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

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

Limited evidence is available about predictors of response to specific medications for ulcerative colitis (UC). OCTN1, an organic cation transporter, with its variants, could modulate the inflammatory response and potentially predict individual response to immune-modulatory therapy (anti-TNFα and vedolizumab).

Aims & Methods

We first confirmed the ability of OCTN1 to differentially modulate IL1β secretion under different stimuli in a human leukemia monocytic cell line (THP-1) and in human peripheral blood mononuclear cells. We therefore prospectively enrolled a cohort of UC patients starting either anti-TNFα or vedolizumab, determined their OCTN1 genotype and evaluated their clinical features at baseline and clinical response to therapy after six months, as well as two years therapy persistance.

Results

OCTN1-deficient THP1 cells showed reduced IL-1β secretion in response to peptidoglycan (PGN) and Fusobacterium nucleatum (Fn), whilst primary monocytes bearing OCTN1 503F variant displayed an increased production of IL-1β in response to PGN and live bacteria. We therefore enrolled 90 patients, of which 50 starting anti-TNFα and 40 vedolizumab. At the multivariate analysis, an overall better response to therapy was observed with the mutated 503F variant (OR=16.72, p=0.011) in comparison to wild type (503L) and heterozygous variants; nevertheless, a significant reduction of clinical response after six months was observed in patients with 503F variant treated with vedolizumab (OR=0.02, p=0.04). Furthermore, the same trends were observed the two years steroid free therapy persistence wa taken inot consideration.

Conclusion

Mutated OCNT1 genotype (503F) could favor an increased IL1β secretion from human leukocytes, thus suggesting a worse disease course and lower response to vedolizumab as compared to homozygous 503L and heterozygous.

Introduction

Inflammatory Bowel Disease (IBD) are multifactorial and debilitating diseases that impact patients' quality of life. A key characteristic of IBD is immune system dysregulation, which contributes to a higher risk of developing additional chronic immune-related disorders, such as chronic rhinosinusitis (CRS). The coexistence of these two conditions can undoubtedly affect patients' life and disease history. This study aims to determine the prevalence of CRS in individuals with IBD and evaluate its impact on their quality of life.

Aims & Methods

We conducted a prospective, observational, single-center pilot study, enrolling consecutive IBD patients. Clinical, demographic, and disease history data were collected. The sino nasal outcome test 22 (SNOT-22) questionnaire was administrated to each patient to assess subjective symptoms of CRS. Participants were stratified into two groups: Group 1 (SNOT-22 < 30) indicating no or mild CRS and Group 2 (SNOT-22 > 30) indicating moderate to severe CRS. Group 2 patients underwent a comprehensive otolaryngological assessment including laboratory testing and a fibrolaryngoscopy to confirm the diagnosis of chronic rhinosinusitis.

Results

We enrolled 100 IBD patients, 43 % were affected by Crohn’s Disease and 57% were affected by ulcerative colitis (UC):

• CD patients stratified by disease location:
  1. Ileum: 14 patients (32%)
  2. Colonic: 8 patients (19%)
  3. Ileum-Colonic: 19 patients (44%)
  4. Upper GI: 2 patients (5%)
• RCU patients stratified by disease location:
  1. E1 (proctitis): 8 patients (14%)
  2. E2 (left sided colitis): 20 patients (35%)
  3. E3 (extensive colitis): 26 patients (46%)

Among them, 37% of patients were naive to biological therapy, while 13% had failed at least two lines of biological therapy. Based on the SNOT-22 score, patients were divided in:

• Group 1 with SNOT-22 < 30 (mild symptoms):
  1. CD (43): 26 patients (60%)
  2. RCU (57): 36 patients (63%)
• Group 2 with SNOT-22 > 30 (moderate to severe symptoms):
  1. CD (43): 17 patients (40%)
  2. RCU (57): 21 patients (37%)

Patients with Crohn’s disease in Group 2 exhibited higher disease activity, as measured by the Harvey-Bradshaw Index (HBI), compared to those in Group 1 (mean HBI: 3.8 vs. 1.38; p = 0.004). In contrast, no significant difference in disease activity was observed among patients with ulcerative colitis between the two groups. At the time of analysis only 15 patients of Group 2 underwent otolaryngological and laboratory evaluation including IgE and eosinophil cationic protein (ECP) and 10 patients showed endoscopic signs of CRS (See Table 1).


