Introduction

Microscopic colitis (MC) refers to two pathologies – Collagenous colitis (CC) and Lymphocytic colitis (LC) that cause chronic watery diarrhoea, urgency, incontinence leading to significantly decreased quality of life¹. It is thought that MC develops due to a pathological immune response to intestinal luminal antigens in genetically predisposed individuals, with microbiota playing an important role^{2, 3}. However, the pathogenesis of MC is still unclear.

Aims & Methods

The aim of this study was to identify and characterize changes in bacterial composition of MC patients in terminal ileum and different colonic segments and determine its relation to the clinical course of disease. Biopsies from terminal ileum and six segments of the colon were collected during diagnostic colonoscopies. DNA extraction was performed using AllPrep DNA/RNA Micro Kit (Qiagen) following the manufacturer’s instructions. To determine bacterial composition, sequencing of the 16S rRNA variable region V3-V4 was conducted using the 27F and 338R polymerase chain reaction primers and sequenced on a MiSeq (2×250 bp; Illumina, Hayward, CA). Bioinformatic analysis was performed using DADA2, and taxonomic classification was carried out with the RDP classifier.

Results

Biopsy samples from 20 active CC patients, 20 active LC patients, and 50 controls demonstrated distinct microbial profiles across different intestinal segments, as revealed by beta-diversity and differential compositional analyses. Compared with controls, CC patients had consistent alterations in three bacterial families throughout the entire colon, with Erysipelatoclostridiaceae and Coriobacteriaceae decreased and Pasteurellaceae increased. Additionally, 35 families had segment-specific changes, and 25 families displayed altered abundance in the terminal ileum.
LC patients exhibited a consistent increase in Erisypelotrichaceae across the entire colon, with 38 other families showing segmental changes, and 12 families displaying altered abundance in the terminal ileum. Comparing LC and CC revealed a significantly different bacterial profile. LC showed lower abundance across many families, particularly in the right colon and terminal ileum. After sample collection, 15 CC patients and 12 LC patients received budesonide, with 3 CC and 2 LC patients having incomplete response. Beta diversity analysis revealed significant differences in the ascending colon and left side of the colon of CC patients based on response to budesonide. Patients with incomplete response to budesonide had an increased abundance of the genus Paucibacter. Similar tendencies were not observed in LC.
1 CC patient exhibited a quiescent disease course, 6 reached a sustained remission after treatment, 7 had a relapsing and 6 had a chronic active disease. Significant differences in beta diversity were observed in transverse, descending colon and rectum. Beta diversity of the descending colon had a medium correlation with disease behaviour. In the LC group 6 patients had a quiescent disease, 8 had a sustained remission after treatment, 3 exhibited a relapsing and 4 had a chronic active disease. No significant correlation between microbiota and disease behaviour was observed in LC.

Conclusion

This study showed significant differences in bacterial composition between CC, LC and controls in the terminal ileum and colon. In both CC and LC, bacterial alterations were not consistent throughout the entire colon but varied between different colonic segments. Microbiome differences based on response to budesonide and disease behaviour were observed in CC, but not LC.

References

1. Verhaegh BPM, Münch A, Guagnozzi D, et al. Course of Disease in Patients with Microscopic Colitis: A European Prospective Incident Cohort Study. J Crohns Colitis. 2021;15(7):1174-1183.
2. Miehlke S, Guagnozzi D, Zabana Y, et al. European guidelines on microscopic colitis: United European Gastroenterology (UEG) and European Microscopic Colitis Group (EMCG) statements and recommendations. United European Gastroenterol J. Published online 2020.
3. Burke KE, D’Amato M, Ng SC, Pardi DS, Ludvigsson JF, Khalili H. Microscopic colitis. Nat Rev Dis Primers. 2021;7(1).

