Introduction

Bowel urgency is a common and disruptive symptom in patients with ulcerative colitis (UC).¹ Fatigue is also common and has been associated with greater disease activity and lower quality of life in these patients.² However, little is known regarding the relationship between bowel urgency remission, bowel urgency clinically meaningful improvement, rectal bleeding remission, or stool frequency remission and improvement in fatigue. We examined the association between bowel urgency remission or bowel urgency clinically meaningful improvement and Fatigue Numeric Rating Scale (NRS) scores in the presence of rectal bleeding remission or stool frequency remission using pooled data from LUCENT-1 (NCT03518086) and LUCENT-2 (NCT03524092) phase 3 trials.

Aims & Methods

Bowel urgency was assessed by the Urgency NRS (UNRS), ranging from 0 (no urgency) to 10 (worst possible urgency). Bowel urgency remission was defined as a UNRS score of 0 or 1; bowel urgency clinically meaningful improvement was defined as a ≥3-point decrease in UNRS score from baseline.³ Rectal bleeding remission was defined as a modified Mayo subscore of 0; stool frequency remission was defined as a subscore of 0 or 1 with ≥1-point decrease from baseline.⁴ Fatigue was assessed by the Fatigue NRS, ranging from 0 (no fatigue) to 10 (worst possible fatigue), using change from baseline in Fatigue NRS score. Mediation analyses were performed to separately examine the relative association between the direct effects of bowel urgency remission and bowel urgency clinically meaningful improvement (predictor variables) and Fatigue NRS scores while adjusting for rectal bleeding remission and stool frequency remission (mediation variables). Analyses were treatment agnostic and combined mirikizumab and placebo treatment groups from LUCENT-1 (N=1162) and LUCENT-2 (N=544).

Results

The direct effect of bowel urgency remission at Week 12 and Week 40 (52 weeks continuous treatment) accounted for 68.3% and 62.1%, respectively, of the improvement in change from baseline in Fatigue NRS score. Substantially greater proportions of the Fatigue NRS score improvements were related to bowel urgency remission versus rectal bleeding remission (Week 12: 13.4% and Week 40: 16.4%) or stool frequency remission (Week 12: 18.3% and Week 40: 21.5%). Results were similar for bowel urgency clinically meaningful improvement at Week 12 (91.8%) and Week 40 (87.4%).

Conclusion

These findings provide strong evidence for a direct association between improvement or remission in bowel urgency and improvement in fatigue in patients with moderately-to-severely active UC.

References

1. Hibi T, et al. Inflamm Intest Dis. 2020;5(1):27.
2. Regueiro MD, et al. Adv Ther. Online Nov 12, 2022. doi: 10.1007/s12325-022-02364-2.
3. Dubinsky MC, et al., J Patient Rep Outcomes. 2022;6(1):114.
4. ClinicalTrials.gov. Updated October 27, 2022. Access December 1, 2022. clinicaltrials.gov/ct2/show/NCT03518086.

Disclosure

D. T. Rubin has been a consultant for and/or received research grants from: AbbVie, AbGenomics, Allergan, Biomica, Boehringer Ingelheim, Bristol Myers Squibb, Celgene/Syneos Health, Check-Cap, Dizal Pharma, Eli Lilly and Company, Galen/Atlantica, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Ichnos Sciences, InDex Pharmaceuticals, Janssen, Narrow River Management, Pfizer, Prometheus Therapeutics and Diagnostics, Reistone Biopharma, Shire, Takeda, and TechLab; is a shareholder at: AbGenomics and Biomica; is on the Board of Trustees at: American College of Gastroenterology; is cofounder and CFO of: Cornerstones Health (non-profit); and is cofounder of: GoDuRn; P. Hindryckx has received consulting fees from: AbbVie, Boston Scientific, Eli Lilly and Company, Janssen, Taewoong Medical, and Takeda; has received speaker fees from: AbbVie, Chiesi, Dr. Falk Pharma, Ferring Pharmaceuticals, Takeda, Tillotts Pharma AG, and Vifor Pharma; and has received research support from: Eli Lilly and Company; T. Hibi has received lecture fees from: AbbVie, EA Pharma, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, Sand K.K., Takeda, and Zeria Pharmaceutical; has received advisory and/or consultancy fees from: AbbVie, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Nippon Kayaku, Takeda, and Zeria Pharmaceutical; has received research grants from: AbbVie, Activaid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan Inc., and Takeda; has received scholarship•contributions from: Mitsubishi Tanabe Pharma, Nippon Kayaku, Pfizer Japan Inc., and Zeria Pharmaceutical; has belonged to study group sponsorship by: Alfresa Pharma, JIMRO, Kyorin, and Mochida Pharmaceutical; and has received grants and/or funds from: MIYARISAN Pharmaceutical Co., Ltd. and Zeria Pharmaceutical; K. McGinnis, T. Hunter Gibble, and A. Keohane are employees and shareholders of:
Eli Lilly and Company; M. Regueiro has received consulting fees from: AbbVie, Allergan, Amgen, Celgene, Eli Lilly and Company, Genentech, Gilead Sciences, Janssen, Miraca Life Sciences, Pfizer, Prometheus Therapeutics and Diagnostics, Salix Pharmaceuticals, Seres Therapeutics, Takeda, Target RWE, and UCB Pharma; and has received research support from: AbbVie, Janssen, Pfizer, and Takeda

