Introduction

Acute appendicitis is a widely encountered emergency across the globe, showcasing the resilience of modern medicine, as it is traditionally addressed through the transformative procedure of appendectomy. Endoscopic Retrograde Appendicitis Therapy (ERAT) has emerged as a minimally invasive alternative; however recurrence is a worry.

Aims & Methods

This multi-center retrospective study aimed to evaluate the long-term safety, efficacy, and recurrence-related risk factors of ERAT to guide clinical decision-making. A total of 435 patients who underwent ERAT for acute appendicitis between October 2017 and October 2024 at three Chinese medical centers were included. Appendicitis recurrence was defined as imaging-confirmed symptoms returning within one-month post-ERAT. Univariate and multivariate regression analysis identified independent recurrence risk variables.

Results

All ERAT procedures were technically successful and achieved a clinical success rate of 92.4%. Over a median follow-up period of 37 months, the overall recurrence rate was 16.1%, with the majority of recurrences (13%) observed within the first year. Independent risk factors for recurrence included recurrent appendicitis (HR=1.916), appendiceal lumen distortion (HR=7.996), absence of stent placement (HR=0.375, protective), and operator inexperience (HR=2.318). Stent implantation effectively minimizes recurrence risk, especially in complicated incidents. ERAT facilitated overseeing appendicolith elimination, which assisted in occurring appendicolith-associated appendicitis.

Conclusion

ERAT is deemed safe and effective for acute appendicitis, with the highest recurrence risk occurring within the first year. Effective stent placement and skilled operators are crucial for reducing recurrence in complex cases. The aforementioned findings put forward significant insights for enhancing ERAT and advancing therapeutic outcomes.

Clinical Case Summary

A 19-year-old man with a long-standing history of recurrent abdominal pain and a recent episode of melena of unknown origin. He presented to the emergency department (ED) with hematochezia and asthenia, with a drop in hemoglobin to 8.9 g/dL. Upper and lower endoscopy were inconclusive. Capsule enteroscopy revealed a double-lumen sign and mildly erythematous mucosa, raising suspicion of Meckel’s diverticulum. A technetium-99m pertechnetate (Tc-99m) scan confirmed the presence of ectopic gastric mucosa. The patient subsequently underwent enterectomy, and histological analysis confirmed gastric mucosal heterotopia.
A 13-year-old man with a history of iron-deficiency anaemia requiring transfusion at 7 years old, and previous episodes of abdominal pain due to ileo-ileal intussusception. He had
undergone an inconclusive exploratory laparoscopy. He was admitted to the ED with melena and hypogastric pain. Blood tests revealed hemoglobin of 12.9 g/dL. Abdominal ultrasound showed thickening of the distal ileum over 11 cm, without signs of intussusception. Capsule enteroscopy revealed a segment of circumferential edema and erythema in the ileum, with absence of a clear villous pattern and an appearance suggestive of gastric mucosa. A Tc-99m scan confirmed the presence of ectopic gastric mucosa. Exploratory laparoscopy identified a 10–15 cm segment with gastric fold-like appearance within otherwise normal small intestinal mucosa, in the absence of a diverticulum. Histological analysis confirmed gastric mucosal heterotopia.
Gastric heterotopia is an important differential diagnosis in patients with gastrointestinal bleeding and can occur independently of the presence of Meckel’s diverticulum. The authors highlight the role of capsule enteroscopy in the diagnostic algorithm.

Introduction

TAK-062 is an orally delivered glutenase computationally designed to degrade immunogenic gliadin peptides. A phase 2 trial of TAK-062 (NCT05353985) did not meet the primary or secondary endpoints; however, the results may still be used to inform endpoints for future clinical studies in celiac disease. This study assessed the trial data for multiple histologic endpoints and determined the outcomes and relative performance of each.

