Clinical Case Summary

CD55 deficiency with Complement Hyperactivation, Angiopathic thrombosis and Protein Losing Enteropathy (CHAPLE) is a rare hereditary immune disease, driven by an overactivation of the complement system, caused by loss-of-function variants of CD55.¹ With fewer than 100 patients diagnosed with CHAPLE worldwide, providing evidence-based care can be complex. Previous studies showed that eculizumab, a complement C5 inhibitor, was broadly effective in patients with CHAPLE disease.² Recently, the FDA approved pozelimab, an anti-C5 antibody, as the first treatment for CHAPLE. This clinical case describes two sisters affected by CHAPLE disease highlighting the diagnostic process as well as their recent treatment with pozelimab, considering both clinical and immunological aspects.

In a Moroccan pedigree, two sisters were diagnosed with Crohn’s Disease (CD) at the ages of 12, and 27. Both sisters’ symptoms included recurrent edemas, abdominal pain, (bloody) diarrhea, nausea and vomiting, and abnormally low serum albumin levels. Treatment with diets, antibiotics, corticosteroids, immunomodulators and biologicals over multiple years had little effect. When a low IgG level was found in the younger sister, we initiated whole exome sequencing. This led to the diagnosis of CHAPLE disease in both sisters. Flow cytometry showed total absence of CD55 antigen on both patients’ blood cells and reduced expression of CD55 on the mother’s blood cells compared to a healthy control. A brother diagnosed with irritable bowel syndrome was genetically affected without clinical CD, demonstrating a highly variable penetrance.

Subcutaneous weekly pozelimab was started and allowed discontinuation of all immunosuppressive medication within 3 months in both sisters. Within a month of treatment, their symptoms resolved and inflammatory markers including fecal calprotectin and plasma albumin, as well as IgG levels, normalized. They have sustained remission since and reported no related adverse events.

References

1. Ozen A, Comrie WA, Ardy RC, et al. CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med. 2017;377(1):52-61. doi:10.1056/NEJMoa1615887
2. Ozen A, Kasap N, Vujkovic-Cvijin I, et al. Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease. Nat Immunol. 2021;22(2):128-139. doi:10.1038/s41590-020-00830-z

Introduction

Advances in non-celiac wheat sensitivity (NCWS) have proved that it should be considered a protean condition in which several potential triggers [e.g. gluten, wheat amylase-trypsin inhibitors, etc.] might determine an intestinal mucosal damage with increased permeability and exposure of foods/microbial peptides to immune cells (1,2), resulting in both a local and systemic inflammatory activation responsible for its gastrointestinal and extraintestinal manifestations (3,4). Up to 75% of NCWS subjects complain of multiple foods hypersensitivities (MFH) (5). These patients usually have clinical, immunological and histological features similar to wheat allergy patients, although without positive gluten/wheat IgE assays, allowing to hypothesize the existence of a non-IgE mediated hypersensitivity. In addition, several studies have reported an association between atopic diseases and NCWS.

Aims & Methods

This study aimed to define the presence and features of atopic diseases and other hypersensitivities (primarily food allergies/intolerances) in NCWS compared with celiac disease (CD) and irritable bowel syndrome/functional dyspepsia (IBS/FD) and to analyze a possible correlation between these diseases and NCWS clinical manifestations. This retrospective, multicenter study included NCWS patients diagnosed by double-blind placebo-controlled challenge with wheat. Their clinical, laboratory and histology data at diagnosis (i.e. before the start of a wheat-free diet) were analyzed and compared to control subjects with CD and IBS/FD. Specific allergology data, other than clinical/laboratory features typical of NCWS, were collected and analyzed: family and personal history of atopic diseases, type of allergens responsible, positivity of skin prick tests (SPT), patch tests and total and food-specific IgE.

