Small bowel capsule endoscopy in refractory celiac disease: a luxury or a necessity?

Introduction

Refractory celiac disease (RCD) is a rare complication of celiac disease (CD). In a recent systemic review, the prevalence of RCD was reported to be 0.31-0.38% in patients with CD [1]. It occurs more commonly in females, older individuals (>50 years), those diagnosed with CD later on in life, and patients with signs suggestive of malabsorption [2-6]. Patients with RCD have traditionally been managed with steroids and/or immunosuppressants, in addition to maintaining a gluten-free diet (GFD). Duodenal histology is repeated at intervals to ensure no progression of RCD type I to type II occurs and to rule out aberrant intraepithelial lymphocytes [7,8]. The prognosis of RCD type II is poor, with a 50% 5-year survival, owing to the development of malignancy, necessitating careful follow-up [9,10]. However, the follow-up interval in these patients and how it should differ between subtypes of RCD remains unclear [3,7,11-13].

Since its introduction in 2000, small bowel capsule endoscopy (SBCE) has enabled the study of several SB pathologies such as CD. Dedicated SB imaging can be helpful to exclude malignancies such as enteropathy associated T-cell lymphoma (EATL) or adenocarcinoma of the SB [14]. However, sometimes pre-malignant or malignant conditions do not necessarily result in lesions of sufficient size to be picked up on imaging, making SBCE a better alternative for delineating these lesions [15]. In addition, SBCE allows the disease extent in the SB to be estimated [16-18]. The relationship between the disease extent and the severity of CD remains unclear. However, the literature suggests that healing of the mucosa in CD patients occurs in a distal-to-proximal manner [16,17,19].

The main aim of this study was to assess the role of SBCE at diagnosis and its impact on subsequent management and course of disease. Secondary aims were to stratify findings on SBCE according to RCD subtype and treatment administered.

Patients and methods

Results

Sixty patients with RCD (40 female, 66.7%) were included in this study. All had a median CD duration of 4 years by the time they had their first SBCE. All patients were on a GFD since diagnosis. Six patients had underlying serology-negative CD and 2 patients were IgA deficient.

HLA DQ2 DQ8 status was available for 50 patients (83.3%), and it varied as follows in the population studied: 12 (24%) HLA DQ2 homozygous, 32 (64%) HLA DQ2 heterozygous, 3 (6%) DQ8 homozygous, 2 (4%) negative for DQ2 and DQ8, 1 (2%) HLA DQ2, and DQ8 heterozygous. The 2 patients who had negative HLA DQ2 and DQ8 heterodimers were positive for the following alleles: DRB1*04, DQA1*03:03, DQB1*03:01 and DQA1*01, DQA1*02; DQB1*03:03, DQB1*06.

Most patients had proximal SB involvement on both first (n=33, 55%) and second (n=38, 63%) SBCEs. Diffuse disease was found in 14 (23%) and 7 (12%) patients on first and second SBCE, respectively (Table 1). The median time between the first and second SBCEs was 17.5 (4-31) months and the median time between subsequent SBCEs was 12 (1-40) months.

Table 1 Extent of celiac disease on small bowel capsule endoscopy

Correlation of histology with features of CD on SBCE

Most patients had histology of Marsh grade 3a or above at the time of their first (n=55, 93.2%) and second (n=47, 83.9%) SBCE (Table 2). Marsh grade of histology did not correlate with percentage of abnormal SB mucosa at first SBCE (Spearman’s rho 0.113, P=0.434), but there was a degree of correlation between Marsh grade of histology and percentage of abnormal SB mucosa at second SBCE (Spearman’s rho 0.528, P=0.001). Features of CD also did not correlate significantly with Marsh grade of histology, except for scalloping (32/55 Marsh 3a or above; P=0.049) and mosaic pattern (31/55 Marsh 3a or above; P=0.016) at second SBCE.

Table 2 Marsh score of histology on duodenal biopsies at first and second small bowel capsule endoscopy

Stratification according to treatment given

Most patients received treatment for RCD (n=46, 76.7%) (P=0.227) (Table 3). There was no statistical difference in the percentage of abnormal SB mucosa between the first and second SBCE according to the type of treatment administered (RCD I P=0.952, RCD II P=0.056). Only 5 (n=24; 20.8%) and 3 (n=11; 27.2%) patients had escalation of therapy prior to undergoing a third and fourth SBCE, respectively.

