Introduction

The prevalence of gallstone disease in patients with ulcerative colitis (UC) is higher than in the general population. However, risk factors of gallstone disease in these patients remain unclear. Thus, we investigated the prevalence and risk factors of gallstone disease in Korean patients with UC.

Aims & Methods

Patients diagnosed with UC who underwent abdominal imaging between 1997–2020 were investigated using a well-established referral center-based large volume inflammatory bowel disease cohort. The prevalence and clinical characteristics of patients with gallstone disease were evaluated and compared with those without gallstone disease.

Results

Overall, 2811 patients with UC were enrolled. During the follow-up period (mean 5.7 years), 198 (7.0%) patients were diagnosed with gallstone disease and compared with those without gallstone disease (n = 2613). The proportion of extensive colitis at maximum extent, primary sclerosing cholangitis (PSC), history of cytomegalovirus, corticosteroid use, immunomodulatory use, colectomy, and appendectomy were significantly higher in the gallstone group (all P < 0.05). In multivariate analyses, age ≥ 60 years at gallstone evaluation (odds ratio [OR] 1.027; 95% confidence interval [CI] 1.002–1.052; P = 0.033), PSC (OR 6.304; 95% CI 3.162–12.565; P < 0.001), and history of colectomy (OR 2.494; 95% CI 1.222-5.087; P = 0.012) were significant risk factors for gallstone disease in patients with UC.

Conclusion

The prevalence of gallstone disease in Korean patients with UC was 7.0%, and age ≥ 60 years at gallstone evaluation, PSC, and history of colectomy were significant risk factors for UC patients with gallstone disease.

References

1. Zhang FM, Xu CF, Shan GD, Chen HT, Xu GQ. Is gallstone disease associated with inflammatory bowel diseases? A meta-analysis. J Dig Dis 2015;16:634-641.
2. Ha JH, Park YS, Seon CS, et al. Increased risk of asymptomatic gallstones in patients with ulcerative colitis. Intest Res 2015;13:122-127.
3. Jeong YH, Kim KO, Lee HC, et al. Gallstone prevalence and risk factors in patients with ulcerative colitis in Korean population. Medicine (Baltimore) 2017;96:e7653.

Introduction

Ulcerative proctitis (UP) is associated with disabling symptoms such as diarrhea, hematochezia and bowel urgency¹. Adequate therapy is crucial for symptom control and may reduce the risk of proximal disease extension. Although prior studies have explored risk factors for disease progression, they are limited by small sample sizes and have conflicting results^2,3.

Aims & Methods

We aimed to (1) assess the incidence and (2) identify risk factors for disease progression in newly diagnosed UP patients. We included all patients diagnosed with UP (inflammation ≤15 cm beyond the anal verge) between January 2000 and January 2024 in a large, non-academic hospital in the Netherlands. Data were collected from diagnosis until the end of follow-up. Disease progression was defined as endoscopic extension of UP (Montreal E1) to either left-sided (E2) or pancolitis (E3). To avoid overestimating the risk of disease progression, we used a Fine & Gray (F&G) regression model to account for patients in long-term remission who had no in-hospital follow-up. Patients who were referred back to primary care and/or had no in-hospital follow-up for ≥2 years were considered in long-term remission, which was used as a competing event in the F&G model. The cumulative incidence of disease progression was calculated at 1-, 5- and 10-years follow-up and compared to the progression rates of traditional Kaplan-Meier survival estimates.

Results

In total, 486 UP patients were included; 283 (58%) were female and median age at diagnosis was 39 years (IQR 29-53). 371 (76%) patients were in clinical remission at last follow-up. Of those, 291 (78%) were treated with topical and/or oral 5-aminosalicylates (5-ASA) and/or topical steroids; 202 (54%) required only topical and/or oral 5-ASA. 50 (10%) patients had refractory UP and required treatment with immunosuppressants or advanced therapies. During a median follow-up of 6.2 years (IQR 2.1-12.2), disease progression occurred in 112 patients (23%), of whom 80 (16%) progressed to E2 and 32 (6.6%) to E3. Median time to progression was 57 months (IQR 22-103). The cumulative incidence of disease progression was 2.8% (95% CI 1.4-4.4%) at 1 year, 13.2% (95% CI 9.9-16.4%) at 5 years and 23.9% (95% CI 19.4-28.4%) at 10 years after diagnosis and would have been overestimated with traditional Kaplan-Meier analysis (5.1% [95% CI 1.9-8.1%] at 1 year, 24.6% [95% CI 14.9-33.3%] at 5 years and 46.3% [95% CI 30.3-58.6%] at 10 years). F&G analyses demonstrated that age <18 years at diagnosis (HR 2.61, p=0.009) and the absence of steroid-free remission at 3 months (HR 1.97, p=0.005) were significant predictors for disease progression (Table 1).

