. Clinical characteristics of RCD patients The primary diagnosis of coeliac disease was made in RCD patients at a median age of 56 years, and 59% of

them were females (Table 1). Diagnostic small-bowel biopsy showed total or subtotal villous atrophy with crypt hyperplasia (Marsh 3b or 3c) in 58%. Only one patient had had a temporary histological response to gluten-free diet. Altogether, 70% had positive serum endomysial or transglutaminase antibodies, 30% being thus seronegative. One of the seronegative had selective IgA deficiency. All nine tested patients had the HLA DQ2 genotype. Twenty-five patients were diagnosed with coeliac disease before olmesartan became available to the market and nine had not used the drug according to the medical records. Three of the remaining patients had positive coeliac serology and three developed ulcerative jejunitis or type II RCD, indicating that the primary diagnosis of coeliac disease was correct. In four patients, the use of olmesartan could not be ruled out given the retrospective nature of the study. The presenting symptoms were predominantly classical (abdominal complaints and anaemia) and no individuals were detected by screening. Three patients had dermatitis herpetiformis as a presenting symptom. The median age at the diagnosis of RCD was 64 years (Table 2). Despite a strict gluten-free diet, 61% had total

Table 1 | Characteristics of refractory coeliac disease (RCD) patients and control patients with uncomplicated disease at the time of the diagnosis of coeliac disease

Female, n (%) Age at diagnosis, median (IQR), years Histology, n (%) Total villous atrophy Partial villous atrophy Unknown atrophy Normal Seronegativity, n (%)* Weight loss, n (%)‡ Diarrhoea, n (%)‡ Blood haemoglobin, mean (range), g/dL Family history of coeliac disease, n (%) Duration of gluten-free diet, mean (range), years Gluten-free diet, n (%) Strict Lapses Malignant diseases, n (%)

RCD all (n = 44)

RCD II (n = 10)

Uncomplicated coeliac disease (n = 866)

P value (between RCD all and uncomplicated coeliac disease)

26 (59) 56 (41–63)

5 (50) 59 (55–63)

672 (76) 44 (33–53)

0.012

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...
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