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: 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: Inter-individual differences in drug clearance are common in inflammatory bowel disease (IBD) patients treated with biologics. Associations between inflammatory markers, clinical features, and drug levels may indicate that the inflammatory immune response influences the pharmacokinetics of biologics. We assessed the impact of inflammatory and immunity-related proteins on drug levels in IBD.

Methods: Serum samples from 144 IBD patients initiating biologics in a prospective multicentre cohort were analysed using AFIAS-3 (Boditech Med Inc. Korea). The primary outcome was drug levels after the end of induction treatment (post-induction), analysed as continuous variables or categorised into high or low groups based on the median. Correlations were assessed using the Pearson’s correlation coefficients with false discovery rate (FDR) adjustment. Predictive capacity of clinical and protein data was evaluated with regularised linear regression models. Analyses were stratified by treatment (infliximab, adalimumab, vedolizumab) and diagnosis (Crohn’s disease (CD), ulcerative colitis (UC)).

Results: Patient demographics and clinical characteristics are provided in Table 1. Median (interquartile range, IQR) post-induction infliximab levels were 5.3 (2.2-9.5) μg/ml in patients with CD (n=34) and 3.8 (1.7-5.6) μg/ml in UC (n=33). The corresponding levels were 12.5 (7.0-16.1) μg/ml (n=36) and 8.8 (5.7-12.7) μg/ml (n=13) for adalimumab, 13.9 (6.4-24.4) μg/ml (n=19) and 17.7 (9.8-22.6) μg/ml (n=9) for vedolizumab. Principal component analyses revealed potential baseline protein profile differences between patients with high vs low post-induction levels for infliximab (p=0.09) and adalimumab (p=0.07) in CD, but no differences for vedolizumab (p=0.78) or UC. Individual protein analyses indicated that patients with higher drug levels post-induction seemed to display lower baseline estimates of inflammatory proteins compared to those with lower drug levels. However, statistical significance after correction for multiple comparisons was only observed for CDCP1 in adalimumab-treated CD patients (PFDR=0.04) (Figure 1). Additionally, baseline Flt31 (r=-0.57, PFDR=0.03) and Wisp1 (r=-0.61, PFDR=0.02) correlated with post-induction s-adali-mumab levels in CD, while Mcp3 (r=-0.89, PFDR=0.04) and Frgamma (r=-0.87, PFDR=0.05) correlated in UC. Integrating baseline protein data in prediction models for post-induction drug levels did not improve their accuracy compared to models based on only clinical and biochemical variables.

Conclusion: Inflammatory protein levels may influence post-induction drug levels in IBD, particularly in adalimumab treated CD patients. This insight could aid in optimising personalised treatment.

Background: Perianal diseases are more common in patients with Crohn's disease (CD) than in the general population, but data are scarce in other inflammatory bowel disease (IBD) subtypes.

Method: Using data from the Swedish National Patient Register (NPR) and SWIBREG, the national quality register for IBD, we estimated the cumulative incidence of perianal fistula/abscess and perianal diseases (fistula, abscess, stenosis, fissure or procedure code for perianal surgery) in relation to diagnosis, and the prevalence in 2023, in individuals with CD, ulcerative colitis (UC) and IBD-unclassified (IBD-U), and in a matched (age, sex, calendar year and region of residence) IBD-free cohort from the general population.

Results: We identified 38,364 patients with incident IBD 2007-2017, and 98,229 patients with prevalent IBD as of 31 December 2022. The cumulative incidence of fistula/abscess was 6.7% at diagnosis, 8.3% at 1 year and 10.4% at 5 years in CD. The corresponding percentages in UC were 0.9%, 1.3% and 2.1%, and in IBD-U 2.4%, 3.1% and 4.5%, respectively. In 2023, 12.8%, 3.1% and 4.1% of patients with prevalent CD, UC and IBD-U had a history of fistula/abscess, compared to 0.8% in the general population. The corresponding numbers for perianal diseases were 19.7%, 7.4%, 8.6% and 2.2%.

Conclusions: The cumulative incidence and prevalence of perianal diseases in Swedish patients with CD was in parity with reports from other countries, and in patients with UC and IBD-U, it was 3-4 times higher than in the population.

