To Örebro University

Data indicate that earlier initiation of anti-tumor necrosis factor alpha (anti-TNF-α) biologic medicines may prevent progression to irreversible bowel damage and improve outcomes for patients with inflammatory bowel disease (IBD), particularly Crohn's disease. However, the high cost of such therapies may restrict access and prevent timely treatment of IBD. Biosimilar anti-TNF-α medicines may represent a valuable opportunity for cost savings and optimized patient outcomes by improving access to advanced therapies and allowing earlier anti-TNF-α treatment initiation. Biosimilar anti-TNF-α medicines have been shown to offer consistent therapeutic outcomes to their reference medicines, yet despite entering the IBD treatment armamentarium over 10 years ago, their implementation in clinical practice remains suboptimal. Factors limiting the 'real' use of biosimilar anti-TNF-α medicines may include an ongoing lack of understanding and acceptance of biosimilars by both healthcare professionals (HCPs) and patients, as well as systemic factors such as formulary decisions outside of the control of the prescriber. In this review, an expert panel of gastroenterologists discusses HCP-level considerations to improve biosimilar anti-TNF-α utilization in IBD in order to support early anti-TNF-α initiation and maximize patient outcomes.

BACKGROUND & AIMS: Interventional clinical trials in ASUC are characterised by substantial heterogeneity due to a lack of consensus in several key areas of trial design - this impedes clinical research efforts to identify novel therapies. The objective of this initiative was to achieve the first consensus and provide clear position statements on ASUC trial design.

METHODS: A modified Delphi consensus approach was employed with a panel of twenty clinicians with international representation and expertise in ASUC trial design and delivery. Agreement was defined as at least 75% of participants voting as 'agree' with each statement.

RESULTS: In total, thirty statements achieved consensus and were approved. Statements centred on proposing suitable eligibility criteria (disease extent, disease severity, prior therapy exposure), optimising trial design (randomisation, stratification, corticosteroid handling, timing of assessments), and recommending primary and secondary endpoints alongside defining key efficacy outcomes (clinical and endoscopic reponse and remission, treatment failure, quality of life).

CONCLUSIONS: The expansion of drugs to treat moderate-severe UC over the past decade, particularly the rapidly acting Janus kinase inhibitors, is promising and has reignited the interest in identifying suitable therapeutic candidates for ASUC. Clinical trials in this high-risk population are challenging to conduct and this consensus provides a framework for future trials to advance drug development.

BACKGROUND: Earlier studies, mainly prior to the widespread use of advanced therapy and implementation of guidelines for thromboprophylaxis indicate a doubled risk of venous thromboembolism (VTE) in patients with inflammatory bowel disease (IBD).

METHODS: Using Swedish healthcare registers, we identified a population-based cohort of patients with incident IBD 2007-2021. Patients were matched by age, sex, calendar year of birth and place of residence with up to 10 reference individuals. The primary outcome was VTE, i.e., pulmonary embolism (PE) and deep vein thrombosis (DVT). Incidence rates (IRs) per 1000 person-years, cumulative incidence and hazard ratios (HRs) were calculated for IBD overall and according to clinical characteristics. The temporal trend of the incidence of VTE by calendar year was presented.

RESULTS: We followed 55,252 IBD patients and 536,067 reference individuals, for a median of 6.5 years. The incidence of VTE in IBD was 5.03 vs. 2.35 per 1000 person-years among reference individuals, corresponding to a doubled risk of VTE (HR = 2.12; 95% confidence interval [CI] 2.02-2.23). Particularly high risks were seen in the first year of follow-up, and among patients with extensive ulcerative colitis (UC), primary sclerosing cholangitis (PSC), extraintestinal manifestations, perianal disease and hospitalization at diagnosis. The occurrence of VTE in IBD did not decrease across calendar years.

CONCLUSIONS: IBD remains linked to an elevated risk of VTE, particularly with disease characteristics associated with a higher inflammatory burden and higher age. Our findings underscore the importance of continuous vigilance and individual assessment of VTE risk in patients with IBD.

Background: Consistent alterations in DNA methylation across the genome have been well-characterised in inception cohorts of North European patients with inflammatory bowel disease [1-3]; these data implicate inherited determinants, active inflammation and the exposome in shaping the methylome. We have recruited a unique group of 155 twin pairs discordant for IBD to allow exploration of the interplay between these factors.