Table 1. Clinical and biological parameters between CRS and non-CRS patients

Conclusion

CRS is frequent among patients with IBD. In line with prior reports, our study identified a CRS prevalence of 10% within IBD patients. Moreover, the higher prevalence of CRS in patients with more severe IBD activity may highlight a potential connection mediated by the gut–lung axis. No significant differences were observed in IgE levels or eosinophil cationic protein values among patients with CRS, suggesting that the pathogenesis of CRS in IBD patients may differ from patients with isolated CRS. Nonetheless, these findings remain preliminary due to the lack of laboratory analyses and otolaryngological evaluations for additional patients. Comprehensive clinical assessments and advanced laboratory investigations are warranted to further elucidate the underlying mechanisms of the gut–lung axis in this context.

Introduction

The Janus kinase inhibitor (JAKi) upadacitinib (UPA) is approved for the treatment of moderate-to-severe ulcerative colitis (UC). However, safety warnings from the US Food and Drug Administration and the European Medicines Agency recommend caution when using JAKis in certain at-risk patients. These drug-class warnings are based on data from the ORAL Surveillance (OS) study, a safety outcomes trial comparing risk of cardiovascular (CV) events with the JAKi tofacitinib plus methotrexate vs a tumor necrosis factor inhibitor (TNFi) plus methotrexate in patients with rheumatoid arthritis (RA) who were ≥50 years of age with ≥1 CV risk factor.¹ An OS study post hoc analysis observed higher major adverse CV event risk with tofacitinib vs TNFi in patients with RA plus a history of atherosclerotic CV disease (ASCVD).² CV risk profiles may be different for patients with UC vs RA.

Aims & Methods

This analysis aimed to describe the CV risk profile for patients with UC relative to the CV risk profile for patients with RA included in the OS study. Patients with UC enrolled in the placebo-controlled UPA U-ACHIEVE and U-ACCOMPLISH induction trials³ were evaluated for the OS study inclusion criteria (age ≥50 years, ≥1 CV risk factor [CV event history, hypertension, diabetes mellitus, smoking/tobacco use, and high-density lipoprotein cholesterol <1.034 mmol/L]). In addition, history of coronary artery disease or ASCVD and 10-year CV disease risk for patients with UC with no prior CV disease were estimated using the American College of Cardiology ASCVD risk score calculation.

Results

Overall, 268/1097 (24.4%) patients with UC met the OS criteria and 624 (56.9%) had ≥1 CV risk factor, regardless of age. Few patients with UC (30; 2.7%) had a history of ASCVD, in contrast to the RA population (640/4362; 14.7%). The distribution of 10-year ASCVD risk scores for patients with UC was similar between the placebo and UPA treatment arms, but markedly different from patients with RA (Table). Most patients with UC were categorized as low risk (938; 85.5%), with another 52 (4.7%) categorized as borderline risk, 51 (4.6%) as intermediate risk, and 26 (2.4%) as high risk.

	Patient Populationa
	Ulcerative Colitis			Rheumatoid Arthritis2
ASCVD riskb, n (%)	Placebo N = 378	UPA 45 mg N = 719		TOFA 5 mg N = 1455	TOFA 10 mg N = 1456	TNFi N = 1451
HxASCVD	10 (2.6)	20 (2.8)		204 (14)	222 (15)	214 (15)
High (≥20%)	6 (1.6)	20 (2.8)		258 (18)	289 (20)	278 (19)
Intermediate (≥7.5% to <20%)	19 (5.0)	32 (4.5)		472 (32)	490 (34)	483 (33)
Borderline (≥5% to <7.5%)	13 (3.4)	39 (5.4)		198 (14)	169 (12)	153 (11)
Low (<5%)	330 (87.3)	608 (84.6)		306 (21)	268 (18)	308 (21)
aIn the rheumatoid arthritis population, the 10-year risk scores were multiplied by 1.5 prior to the derivation of risk categories; in ulcerative colitis, no multiplier was used. bASCVD risk score was calculated based on the following factors: patient age, sex, race, systolic blood pressure, total cholesterol, HDL, history of diabetes [Y/N] or smoking [Y/N], and hypertension treatment [Y/N]). ASCVD, atherosclerotic cardiovascular disease; HxASCVD, history of ASCVD; TNFi, tumor necrosis factor inhibitors, TOFA, tofacitinib; UPA, upadacitinib

