Introduction

Patients with inflammatory bowel disease (IBD) often come to the clinic with a simple question; “what should I eat?”. We therefore designed The PRognostic effect of Environmental factors in Crohn’s and Colitis (PREdiCCt) study to determine which aspects of habitual diet are associated with disease flare in IBD.

Aims & Methods

2629 patients with Crohn’s disease (CD) and ulcerative colitis (UC) in clinical remission were prospectively recruited from 49 adult and paediatric UK centers between 17/11/2016 and 31/03/2020. Main exclusion criteria were active steroid use, recent surgery or change in IBD therapy. Detailed baseline data were collected along with stool for microbial metagenomics and calprotectin (FCAL). Habitual diet over the prior 2-3 months was assessed using Food Frequency Questionnaire (FFQ). Patients were followed up for a minimum of 2 years by monthly electronic questionnaire, with end-of-study phenotyping from the patient records.The primary endpoint was time to first flare. 'Soft flares' were derived from IBD-Control response; 'hard flares' were defined as increase in symptoms plus elevation in CRP/FCAL and a change in IBD therapy. Only cases with complete FFQ, sex, smoking status and social deprivation data were included in this analysis (n=1017;CD=497, UC=520). Dietary intake measures were divided into quartiles, with hazard ratios calculated using Cox frailty regression for risk of flare. Analyses were adjusted for smoking, total energy intake, gender and social deprivation score with a random effect for sites.

Results

The hard flare rate was 5.6 % per year with no difference by IBD subtype; in contrast patient reported soft flares accumulated rapidly. Median follow up was 1481.5 (IQR: 1111-1805) days. Baseline FCAL predicted hard flare not only with levels of >250mcg/g, but also at 50-250mcg/g in both CD and UC. Baseline total protein intake was 91.9 g/day of which 35.8 g/day was from meat sources. Habitual meat intake was associated with hard flare in UC but not CD. The hazard ratio between highest and lowest quartiles of meat intake in UC was 2.08 (95% CI 1.14-3.80; p=0.017). No associations with hard flare were seen for total dietary fiber intake, N-6 polyunsaturated acids and ultra processed foods (using the NOVA score).

Conclusion

These are the first prospective data of habitual diet and IBD flare in a Western population. We show that habitual meat intake is associated with an increased risk of flare in patients with UC. Thus dietary modification merits investigation as a method of reducing flare risk. These data are consistent with data that meat intake is associated with increased risk of UC development. We hypothesize that this link is due to diet-induced alterations in the gut microbiome and will further explore this once metagenomic sequences of the PREdiCCt stool samples are complete.

Disclosure

Professor Charlie Lees has acted as a speaker and/or consultant to AbbVie, Janssen, Takeda, Pfizer,
Galapagos, GSK, Gilead, Vifor Pharma, Ferring, Dr Falk, BMS, Boehringer Ingelheim, Novartis, Sandoz,
Celltrion, Cellgene, Amgen, Samsung Bioepis, Fresenius Kabi, Tillotts, Trellus Health and Iterative Scopes.

Introduction

Inflammatory bowel disease (IBD) especially during flare periods, seems to be associated with an increased risk of thromboembolic and cardiovascular (CV) events[1]. After the results of the ORAL Surveillance study[2] enrolling patients with rheumatoid arthritis, several concerns have also been raised on the intrinsic risk of Janus kinase inhibitors (JAK-i), but population enrolled was predominantly >50 years old and had several CV risk factors. Accordingly, regulatory agencies recommend that JAK-i should be used only if no suitable treatment alternatives are available in patients at increased CV risk for all indication[3]. However, the real prevalence of CV risk factors (CVRF) and the risk related to JAK-i seem to be lower for patients with Ulcerative Colitis (UC).