BACKGROUND AND AIMS: Over 10% of patients with Crohn's disease require permanent ileostomy. We aimed to summarize the existing data on diagnosis, definitions of recurrence, and management of Crohn's disease patients with permanent ileostomy.

METHODS: MEDLINE, Embase, and CENTRAL databases were searched from inception to February 6, 2024. Randomized controlled trials, cohort and cross-sectional studies, and case series of more than five patients reporting on postoperative recurrence or the need for surgery in patients with Crohn's disease and permanent ileostomy were included. Search results were independently screened, and full text of all titles meeting eligibility criteria were obtained. Outcomes of interest included diagnostic techniques, recurrence definitions, and management approaches. We estimated pooled rates [with 95% confidence interval] of recurrence.

RESULTS: Thirty cohort studies including 2,055 Crohn's patients with permanent ileostomy were included (53% female, median age at time of ileostomy creation 32 years, most common reason for ileostomy was refractory disease). The postoperative recurrence rate was 27% (95% CI, 21.3-33.3, 26 studies, 451/1805 patients). Modalities for diagnosis of Crohn's disease recurrence were symptoms (15 studies), endoscopy (4 studies), histology from endoscopic biopsies (2 studies), imaging (5 studies) and surgery (22 studies). The reported definitions of recurrence for each modality were heterogeneous.

CONCLUSIONS: There is a lack of standardized monitoring tools and criteria for diagnosing recurrence in patients with Crohn's disease and permanent ileostomy. The results of this systematic review will form the basis of a global expert recommendation exercise focused on developing management standards and trial endpoints for this condition.

Background: Ulcerative colitis (UC), a major subtype of inflammatory bowel disease, is characterized by chronic inflammation of the colon and rectum. Enteric glial cells (EGC) play a crucial role in gut barrier maintenance and may contribute to UC pathophysiology. This study aims to investigate EGC and their associated proteins in patients during clinically active disease and in clinical remission following anti-inflammatory treatment.

Methods: Colonic or rectal biopsies were obtained at baseline from both inflamed and non-inflamed segments in 14 patients with clinically active UC initiating anti-inflammatory therapy and from the same segments when the patients were in clinical and endoscopic remission during follow-up. As control groups, colonic biopsies from 16 patients with irritable bowel syndrome (IBS)-Mixed and 16 healthy controls were included. Immunofluorescence staining assessed two EGC markers: the glial fibrillary acidic protein (GFAP+) and S100 calcium-binding protein B (S100β+). Relative estimates of inflammatory proteins in biopsies were analysed using Olink technology, In vitro, the EGC cell line CRL-2690 was exposed to interleukins (IL)-4, IL-6, and IL-18 at varying concentrations and durations, with GFAP expression analysed by western blot.

Results: In patients with UC, immunofluorescence analysis revealed significantly higher GFAP+ and S100β+ EGC counts in inflamed biopsies during active disease compared to macroscopically non-inflamed biopsies obtained during clinical and endoscopic remission. Compared to baseline biopsies from macroscopically non-inflamed mucosa, GFAP expression significantly decreased during follow-up (Figure 1), while S100β levels remained unaltered. Regardless of mucosal inflammatory status, patients with UC exhibited higher EGC counts than IBS-mixed patients and healthy controls. Our findings also showed a significant upregulation of EGC-associated pro-inflammatory proteins, such as IL-6, IL-8 and TNF in inflamed biopsies from patients with clinically active UC, compared to biopsies obtained when the patients were in remission as well as to healthy controls. Notably, these protein levels decreased during inactive UC, approaching levels observed in the healthy controls. In vitro, IL-6 upregulated GFAP expression dose- and time-dependently, while IL-4 and IL-18 induced expression in a less predictable pattern.

Conclusion: Elevated EGC counts, and pro-inflammatory proteins characterise inflamed mucosa in UC during clinical active disease highlighting their potential roles in UC related inflammation. These findings may suggest that EGC could be explored as a potential therapeutic target and may contribute to the discovery of novel biomarkers for disease monitoring.

Background: The Epi-IBD cohort is a prospective European population-based cohort of 1,508 patients diagnosed in 2010 and 2011 with inflammatory bowel disease (IBD) according to Copenhagen criteria in centres across 17 European countries. The study aims to describe treatment strategies, disease course and prognosis of IBD unclassified (IBDU) across Europe.

