Lymphocytic Enteritis and Suspected Coeliac Disease: Gluten vs Placebo

Patients with lymphocytic enteritis (LE), HLA-DQ2/8+, negative celiac serology and clinical and histological response to a gluten-free diet (GFD) do not fulfil the diagnostic criteria of coeliac disease (CoD). At present it remains unclear whether they suffer from coeliac gluten sensitivity (CGS) or non-coeliac gluten sensitivity (NCGS). There are specific tissue markers of CoD such as anti-transglutaminase deposits (tTG) and intraepithelial lymphocytes expressing T-cell receptor (TCR) gamma/delta+.

Aim: To demonstrate the existence of CGS in these patients despite having negative celiac serology.

Methods: Double-blind randomized clinical trial of gluten vs placebo rechallenge for 6 months in patients with LE on a GFD. Inclusion criteria: \>18 years, initial presentation with GI symptoms, HLA-DQ2/8+, negative celiac serology, good clinical and histological response to GFD. Patients were randomised to gluten (20 g/day) and placebo (maltrodextrin) (identical powder sachets mixed with meals). Clinical symptoms were analysed using visual analogue scales. Quality of life (GIQLI), adherence to diet, serology, and histological changes including gamma/delta+ IEL and tTG deposits were evaluated.

Duodenal intraepithelial lymphocytosis (lymphocytic enteritis, LE) is defined by normal villous architecture and intraepithelial lymphocytes (IEL) \>25/100 enterocytes. It is a frequent finding present in 2% to 5,4% of duodenal biopsies.

LE is secondary to coeliac disease (CoD) in only a minority of patients, since it may be a response to other inflammatory processes in the gut. Other possible aetiologies of LE include infections (Helicobacter Pylori), drugs (nonsteroidal anti-inflammatory or acetylsalicylic acid) and autoimmune disease. Observational studies have established CoD to account for 10% to 43% of cases with LD and positive HLA-DQ2/8 after undertaking an exhaustive diagnostic work-up. These 'minor' forms of CoD may have similar clinical manifestations to those with villous atrophy.

However, these patients with 'minor' CoD have often negative celiac serology, and then do not fulfil the present criteria to diagnose CoD. In fact, using the present diagnostic criteria they should be included in the definition of non-celiac gluten sensitivity (NCGS). For diagnosing NCGS it is necessary to rule out CoD by means of negative serology -endomysial and tissue transglutaminase IgA antibodies- and a duodenal biopsy with absence of villous atrophy on a gluten-containing diet. As such it is accepted that NCGS patients might have LE. A recent systematic review on NCGS revealed that 44% of patients presented HLA-DQ2/8 haplotypes, suggesting that a subgroup of patients with NCGS may actually belong in the spectrum of CoD, which some authors have so-called 'coeliac lite' disease.

The gold-standard assay for confirming NCGS requires dietary elimination, followed by double-blind, randomized, placebo-controlled food challenge. This procedure is difficult to adopt routinely in clinical practice. To date two double-blind placebo-controlled dietary interventions in patients with presumptive NCGS have been published. The first gluten vs placebo rechallenge trial showed that patients who received gluten had significantly more abdominal symptoms than those on placebo (68% vs 40%). The second study that investigated the specific effects of gluten after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates (FODMAPs) in subjects believed to have NCGS, showed no symptomatic worsening after gluten challenge as compared to placebo. Thus, there was no evidence of specific or dose dependent effect of gluten on NCGS patients placed on a diet low in FODMAPs. It is worth mentioning that patients included in these trials were HLA-DQ2/8 negative, and if positive they had a normal duodenal biopsy (Marsh 0) while on a gluten containing diet. Besides, a GFD has been shown to be more effective in IBS-D patients with negative CoD serology but HLA-DQ2/8+ than in those with a negative genetic study.

The recent ESPGHAN guidelines for CoD diagnosis suggest that in cases with low-grade enteropathy (including LE) both a high γδ IEL count and the presence of Ig A anti-tissue transglutaminase (anti-TG2) deposits in the mucosa increase the likelihood of CoD. In contrast to CoD, there is stated that in NCGS there is not an increase of T-cell receptor γδ IELs. However, these parameters have only been scarcely used to rule out CoD in patients with NCGS in literature.

The aim of study was demonstrate the existence of gluten sensitivity in patients with HLA-DQ2/8+, LE and negative celiac serology, who had presented a clinical and histological response to a gluten-free diet (GFD), using a gluten vs placebo-controlled challenge. In addition, to assess the presence of tissue markers of CoD before and after gluten challenge, thus confirming the existence of a 'coeliac-lite' disease.

Eligibility Criteria:
Inclusion Criteria:

1. Giving written informed consent
2. Patients with age ≥18 years
3. Histological diagnosis confirmed of lymphocytic enteritis (LE)
4. Celiac genetic study (HLA-DQ2 and /or HLA-DQ8 positive)
5. Negative serology of celiac disease
6. Previous complete clinical and histological response to gluten-free diet
7. Initial (at diagnosis) GI symptoms with or without extraintestinal manifestations.
8. No previous studies on both IEL cytometric pattern and anti-TG2 IgA subepithelial deposits.

Exclusion Criteria:

1. Patients who are unable to adhere to the study visit schedule and other protocol requirements according to the investigator.
2. Participation in a clinical trial in the last 30 days, simultaneous participation in a trial or prior participation in this study.
3. Previous diagnosis with gluten-sensitive enteropathy with villous atrophy and positive serology.
4. Patients with LE and initial response to gluten free diet but that at the time of inclusion are on a normal gluten-containing diet.
5. Severe co-morbidities.
6. Drug or alcohol abuse.
7. Pregnancy or breast-feeding.

At the initial diagnosis, other LE aetiologies, like non-steroidal anti-inflammatory drugs intake, parasitic infection, and Helicobacter pylori infection, were appropriately ruled out.