Aims & Methods

The aim of our study is to explore the prevalence of thromboembolic and CV risks factors in a large cohort of UC patients suitable for advanced therapies.
We conducted a single-center study including all consecutive adult patients with UC, who initiated advanced therapies from June 2020 to December 2023. To assess thrombosis and CV risks, an online questionnaire was administered, collecting following variables: BMI, smoking status, varicose vein (presence or previous surgery), personal or family history of (FHx) venous thromboembolism (VTE), presence of known genetic thrombophilic factors, active or previous cancer, admission to hospital in the last 6 months, leg or hip fractures or surgery in the last month, C reactive protein (CRP) serum levels, history of (h/o) abortion, ongoing treatment with estrogen or hormone replacement therapy (HRT), presence of heart failure, chronic kidney disease (CKD), chronic obstructive pulmonary disease, h/o acute myocardial infarction (AMI), hypertension, atrial fibrillation (AF), h/o stroke or TIA, diabetes, FHx CV disease and serum lipids levels. The International Physical Activity Questionnaire (IPAQ) was used to assess sedentary lifestyle.

Results

Out of 320 patients surveyed, 305 responded (95.3%): of whom 54% male, with a mean age was 45 years (±SD 15.4) and a median disease duration of 7 years (IQR 2.9-16). Elderly patients (≥60 years) were 21.3%. The average BMI was 23.9 (±SD 14.1), with 34.8% being overweight and 8.5% obese. Active and former smokers accounted for 19.7% and 41.6% of the cohort, respectively; 54.1% were sedentary. Overall, 119 patients (39%) were biologic-naïve; 21.6% of patients started a JAK-i. Overall, 19% were recently hospitalized and in 86% of cases for IBD-related reasons. A genetic predisposition for thrombosis was identified in 4.6% of patients; varicose vein disease in 14.1%. CRP was high in 44.9% of patients. Of the female population 17.9% had h/o abortion, 7.1% were taking estrogen and 2.1% in HRT. Cumulatively only 27 patients (8.8%) had 4 thrombotic risk factors, 11 (3.6%) five, and 6 (2%) had ≥6.
Regarding CV risks, 15.1% of the population were hypertensive, 4.9% were diabetic, 4.3% had h/o AMI, 1.3% had h/o stroke or TIA, 2.3% had AF and 3.9% had CKD stage III. Total cholesterol values were available for 212 patients (69.5%), and 8% had cholesterol >240 mg/dl. The total cholesterol/HDL ratio was available for 171 patients (56.1%); 10.5% had values > 5 (medium risk). Overall, 92 (30.2%) had 1 CVRF, 17 (5.6%) had 2 CVRF, and 5 patients (1.65%) had more than 3 CVRF.

Conclusion

Our study confirms the prevalence of thrombotic and CV risk factors among patients affected by UC is quite low. Accordingly, the concerns regarding the use of JAK-i observed in rheumatological cohorts, may not be applicable for patients with UC.

References

[1] Fumery M, Xiaocang C, Dauchet L, Gower-Rousseau C, Peyrin-Biroulet L, Colombel J-F. Thromboembolic events and cardiovascular mortality in inflammatory bowel diseases: A meta-analysis of observational studies. Journal of Crohn’s and Colitis 2014;8:469–79. https://doi.org/10.1016/j.crohns.2013.09.021.
[2] Ytterberg SR, Bhatt DL, Mikuls TR, Koch GG, Fleischmann R, Rivas JL, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med 2022;386:316–26. https://doi.org/10.1056/NEJMoa2109927.
[3] EMA confirms measures to minimise risk of serious side effects with Janus kinase inhibitors for chronic inflammatory disorders | European Medicines Agency n.d. https://www.ema.europa.eu/en/news/ema-confirms-measures-minimise-risk-serious-side-effects-janus-kinase-inhibitors-chronic-inflammatory-disorders (accessed April 25, 2024).

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.

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.

Introduction

Patients with inflammatory bowel disease (IBD) experiencing severe flares are at increased risk of opportunistic infections, particularly cytomegalovirus (CMV), due to immunosuppressive therapy.