Results

Atopic disease prevalence was higher in NCWS (32.8%) than in CD (19.3%) and IBS/FD (21.5%) (P=.001 for both). Similarly, NCWS subjects had a higher frequency of MFH (39.8%) and self-reported milk intolerance (SRMI) (65.9%) compared to the controls (P <.001 for both). Allergic asthma, either alone (P=.03) or associated with allergic rhinitis (P=.005), was more prevalent in NCWS compared to IBS/FD, which was more often associated with allergic conjunctivitis (P=.004) or allergic rhinitis alone (P=.02). Graminaceae hypersensitivity and nickel allergic contact dermatitis (Ni-ACD) were more frequent in patients with NCWS (70.1% and 17.8%) vs both CD (48.7% and 9.4%, P=.03 and P=.01, respectively) and IBS/FD (50.8% and 6.7%, P=.01 and P<.001, respectively). On multiple logistic regression analysis, a coexistent atopic disease (OR 1.481), MFH (OR 3.882) and SRMI (OR 2.259) were associated with the NCWS diagnosis. NCWS subjects with atopy compared to those without more frequently had Ni-ACD (P<.001) and SRMI (P=.03), positive patch test (P<.001), SPT for foods (P=0.001) and both total and food-specific serum IgE (P=.02 and P=.002, respectively). On multiple logistic regression analysis, positivity to patch test (OR 2.955), SPT for foods (OR 5.799), and food-specific serum IgE (OR 3.101) were confirmed as differentiating the 2 subgroups.

Conclusion

NCWS subjects have a higher frequency of atopic disease, MFH and SRMI compared to both CD and IBS/FD ones. These conditions could be expression of an underlying hypersensitivity milieu characterizing NCWS and might be of support in the differential diagnosis between NCWS and functional gastrointestinal disorders, if inserted into a broader diagnostic panel.

References

1) Zevallos VF, Raker V, Tenzer S, Jimenez-Calvente C, Ashfaq-Khan M, Rüssel N, et al. Nutritional Wheat Amylase-Trypsin Inhibitors Promote Intestinal Inflammation via Activation of Myeloid Cells. Gastroenterology. 2017;152:1100-1113.e12.
2) Uhde M, Ajamian M, Caio G, De Giorgio R, Indart A, Green PH, et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016;65:1930–7.
3) Volta U, De Giorgio R, Caio G, Uhde M, Manfredini R, Alaedini A. Nonceliac Wheat Sensitivity. Gastroenterol Clin North Am. 2019;48:165–82.
4) Catassi C, Elli L, Bonaz B, Bouma G, Carroccio A, Castillejo G, et al. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts’ Criteria. Nutrients. 2015;7:4966–77.
5) Carroccio A, Mansueto P, Iacono G, Soresi M, D’Alcamo A, Cavataio F, et al. Non-Celiac Wheat Sensitivity Diagnosed by Double-Blind Placebo-Controlled Challenge: Exploring a New Clinical Entity. American Journal of Gastroenterology. 2012;107:1898–906.

Disclosure

This study is funded by the European Union - Next Generation EU, Mission 4, Component 1 CUP B53D23031860001, Project Code: P2022Z9RZY_001.

Introduction

Confocal laser endomicroscopy (CLE) can detect acute duodenal epithelial disruption in response to food application, potentially identifying personalized elimination diets (1). A pilot study in functional dyspepsia (FD) showed that the 6-food elimination diet (6FED) provided symptom relief. (2). Earlier research in FD, however, showed that the high rate of acute food-induced mucosal alterations on CLE were not associated with altered permeability or changes in mast cell activation ex vivo (3).

Aims & Methods

To evaluate a personalized elimination diet in patients living with FD based on results of CLE, assessing duodenal mucosal changes to locally applied food solutions from the 6FED.
A randomized, double-blind, cross-over, sham-controlled trial was conducted in 17 Rome IV FD patients, in whom immunoglobulin E (IgE) sensitization to nutrients was excluded via food-specific serum IgEs. Baseline symptoms were assessed using the Leuven Postprandial Distress Scale (LPDS) and Patient Assessment of GI Disorders–Symptom Severity Index (PAGI-SYM). Index upper GI endoscopy (EGD) was followed at least 2 weeks later by an EGD with CLE. During CLE, duodenal mucosa was visualized at baseline and after consecutive, random administration of egg white, soy, milk, wheat, lyophilized fish/shellfish and nuts solutions. In case of a reaction to the first 2 food solutions, an additional CLE was scheduled. All patients underwent a crossover dietary intervention excluding foods to which they tested positively (real diet, RD) and negatively (sham diet, SD) in random order. Following 4 weeks of diet, LPDS and PAGI-SYM scores were reevaluated. Missing data were considered non-responder, based on an extreme case approach. Data are reported as mean ± SEM. Comparisons were done using a paired t-test or related-Samples Wilcoxon test, as applicable. Response rate was evaluated using a McNemar test. P<.05 is considered significant.