Table 1. F&G risk factor assessment of proximal disease progression in UP
Variables	Hazard ratio (95% CI)	p-value
Age < 18 at diagnosis	2.61 (1.27-5.35)	0.009
Age >40 at diagnosis	0.98 (0.66-1.45)	0.92
Need for systemic steroids <1Y after diagnosis	1.54 (0.64-3.75)	0.34
Absence of steroid-free remission at 3M	1.97 (1.23-3.16)	0.005
Abbreviations. UP = ulcerative proctitis; CI = confidence interval; 3M = three months; 1Y = one year

Conclusion

In this large cohort of newly diagnosed UP patients, the 10-year cumulative incidence of disease progression was 23.9%. Most patients responded well to conventional treatment, as 60% reached clinical remission with only topical and/or oral 5-ASA and/or topical steroids. Absence of steroid-free remission at 3 months and age <18 at diagnosis were significant predictors for disease progression. Better prediction of disease progression could help identify high-risk patients who may benefit from tailored monitoring strategies, as well as low-risk patients that may be suitable for referral back to primary care.

References

1. Meucci G, Vecchi M, Astegiano M, et al. The natural history of ulcerative proctitis: a multicenter, retrospective study. Gruppo di Studio per le Malattie Infiammatorie Intestinali (GSMII). Am J Gastroenterol. 2000;95(2):469-473
2. Huguet JM, Ferrer-Barceló L, Suárez P, et al. Endoscopic progression of ulcerative proctitis to proximal disease. Can we identify predictors of progression?. Scand J Gastroenterol. 2018;53(10-11):1286-1290.
3. Walsh E, Chah YW, Chin SM, et al. Clinical Predictors and Natural History of Disease Extension in Patients with Ulcerative Proctitis. Inflamm Bowel Dis. 2017;23(11):2035-2041.
4. Andersen PK, Geskus RB, de Witte T, Putter H. Competing risks in epidemiology: possibilities and pitfalls. Int J Epidemiol. 2012;41(3):861-870.

Disclosure

RJBP, JH, RAJP, REAvD and AGLB have nothing to disclose. LAAPD has served on advisory boards for Abbvie, Janssen, Galapagos, and Pfizer, and has received independent research funding from Pfizer. ACdV has has served on advisory boards for Takeda, Janssen, Bristol Myers Squibb, Abbvie, Pfizer, and Galapagos and has received unrestricted research grants from Takeda, Janssen, and Pfizer.

Introduction

Ulcerative colitis (UC) disease course is unpredictable at the diagnosis and its management is still based on a "one-size-fits-all" approach.

Aims & Methods

We aimed to investigate the predictive factors of a rapidly progressive disease course in pediatric UC.
This was a retrospective case-control study conducted at the Pediatric Gastroenterology Unit of Umberto I Hospital in Rome. We included newly diagnosed UC patients aged < 18 years, with a minimum follow-up of 24 months. Demographic data, clinical features, laboratory, endoscopic and histologic findings at the diagnosis were collected and compared between patients with indolent UC and those with a rapidly progressive (RP) course. Children were classified as having a RP course if they experienced at least one of the following within the first 24 months after diagnosis: acute severe colitis, need for colectomy, necessity to transition to anti-TNFα therapy, or initiation of second-line biologic therapy.

Results

One hundred-sixteen patients were included, 67 (58 %) with a RP course and 49 (42 %) with an indolent disease. RP Children had higher age (11.5 vs 9, p=0.0008), PUCAI (50 vs 40, p=0.0005) and UCEIS (4 vs 3, p=0.002) at the diagnosis than those with indolent course. Hemoglobin was lower in the RP group (11.5 vs 12.3 g/dL, p=0.05). RP children had higher rate of cecal patch at endoscopy (18 % vs 2 % p=0.007) and a lower rate of sclerosing cholangitis (0 vs 8.2%, p=0.02). No differences were observed for all other clinical, laboratory, and histologic findings. Multivariate analysis confirmed that age and the presence of a cecal patch were associated with the risk of RP course (p=0.02, and p=0.04, respectively).