Methods: Whole blood from twins discordant for diagnosis of IBD was profiled using methylation microarrays (Figure) in two cohorts (UK-1 & Scandinavia-2). We performed analysis of both cohorts with epigenome-wide association study (EWAS), investigation of methylation Shannon’s entropy, methylation variance, and the epigenetic age. Analysis of the methylation correlates of disease activity in cohort 1 (UK) was performed. Additionally, smoking-related methylation was explored.

Results: The discovery cohort (UK-1) included 64 di- and monozygotic twin pairs while the replication cohort (Scandinavia-2) included 91 sex-matched IBD-discordant twin pairs. The mean age in both cohorts was 53 years and the mean disease duration was 24 years. IBD-discordant twin pairs differed in Shannon’s entropy at individual probes (located in/near IL10RA, IL2RA, IL18RAP, VMP1, CEP72/AHRR), of which three replicated (cg11498228-ARHGEF10, cg07664915-KCTD13/MAPK3, cg20859708-NAA35), and many were located in IBD GWAS regions (such as FOXP1, LPP, MICA). The entropy findings from IBD GWAS regions were partially confirmed in monozygotic twins alone (e.g., TNXB in MHC class III region, bootstrap p.fdr<10-118), despite near-perfect controlling for genetics and early-life exposome. Sites highlighted by differential variance analysis included IBD genes, such as TAS1R3, GALNT2 and CACNA1H (all q-values<5×10-6). No epigenetic age acceleration was identified in patients with IBD. Clinical activity of IBD exhibited a number of associations with the whole blood methylome, including a negative correlation between methylation at a key IBD site RPS6KA2 with faecal calprotectin (Table). In patients with IBD and controls, cross-cohort smoking EWAS replicated multiple smoking-related sites at genome-wide significance, many of which located in AHRR and ALPI loci, both of which are implicated in IBD.

Conclusion: Methylation level at individual probes related to IBD activity and showed IBD-associated differences in methylation entropy and variance between twins despite shared genetics and early-life exposome, adding new context for understanding established IBD loci and strengthening their role.

References:

1. Ventham et al. Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease. Nat Commun. 2016;7:13507.

2. Kalla et al. Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome. J Crohns Colitis. 2023;17(2):170-184.

3. Ventham et al. Genome-Wide Methylation Profiling in 229 Patients With Crohn's Disease Requiring Intestinal Resection: Epigenetic Analysis of the Trial of Prevention of Post-operative Crohn's Disease (TOPPIC). Cell Mol Gastroenterol Hepatol. 2023;16(3):431-450.

BACKGROUND AND AIMS: The diagnostic and prognostic properties of anti-integrin αvβ6 IgG autoantibodies in ulcerative colitis (UC) are poorly understood. We aimed to assess the diagnostic performance of anti-integrin αvβ6 autoantibodies and examine their association with disease outcomes.

METHODS: Serum samples from a Swedish inception cohort of patients with suspected inflammatory bowel disease (IBD, n=473) were analysed using an in-house fluorescence enzyme immunoassay based on EliA™technology. Findings were validated in a Norwegian population-based inception cohort (n=570). Diagnostic performance was assessed by calculating the area under the curve (AUC) with 95% confidence intervals (CIs) and determining sensitivity and specificity. Reclassification was evaluated using the net reclassification index.

RESULTS: In the discovery cohort, patients with UC, IBD-unclassified, or colonic Crohn's disease exhibited higher median autoantibody levels compared to symptomatic and healthy controls. In the validation cohort, the autoantibody demonstrated 79% sensitivity and 94% specificity for UC vs symptomatic controls at a cut-off of 400 UA/l. Its diagnostic performance (AUC=0.92, 95%CI 0.89-0.95) was superior to hs-CRP (AUC=0.65, 95%CI 0.60-0.70, P<0.001) and faecal calprotectin (fcalpro) (AUC=0.88, 95%CI 0.84-0.92, P=0.09). Combining the autoantibody with fcalpro further improved diagnostic accuracy (AUC=0.97, 95%CI 0.95-0.98) and patient reclassification (P<0.001). Autoantibody positivity was associated with a severe phenotype of UC, characterised by increased inflammatory activity and higher IL-17A and granzyme B levels. Higher autoantibody levels were linked to an aggressive disease course, remaining stable in aggressive UC but decreasing in indolent disease (P=0.003).

