Introduction

Mirikizumab, a p19-directed interleukin-23 monoclonal antibody, is efficacious in inducing clinical response at Week(W) 12 and maintaining clinical remission through W52 in patients with moderately-to-severely active Crohn’s disease (CD) as shown in the phase 3 treat-through trial VIVID-1 (NCT03926130).¹ Here, we present analysis of maintenance outcomes through W52 for Patient-Reported Outcome (PRO) clinical responders and nonresponders at W12.

Aims & Methods

The analysis set includes patients randomized to mirikizumab at baseline, who did or did not achieve PRO clinical response at W12 after intravenous (IV) induction treatment (900 mg mirikizumab IV every 4 weeks [Q4W]) before entering subcutaneous (SC) maintenance treatment (300 mg mirikizumab SC Q4W). Descriptive statistics are used to summarize the data, applying nonresponder imputation for missing binary endpoints. As a treat-through study, no rerandomization was applied.

Results

From a total of 551 patients who entered SC maintenance treatment, baseline characteristics of age, duration of CD, and baseline Crohn’s Disease Activity Index (CDAI) were similar between W12 PRO responders (n=402, 73.0%) and W12 PRO nonresponders (n=149, 27.0%). PRO responders at W12 had a higher objective inflammatory burden at baseline (faecal calprotectin, c-reactive protein, and Simple Endoscopic Score-CD), whereas concomitant or prior medication usage was similar between the groups. For W12 PRO responders, SC mirikizumab treatment from W12 to W52 resulted in an increase in CDAI clinical remission from 52.2% to 65.4%, PRO clinical remission from 53.2% to 65.4%, and endoscopic response from 35.1% to 54.7%, respectively (Table 1). Among W12 PRO nonresponders, PRO response was achieved by 39.6% at W16, 45.6% at W20, 44.3% at W24, and 56.4% at W52 with continued mirikizumab SC treatment, while CDAI clinical remission and PRO clinical remission were achieved by 33.6% and 31.5% at W52, respectively. Endoscopic response increased from 30.2% at W12 to 40.3% at W52 among W12 PRO nonresponders (Table 1).

		PRO Nonresponders at W12 (N=149)	PRO Responders at W12 (N=402)
CDAI clinical remission, n (%)a	W12	8 (5.4%)	210 (52.2%)
	W16	16 (10.7%)	208 (51.7%)
	W20	28 (18.8%)	243 (60.4%)
	W24	35 (23.5%)	242 (60.2%)
	W52	50 (33.6%)	263 (65.4%)
Endoscopic response, n (%)a	W12	45 (30.2%)	141 (35.1%)
	W52	60 (40.3%)	220 (54.7%)
aPercentage of response is calculated by n/Nx*100%. CDAI, Clinical Disease Activity Index; PRO, patient-reported outcome

Table 1.

Conclusion

Subcutaneous mirikizumab maintenance treatment over 40 weeks leads to incremental and sustained improvements in rates of clinical and endoscopic response regardless of PRO clinical response status after induction. A substantial proportion of clinical nonresponders at W12 improved early during maintenance treatment suggesting continued treatment with mirikizumab can be beneficial and lead to long-term response.

References

1. Ferrante, Marc et al. Efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn's disease: a phase 3, multicentre, randomised, double-blind, placebo-controlled and active-controlled, treat-through study. Lancet. 2024;404(10470):2423-2436. doi:10.1016/S0140-6736(24)01762-8

Clinical Case Summary

Introduction: In Crohn’s disease (CD), fistula formation is an aggressive and difficult to treat phenotype that affects up to 50% of patients and requires a multidisciplinary approach. Malignant transformation of CD fistulas is rare, and pathogenesis is not fully understood. Data concerning incidence, diagnosis, and treatment is scarce.
Case: We report the case of a 56-year-old female with penetrating CD (A2, L2, pB3), diagnosed at the age of 22. She was initially treated with infliximab, but therapy was switched to adalimumab and azathioprine as a result of severe allergic reaction. Due to refractory perianal disease, a diverting stoma was created at the age of 43 and was submitted to proctosigmoidectomy five years later. A fistula between the vagina and the supra-anal space persisted. The patient has maintained the previous therapy since then, without symptoms. Eight years after the last surgery, she was admitted due to pelvic pain and bloody fetid vaginal discharge. A pelvic magnetic resonance imaging (MRI) revealed a 3,9 cm nodular image with necrotic center, suggestive of an abscess in the posterior vaginal wall. Abscess drainage under general anesthesia was performed, and biopsies of the fistula through the remnant rectovaginal septum revealed signet ring mucinous adenocarcinoma suggestive of gastrointestinal origin. A bone scintigraphy revealed multiple metastasis. She underwent pelvic palliative radiotherapy but died eight months after the diagnosis.
Discussion: Malignant transformation, although rare, should be considered in the context of a non-healing fistula in CD, being MRI the best modality for diagnosis. There is no surveillance protocol, but a high index of suspicion, close follow-up, and biopsies of any masses or accessible fistulous tracts are mandatory for an early diagnosis. The authors highlight this rare case of malignant transformation in a persistent fistula after surgery.

