Introduction

The immune regulatory proteins, such as cytotoxic T lymphocyte antigen (CTLA)-4 as well as programmed death (PD)−1 and its ligand PD-L1 are important immune regulatory proteins collectively referred to as immune checkpoint receptors. These pathways can be used by malignant tumors as a mechanism to avert antitumoral immune responses.
Immune checkpoint inhibitors (ICIs) target these immune checkpoint receptors. ICIs have demonstrated impressive clinical activity and are now approved for the treatment of diverse malignant neoplasms. However, inhibition of these regulatory receptors leads to loss of tolerance and a wide spectrum of inflammatory toxicities known as immune-related adverse events (ir-AEs). Colitis or enterocolitis are the most frequent GI irAEs, affecting 15%–20% of patients who undergo endoscopic evaluation. When severe, irAEs can necessitate ICI therapy interruption, discontinuation, and treatment escalation with powerful immunosuppressive agents.
Isolated ICI-associated duodenitis has been reported after treatment with different immunotherapies.
Interestingly, de novo celiac disease (CeD) specific antibodies (serum tTG antibodies) with
histological features consistent with CeD in the setting of treatment with ICIs have been reported.

Aims & Methods

A literature search in Pubmed and Scopus to identify original reports in which CeD was documented histologically in patients treated with ICIs. Clinical, endoscopic and histopathological and immunological background were reviewed.

Results

Eleven papers were identified, all case reports or case series. A total of 26 pts were described. Twelve patients had a serologic and histological diagnosis of CeD.
CeD has been rarely observed during treatment with ICIs and is morphologically similar to ICI-CeD
enteropathy. Endoscopically, duodenal congestion, nodularity, or erythema were seen in 67% of patients with ICI-duodenitis, compared with 33% of patients with ICI-CeD. Few patients had concomitant upper and lower GI tract mucosal inflammatory changes.
Correlation with medication history, the finding of typical histologic changes, and re-evaluation of pathologic changes after checkpoint receptor inhibitor therapy will help confirm if an injury is likely to be an irAE.
Patients with ICI-CeD were reported to improve on a gluten free diet (GFD) as the single therapy, while some patients required the addition of immunosuppression with variable improvement in symptoms.

Conclusion

Whether ICI-associated celiac disease (ICI-CeD) reflects new onset gluten sensitivity or unmasking of previously asymptomatic CeD remains to be answered.
There is some evidence that ICI-CeD is biologically similar to ICI-duodenitis, but treatment strategies differ. ICI-CeD often improves with GFD alone, whereas ICI-duodenitis may require systemic immunosuppression.
In patients with atypical digestive symptoms in the context of ICI treatment, there is a necessity of complementary/additional investigation. Celiac disease specific antibodies (tTG-IgA assay) and duodenal biopsy are required. In the case of morphological lesions resembling CeD, serological and genetic testing should be performed for differentiating true CeD from ICI-drug-induced villous atrophy.
It might be useful to check for CeD before scheduled ICI therapy in patients with known high susceptibility to CeD, such as a family history of CeD, dermatitis herpetiformis, or chronic unexplained bowel symptoms.

Clinical Case Summary

A 38 year old female with jaundice, multiple limb bruises and a left breast haematoma on a background of decompensated alcohol related cirrhosis, presented to our hospital’s emergency department in December 2024 with spontaneous oropharyngeal bleeding. There was no history of any oropharyngeal infections, trauma, tongue bite or alcohol withdrawal seizure. She lost a litre of blood in a four-five hour period following her presentation in the emergency department. Initial interventions by ENT surgery team and Maxillofacial surgery teams proved unsuccessful in achieving definitive haemostasis in the glossal bed. This resulted in airway compromise which was managed by intubation by the anaesthetics team. Following input from the interventional radiology team, patient underwent angiograms of the right and left external carotid and common carotid arteries and a vascular blush was identified. She underwent successful embolization of the right sided facio-lingual and left sided lingual vessels and haemostasis was achieved.
Patient remained intubated in ITU and received management for ongoing coagulopathy and hepatic encephalopathy. Following step down to the Gastroenterology ward, extensive dietitian, physiotherapy, speech and language therapy input was required. She achieved baseline status after one month of extensive medical management and her cognitive function improved. She was eventually discharged to a rehabilitation assessment bed.
Spontaneous lingual artery haemorrhage is a rare manifestation of coagulopathy secondary to cirrhosis with other cases in literature stemming mainly from a co-existing asymptomatic pseudoaneurysm. This case illustrates an atypical presentation of decompensated liver cirrhosis with an acute spontaneous lingual artery haemorrhage requiring embolization of bilateral facio-lingual vessels. It emphasizes the need for early joined up multidisciplinary care and intervention to achieve haemostasis and a successful outcome in these patients.