Conclusion

Among the clinical and easily obtainable information at the diagnosis in children with UC, an older age at the diagnosis, along with an endoscopic finding of a cecal patch seem associated with the risk of a more aggressive disease. Such results warrant confirmation in larger prospective cohorts for a future personalized approach to UC.

Introduction

This retrospective study analysed the real-world use patterns and clinical outcomes of 5-aminosalicylic acid (5-ASA) treatment in Korean patients with ulcerative colitis (UC) based on the records from national health insurance claims database (NHICD).

Aims & Methods

The records of individuals aged ≥15 years, first diagnosed as having UC between 1 January 2009 and 30 September 2018, were considered eligible for the study if 5-ASA was prescribed for ≥30 days within six months after the diagnosis. The data were extracted until the events of interest, patient’s death, or 31 March 2019, whichever occurred earlier. The events of interest were defined as UC-related hospitalisation, UC-related surgery, and 5-ASA non-response, the latter corresponding to the prescription of steroids, immunosuppressants, and/or biological medications during the follow-up period. The yearly proportions of patients in each average daily dose (ADD) group, i.e., rectal monotherapy (RM), oral low dose (<2 g/day) monotherapy (OML), oral standard-to-high dose (2 g/day to ≥3 g/day) monotherapy, oral low dose combination(oral+rectal) therapy (OCL), and oral standard-to-high dose combination(oral+rectal) therapy (OCSH) group, were presented. Odds ratio for prescribing high dose 5-ASA was calculated from a logistic regression model. The incidence of the events of interest was expressed per 1000 person-years (PY). Hazard ratios for 5-ASA insufficient-response and UC-related hospitalisation in each ADD group were obtained from a Cox proportional hazard model, with OML as a reference group. Treatment adherence was expressed as a proportion of days covered (PDC) within the first 12 months from the prescription index date.

Results

The analysis included the data of 11,338 patients (mean age 42.15 years, 59.53% of males). During a median observation period of 1,720 days, a tendency to a decrease in RM proportion was observed, along with an increase in the proportions of oral + rectal combination therapies. The odds of prescribing high-dose 5-ASA increased significantly since 2013. The proportion of OCSH increased from 18.1% in 2009 to 39.5% in 2018, whereas OML and OCL proportions decreased from 17.5% to 6.6% and from 11.6% to 6.6%, respectively. Incidence rates of 5-ASA insufficient-response and UC-related hospitalization were significantly lower in the RM group than in the OML group, with no significant differences between the OML group and other ADD groups. Mean PDC in overall population was 0.70, ranging from 0.65 to 0.76 across the ADD groups. 82.4% of patients responded to 5-ASA, and Mean PDC in overall population was 0.70, ranging from 0.65 to 0.76 across the ADD groups.

Conclusion

A tendency to a more frequent prescription of standard to high-dose 5-ASA as combination therapy was observed in 2009-2018, along with a decrease in RM prescription frequency, which is consistent with the current guidelines.

Introduction

Advanced Therapy (AT) should be carefully considered for patients who have both inflammatory bowel disease and a malignancy. The aim of administering AT is to avoid hospitalization and surgery in patients with otherwise intractable inflammatory bowel disease; however, the AT may result in exacerbation or recurrence of the malignancy. After careful consideration, we have been treating patients with both inflammatory bowel disease and a malignancy with AT. We here report the results of AT in patients with ulcerative colitis (UC) and malignant disease.

Aims & Methods

From January 2012 to December 2023, we treated five patients with UC and malignant disease (excluding colitic cancer) at the Ikoma Gastroenterology and Proctology Clinic. Age, sex, disease duration, disease extent, severity, clinical course, intractable or not, use or not of azathioprine, type of AT, duration of AT, curability of malignant disease, type and duration of AT after onset of malignant disease, whether the onset of malignant disease was diagnosed during AT, duration of follow-up after onset of malignant disease, outcome of UC after onset of malignant disease, and outcome of malignant disease.

