Celiac disease and non-celiac enteropathies

Structured Abstract

Purpose of review:

This review highlights recent research in the field of celiac disease (CD).

Recent findings:

Epidemiological studies continue to identify CD-associated diseases such as inflammatory arthritis, irritable bowel syndrome, and cardiovascular disease. Recently published consensus guidelines provide recommendations for the long-term management and monitoring of patients with CD. There are multiple pharmaceutical therapies for CD under investigation, and recent phase I and phase II trials are reviewed here. Finally, a recent trial of patients with non-celiac gluten sensitivity demonstrates a significant nocebo effect in this condition.

Summary:

Recent advances in celiac disease include the development of new clinical guidelines as well as promising new therapeutics. Continued high-quality research is needed to improve the outcomes of patients with CD and non-celiac enteropathies.

Introduction: Epidemiology of Celiac Disease

Celiac disease is common in the general population, with an estimated worldwide prevalence between 0.5 to 1 percent (1, 2). In the industrialized world, the incidence of CD appears to be rising over the past several decades (3). While improved awareness and screening capabilities play important roles in this rise, diagnostic factors alone may not be sufficient to explain more recent trends. A recent population-based cohort study in Canada demonstrated that the incidence of celiac serological autoimmunity (defined as the first positive transglutaminase IgA antibodies) increased between 2015 and 2020 despite stable testing rates (4). Such findings suggest that environmental factors, such as dietary and microbial influences, may be an important part in the changing epidemiology of CD.

Gastrointestinal symptoms in CD are varied, and include abdominal discomfort, bloating, and diarrhea. While such symptoms may be related to CD itself, recent epidemiological studies suggest that CD is associated with several other gastrointestinal diseases. In Italy, for instance, a 20-year follow-up study of patients with CD and persistent symptoms found a high prevalence of functional gastrointestinal disorders (5). A Swedish population-based study also demonstrated that the risk of irritable bowel syndrome (IBS) is increased in individuals with CD, both before and after their CD diagnosis (6).

It is also known that CD is associated with other autoimmune conditions, including autoimmune thyroid disease, type 1 diabetes, and systemic lupus erythematosus (7–10). But in recent years, multiple other CD-associated conditions have been reported globally. A recent population-based study demonstrated that children with CD develop juvenile idiopathic arthritis nearly 3 times as often as the general population, and adults with CD develop rheumatoid arthritis nearly 2 times as often (11). Individuals with CD also have increased risk of malignancy (12), higher rates of cardiovascular disease(13), and increased overall mortality (14). For clinicians caring for patients with CD, awareness of these associated conditions can lead to earlier diagnosis and treatment.

Testing and Diagnosis

In genetically susceptible individuals with CD, dietary gluten peptides from the ingestion of wheat, barley and rye activate a T-cell mediated pro-inflammatory response, leading to autoantibody formation and intestinal mucosal injury. The diagnosis of CD in adults is defined serologically by the presence of these autoantibodies (most commonly transglutaminase IgA) and histologically by duodenal villous atrophy and intraepithelial lymphocytosis.

It is important for clinicians to recognize that there are other causes of villous atrophy in the duodenum beyond CD, which makes corroborative serological biomarkers critical. A recent study by Ching et al noted that, among patients with duodenal villous atrophy and no prior CD serologies, 31% were subsequently found to have an elevated tTG IgA and another 8.9% were ultimately diagnosed with seronegative CD; the remainder of patients were found to have either infectious etiologies, medication-induced changes, inflammatory bowel disease, or villous atrophy of indeterminate cause (15).

In recent years, there has been increasing evidence in support of a biopsy-free diagnosis in CD if serum tTG IgA levels are sufficiently elevated. The European Society for Pediatric Gastroenterology and Nutrition adopted a biopsy-free approach to CD diagnosis in children in 2012 (16), and in 2023 the American College of Gastroenterology suggests this approach as a conditional recommendation in children (17). In adults, however, recommendations have not followed suit given less data at this time. A recent systematic review and meta-analysis in adults sought to determine the positive predictive value (PPV) of IgA tTG levels ≥10 times the upper limit of normal in predicting villous atrophy (18). It found that this degree of IgA tTG elevation had PPV of 88% and 95% in populations deemed to have CD prevalence of 4% and 10%, respectively, but the PPV dropped to 65% in populations with CD prevalence of 1%. The authors concluded that select adults in high prevalence groups may be diagnosed with serology alone, while acknowledging that there are often limitations to predicting an individual’s pretest probability of CD in clinical practice.

Celiac disease management and monitoring

The only current treatment for CD is a lifelong gluten-free diet (GFD), which can reverse villous atrophy, decrease serological biomarkers of CD, and improve patient-reported symptoms (19, 20). Long-term management of patients with CD has varied significantly among gastroenterologists (21). To address this, Elli et al published new clinical guidelines for evidence-based practices in monitoring adult patients with established CD, which were endorsed by American and European scientific CD societies (22).