Table 3 Type of treatment administered to patients with refractory celiac disease (RCD) of different type

Comparison of capsule endoscopies along disease course

All patients had at least 2 SBCEs. Twenty-four patients had at least a third SBCE. Overall, 26 patients (49.1%) had an improved percentage extent of abnormal SB mucosa on undergoing a second SBCE (median 27.6% vs. 18.1% P=0.007). However, the improvement was not sustained in subsequent SBCEs and there was no statistically significant difference between the first and the last SBCE (P=0.655) (Table 4). The improvement in percentage extent of disease between the first 2 SBCEs contrasted with repeat duodenal histology, which showed no overall improvement (P=0.062).

Table 4 Gastric, small bowel passage time and extent of disease on small bowel capsule endoscopy

Complications in patients with RCD

Nine patients (15%) developed RCD-related complications. Five patients developed ulcerative jejunoileitis (Fig. 1). All changes were detected on SBCE. They received cladribine (1 patient), budesonide (2 patients), budesonide and cladribine (1 patient), azathioprine and methylprednisolone (1 patient). Three patients with RCD developed EATL. In one of these patients EATL was diagnosed on post mortem examination. This patient was not on treatment for RCD. In another patient, EATL was diagnosed on the third SCBE (Fig. 2) and confirmed by histological specimens obtained from the SB during single balloon enteroscopy a year following the diagnosis of CD. The patient was on budesonide to treat RCD. EATL was confirmed on imaging, including PET scan, in a third patient. He was on mycophenolate for RCD and was being managed with cladribine when the diagnosis of EATL was made. One patient developed cutaneous T-cell lymphoma 3 years from when she was diagnosed with CD. Her RCD was managed with mycophenolate and budesonide. She was given cladribine when she was diagnosed with lymphoma.

Figure 1 Image from small bowel capsule endoscopy of a patient with ulcerative jejunoileitis, showing fissuring and mosaic pattern of mucosa, and an ulcer

Figure 2 Enteropathy-associated T-cell lymphoma in a patient with refractory celiac disease

All patients who developed complications had underlying RCD II, except for 1 patient who developed cutaneous T-cell lymphoma. There was no statistical difference in percentage extent of disease at the first (P=0.960, 0.152%) and second (P=0.403, 0.910%) SCBEs between patients who developed or did not develop complications and had RCD type I or II, respectively.

Discussion

This is the largest, study to demonstrate the role of SBCE in the diagnosis and subsequent management of patients with RCD. It is the first study that portrays monitoring and the use of successive SBCEs in addition to duodenal histology during the disease course of patients with RCD. We also stratified differences in the features of CD in the SB according to symptoms, CD serology, histology, type of RCD, and type of treatment administered.

A few studies have reported on the use of SBCE in patients with RCD. The main focus in these studies was the exclusion of pre-malignant and malignant complications and reporting of CD features [28-31]. Most of these studies were small and therefore have had limited impact on the management of patients with RCD.

Previous studies have reported on the improvement in the extent of disease in the SB on SBCE in patients with uncomplicated CD following initiation of a GFD. There was an improvement in the extent of disease in 79% of patients following 6 months of GFD in a study by Murray et al [16]. A more recent study by Lidums et al showed an improvement in macroscopic villous atrophy in 12 patients with CD after 12 months of GFD [17]. We showed improvement in the extent of disease in a smaller group of patients with RCD following treatment with steroids and/or immunosuppressants in a previous study [19]. We have confirmed the same findings in this larger study carried out in 2 European centers. Interestingly, the same improvement noted in percentage extent of disease between the first and second SBCEs was not sustained during the third and subsequent SBCEs. This raises several questions about the effectiveness of current regimens used to treat patients with RCD and the timing interval between SBCEs. Even though the importance of repeating duodenal histology and SBCE in patients with RCD is recognized, no follow-up protocol has been proposed in the literature [13,32]. The poor prognosis of patients with RCD type II suggests that these patients should be followed-up more closely than those with RCD type I [4,9]. More such studies are needed to provide evidence concerning the optimum time interval to follow-up these patients. We have also shown the lack of any long-term impact of steroids ± immunosuppressants beyond a few months of treatment, highlighting the possibility that these patients are being undertreated and further escalation of therapy is not being considered. Only a small number of patients (n=5, 20.8%, and n=3, 27.2%) underwent a treatment addition or change prior to undergoing a third and fourth SBCE, respectively. This might have contributed to the lack of improvement in the extent of disease on SBCE in these patients.