Methods: Patients with IBDU were defined as not fulfilling the Copenhagen diagnostic criteria of Crohn’s disease (CD) or ulcerative colitis (UC), but still required IBD related treatment and monitoring. They were followed prospectively from the time of diagnosis until December 31st, 2020, death, emigration or loss of follow-up. Clinical data on surgery, hospitalizations, and medical treatment were captured throughout the follow-up period and entered into a validated web-database, www.epi-ibd.org. Patients with IBDU were categorised as CD-like, UC-like or mixed CD-UC based on disease location and continuity of the affected bowel segments at diagnosis.

Results: In total, 129 IBDU patients aged ≥15 years from 22 centres were included. They comprised 8.5% (N=129/1,508) of the total cohort. The disease location was reported in Table 1 where 4 patients had unknown disease location at baseline. At diagnosis, 16% (N=25/129) were CD-like, 52% (N=62/129) were UC-like and 32% (N=42/129) were mixed CD-UC.During the 10-year follow-up, 32% (N=41/129) were re-classified as either CD (N=16) or UC (N=25). The crude 1-, 5-, and 10-year rates for re-classification of diagnosis were 19%, 26% and 32%. The time to initiation of therapies and the distribution of therapies according to re-classification of IBDU diagnosis at baseline are presented in Figure 1 A-B . Advanced therapies were used in 13% (N=17/129) of patients over the 10-year follow-up, and was initiated after a median period of 1.9 years (inter-quartile range 0.9-8.1). An intestinal resection was required in 7% (N=9/129). After 1, 5, and 10 years, 9%, 19% and 26% of the patients diagnosed with IBDU at baseline, respectively, required hospitalisation.

Conclusion: After 10 years of follow-up, a third of patients initially diagnosed with IBDU were re-classified as either CD or UC. The disease course was in general mild with a low number of patients requiring advanced therapy, intestinal resection, and hospitalization. However, patients who were re-classified as CD or UC were more frequently treated with medical therapies.

Background: Mirikizumab (MIRI), an anti-IL-23p19 antibody, has demonstrated efficacy and safety in adults with moderately to severely active ulcerative colitis (UC) in two Phase 3 trials (LUCENT-1/-2; NCT03518086, NCT03524092). [1] As novel therapies for UC are not well studied in adults ≥60 years (older adults), we aimed to evaluate the efficacy and safety of MIRI compared to placebo (PBO) during induction and maintenance treatment among this especially vulnerable subgroup of patients with UC. [2. 3].

Methods: In LUCENT-1, patients with UC were randomized to receive 3 intravenous (IV) doses of 300mg MIRI or PBO every four weeks (Q4W) at W0, W4, and W8. In LUCENT-2, responders to MIRI induction at W12 were re-randomized to subcutaneous (SC) 200mg MIRI or PBO Q4W for another 40 weeks (until W52 of continuous treatment). Endpoints evaluated in this post-hoc analysis included clinical response, clinical remission, symptomatic remission, endoscopic remission, corticosteroid (CS)-free remission (W52 only), histologic-endoscopic mucosal improvement (HEMI), histologic-endoscopic mucosal remission (HEMR), and bowel urgency (clinically meaningful improvement and remission). Efficacy in the subgroup of older adults was assessed at W12 and W52 using Fisher’s Exact tests. Safety data were summarized among patients aged 60 and older who received at least one dose of study treatment.

Results: At LUCENT-1 baseline, 13.3% of patients (n=154/1162) were ≥60 years, with a median age of 65 [Quartile (Q)1: 62.0, Q3: 69]. Apart from higher prevalence of comorbidities, longer disease duration, older age at diagnosis, and lower frequency of concomitant treatment with thiopurines, the baseline demographics and characteristics were similar to the overall patient population, including disease activity (per modified Mayo Score and Mayo Endoscopic Subscore), disease extent, and prior advanced therapy failure. At W12 and W52, a significantly greater proportion of older adults treated with MIRI vs. PBO achieved clinical response and symptomatic remission (Table 1). While the studies were not powered to detect differences between MIRI and PBO in this subgroup, there were numerically higher response rates for MIRI vs. PBO for all other outcomes. The safety profile for MIRI in older patients was consistent with the overall study population. There were no deaths and no discontinuations due to adverse events among MIRI-treated older adults (Table 2).

