Introduction

Esophageal dysphagia is a common complaint in daily clinical practice. After excluding structural and motility disorders, it may be related to functional disorders, which are challenging to diagnose and manage, leading to high health care utilization and both patient and physician dissatisfaction.

Aims & Methods

This is a prospective multicentric 6-months follow-up study to characterize dysphagic patients with normal esophageal motility, in terms of epidemiology and clinical aspects, focusing on patient-reported outcome measures, and evaluate their evolution at 6-months.

Results

From 2021-2024, 91 patients were recruited, 78.0% female, with a median age of 65 years [22-88]. Of these, 27.5% (n = 25) suffered from rheumatologic or endocrinologic disorders, and 56.0% were previously exposed to medical therapies.
Dysphagic symptoms had a median duration of 3 years [1-31], with a median Eckardt of 3 [0-9], PROMIS GI Disrupted Swallowing (PDS) of 60.4 [40.3-84.1], EuroQol-5D TTO of 0.592 [-0.055-1] and VAS of 70 [0-100].
Compared to non-dysphagic participants (n=123), these patients had significantly worse Eckardt, EuroQol-5D and PDS scores (p-values <0.001).
Compared to esophageal motility disorders (Chicago V4.0), the Eckardt and PDS scores in this group were significantly lower when compared to EGJ outflow disorders (p-value <0.001 and 0.003), without differences regarding EuroQol-5D.
Regarding gastroesophageal reflux, 24 (26.4%) patients had a positive GERD-Q questionnaire and 3 had an objective GERD diagnosis. Even though, compared to motility disorders, this score was significantly lower in this group when compared to EGJ outflow disorders (p-value 0.001).
Medical treatments (PPI, amitriptyline) were optimized in 6 patients (6.6%), without any differences in Eckardt or EuroQol-5D scores at 6-months. However, at 6-months, the PDS improved in untreated patients (p-value <0.001).

Conclusion

Non-obstructive dysphagia with normal esophageal motility has a negative impact on quality of life. However, symptoms tend to have a favorable course independently of treatment, therefore mandating a holistic management.

Introduction

Treatment of non-obstructive esophageal dysphagia (NOD) should consider not only the primary condition, but also its impact on patients’ daily function, their perception and surgical risk. Between surgical, endoscopic, and medical therapies, there is a wide range of choices, most without well-established indications or outcomes.

Aims & Methods

This is an ongoing prospective multicentric study to evaluate the real-life approach to NOD in 7 centers, by comparing the efficacy of different treatments [per-oral endoscopic myotomy (POEM), botulinic toxin (BT), pneumatic dilation (PD), optimization of proton-pump inhibitors (PPI) and expectant], through the Eckardt, EuroQol-5D (TTO and VAS) and PROMIS GI Disrupted Swallowing (PDS) scores.

Results

According to Chicago V4, it included 97 esophagogastric junction (EGJ) outflow disorders, 24 spastic motility disorders, 38 hypomotile disorders and 91 dysphagia with normal manometry. Fifty-seven (22.8%) patients were submitted to therapy.
Forty-three (44.3%) patients with EGJ outflow disorders were treated (31 POEM, 5 BT, 2 PD, 1 surgical and 4 medical). In contrast to untreated, treated patients showed better differences in Eckardt, PDS and EuroQol-5D VAS scores (p-values <0.005) after 6 months.
PPI was introduced and/or optimized in five (13.2%) patients with hypomotile disorders. There were no differences in Eckardt, EuroQol-5D and PDS at 6-months in treated or untreated patients.
Three (12.5%) patients with spastic motility disorders were treated (2 BT and 1 calcium-channel blocker). Both treated and untreated showed no differences in Eckardt or EuroQol-5D scores at 6 months.
Regarding dysphagic patients with normal manometry, medical treatments were optimized in 6 patients (6.6%), without any differences in Eckardt and EuroQol-5D scores at 6-months. Interestingly, the PDS showed a better difference at 6 months in untreated patients (p-value <0.001).

Conclusion

Apart from EGD outflow disorders, which have well-established treatment options, real-life approach of NOD is heterogeneous and showed no clear benefit. To improve clinical results, specialized clinics must be created.