Introduction

A male patient in his twenties presented with clinical aspects of primary sclerosing cholangitis (PSC), chronic cholestatic liver disease, and hypothyroidism. PSC is a rare, chronic cholestatic liver disease characterized by biliary strictures and peribiliary fibrosis (1). Susceptible loci were identified in GWAS but the correlation between genetic background and disease pathogenesis needs further investigation (2). In the index patient we identified a heterozygote candidate variant in the ABCC6 gene (c.2279G>A, p.(Arg760Gln)). Dysfunctional ABCC6 was described to cause ABCB11 and ABCG5/G8 genes overexpression, leading to imbalanced bile composition resulting in gallstone formation and cholestasis (3). ABCC6 variants were previously described in cases with low phospholipid-associated cholelithiasis (LPAC) and intrahepatic cholestasis of pregnancy (ICP)(4-6) . Subsequently, we aimed to investigate rare variants in ABCC6 gene in whole exome sequencing (WES) results from patients with suspected cholestatic liver disease.

Aims & Methods

Variant evaluation and annotation analysis was carried out on WES data, with focus on loss of function and missense variants, presenting allele frequency (AF) of ≤1% based on gnomAD database (https://gnomad.broadinstitute.org). Variants were filtered to include only those in genes relevant to the patients’ clinical phenotype. For each rare variant, a comprehensive in silico assessment was performed using tools such as REVEL, AlphaMissense, EVE, SIFT, and MetaLR to evaluate potential pathogenicity. Filtered were prioritized and interpreted using ACMG-AMP guidelines. This systematic approach ensured a clinically meaningful and evidence-based evaluation of the identified variants.

Results

Nine different rare heterozygote variants were identified in fifteen samples of 247 WES results. Among these, the missense variants c.179G>A, p.(Arg60Gln) and c.3139C>T, p.(Arg1047Cys) were found in two LPAC patients. Additionally, the c.1171A>G, p.(Arg391Gly) variant was observed in two related cases: a mother with ICP and her child with elevated gamma-glutamyl transferase (GGT) levels and jaundice. Moreover, this variant was also detected in another patient with elevated transaminases. c.3871G>A, p.(Ala1291Thr) and c.955A>G, p.(Ile319Val) were seen in patients with ICP and cholestasis, respectively. Three other variants were also identified in patients with liver disease of unknown etiology (c.1540G>A, p.(Val514Ile) and c.2707G>C, p.(Glu903Gln) and c.4397G>A, p.CYS1466Tyr). Additionally one splicing variant (c.37-1G>A, p,?) was also detected in a patient with cholangiocarcinoma (CCA). All variants were observed in heterozygote state and classified as variants of uncertain significance (VUS).

Conclusion

An in-depth analysis of WES data led to the identification of several potentially disease-relevant variants in the ABCC6 gene. These variants may play a contributory role in the observed hepatic phenotypes, suggesting a broader functional involvement of ABCC6 beyond its well-established association with pseudoxanthoma elasticum (PXE). Our findings highlight the importance of integrating genetic data with detailed clinical phenotyping to enhance understanding of genotype–phenotype correlations and reveal novel roles for known genes in atypical or organ-specific presentations.