CONCLUSIONS: Anti-integrin αvβ6 is a reliable diagnostic and prognostic marker for UC, with potential clinical implementation.

OBJECTIVES: Inflammatory bowel disease (IBD) is a chronic disorder linked to cardiovascular disease (CVD). However, the impact of histologic and clinical activity on this association remains unclear.

METHODS: We conducted a nationwide cohort study in Sweden involving 59,168 IBD patients diagnosed in 1969-2017 with histologic evaluation and 91,800 patients diagnosed in 1969-2020 with assessment of clinical activity in 2006-2021. The primary outcome was incident major adverse cardiovascular events (MACE), a composite outcome encompassing ischemic heart disease, stroke, and heart failure. Cox proportional hazards model estimated adjusted hazard ratios (aHRs) of MACE and its subcomponents.

RESULTS: We found an increased MACE risk following histologic inflammation (n = 868, incidence rate [IR]: 86.3/10,000 person-years) compared to remission (n = 558, IR = 71.3) (aHR = 1.16 [1.04-1.30]). This excess risk was evident in Crohn's disease (aHR = 1.30 [1.03-1.64]) and ulcerative colitis (aHR = 1.13 [1.01-1.27]). Histologic inflammation was associated with an increased risk of ischemic heart disease, myocardial infarction, ischemic stroke, and heart failure, but not with hemorrhagic stroke. Compared to clinically quiescent IBD, active IBD was associated with an increased MACE risk (IR: 131.4 vs. 93.7; aHR = 1.54 [1.46-1.63]) and all MACE subcomponents. In patients with clinically quiescent IBD, histologic inflammation remained linked to myocardial infarction (aHR = 1.29 [1.06-1.58]) and heart failure (aHR = 1.19 [1.00-1.43]).

CONCLUSION: Both histologic and clinical activities of IBD were associated with an increased MACE risk, suggesting that improved disease control may reduce MACE risk in IBD.

BACKGROUND: Cancer incidence data including absolute risk differences are needed for clinical risk communication to patients receiving modern-day treatments for ulcerative colitis (UC).

METHODS: We linked nationwide Swedish health registers and assessed incident cancers in patients with UC in 2007-2022. We computed age-stratified incidence rates (IRs), IR differences and hazard ratios (HRs) in a naïve cohort with no immunomodulatory treatment, and in cohorts treated with thiopurine or targeted therapies. General population comparator subjects were matched (by age, sex, calendar year, and area of residence) to each treatment cohort. We used a once-exposed - always exposed design.

RESULTS: We identified 63,925 patients with UC in partly overlapping cohorts and 593,072 comparators with a total follow-up time of 5,800,089 years (median 8.1 years).The IRs were elevated compared to the general population in naïve patients: 2.7 extra cancer cases per 1000 person years (HR:1.12, 95%CI:1.09-1.16), in thiopurine-treated patients: 3.4 extra cases (HR:1.48;1.37-1.61), TNFi-treated: 2.7 extra cases (HR:1.41;1.24-1.62), Thiopurine+TNFi-treated: 2.42 extra cases (HR:1.44;1.19-1.75), vedolizumab-treated: 2.88 extra cases (HR:1.27;0.90-1.79). The IR differences were not significantly increased in patients treated with ustekinumab 0.57 (HR:0.87;0,39-1.93) and tofacitinib -0.69 (HR:0.84;0.25-2.77). Across all treatment groups, the IR differences compared to the general population were highest in patients ≥60 years. The differences were driven by colorectal cancer, hepatobiliary cancer, lymphoma, and basal cell skin carcinoma.

CONCLUSION: Elevated cancer incidence was observed in patients with UC amounting to around 3 extra cases of cancer per 1000 years. Cancer risks varied more among groups defined by age than by treatment.

BACKGROUND: Recent genetic and transcriptomic data highlight the need for improved molecular characterisation of inflammatory bowel disease (IBD). Proteomics may advance the delineation of IBD phenotypes since it accounts for post-transcriptional modifications. AIM: We aimed to assess the IBD spectrum based on inflammatory serum proteins and identify discriminative patterns of underlying biological subtypes across multiple European cohorts.

METHODS: Using proximity extension methodology, we measured 86 inflammation-related serum proteins in 1551 IBD patients and 312 healthy controls (HC). We screened for proteins exhibiting significantly different levels among IBD subtypes and between IBD and HC. Classification models for differentiating between Crohn's disease (CD) and ulcerative colitis (UC) were employed to explore the IBD spectrum based on estimated probability scores.