Duodenal sampling during gastroduodenoscopy is important, as it confirms persistent villous atrophy and can identify aberrant IELs with monoclonality of TCRs [20,21]. Flow cytometry is also useful for evaluating aberrant IELs [33]. Duodenal histology unfortunately cannot provide valuable information on the extent of disease and RCD-related complications beyond the duodenum. These factors can instead be assessed using SBCE and dedicated SB imaging [28,29,34,35]. As in previous studies, our data did not show a correlation between Marsh grade of histology and extent of disease in the SB at the first SBCE [17,16]. Moreover, duodenal biopsies do not always show an improvement in the grade of histology when repeated after a time interval in patients with either uncomplicated [17] or complicated CD [19,36]. These arguments call for the use of gastroduodenoscopy to enable duodenal histology and SBCE, to be used together at intervals for surveillance of patients with RCD.

In our study, we failed to show a statistical correlation between CD symptoms and serology and extent of disease in the SB. Literature on these aspects has been contradictory to date. Two studies report on a positive qualitative association between extent of disease on SBCE and symptomatology in patients with CD [37,38]. A study by Lidums et al correlated the extent of affected SB with an improvement in the symptom score following a GFD. However, the same study was unable to demonstrate a correlation between extent of disease and symptomatology at baseline [17]. Another study by Murray et al failed to confirm this association [16]. The same study, also demonstrated more extensive disease in patients with positive EMA and a positive correlation with anti-TTG in 38 patients [16]. Findings from these studies and evidence from the literature suggest that follow-up and further investigations of patients with RCD should be independent of their symptoms and CD serology.

From the literature, we know that patients with RCD II have a more severe disease pattern than patients with RCD type I. They have a worse 5-year survival (45-58%) compared to those with RCD I (80-96%) [4,9]. Patients with RCD II often require stronger therapeutic agents than patients with RCD type I, such as cladribine or anti-interleukin 15 monoclonal antibody [39,40]. Refractoriness to treatment with immunosuppressants is more often described in patients with RCD type II than type I [41-44]. Patients with RCD type II had more extensive mucosal changes than those with RCD type I. This is consistent with the findings described in a smaller study by Barret et al [30]. Patients with RCD type I showed greater improvement on second SBCE than those with RCD type II. Both the findings from our study and evidence from the literature reflect on the severity of disease equating to extent of disease, which so far has not been well described.

In this study, 6 patients had negative serology. Although RCD has predominantly been studied in patients with underlying serology-positive CD (at the time of diagnosis), complications can also occur in patients with serology-negative CD who have responded to a GFD initially, and in whom the clinical disease course resembles that of CD patients [22,45].

Two patients in this study encoded neither DQ2 nor DQ8 heterodimers. This is reported to exist in the literature in up to 2% of patients with CD [46-48]. For the few patients who are HLA DQ2, DQ8 negative, there is no clear association with any other DQ molecule. In these patients, the diagnosis of CD is based on serology, duodenal villous atrophy and response to a GFD.

Although SBCE can be used to diagnose pre-malignant and malignant conditions, as demonstrated in this study, the extent of disease in the SB does not predict those likely to develop further complications. SBCE is particularly useful in patients with the pre-malignant condition ulcerative jejunoileitis, where the superficial mucosal changes are unlikely to be picked up on SB imaging.

One of the limitations of this study was a small number of patients in each subgroup, making subgroup analysis more difficult to perform. However, in comparison to the available literature, this is the largest study of its kind and the only study that provides temporal follow up of SB mucosal changes in a cohort of RCD patients along their course of disease [4,28-30,34,35,36,39,40,42,44,49-59]. Both centers included in this study are tertiary centers for the management of patients with CD. The retrospective nature of this study resulted in some missing data, such as not all patients having duodenal histology taken and CD serology measured at the time that they underwent SBCE. All patients underwent at least 2 SBCEs. However, the number of patients who underwent subsequent SBCEs was small. This probably affected the statistical analysis of data involving third and subsequent SBCEs. Another limitation is the lack of standardization of reporting and the absence of prior interobserver agreement studies between reviewers from both centers. However, reviewers from both centers were international SBCE experts with experience in reviewing CD videos.

In conclusion, this study suggests that the extent of disease can be assessed on sequential SBCEs along the course of disease in patients with RCD. Whereas histology gives information on aberrant IELs, SBCE can help assess mucosal healing and rule out pre-malignant and malignant complications. However, disease extent in the SB was not predictive of complications, while improvement in the disease extent was not sustained on sequential SBCEs. Therefore, the use of SBCE in the clinical management of patients with RCD remains exploratory, and more such studies are required before its use is advocated routinely in these patients. Findings in this study suggest that patients with RCD type II suffered from more extensive disease and were less likely to improve on repeat SBCE compared to those with type I disease. This reflects on the poorer prognosis and higher likelihood of complications in patients with RCD type II described in the literature.