References

1. Reich M, Spomer L, Klindt C, Fuchs K, Stindt J, et al. Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J Hepatol. 2021;75(3):634-46.
2. Goode EC, Fachal L, Panousis N, Moutsianas L, McIntyre RE, Bai BYH, et al. Fine-mapping and molecular characterisation of primary sclerosing cholangitis genetic risk loci. Nat Commun. 2024;15(1):9594.
3. Ibold B, Faust I, Tiemann J, Gorgels T, Bergen AAB, Knabbe C, et al. Abcc6 deficiency in mice leads to altered ABC transporter gene expression in metabolic active tissues. Lipids Health Dis. 2019;18(1):2.
4. Liu X, Lai H, Xin S, Li Z, Zeng X, Nie L, et al. Whole-exome sequencing identifies novel mutations in ABC transporter genes associated with intrahepatic cholestasis of pregnancy disease: a case-control study. BMC Pregnancy Childbirth. 2021;21(1):110.
5. Liu X, Zheng J, Xin S, Zeng Y, Wu X, Zeng X, et al. Whole-exome sequencing expands the roles of novel mutations of organic anion transporting polypeptide, ATP-binding cassette transporter, and receptor genes in intrahepatic cholestasis of pregnancy. Front Genet. 2022;13:941027.
6. Romeo M, Dallio M, Federico A. Is it time to reconsider the MRP6 role in bile secretion and LPAC genetic signature? J Hepatol. 2023;79(4):e152-e4.

Disclosure

The authors declare that they have no conflict of interest.

Introduction

Pain is the hallmark and most disabling symptom of chronic calcific pancreatitis (CCP), often severe and significantly impairing patients' quality of life. Its pathophysiology involves increased intraductal pressure, chronic inflammation, and neuropathic changes.

Aims & Methods

This study aimed to assess the prevalence of pain in CCP and to identify factors associated with its occurrence and severity.
This was a retrospective analytical study including patients followed for CCP. We collected data on disease duration, etiology, clinical manifestations, complications, analgesic treatments (AT), and symptom evolution under treatment. Pain intensity and impact on quality of life were assessed using the Izbicki Score (IS), which categorizes pain as mild (0–20), moderate (21–40), severe (41–60), or very severe (>60). Incomplete records that prevented IS calculation were excluded. Data were entered and analyzed using SPSS software, with statistical significance set at p < 0.05.

Results

We included 22 patients (14 men and 8 women), with a mean age of 55.6 years [27–80 years]. The most common symptoms were epigastric pain (n=18), weight loss (n=13), and chronic diarrhea (n=6). The mean delay between symptom onset and diagnosis was 25 months [1–120 months]. Etiologies included hyperparathyroidism (n=6), alcohol use (n=2), pancreas divisum (n=2), autoimmune causes (n=2), and were undetermined in 10 cases. The IS ranged from 0 to 93.75, with a mean of 40.22. Eight patients had an IS >40. Morphine was required in four cases; paracetamol was prescribed for 12 patients, and tramadol for two. Endoscopic treatment was indicated in three cases, while one patient underwent a Wirsungojejunostomy.
In univariate analysis, alcohol consumption was significantly associated with the occurrence of epigastric pain (p=0.01). Smoking and alcohol use were both linked to a higher IS (>50) (p=0.04). Smoking cessation was associated with a better analgesic response (p=0.04). Morphine use was significantly more frequent among alcoholic patients (p=0.01), and their treatment response was often unfavorable (p=0.02).

Conclusion

In our cohort, 80% of patients with CCP experienced pain, which was severe to very severe in nearly half the cases. Pain intensity was significantly associated with tobacco and alcohol consumption, while cessation improved treatment response. These findings underscore the importance of therapeutic education focused on smoking and alcohol cessation, in addition to analgesic management, to slow disease progression and improve pain control.

Introduction

Avoidant/restrictive eating is common in people with neurogastroenterology disorders including functional dyspepsia (FD). There is debate on whether avoidant/restrictive food intake disorder (ARFID) is an expected response to severe symptoms or simply a common comorbid disorder. To address this, among adults with FD, we aimed to contrast those with and without ARFID on FD symptoms, quality of life, psychosocial factors, nutrient tolerance, and gut transit.