Introduction

Dysphagia is a common condition with consequences surpassing the physical dimension and extending to the patient’s psychological, personal, and professional life. However, when referring to non-obstructive esophageal dysphagia (NOD) and motility disorders, data is still scarce.

Aims & Methods

Our study consists in a prospective and multicentric evaluation of the severity of dysphagia and its impact on quality of life, that was measured with the Eckardt, EuroQol-5D (TTO and VAS) and PROMIS GI Disrupted Swallowing (PDS) scores, in patients with NOD and underlying motility disorders. We included 373 individuals (250 with NOD and 123 without dysphagia).

Results

Among patients with NOD, 97 had esophagogastric junction (EGJ) outflow disorders on manometry according to Chicago V4.0, 24 spastic motility disorders, 38 hypomotile disorders and 91 normal motility. Compared with non-dysphagic individuals, dysphagic patients had significantly worse scores of both EuroQol-5D and PDS (p-values <0.001).
Among esophageal motility disorders, Eckardt score was significantly different between groups (p-value <0.001) as determined by ANOVA. Specifically, it was significantly higher in EGJ outflow disorders (mean of 5.2), when compared to spastic motility disorders (mean of 3.3) or dysphagic patients with normal motility (mean of 3.2).
With respect to Patient-reported outcomes, PDS score was statistically different between groups (p-value 0.003), being higher in the EGJ outflow disorders (mean T-score of 64.1) when compared to hypomotiity disorders (mean of 60.2) and dysphagic patients with normal motility (mean of 60.3).
Regarding patient-reported quality of life, there were no differences between groups in terms of EuroQol-5D TTO or VAS score (p-value of 0.156 and 0.368, respectively).

Conclusion

Our findings highlights the impact of NOD on the quality-of-life of patients. Although physician and patient reported symptoms’ severity were worse on EGJ outflow disorders, overall quality of life seems equally affected among all esophageal motility profiles.

Introduction

Chronic fatigue is a debilitating symptom and has major impacts on the quality of life of patients with chronic inflammatory conditions. In IBD, an estimated 50% of patients suffer from persistent fatigue despite successful treatment of intestinal inflammation. During active disease flares, this number jumps to 80% (Borren et al. 2018). Tryptophan metabolites are not only associated with disease activity in UC and CD, but also with chronic fatigue (Kavyani et al. 2022). Thus, our aims are (1) to characterize the relationship between fatigue and tryptophan derivatives and (2) to understand the metabolic dynamics arising when fatigue symptoms improve following therapeutic intervention.

Aims & Methods

In a prospective open label cohort of patients with moderate-to-severe Crohn’s disease (CD, n = 71) and ulcerative colitis (UC, n = 94) assigned to biologics therapy or JAK inhibitors, fatigue was assessed by the fatigue subscale of the Functional Assessment of the Chronic Illness Therapy – Fatigue (FACIT-F) questionnaire at therapy induction and 2 and 14 weeks thereafter. A FACIT-F score of <30.1 was considered severe fatigue while a score of >40 was considered no relevant fatigue. Clinical response at week 14 was defined as Crohn’s Disease Activity Index (CDAI) <150 and reduction of Partial Mayo Clinical Score (PMCS) >50% vs. baseline, respectively. We used targeted mass spectrometry to quantify the levels of 13 tryptophan derivatives and neopterin in a subset of patient serum in the weeks following therapy induction (at 0, 2, and 14 weeks, n = 120 individuals).

Results

Half of the recruited patients had severe fatigue at baseline (50.3%). Of the 120 patients who reached week 14 and had FACIT-F scores available, severe fatigue was experienced by 45.9% of the patients who did not respond to therapy and the rate was reduced to 13.2% in therapy responders. We found 8 metabolites positively associated with FACIT-F: tryptophan, kynurenic acid, kynurenine, picolinic acid, xanthurenic acid, serotonin, indole-3-proprionic acid, and quinaldic acid, while neopterin was negatively associated (FDR < 0.05). Four of these metabolites changed dynamically as a function of the extent of fatigue improvement: tryptophan, kynurenine, xanthurenic acid, and serotonin (FDR < 0.05). In all cases, the rate of change of these metabolites increased as a function of fatigue improvement.