References

1. Ng ZQ, Hew N, Benny R. Perianal Crohn's Fistula with Malignant Transformation. J Gastrointest Surg. 2021 Jan;25(1):327-328.
2. Yamamoto T, Kotze PG, Spinelli A, Panaccione R. Fistula-associated anal carcinoma in Crohn's disease. Expert Rev Gastroenterol Hepatol. 2018 Sep;12(9):917-925.
3. Thomas M, Bienkowski R, Vandermeer TJ, Trostle D, Cagir B. Malignant transformation in perianal fistulas of Crohn's disease: a systematic review of literature. J Gastrointest Surg. 2010 Jan;14(1):66-73.

Introduction

Autoimmune hepatitis (AIH) and its variants are uncommon causes of chronic liver disease (CLD) in India [1]. Concomitant metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with autoimmune hepatitis (AIH) is a distinct entity [2]. We aimed to explore the frequency and impact of concomitant MASLD in patients with AIH [3].

Aims & Methods

This is a retrospective study conducted at Sanjay Gandhi Post Graduate Institute of Medical Sciences and King George Medical University, Lucknow, India. Data of patients with AIH who underwent treatment between 2013-2022 were collected from a prospectively filled-up electronic database. Standard criteria were used to diagnose AIH and MASLD [3][4]. Patients presenting with acute severe-AIH, acute-on-chronic-liver-failure, simple steatosis without any metabolic dysfunction, and hepatocellular carcinoma HCC) were excluded.Criteria to diagnose MASLD were applied to patients with AIH. Their demographic, clinical, biochemical, serological parameters, treatment response and long-term outcomes were measured and compared.

Results

Of 175 patients with AIH, 51 were excluded. A total of 122 patients [median age: 46 (34-54) years; 69.6% female] were included in the final analysis. The median follow-up period was 61 (50-76) months. Of the 122 patients, 38 (31%) had concomitant MASLD (AIH-MASLD). Patients withAIH-MASLD had higher baseline liver enzymes [aspertate aminotranferase 226 (121-278) vs 174 (113-225); p= 0.033, alanine aminotranferase: 115 (113-189) vs 97 (47-169); p=0.041]. A higher number of patients with AIH-MASLD presented with advanced fibrosis and decompensation (20.4% vs 10.7%; p=<0.001,30.3% vs 25%; p=0.030, respectively). Following immunosuppression, Patients with MASLD-AIH had attenuated remission rates compared to AIH alone (34.2% vs 77.4%; p=<0.001) [table: 1].

Table: 1
Outcome of patients with AIH and MASLD-AIH

Outcome	Overall	AIH	MASLD-AIH	p-value
Biochemical Remission at six months	82 (67.2%)	62 (74%)	20 (52.6%)	0.016
Non-response to steroid after two weeks	32 (26.2%)	12 (14.2%)	20 (52.6%)	0.001
Advanced fibrosis	25 (20.4%)	9 (10.7%)	16 (42.1%)	<0.001
Steatohepatitis	13 (10.6%)	5 (5.9%)	8 (21%)	0.012
Adverse events to steroid	44 (44.2%)	34 (47.6%)	21 (55.2%)	0.068
Presentation with Decompensation	37 (30.3%)	21 (25%)	16 (42.1%)	0.030
New Decompensation among patients with c-ACLD	26 (30.5%)	14 (16.7%)	12 (31.5%)	0.002
HCC	2 (1.6%)	0	2 (5.2%)	0.034
Mortality	25 (20.4%)	13 (15.4%)	12 (31.5%)	0.012

On multivariate analysis, liver biopsy suggestive of concomitant Metabolic dysfunction-associated steatohepatitis (MASH) [OR 5.25 (95% CI 2.27 - 12.16); p<0.001), concomitant MASLD [OR: 3.07 (95% CI1.02 - 9.24); p=0.045], advanced fibrosis [ OR: 2.69 (95% CI1.07 - 6.59); p=0.035], and presentation with decompensation [OR: 2.66 (95% CI:1.07 - 6.59); p=0.035] were associated with non-responsiveness to steroid.

Conclusion

About a third of patients with biopsy-proven AIH have concomitant MASLD. A significant number of patients with AIH-MASLD present with higher liver enzymes, advanced fibrosis, and decompensation compared to AIH alone. Patients with AIH-MASLD respond poorly to steroids and have a lower remission rate. Proper work-up is necessary in patients with steroid non-responsive-AIH to rule out concomitant MASLD.