RESULTS: Levels of multiple proteins, such as IL-17A, MMP-10, and FGF-19, differed (fold-change>1.2; FDR<0.05) between ileal vs colonic IBD. Using multivariable models, a protein signature reflecting the IBD spectrum was identified, positioning colonic CD between UC and ileal CD, which were at opposite ends of the spectrum. Based on area under the curve (AUC) estimates, classification models more accurately differentiated UC from ileal CD (median AUCs>0.73) than colonic CD (median AUCs<0.62). Models differentiating colonic CD from ileal CD demonstrated intermediate performance (median AUCs 0.67-0.69).

CONCLUSION: Our findings in serum proteins support the presence of a continuous IBD spectrum rather than a clear separation of CD and UC. Within the spectrum, disease location may reflect a more similar disease than CD vs UC, as colonic CD resembled UC more closely than ileal CD.

Purpose: There is a need for diagnostic and prognostic biosignatures to improve long-term outcomes in inflammatory bowel disease (IBD). Here, we describe the establishment of the Swedish Inception Cohort in IBD (SIC-IBD) and demonstrate its potential for the identification of such signatures.

Participants: Patients aged >= 18 years with gastrointestinal symptoms who were referred to the gastroenterology unit due to suspected IBD at eight Swedish hospitals between November 2011 and March 2021 were eligible for inclusion.

Findings to date: In total, 367 patients with IBD (Crohn's disease, n=142; ulcerative colitis, n=201; IBD-unclassified, n=24) and 168 symptomatic controls were included. In addition, 59 healthy controls without gastrointestinal symptoms were recruited as a second control group. Biospecimens and clinical data were collected at inclusion and in patients with IBD also during follow-up to 10 years. Levels of faecal calprotectin and high-sensitivity C-reactive protein were higher in patients with IBD compared with symptomatic controls and healthy controls. Preliminary results highlight the potential of serum protein signatures and autoantibodies, as well as results from faecal markers, to differentiate between IBD and symptomatic controls in the cohort. During the first year of follow-up, 37% (53/142) of the patients with Crohn's disease, 24% (48/201) with ulcerative colitis and 4% (1/24) with IBD-U experienced an aggressive disease course.

Future plans: We have established an inception cohort enabling ongoing initiatives to collect and generate clinical data and multi-omics datasets. The cohort will allow analyses for translation into candidate biosignatures to support clinical decision-making in IBD. Additionally, the data will provide insights into mechanisms of disease pathogenesis.

BACKGROUND AND AIMS: Tofacitinib and upadacitinib are Janus kinase (JAK) inhibitors that are increasingly used for the treatment of acute severe ulcerative colitis (ASUC). However, comparative analyses of safety and effectiveness have not been performed for their use in this setting.

METHODS: This multicenter, retrospective study enrolled hospitalized adult patients treated with tofacitinib or upadacitinib for ASUC between January 2019 and June 2024. The main outcomes were clinical response, clinical remission, and colectomy-free survival. Propensity-adjusted analyses using inverse probability treatment weighting (IPTW), and double robust estimations (DRE) were used to control for confounding factors.

RESULTS: In total, 111 patients (60 tofacitinib, 51 upadacitinib) were enrolled across 23 international centers. JAK inhibitors were used to induce response in 86 (77%) patients and used to maintain response after adequate intravenous steroid response in 25 (23%). The median follow up was 31 weeks (IQR 13-64). Between days 3-7 after treatment initiation, upadacitinib was associated with greater response rates 84% vs.54%,p=0.02 but response/remission were comparable at day 98 (45%/36% vs 55/48%) and day 182 (29/29% vs. 39/34%). Sub-analyses for JAK inhibitor use as salvage therapy (tofacitinib (n=35) vs. upadacitinib (n=31)) showed similar effectiveness outcomes across both groups. The probabilities of colectomy-free survival at days 98/182 for tofacitinib and upadacitinib were 79%/75% and 80%/78%, respectively, with no significant differences in the comparison of survival curves, p=0.99. Treatment failure rates (where JAK inhibitor was used to maintain remission) were similar at days 98 and 182. The frequency of adverse events was comparable.

CONCLUSION: Tofacitinib and upadacitinib appear to have similar effectiveness and safety profiles when used for the treatment of ASUC.