Results

AT	One drug: UST, ADA (2 patients) Two drugs: GLM→TOF (1 patient)
	Three drugs: IFX→UST→TOF→UST (1 patient)
	Five drugs: ADA→GLM→VED→TOF→UST (1 patient)
Duration AT: range (median) (months)	24–83 (41)
Curability of malignancy: yes/no	5/0
Type and duration of AT after onset of malignant disease (months）	UST　(30), VED　3→TOF　24→UST　36（total 63） UST 30, GLM　1→TOF　59（total 60）
Malignancy first diagnosed during AT: yes/no	Yes: TOF, GLM, ADA (3 patients)/no (2 patients)
Duration of follow-up after onset of malignant disease: range (median)（months）	30–378 (52)
Outcome of UC after onset of malignant disease: remission/relapse	5/0
Outcome of malignant disease: exacerbation or recurrence/no exacerbation or recurrence	0/5

(AT:Advanced Therapy、UST:Ustekinumab、ADA:Adalimumab、GLM:Golimumab、TOF:Tofacitinib、IFX:Infliximab、VED:Vedolizumab)

The results are shown in the Table. Age: range (median) (years) : 45-69(56). Sex:Male/Female: 0/5. Disease duration: range (median）（months）: 114–289 (245) . Extent of UC : total colon/left colon: 1/4. Severity of UC : Severity :severe/moderate : 0/5. Clinical course: chronically persistent/relapsing–remitting: 0/5. Use of azathioprine: yes/no: 0/5.Three patients developed malignant disease during AT (cervical cancer, breast cancer, squamous cell carcinoma of the scalp), the remaining two (breast cancer, thyroid cancer) commencing AT only after the cancer’s onset. Four of the patients continued AT, the exception (a patient with squamous cell carcinoma) received adalimumab. After the onset of malignant disease, UC remained in remission in all patients and no new malignant disease developed.

Conclusion

In patients with UC who develop a malignancy before or during AT and achieve cure of that malignancy, continuing AT can prevent progression of the UC without exacerbation or recurrence of the malignant disease.

Introduction

Cytomegalovirus (CMV) infection frequently affects patients with Ulcerative Colitis (UC) and it has been associated with disease relapse and increased severity.

Aims & Methods

Our study aimed to assess clinical and biochemical differences between CMV-positive UC patients with moderate to severe disease relapse and those without CMV infection.
We retrospectively included all patients with UC who were followed for at least one year at the Unit of Gastroenterology of the Azienda Ospedale Università Padova and that were studied for CMV infection at the time of a moderate/severe reactivation (pMayo ≥5 and/or fecal calprotectin ≥ 250 and/or endoscopic Mayo ≥ 2) from May 2019 to October 2023. Patients were considered CMV-positive if CMV antigens were revealed by immunohistochemistry (at least 1 CMV intranuclear inclusion body in routine hematoxylin and eosin-stained sections and/or immunohisto-chemical staining) and/or a positive tissue viral load was detected by qualitative real-time PCR on colonic biopsies. Demographic and clinical features, fecal calprotectin, and previous and ongoing UC therapy were compared between CMV-positive patients and those who tested negative. Finally, the anti-CMV therapy administered was reported. Differences between the two study groups were assessed using the independent-samples t-test, while differences in the categorical analysis were analyzed using the Chi-squared test. A p-value <0.05 was considered significant. STATA 11 was used for statistical analysis.

Results

We retrospectively included 122 UC patients with moderate-to-severe disease (58.2% females, mean age at study 51 ± 17 years, time from diagnosis 11 ± 10 years). 24 patients (19.7%) were positive for CMV infection; no differences in gender, age, and time from diagnosis were observed between CMV-positive and negative patients. Serum quantitative CMV-DNA was tested in 18 patients and > 1000 copies/ml in 4 patients (22.2%) were detected. Approximately half of the patients were treated with immunomodulatory therapy during disease relapse with a similar distribution between CMV-positive and negative patients (p = 0.7). 95.2% of CMV-positive patients had diarrhoea compared to 71.6% of patients without CMV infection (p = 0.02), and abdominal pain was present in 71.4% CMV-positive compared to 42.1% CMV-negative patients (p = 0.015). In contrast, symptoms like fever and bloody diarrhoea had similar rates in the two groups (p=ns). Mean levels of fecal calprotectin were similar between the two groups (p = 0.07). Hospitalization was necessary in 91.7% of CMV-positive patients compared to 30.2% of CMV-negative patients. CMV-positive patients were treated with oral or intravenous steroids and switched to UC biological therapy more frequently than CMV-negative patients (p < 0.05). In parallel, 14/24 CMV-positive patients were treated with Ganciclovir for 3-5 days, and 13/14 were subsequently treated with Valganciclovir for another 2-6 weeks. Ten patients were only treated with oral Valganciclovir.