Aims & Methods

This study aimed to assess the prevalence and risk factors associated with CMV infection during severe acute colitis.
We conducted a retrospective analytical study on hospitalized patients with severe acute colitis. CMV infection was confirmed by positive anti-CMV IgM serology, positive colonic biopsy PCR for CMV DNA, or histological evidence of CMV cytopathic effect. Patients were divided into two groups: Group 1 (CMV-positive) and Group 2 (CMV-negative). Clinical, biological, and therapeutic data were compared (SPSS, p<0.05).

Results

Among 41 patients (mean age 39.8 years, 14 men), 17 (41.5%) had confirmed CMV infection. CMV was diagnosed by PCR (n=13), serology (n=3), or histology (n=1). Most received antiviral therapy (Ganciclovir or Valganciclovir). One patient required emergency colectomy; three experienced relapse, with two receiving Foscarnet and one undergoing colectomy for bleeding. No significant association was found between CMV infection and age, sex, disease duration, corticosteroid or immunosuppressant use, anemia, hypoalbuminemia, or CRP >45 mg/L. However, CMV infection was significantly associated with steroid resistance (p=0.003).

Conclusion

CMV infection is frequent during severe IBD flares and is strongly associated with corticosteroid resistance. Early recognition of this risk factor is essential for timely diagnosis and management to avoid complications.

Introduction

A significant proportion of patients with inflammatory bowel diseases (IBD) have extraintestinal manifestations (EIM), which may be very disabling. The presence of EIM and immunomediated diseases (IMIDs) may influence the selection of the biologic agent. On the other hand, biologic agents have been associated with the onset of IMIDs.

Aims & Methods

Aim: To evaluate the impact of ustekinumab on EIMs and IMIDs in a cohort of ulcerative colitis (UC) patients in real life.
Methods: Retrospective, multicenter study including UC patients who had received the first ustekinumab dose at least 16 weeks before the inclusion. Patients were followed-up from the first ustekinumab dose to treatment discontinuation or last visit, whichever came first. The evolution of previous EIMs and IMIDs was evaluated based on clinicians’ judgment. The onset of new EIMs and IMIDs under ustekinumab treatment was recorded.

Results

376 patients have been included so far (91% had PMS >2 at ustekinumab initiation, 96% had been previously exposed to biologics, and 25% had failed to anti-TNF, vedolizumab and tofacitinib). Median follow-up was 12 months (m). A total of 122 patients (32%) had previous EIM and/or IMIDs at ustekinumab start. A total of 80 patients (21%) had at least one EIM and/or IMIDs inactive at ustekinumab start, being the most frequent ones peripheral arthropathy (5%), axial spondyloarthropathy (3%) and psoriasis (3%). Some patients worsened from these conditions: a patient (6%) with peripheral arthropathy (partial response of UC), 2 (15%) patients with axial spondyloarthropathy (one in remission and one non-responder), a patient (33%) with rheumatoid arthritis (non-responder) and a patient (20%) with uveitis (non-responder). A total of 65 patients (17%) had active EIM and/or IMIDs at ustekinumab start; the outcomes of these patients are summarized in table 1. A total of 15 patients (4%) developed EIM and/or IMIDs after ustekinumab start: 6 (1.6%) patients developed peripheral arthropathy, 2 (0.5%) patients erythema nodosum, a patient (0.3%) was diagnosed with primary sclerosing cholangitis, a patient (0.3%) was diagnosed with vasculitis, and 6 (1.6%) patients developed other conditions.

Conclusion

In patients with active EIM at the start of ustekinumab treatment, improvement of those related to disease (UC) activity was observed. Other EIM and IMIDs not related to disease activity (axial spondyloarthropathy, uveitis, or rheumatoid arthritis) worsened. Treatment with ustekinumab does not appear to be associated with an increased risk of developing EIM or IMIDs.

Disclosure

This is an investigator-initiated study with financial support from Janssen (CNTO1275UCO4008).