Results

Dietary outcome was available from 17 patients (age 35±3.7y, 16 female, BMI 22±0.7 kg/m2). In 7% of exams (n=2), acute alterations were already present at baseline. Twelve patients (71%) underwent a second CLE procedure. One patient dropped out after the first diet (which was RD). Three patients did not have a reliable RD/SD comparison due to non-response (n=1) or early response on CLE (n=2), underwent a standardized control diet, and were excluded from the analysis. Among the 14 patients in the cross-over dietary intervention, the proportion with a clinically significant 0.7 decrease in LPDS was similar for both diets (RD 4/14 vs. SD 2/14, p=0.41). No significant differences were found in LPDS subdomains or in the total PAGI-SYM score or PAGI-SYM fullness domain between the two diets (all p>.05).

Conclusion

In patients with FD, without systemic IgE-sensitization, CLE visualized a high rate of acute, food-induced, mucosal alterations, which could not be translated in symptom benefit following a dietary intervention excluding these foods vs. foods that did not trigger a reaction in this double-blind, controlled diet intervention study. None of the analyzed clinical outcome measures differed between the two diets. Given the results of this first double-blind controlled diet intervention in patients living with FD, CLE-based diets cannot be recommended in this population.

References

1. Fritscher-Ravens A, Schuppan D, Ellrichmann M, Schoch S, Rocken C, Brasch J, et al. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology. 2014;147(5):1012-20 e4.
2. Schol J, Vanuytsel T, Routhiaux K, Huang I, Balsiger L, Van Den Houte K, et al. The six-food elimination diet improves symptoms of functional dyspepsia. Submitted for publication. 2025.
3. Van de Bruaene C, Schol J, Balsiger L, Raymenants K, Toth J, Farre R, et al., editors. Observation of local, food-induced changes of the duodenal mucosa in functional dyspepsia cannot be translated in permeability alterations or changes in mast cell activation ex vivo. F; 2024; Bangkok, Thailand: Neurogastroenterology And Motility.

Introduction

Gastric intestinal metaplasia (IM), a precancerous lesion, requires precise assessment for surveillance. The Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) staging system, based on histopathology, is the international standard for IM risk stratification. ESGE guidelines recommend endoscopic surveillance for advanced IM (OLGIM stages 3/4). Developed as a substitute, the Endoscopic Grading of Gastric Intestinal Metaplasia (EGGIM) score assesses IM across five gastric regions using a 30% threshold. Two large-scale studies demonstrated excellent performance in predicting advanced IM (OLGIM stage 3/4).

Aims & Methods

To optimize the EGGIM scoring system by refining threshold criteria, incorporating IM morphology, and evaluating simplified scoring approaches.
In this retrospective cohort study, patients undergoing structured gastroscopy at the National Taiwan University Cancer Center were analyzed from February 2022 to September 2024. EGGIM scoring was performed using high-resolution white-light and narrow-band imaging, with histopathological confirmation per the updated Sydney protocol. Three modifications were proposed: (1) EGGIM-15, an extended scoring system with 0–3 per site (0: no IM; 1: IM <30%; 2: 30–60%; 3: >60%); (2) EGGIM-M, integrating morphology (small patches, large patches, carpet-like); and (3) EGGIM-S, a simplified version using only the angle and LC body,. Their diagnostic performance in predicting advanced IM (OLGIM stage 3/4) was evaluated and compared to the original EGGIM score.

Results

Among 944 patients (56% female; median age: 64 years), 64 (6.8%) had advanced IM. The original EGGIM score yielded an AUC of 0.83. EGGIM-15 achieved a similar AUC of 0.82. EGGIM-M reached an AUC of 0.83 in a random forest model, though feature importance remained highest for the original EGGIM (0.786). EGGIM-S demonstrated an AUC of 0.83, which is non-inferior to the original score, while using fewer assessed regions and achieving fewer false positives at a cutoff ≥4.

Conclusion

Neither expansion of scoring thresholds (EGGIM-15) nor inclusion of morphology (EGGIM-M) significantly improved diagnostic accuracy over the original EGGIM. However, the simplified model (EGGIM-S) offers similar performance with practical advantages in efficiency and applicability. This suggests potential for streamlined risk stratification in clinical settings without compromising diagnostic yield.