Disclosure

The authors declare no conflict of interest

Introduction

Both the effectiveness and tolerability of Helicobacter pylori (H.p.) eradication therapy regimens are important in the management of H.p. infection, since the presence of side effects significantly reduces compliance between the doctor and the patient and sometimes can lead to treatment interruption. Our study aimed to compare the efficacy and tolerability of eradication therapy depending on the addition of Saccharomyces boulardii or a synbiotic complex.

Aims & Methods

The study included 78 patients (54 women and 24 men) with confirmed H.p. infection using validated tests, without previous eradication in the anamnesis. All patients underwent a course of eradication therapy, which included proton pump inhibitor (PPI) + amoxicillin (A) + clarithromycin (C) + bismuth subcitrate (B). Patients were divided into 2 groups: in group A (37 patients, 25 women, 12 men, mean age 44±3.2 years) S. boulardii CNCM I-745 was added to the mentioned regimen. In group B (41 patients, 29 women, 12 men, mean age 47±2.8 years), a synbiotic complex containing strains of probiotic bacteria Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus fermentum, Lactobacillus rhamnosus, Lactobacillus casei subsp. сasei, Streptococcus thermophilus, Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium adolescentis, Propionibacterium freudenreichii subsp. Shermanii, prebiotics inulin and lactulose were added to the indicated regimen. The duration of eradication therapy was 10 days. The duration of taking the probiotic and synbiotic complex ‒ 15 days.

Results

In group A, the effectiveness of the PPI+A+C+B regimen with the addition of S. boulardii was 75.7%. In group B (with the addition of a synbiotic) - 87.8%. We compared the tolerability of the indicated regimens. In no case (in both groups) was the treatment interrupted due to the presence of serious side effects. In total, 20 (54.1%) patients from group A and 17 patients (41.5%) from group B reported non-serious adverse events, including nausea (group A ‒ 8 patients (21.6%), group B ‒ 6 (14.6%), bitter taste in the mouth (group A ‒ 16 patients (43.2%), group B ‒ 15 (36.6%), and diarrhoea (group A ‒ 6 patients (16.2%), group B ‒ 0 (0%). No other adverse events were documented. Comparing gastrointestinal symptoms using the Gastrointestinal Symptom Rating Scale (GSRS) showed that in group A, mean values of the total score before treatment were 35.9±3.14 points, vs 26.2±1.64 points 20 days after the eradication course (p<0.05). In group B 34.1±2.44 points before treatment, vs 21.7±1.98 points 20 days after the eradication course (p<0.05). Comparing the total score of the GSRS questionnaire after treatment between groups A and B also showed a significant difference: 26.2±1.64 points in group A vs 21.7±1.98 points in group B (p<0.05).

Conclusion

Our study revealed better efficacy (87.8%) of the eradication regimen PPI+A+C+B with the addition of a synbiotic compared to the similar regimen with the addition of Saccharomyces boulardii (75.7%) in patients from Vinnytsia region, Ukraine. In addition, it was found that when the synbiotic complex was added, side effects of eradication therapy were noted in a smaller percentage of patients and significantly (p<0.05) lower values of the total score of the GSRS questionnaire were noted 20 days after treatment, in contrast to the regimen with the addition of Saccharomyces boulardii.