Aims & Methods

The efficacy of TAK-062 vs placebo was assessed over a 24-week treatment period. Eligible patients were aged ≥18 years and had biopsy-confirmed celiac disease defined as a villous height to crypt depth ratio (Vh:Cd) of <2.5 at screening endoscopy (Week –4). All patients received simulated inadvertent gluten exposure (SIGE), consisting of a bar containing 500 mg of gluten three times per week throughout the treatment period. Duodenal biopsies taken at baseline and Week 24 were fixed in formalin and stained with hematoxylin and eosin for Vh:Cd analysis. Vh:Cd measurements were made by multiple readers with a proprietary digital pathology platform and averaged. CD3- and CD8-stained biopsy samples were used to count intraepithelial lymphocytes (IELs) and CD8 T cells, respectively, using a proprietary semi-automated counting software. The above measures were used to calculate two composite endpoints: (i) Vh:Cd and IEL counts (VCIEL), and (ii) Quantitative-Mucosal Algorithmic Rules for Scoring Histology (Q-MARSH). Qualitative assessment of Marsh–Oberhuber classification was conducted by a single pathologist. The variability and effect size of each outcome was determined.

Results

Analysis of the source of variability in the Vh:Cd measurement showed that 52% of the variability was at the patient level and 23% at the biopsy level. Only 1% of the variability was due to reader effects. Most other histology endpoints showed a similar response trend as observed with Vh:Cd. Determination of Vh, Cd, IEL counts, VCIEL, Q-MARSH and Marsh–Oberhuber scoring all showed significant worsening relative to baseline with TAK-062 treatment. Comparison of effect sizes for each endpoint showed that no endpoint outperformed Vh:Cd. Use of a statistically meaningful target criterion for response (Vh:Cd change of 0.4) found that 13.3% of patients in the placebo arm and 3.4% of patients in the TAK-062 treatment arm achieved this target response. Using a stringent remission criterion (Vh:Cd ≥ 2.7), 8.3% of the placebo arm and 1.7% of the TAK-062 arm achieved remission.

Conclusion

Although TAK-062 did not demonstrate efficacy in the phase 2 trial, learnings from this study emphasize the need for well-trained readers with clear scoring criteria to help to minimize variability in quantitative scoring. Furthermore, Vh:Cd shows good performance and is recommended as a key endpoint for assessing changes in gut architecture in celiac disease studies.

Disclosure

JM, JC, MZ, and DAL, are employees and shareholders of Takeda Development Center Americas, Inc. and receive stock or stock options.
JI is the founder and owner of Jilab, Inc., which received funding from Takeda for work undertaken as part of this study, is a full Professor at Tampere University, Medical Faculty, and has a consulting agreement with Takeda.
AV has nothing to disclose.
MER is a consultant for Alimentiv, Bristol Myers Squibb, Perspectum, Teva Pharmaceutical Industries Ltd., Anokion and Takeda, and has received a grant from AstraZeneca.

Clinical Case Summary

A 27-year-old male with diarrhea and rectal bleeding was diagnosed with moderate ulcerative colitis (UC) (Montreal: E3, Mayo endoscopic subscore: 2). He was started on mesalazine 4 g/day and oral prednisolone 40 mg/day, with clinical remission after 2 weeks. Prednisolone was successfully tapered off over the course of 8 weeks. He was not taking other medications. After starting therapy, the patient reported intermittent red urine discoloration, without other symptoms or association with respiratory tract infections.
Extensive investigation of hematuria was negative, including ANA, ANCA, anti-dsDNA and anti-GBM antibodies and imaging studies. Urine samples were macroscopically normal, with no red blood cells, casts or crystals. Urethrocystoscopy and urine cytology were unremarkable. Renal biopsy was considered.
The patient remained on mesalazine, with clinical, analytical and endoscopic response. During one episode, he noticed that the urine only became reddish after contact with toilet water disinfected with bleach. After stopping bleach toilet disinfection, there was no recurrence. He was diagnosed with mesalazine induced pseudohematuria and did not undergo further investigation.
Mesalazine is the first-line treatment for mild-to-moderate UC. Although uncommon, nephrotoxicity has been described and may result in urine discoloration or hematuria. Mesalazine is excreted in the urine and, when in contact with sodium hypochlorite (the active component of household bleach), oxidises, resulting in red-brown urine discoloration. Rare cases of patients reporting similar situations have been described in the literature. The role of gastroenterologists in recognizing this phenomenon is crucial, since mesalazine is a widespread efficient drug with an otherwise favorable safety profile. As our case illustrates, knowledge of this harmless reaction is desirable to avoid additional tests and potentially harmful unnecessary interventions, such as renal biopsy.

References

Figure 1 - Reaction between the urine of a patient taking mesalazine and the sodium hypochlorite present in household bleach (1A - before addition of bleach; 1B - after addition of bleach).

Disclosure

No conflict of interest to declare.