These expert guidelines strongly recommended that all patients with CD be evaluated by a dietitian with special expertise in CD to ensure optimal nutritional status and encourage GFD adherence (22). This is particularly important given the difficulty of adherence to a GFD, and the fact that it has been associated with lower quality of life, social isolation, and nutritional deficiencies (23–27). These guidelines also recommended that serological markers, particularly anti-tTG IgA levels, be monitored to assess response to a GFD, as these antibodies typically decline within the first year of a GFD (22). Although routine repeat endoscopy with duodenal biopsies in all patients with CD was not endorsed by this working group, it was suggested for any patients with ongoing GI symptoms or other alarm features despite adherence to a GFD. The authors of this expert working group noted that many of these recommendations were made with low levels of evidence, suggesting that further research in these areas is needed.

In recent years, the detection of excreted gluten immunogenic peptides (GIPs) in urine and stool has emerged as a potential non-invasive tool for monitoring adherence to the GFD by means of measuring inadvertent gluten exposure. A recent prospective study of 94 adult patients on a GFD found serial urinary GIP measurements to be a better predictor of villous atrophy than either serological biomarkers, symptoms, or patient dietary questionnaires (28). Similarly, a recent randomized, double-blind low-dose gluten versus placebo challenge among patients with CD found that stool GIP was more sensitive than urine GIP, serologies, and symptoms in detecting gluten exposure (29). Although the level of evidence was deemed very low, consensus guidelines recommend the use of stool or urinary GIP in non-responsive CD when gluten intake is suspected (22). More research is needed to determine the optimal frequency and duration of urinary or stool GIP determination, however, as there is a lack of standardized protocols for their routine use in clinical practice. Although at-home, direct-to-consumer GIP testing kits are available in the United States (Glutenostics, Inc.), they are not currently covered by insurance, which has limited their widespread adoption.

Many individuals with CD have ongoing gastrointestinal symptoms despite serological and histological remission on a GFD. A recent Norwegian randomized control trial (RCT) found that a diet low in fermentable oligo-, di-, monosaccharides and polyols (FODMAP) should be considered in the management of these patients (30). Study participants receiving a low FODMAP-GFD for four weeks (n=34) had significantly reduced gastrointestinal symptoms and improved CD-specific health relative to participants on a GFD only (n=36). Whether this improvement in symptoms is due to CD and IBS overlap or if a low-FODMAP diet reduces low-grade inflammation in well-controlled CD remains unclear.

Potential pharmacological therapies for celiac disease

Although adherence to a GFD remains the cornerstone of CD management, recent years have seen significant investment in new pharmacological therapies for patients with CD. Most of the drug targets under current evaluation aid in the degradation and/or deamidation of intraluminal gluten, attempt to attenuate the downstream immune response, or attempt to induce immune tolerance of gluten peptides.

Orally administered drugs that support gluten degradation in the stomach, and thereby prevent gluten exposure and subsequent immune activation in the small intestine, are an emerging class of pharmaceuticals for CD. Latiglutinase (IMGX003, formerly ALV003) is a combination of two gluten-targeting proteases that can be given as a liquid formulation with meals and has shown promise in phase I and II trials (31–33). Most recently, Murray, et al published results from a phase IIb RCT of latiglutinase given to patients with well-controlled CD who had been on a GFD for at least a year (34). Relative to placebo, latiglutinase attenuated histologic, serologic, and symptomatic worsening in patients exposed to a six-week gluten challenge. Latiglutinase also reduced the amount of detectable GIP in urine by 95% relative to placebo. A separate drug in development, TAK-062, is an engineered endopeptidase that may degrade nearly 99% of ingested gluten in the stomach and has an acceptable safety profile, according to a recent phase I dose escalation study study (35). Both latiglutinase and TAK-062 have ongoing phase II trials to further investigate their safety and efficacy.

Transglutaminase-2 (TG2) inhibition, designed to prevent the deamidation of gluten and subsequent proinflammatory cytokine production in the small intestine, is also actively being investigated. A recent RCT of ZED-1227, an oral TG2 inhibitor, was completed in adults (n=163) with well-controlled CD on a GFD (36). ZED-1227 was found to attenuate the villous height to crypt depth ratio relative to placebo during a six-week gluten challenge. In an ongoing phase IIb trial, the efficacy of ZED-1227 is being assessed in different patient population: individuals with CD who have persistent symptoms despite a GFD.

A separate class of pharmaceutical therapies for CD have been designed to induce gluten immune tolerance in patients with CD, although the outcomes have been mixed to date. Nexvax2 is an antigen-specific immunotherapy agent designed to suppress the systemic release of serum interleukin (IL)-2, which is thought to play a critical role in the immune response to gluten exposure responsible for acute symptoms in CD. In the RESET CeD trial, Nexvax2 was given as a subcutaneous injection to adults with well-controlled CeD who had been on a GFD for at least one year (37). The trial was terminated early after an interim analysis showed that Nexvax2 did not modify patient-reported symptoms or improve serum IL-2 serum levels following gluten exposure relative to placebo. In a post hoc analysis, however, Nexvax2 did attenuate villous height change after gluten exposure relative to placebo, but the absolute difference in villous height between the groups was small, and there were no significant changes in IELs (37).