References

1. Choudhuri G, Somani SK, Baba CS, et al. Autoimmune hepatitis in India: profile of an uncommon disease. BMC Gastroenterol. 2005 Aug 15;5:27. doi: 10.1186/1471-230X-5-27. PMID: 16098234; PMCID: PMC1236920.
2. Zachou K, Azariadis K, Lytvyak E, et al; International Autoimmune Hepatitis Group (IAIHG). Treatment responses and outcomes in patients with autoimmune hepatitis and concomitant features of non-alcoholic fatty liver disease. JHEP Rep. 2023 Apr 22;5(8):100778. doi: 10.1016/j.jhepr.2023.100778. PMID: 37456672; PMCID: PMC10339258.
3. Wang G, Tanaka A, Zhao H, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidance: the diagnosis and management of patients with autoimmune hepatitis. Hepatol Int. 2021 Apr;15(2):223-257. doi: 10.1007/s12072-021-10170-1. Epub 2021 May 4. PMID: 33942203; PMCID: PMC8144150.
4. Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020 Jul;73(1):202-209. doi: 10.1016/j.jhep.2020.03.039. Epub 2020 Apr 8. PMID: 32278004.

Introduction

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We investigated baseline transcriptomic, proteomic and microbiome features associated with response and created a multi-omic machine learning model to predict response in UC patients treated with tofacitinib.

Aims & Methods

Moderate to severely active UC patients were included in this prospective, open-label study and treated with tofacitinib 10mg BID for 8 weeks. Clinical, biochemical, endoscopic and histological data at baseline and at week 8 were recorded. Histo-endoscopic mucosal improvement (HEMI) was defined as an endoscopic Mayo score (EMS) ≤1 combined with histologic remission (Robarts Histopathology Index ≤3 without mucosal neutrophils). Baseline mucosal biopsies were used for transcriptomic analysis (bulk RNA sequencing), proteomic analysis (Olink Explore 384 panel) and faecal microbial composition (16S). Baseline blood samples were used for transcriptomic analysis (bulk RNA sequencing). All data were integrated in a comprehensive dataset. Using HEMI at week 8 as primary outcome measure, we generated a predictive model by using an extra-trees machine learning algorithm. A two-step approach was used for feature selection using variance thresholding and univariate selection based on ANOVA f-score. The settings for feature selection were optimized on each individual omic layer separately. The multi-omics model was trained with a leave-one-out cross-validation approach and performance was measured on the combined left-out samples by calculating the area under the receiver operating characteristics curve (AUROC). The individual importance of separate multi-omics features was calculated using permutation feature importance.

Results

Forty patients were included, the majority of which (65%) had severe endoscopic disease (EMS 3) at inclusion, involving at least the left colon (E2: 53%, E3: 43%). Prior treatment included anti-tumour necrosis factor agents (78%), vedolizumab (55%) or both (43%). Fifteen patients (38%) achieved HEMI at week 8. Complete omic sampling was available in 27 patients, which included fourteen responders (52%) and thirteen non-responders (48%) according to HEMI. The top 10 most important features to predict response at week 8 for each separate omic layer are shown in Table 1. Our multi-omics model included 50 features, mainly consisting of transcriptomic features in tissue and blood, as these were the most important in predicting response. Our model predicted HEMI with tofacitinib with an AUROC of 0.744 (± 0.034).

Table 1. Most important features for each individual omic layer, from most important (1) to less important (10). Features that are also included in the multi-omics model are shown in bold.

Importance 1	Transcriptome (tissue) HBQ1	Transcriptome (blood) SYNCRIP	Proteome Hsp90 co-chaperone Cdc37	Microbiome Lachnospiraceae UCG-004
2	RBM23	RPL10	Gamma-glutamyl hydrolase	Dorea
3	SDC4	DOK3	Nidogen-1	Blautia
4	TAF7	MTDH	Progranulin	Anaerostipes
5	USP53	ERLEC1	Aggrecan core protein	Anaerostipes
6	VCPIP1	HMGN4	Isopentenyl-diphosphate delta-isomerase 2	Blautia
7	DUSP16	RFK	Tumor necrosis factor ligand superfamily member 6	Anaerostipes
8	MTMR10	FAM162A	Mucin-16	Agathobacter
9	DOCK1	EIF2S1	Protein amnionless	Streptococcus
10	C7orf49	RASSF7	Cathepsin D	Lachnospiraceae NK4A136 group

Conclusion

Histo-endoscopic mucosal improvement was achieved in 38% of UC patients after 8 weeks of tofacitinib. A multi-omics machine learning algorithm was able to predict response to tofacitinib in UC patients with good performance. However, before application in clinical practice, further validation is warranted.

Disclosure

This study was sponsored by Amsterdam UMC. The study was funded and supported by Pfizer.