Conclusion

The majority of patients in the UC trials had low estimated CV risk, while the majority of patients with RA included in the OS study were at intermediate or high CV risk. Caution should be used when extrapolating adverse events data from patients with RA to risk discussions for patients with UC.

References

1. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med 2022;386:316-326.
2. Charles-Schoeman C, Buch MH, Dougados M, et al. Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. Ann Rheum Dis 2023;82:119-129.
3. Danese S, Vermeire S, Zhou W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet 2022;399:2113-2128.

Disclosure

L Peyrin-Biroulet has received personal fees from Galapagos, AbbVie, Janssen, Genentech, Alimentiv, Ferring Pharmaceuticals, Tillotts Pharma, Celltrion, Takeda, Pfizer, InDex Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Inotrem, Allergan, MSD, Roche, Arena Pharmaceuticals, Gilead, Amgen, Bristol Myers Squibb, CSL Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSE Immunotherapeutics, Enthera, Theravance Biopharma, Pandion Therapeutics, Gossamer Bio, Viatris, and Thermo Fisher Scientific; grants from AbbVie, MSD, Takeda, and Fresenius Kabi; and stock options from CTMA.
RK Cross is an advisory board member and consultant for AbbVie, Adiso, BMS, Fresenius Kabi, Fzata, Janssen, Magellan Health, Pfizer, Samsung Bioepis, Sebela, and Takeda; and a member of the Executive Committee for the IBD Education Group and Scientific Co-Director of CorEvitas.
KM De Felice is an advisory board member and honorary speaker for AbbVie and BMS.
D Ilo, B Duncan, J Liu, and CTJ Holweg are employees of AbbVie Inc. and may hold AbbVie stock and/or stock options.
R Chowdhury has no conflicts of interest to declare.
This study was funded by AbbVie. Medical writing and editorial assistance were provided by Jeffrey Kohn, PhD, and Lauren Smith, BA (Hons), from Complete HealthVizion, an IPG Health Company, funded by AbbVie.

Introduction

The therapeutic armamentarium for inflammatory bowel disease (IBD) includes several biological agents: infliximab (IFX), adalimumab (ADA), vedolizumab (VED) and ustekinumab (UST). Persistence in therapy with these drugs is not satisfactory, not only due to the loss of clinical response over time but also due to adverse events. Acute infusion reactions (AIRs) occur during or within 24 hours of the infusion. The intensity of AIRs ranges from mild (flushing, dizziness, headache, itching, rash) to severe (anaphylactic).

Aims & Methods

The primary aim of this study was to compare the prevalence rates of AIRs due to the different biological agents in a large cohort of patients with IBD and to assess risk factors for AIRs.
All reports of AIRs occurring from January 2021 to October 2023 in IBD patients treated with different biological agents (IFX, ADA, VED and UST) in a tertiary IBD center were retrospectively reviewed. The electronic records of the identified patients were checked for the type of IBD, whether Crohn's disease (CD) or ulcerative colitis (UC), type of biological agent, route of administration (intravenous or subcutaneous), concomitant immunosuppressive therapies, atopic status. Furthermore, the type of treatment for the AIRs and the subsequent therapy undertaken for IBD were also recorded.