Conclusion: Mirikizumab induced and maintained clinical response and was well tolerated in patients 60 years of age and older with moderately to severely active UC.

References:

1)D’Haens G, Dubinsky M, Kobayashi T, et al. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis [published correction appears in N Engl J Med. 2023 Aug 24;389(8):772. doi: 10.1056/NEJMx230004]. N Engl J Med. 2023;388(26):2444-2455. doi:10.1056/NEJMoa2207940

2)Ananthakrishnan AN, Nguyen GC, Bernstein CN. AGA Clinical Practice Update on Management of Inflammatory Bowel Disease in Elderly Patients: Expert Review. Gastroenterology. 2021;160(1):445-451. doi:10.1053/j.gastro.2020.08.060

3)Sturm A, Maaser C, Mendall M, et al. European Crohn’s and Colitis Organisation Topical Review on IBD in the Elderly. J Crohns Colitis. 2017;11(3):263-273. doi:10.1093/ecco-jcc/jjw188

Sandoz-adalimumab (SDZ-ADL; Hyrimoz®, GP2017) is an adalimumab (ADL) biosimilar approved for the treatment of immune-mediated inflammatory diseases. Here, we review the available literature on SDZ-ADL from controlled and real-world evidence studies. A literature search was carried out to identify articles published up to July 2023 reporting data on efficacy, safety, immunogenicity, and treatment retention rates for SDZ-ADL. In randomized clinical trials, the efficacy, safety, and immunogenicity of SDZ-ADL were comparable to those observed for reference-adalimumab (ref-ADL) and not altered after single or multiple drug switches. Real-world studies confirmed the effectiveness and safety of treatment initiation with SDZ-ADL and of switching to SDZ-ADL from ref-ADL or from other ADL biosimilars. This literature review provides evidence that SDZ-ADL is as effective and safe as ref-ADL in both biologic-naïve and biologic-experienced patients.

Background: Perinuclear-antineutrophil cytoplasmic antibodies (P-ANCAs) have been identified in familial ulcerative colitis (UC), but the precise mechanism underlying their expression remains elusive. We assessed the role of genetic predisposition, environmental factors and systemic subclinical inflammation in the development of P-ANCA in a twin cohort with UC.

Methods: A total of 48 twin pairs (Leuven, Belgium n=4, Maastricht, The Netherlands n=6 and Örebro, Sweden n=38) with UC were included. Among these, 18 were monozygotic (3 concordant and 15 discordant for UC) and 30 were dizygotic (1 concordant and 29 discordant for UC). P-ANCA was detected through standardised ELISA, an indirect immunofluorescence assay and DNase treatment. In addition to high sensitivity C-reactive protein (hs-CRP), 92 inflammatory protein markers were measured in serum by proximity extension assay (Olink proteomics).

Results: P-ANCA was present in 16/52 (31%) of UC twins vs. 4/44 (9%) healthy twin siblings (p=0.01). No agreement in the presence of P-ANCA or their levels was observed between twin siblings in monozygotic pairs discordant for UC [intraclass correlation coefficient (ICC)=0.09] or dizygotic pairs (ICC=-0.20). Female sex was associated with an increased likelihood of P-ANCA (odds ratio, OR 5.49; 95% confidence interval, CI 1.47-20.57) and higher ANCA levels (ratio of geometric means 1.80; 95% CI 1.12-2.88). Active smoking was associated with lower concentrations of ANCA (ratio of geometric means 0.33; 95% CI 0.15-0.75) and potentially reduced the likelihood of P-ANCA (OR 0.23; 95% CI 0.02-2.21) in twins with UC but not in their healthy siblings. In twin siblings without UC, significant correlations between ANCA levels and hs-CRP, CDCP1, IL17A, CXCL9 and IL5 (correlation coefficients 0.36-0.41, p-values <0.05) were observed.

Conclusion: Female sex and tobacco smoking outweighed genetics regarding the generation and levels of P-ANCA and ANCA antibodies. The correlations between ANCA levels and inflammatory markers in healthy twin siblings suggest that P-ANCA may result from subclinical inflammation in these healthy siblings.