Conclusion

Fatigue is linked to a diverse array of tryptophan metabolites. Notably, all of the significantly associated tryptophan derivatives were positively associated with FACIT-F, meaning that as fatigue symptoms improve, tryptophan metabolite levels increase. Many of these metabolites have previously been linked to symptom severity in IBD: for example, tryptophan, kynurenic acid and xanthurenic acid all tend to increase with symptom alleviation (Nikolaus et al. 2017, Michaudel et al. 2022). While the kynurenine-to-tryptophan ratio is elevated in active IBD (Nikolaus et al. 2017), this ratio did not convey a specific, fatigue-related signature. Considering that some patients continue to suffer from persistent fatigue even during disease quiescence, further work is needed to disentangle the impact of tryptophan metabolism on therapy response from its role on fatigue improvement.

Disclosure

F. Tran receives scientific funding from Sanofi, received consulting fee's from LEK Consulting and speaker's fees from Lilly, Janssen, Falk, Abbvie, Celltrion, onkowissen.de, CED Service GmbH. S. Schreiber reports consulting fees from Abbvie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, Prevention Bio, Protagonist and Falk.

Introduction

Colorectal polyposis, characterized by more than 10 adenomas, indicates a higher risk of malignancy and necessitates more frequent screening and genetic assessment. However, there are still a large number of polyposis patients with negative genetic test results. This study aimed to explore the risk genetic variants associated with non-hereditary colorectal polyposis through a genome-wide association study (GWAS).

Aims & Methods

Among patients who underwent colonoscopy at a single referral university hospital from January 2012 to September 2021, a total of 638 patients with 10 or more biopsy-proven cumulative polyps on colonoscopies and without genetic mutations or family history related to colorectal polyposis were included in this study. For the control group, a total of 7087 people who underwent colonoscopy for the purpose of health check-up at the Korea Medical Institute and were normal at least twice in a row were included. To find susceptible loci to non-hereditary colorectal polyposis, GWAS was performed and a genome-wide p-value threshold of 5 × 10^-7 was set to assess statistical significance.
We compared the genetic differences between two groups of patients with non-hereditary colorectal polyposis: those with 10 or more polyp recurrences observed during follow-up colonoscopies and those without such recurrences. We utilized SNPs that were identified as risk variants for non-hereditary colorectal polyposis in this GWAS. For each SNP, we defined the risk allele as the allele associated with increased risk of non-hereditary colorectal polyposis as identified in this GWAS. Genotypes were coded as 0, 1, or 2 based on the number of risk alleles identified at each SNP. We used a polytomous logistic regression model to identify SNPs that significantly increased the risk of polyp recurrence compared to the group without recurrence. Results of all regression analyses were adjusted for age, sex, BMI, smoking history, alcohol consumption history, family history of cancer, history of cancer other than colorectal cancer, comorbidities, and history of medication use.

Results

A total of 71 risk variants were discovered, which were new single-nucleotide polymorphisms (SNPs) not found in previous GWAS associated with colorectal cancer and polyp (Figure 1). 5 genes (UPF3A, BICRA, CBWD6, PDE4DIP, ABCC4) nearest or overlapped with 7 SNPs (rs566295755, rs2770288, rs1012003, rs201270202, rs71264659, rs1699813, rs149368557) previously reported directly or indirectly related to the development of colorectal cancer were proven to be risk variants significantly associated with non-hereditary colorectal polyposis. In addition, two new genes (CNTN4, CNTNAP3B) that have not previously been reported to be associated with colorectal cancer or polyp were newly identified.
The SNP rs149368557 was identified as being significantly associated with an increased risk of polyp recurrence in non-polyposis hereditary colorectal cancer (p-value: 0.049, odds ratio: 2.991, 95% confidence interval: 1.006–8.899).

Conclusion

In this study, we found 71 novel risk variants associated with non-hereditary colorectal polyposis. The SNP rs149368557 was identified as being significantly associated with an increased risk of polyp recurrence in non-hereditary colorectal polyposis. The risk variants and genes discovered in this study might be utilized as novel targets to prevent colorectal cancer in the future.