Results

22 AIRs were recorded out of 1911 patients (1.1%). Of these, 16/550 in patients on IFX biosimilars (2.9 %), 4/590 (0.7%) in patients on ADA biosimilars, 2/318 (0.6%) in patients on VED and 0/453 (0%) in patients on UST (Table 1). The difference in the prevalence of AIR rates observed with the different biological agents was statistically significant (p<0.01). 7 of 16 post-IFX AIRs were moderate-severe, with two episodes of anaphylaxis occurring in patients with CD. The two patients treated with VED experienced only mild symptoms, and no anti-reactive treatment has been used; two mild and two moderate AIRs, respectively, have been reported among patients on ADA. 12 of 22 AIRs occurred during the induction period (from the first to the third administration). 7 of 22 patients had previous allergic reactions.

		Infliximab (n=16)	Adalimumab (n=4)	Vedolizumab (n=2)
Type of IBD, n (%)	Ulcerative colitis	8 (50)	2 (50)	2 (100)
Age, y. Median (range)		34.81 (20-62)	47 (42-50)	62.5 (50-75)
Sex, n (%)	Female	7 (43.8)	2 (50)	0 (0)
Duration of IBD, y. median (range)		6.1 (1-22)	12.2 (7-15)	8.5 (6-11)
AIRs’ severity	Mild	9 (56.2)	4 (100)	2 (100)
	Moderate-Severe	7 (43.8)	0 (0)	0 (0)
Infusion number, (when AIR occurred) n (%)	1-3	10 (62.5)	1 (25)	1 (50)
	4-7	5 (31.25)	0 (0)	1 (50)
	>7	1 (6.25)	3 (75)	0 (0)

Conclusion

Our real-world data on a large population of IBD patients treated with biologic agents confirm that AIRs are rare and occur mainly in patients treated with IFX biosimilars. Most patients who experienced AIRs were atopic. Almost all patients after AIRs changed biological agents within or out of the same biological class. Further studies are necessary to confirm our results and better characterise the profile of patients at greater risk of AIRs.

Introduction

Acute severe ulcerative colitis (ASUC) is a life-threatening complication of ulcerative colitis, requiring hospitalization and potentially surgery. Initial treatment relies on intravenous corticosteroids, but non-responders require rescue therapies such as infliximab or cyclosporine. Janus kinase inhibitors (JAKi), including upadacitinib, and tofacitinib, rapidly modulate immune response and have shown promise in managing ASUC, based on small-scale studies.

Aims & Methods

This single-center retrospective study evaluated the efficacy of JAK inhibitors, upadacitinib and tofacitinib, as a rescue therapy in patients with ASUC not responding to intravenous corticosteroids and/or infliximab who were hospitalized during the period from May 2023 to October 2024. Upadacitinib was administered at a dose of 45 or 60mg/day during hospitalization, with the higher dose reduced to 45mg/day upon discharge. Tofacitinib was administered at 30 mg/day during hospitalization, with the dose reduced to 20mg/day upon discharge. Patient outcome was assessed by partial Mayo score, endoscopic Mayo score (eMayo), and laboratory markers (CRP, hemoglobin, albumin, and fecal calprotectin).

Results

The cohort included 15 patients with ASUC who received JAKi as rescue therapy (8 males, 10 with extensive colitis; 73.3% with prior failure of infliximab): 13 upadacitinib (45mg and 60mg daily in 4 and 9 patients, respectively) and 2 tofacitinib. All patients had failed on intravenous corticosteroids, and one also failed on infliximab as a rescue therapy. All but one patient responded to JAKi and were discharged. One patient with no response underwent a colectomy. Endoscopy was performed at a median time of 8 weeks, with 57 % of patients achieving endoscopic remission (eMayo ≤ 1). During a median follow-up of 26 weeks after initiation of JAKi, 9 patients continued the treatment, 8 on upadacitinib and 1 on tofacitinib. One patient required colectomy, four were switched to another biologic, and one patient (a 76-year-old woman) died of pneumonia one month after starting therapy with JAKi. Within the first 3 months after hospital discharge, no further patients underwent a colectomy.

Conclusion

JAK inhibitors seem to be an effective rescue therapy for ASUC in patients who have already failed infliximab treatment. However, caution is needed in elderly patients.