An intravenous drug called TAK-101 has also been designed to induce gluten-specific tolerance and was well-tolerated in a phase I trial (38). After a 14-day gluten challenge in a placebo-controlled phase II trial, TAK-101 induced an 88% reduction in production of interferon-gamma units, which are thought to play a central role in gluten-stimulated immune activation and intestinal damage (38). The villous height to crypt depth ratio declined significantly after gluten challenge in the placebo group and did not decline significantly in the TAK-101 group, though the comparison between drug and placebo regarding this secondary outcome fell short of statistical significance (p=0.08). A third drug within this class, KAN-101, has demonstrated a good safety and tolerance profile in a recent phase I human trial, and is pending further phase II trials to assess its efficacy (39).

Standardizing randomized controlled trials in celiac disease

Although multiple phase I and phase II clinical drug trials for CD have been published in recent years, to date no pharmaceutical agents have demonstrated efficacy in a phase III RCT. In April 2022, the U.S. Food and Drug Administration (FDA) published guidance for the development of drugs for adjunctive treatment to a GFD in patients with celiac disease. Despite this guidance, there remains significant variability in the methodologies and primary endpoints being used in RCTs for CD drug development.

To better facilitate high-quality RCTs in CD, an international panel of 18 experts recently published an appropriateness study to address questions of specific inclusion and exclusion criteria, gluten challenge methodologies, and trial outcome measures in this population (40). For trials evaluating prevention of relapse after a gluten challenge, the panel recommended including only patients with normal or near-normal histopathology after at least 12 months on a GFD. The panel also recommended that histological outcomes be a primary endpoint, and that patient reported symptoms be included as a co-primary or secondary endpoint. For trials evaluating the reversal of villous atrophy in patients on a GFD, the panel recommended including patients with baseline villous height to crypt depth ratio of ≤2 to assess meaningful clinical improvement from a study drug.

One of the most variable methodological aspects of many CD trials is the amount, duration, and administration of a gluten challenge. While many studies to date have used two- to six-week gluten challenges involving daily gluten intake of 2–3g (34, 36, 38), for instance, the recent RESET CeD trial measured response to a one-time 10g gluten bolus (in addition to IL-2 measurement) (37). The international panel recommended a daily maximum gluten dose of 9g and a gluten formulation low in FODMAPS (40). They also suggested that trials include a sham gluten arm before gluten challenge to assess nocebo effects, defined as negative symptoms experienced by patients when they are told they are ingesting gluten despite actually receiving gluten-free food. The panel also encouraged a placebo run-in period with the gluten challenge to ensure sufficient symptoms in the gluten-exposed group, but did not come to a consensus regarding the appropriate duration of a gluten challenge.

Non-celiac gluten sensitivity

Individuals with non-celiac gluten sensitivity (NCGS) experience symptoms attributed to gluten intake but lack serological or histological markers of celiac disease. It remains unclear whether common symptoms of NCGS, such as abdominal discomfort and bloating, are due to an immunologic response to gluten, a sensitivity to non-gluten wheat components, or a nocebo effect.

To further interrogate the role of nocebo effect, de Graaf et al recently published a randomized, double-blind, placebo-controlled study on patients with NCGS (41). Subjects, who had celiac disease excluded with serological testing, were randomized into four groups based on actual gluten administration (given either gluten-containing or gluten-free oat bread) and gluten expectancy (being told that their bread contained gluten or not). They found that the expectation of gluten intake, regardless of actual gluten ingestion, was associated with worse post-prandial symptoms. These findings were consistent across multiple sensitivity analyses and when controlling for baseline levels of anxiety, depression, IBS, and functional dyspepsia. The study does not address the potential role that expectancy may play in people with celiac disease, for whom gluten exposure predictably causes immune activation but a very variable degree of symptoms. Nonetheless, this study effectively demonstrates that the nocebo effect of gluten is a powerful contributor to NCGS, which is one of many gastrointestinal syndromes that appear to be shaped by a patient’s expectation of receiving certain foods.

Conclusion

This review highlighted recent research in the field of CD. Notable advances include the development of new clinical guidelines for the long-term management and monitoring of patients with CD, as well as multiple pharmaceutical therapies currently under investigation to supplement the GFD. More high-quality research is needed for drug development in CD, and we highlighted a recent appropriateness study published by an international panel of experts to help standardize RCTs in this area. Finally, we reviewed a recent trial of patients with NCGS, which demonstrated a significant nocebo effect of gluten expectancy.

Key points:

• Population-based studies in recent years have shown that celiac disease (CD) is associated with inflammatory arthritides, cardiovascular disease, and increased rates of malignancy and mortality.

• Increasing evidence supports biopsy-free diagnosis of CD in children, but less data exists for adults currently.

• New expert clinical guidelines have been published to standardize evidence-based practices for monitoring adult patients with established CD.

• Multiple promising pharmaceutical therapies for CD are under investigation in ongoing randomized clinical trials.