Aims & Methods

Adults with Rome-IV confirmed FD and healthy controls (HC) from an ongoing study participated. ARFID diagnosis was assigned based on a semi-structured DSM-5 diagnostic interview. Surveys: Patient Assessment of GI Disorders Symptom Severity Index (PAGI-SYM), Short Form Nepean Dyspepsia Inventory (SF-NDI), Nine-Item ARFID Screen (NIAS), Fear of Food Questionnaire (FFQ), Visceral Sensitivity Index (VSI), and Hospital Anxiety/Depression Scale (HADS). Nutrient Drink Test (NDT) measured gastric tolerance—liquid nutrient ingestion at 30mL/minute until subject reported unbearable fullness. Wireless Motility Capsule (WMC) measured gut transit. Height/weight was measured for body mass index (BMI).

Results

Sample (80% female, M_age=37.1±14.4y) included 37 FD+ARFID, 14 FD only, and 18 HC. Groups did not significantly differ in sex or age. Adjusted pairwise comparisons showed small (r=.1-.2) non-significant differences between FD and FD+ARFID on FD symptoms by PAGI-SYM and SF-NDI (Table 1). However, FD+ARFID had significantly worse scores compared to FD with medium effects (r=.3-.4) on: FD-related quality of life by SF-NDI, Fear of Food by NIAS-Fear and FFQ, GI-anxiety by VSI, and anxiety by HADS. FD+ARFID vs FD also had small differences (rs=.2) on: feeling more bothered by FD symptoms on SF-NDI, worse depression by HADS, lower BMI, and less NDT consumption. Compared to HC, FD and FD+ARFID had significantly worse survey scores with large effects for FD+ARFID (r=.6-.8) and medium effects for FD vs HC (r=.3-4). For the NDT, FD+ARFID consumed significantly less than HC with large effect (r=.6) but with a trend medium effect for FD consuming less than HC (r=.3). Groups did not significantly differ in WMC transit times.

Conclusion

Our findings suggest ARFID, when present in FD, does not reflect a response to more severe FD symptoms. Thus, ARFID is a legitimate secondary condition in FD. ARFID may reflect more profoundly altered distress around symptoms (e.g., fear of symptoms, anxiety sensitivity) and greater negative impacts (e.g., FD-related quality of life, lower liquid nutrient tolerance).

Clinical Case Summary

We present the case of a 43-year-old black male with a relevant medical history of arterial hypertension, alcoholism, and epilepsy. He was admitted to the emergency department for cough with purulent sputum, shortness of breath and chest pain for the past week. On observation, he presented several perianal fistula openings with bloody and purulent discharge. A computed tomography (CT) revealed perirectal densification, fistulous tracts to the ischioanal fossae, ascites, mesenteric fat densification and necrotic inguinal adenopathies. Due to the presence of hematochezia, a rectosigmoidoscopy was performed which showed deep ulceration causing destruction of the posterior wall of the distal rectum, involving one third of its luminal circumference, with bloody and purulent discharge. The patient developed septic and hemorrhagic shock and was admitted to the intensive care unit. He underwent urgent surgery for hemostasis of the rectal ulcer, partial fistulectomy, seton placement in the other three fistulous tracts, and loop colostomy. Analysis of the perianal discharge detected Mycobacterium tuberculosis by polymerase chain reaction. Sputum acid-fast bacilli smear was also positive, and a thoracic CT scan showed cavitating consolidations in the upper pulmonary lobes and a tree-in-bud pattern reflecting active tuberculosis (TB) with endobronchial spread. Remarkably, the patient was HIV-negative and did not have other causes for immunosuppression besides the chronic alcoholism. He was started on antitubercular medication and evolved favorably.
Gastrointestinal TB represents less than 1% of all tuberculosis cases. Anorectal involvement is even rarer, being present in 1% of all cases of gastrointestinal TB. Its most common presentation is complex perianal fistulizing disease. In most cases, pulmonary TB is also present. Although it is more prevalent in immunosuppressed patients, it should be included in the differential diagnosis of complex perianal fistulizing disease.

References

1- Photographs of perianal fistulizing disease with purulent discharge;
2- CT scan suggesting disseminated TB;
3- Rectosigmoidoscopy showing destruction of the distal rectal wall.