Conclusion

CMV-positive UC patients required systemic steroid therapy and hospitalization more frequently than non-infected patients, suggesting a more challenging management of the disease. Moreover, symptoms such as abdominal pain and diarrhoea emerged as potential indicators of CMV infection when compared to other clinical presentations.

Introduction

We lack reliable biomarkers to identify patients with inflammatory bowel disease (IBD) at a greater risk of severe disease course. With emerging evidence that early step-down treatment in severe patients leads to better disease outcomes, alongside worries about overtreatment of mild patients, there is a clinical need to identify such biomarkers.

Aims & Methods

In this study, we explore genetic variants associated with severe disease course for ulcerative colitis (UC) in a nationwide cohort of 4491 patients from Denmark.
We genotyped 4491 patients with UC (4153 from Danish birth blood spot archive; 338 from NorDIBD regional cohort), linking them with registry data capturing medical interactions throughout patients’ lifetimes. Patients who required 2+ IBD-related hospitalizations, 2+ IBD-related major surgeries, 1 IBD-related hospitalization and 1 IBD-related major surgery or use of systemic corticosteroids (≥5000 mg) in the first 3 years of diagnosis were defined as severe. We conducted a genome-wide association study comparing severe patients (N=1203) to those with a less severe disease course (N=3288).

Results

The GWAS identified a signal within the HLA region, with the HLA-DRB1*01:03 allele driving the association (OR=3.30 [2.23-4.87], P=2.08×10^-9, UC carriage rate=2.8%). We did not observe an association with CD severity in a similarly ascertained cohort of 3688 individuals (P=0.79).
Remarkably, carriage of DRB1*01:03 was associated with a seven-fold increase of major surgery risk (OR=7.05 [4.55-10.91], P=2.31×10^-16) (Table 1). At the point of diagnosis, carriage of DRB1*01:03 was associated with higher CRP levels (β=2.68, P=1.70×10^-7), f-cal levels (β=1.92, P=4.42×10^-3) and a higher rate of hospitalization at diagnosis (OR=1.64, P=0.014), suggesting that the effect on severity is not limited to disease progression.

Outcome	N	OR [95% CI]	P-value
Main analysis	1203 vs. 3288	3.30 [2.23 - 4.87]	2.08E-09
≥5000 mg corticosteroids	821 vs. 3288	2.29 [1.42 - 3.69]	1.06E-03
≥2 hospitalizations	692 vs. 3288	5.16 [3.44 - 7.73]	1.72E-14
≥2 hospitalizations without major surgery	555 vs. 3288	5.93 [3.71 - 9.49]	2.28E-12
≥2 major surgeries	242 vs. 3288	7.24 [4.35 - 12.04]	1.49E-12
Major surgery	358 vs. 3266	7.05 [4.55 - 10.91]	2.31E-16
Intestinal resection	210 vs. 3266	7.42 [4.46 - 12.32]	2.33E-12
Enterostomy	151 vs. 3266	8.38 [4.67 - 15.03]	1.54E-10
Colectomy	338 vs. 3266	7.34 [4.73 - 11.40]	8.23E-17

Table 1: HLA-DRB1*01:03 has a consistent direction of effect and magnitude across different conditions that define patient severity; it is associated with multifaceted patient severity, rather than one particular factor entirely driving the association.

Conclusion

In this large-scale, unselected nationwide cohort study, we find that HLA-DRB1*01:03 is a biomarker of UC disease course that is associated with a more severe presentation at diagnosis, as well as higher subsequent risk of surgery and hospitalization. Demonstrating the association at a genome-wide significance level for the first time, this study revitalizes findings from smaller studies at the beginning of the genetic era which explicitly recruited severe patients and made estimating carriage effects difficult.
While HLA-DRB1*01:03 is a low-frequency allele, patients who carry it are at a much higher risk of severe UC. As the cost of typing a single HLA allele is low (under 50 EUR) and several pharmacogenetic variants are beginning to be tested at diagnosis, we argue that it is a valuable addition to the arsenal of personalized healthcare tools.