Introduction

Inhibition of interleukin (IL)-23 has been demonstrated as a safe and effective mechanism of action for treating various chronic inflammatory diseases, including Crohn's disease (CD). The phase 3b SEQUENCE study directly compared the efficacy and safety of risankizumab (RZB), a selective IL-23 p19 subunit inhibitor, and ustekinumab (UST), an IL-12/IL-23 p40 subunit inhibitor, in patients (pts) with moderate to severe CD.

Aims & Methods

SEQUENCE, an open-label, multicenter, randomized, efficacy assessment-blinded study, enrolled pts who previously failed ≥1 anti-TNF therapies and had a CD Activity Index score of 220-450, Simple Endoscopic Score for CD ≥6 for ileocolonic or colonic disease (≥4 for isolated ileal disease) excluding the presence of narrowing component, plus an average (avg) daily stool frequency ≥4 and/or avg daily abdominal pain score ≥2. In Part 1 of the trial, described herein, pts were randomized 1:1 to receive RZB (600 mg IV induction dosing at baseline [BL], weeks [wks] 4 and 8, followed by 360 mg SC maintenance dosing every 8 wks [Q8w] starting at wk12) or UST (a single weight-based IV induction dose, followed by 90 mg SC maintenance dosing Q8w starting at wk8) over a period of 48 wks.¹ Randomization was stratified by number of anti-TNF therapies failed (1, >1) and steroid use at BL (Y, N). A mandatory steroid taper started at wk2. Two primary endpoints were clinical remission at wk24 (non-inferiority of RZB vs UST in 50% of planned subjects) and endoscopic remission at wk48 (superiority of RZB vs UST). Ranked secondary endpoints included clinical remission at wk48, endoscopic response at wks 48 and 24, steroid-free (SF) endoscopic remission at wk48, and SF clinical remission at wk48 (all tested for superiority of RZB vs UST). Safety was assessed throughout the trial.

Results

Variable	RZB N=255 n/N (%)	UST N=265 n/N (%)	Treatment Difference RZB – UST % [95% CI]
Primarya 1. Clinical remission at wk 24 (ITT-1Hb) 2. Endoscopic remission at wk 48 (ITT-1d) Ranked Secondarya,d 1. Clinical remission at wk 48 2. Endoscopic response at wk 48 3. Endoscopic response at wk 24 4. Steroid-free endoscopic remission at wk 48 5. Steroid-free clinical remission at wk 48	75/128 (58.6%) 81/255 (31.8%) 155/255 (60.8%) 115/255 (45.1%) 115/255 (45.2%) 80/255 (31.4%) 155/255 (60.8%)	54/137 (39.5%) 43/265 (16.2%) 108/265 (40.8%) 58/265 (21.9%) 70/265 (26.4%) 41/265 (15.5%) 107/265 (40.4%)	Non-inferiorityc met; 18.4 [6.6, 30.3] 15.6 [8.4, 22.9], P<0.0001 19.7 [11.3, 28.1], P<0.0001 23.3 [15.4, 31.2], P<0.0001 18.9 [10.9, 26.9], P<0.0001 15.9 [8.8, 23.1], P<0.0001 20.1 [11.7, 28.4], P<0.0001
Treatment Emergent Adverse Events (AEs)e	RZB N=262 PYs = 257.6 Events (E/100PYs)f	UST N=265 PYs = 269.9 Events (E/100PYs)f	Treatment Difference RZB – UST % [95% CI]
All TEAEs Investigator-defined drug-related AEg,h Severe AE Serious AE AEs leading to study drug discontinuation Death Adverse Events of Special Interest Adjudicated MACE/Extended MACEi Serious infections Active tuberculosis Opportunistic infections excluding tuberculosis and herpes zosterj Herpes zoster Malignant tumoursk Non-melanoma skin cancer (NMSC) Malignancies excluding NMSC Hypersensitivity Serious hypersensitivity Adjudicated anaphylactic reaction Hepatic events Injection site reactions	879 (341.2) 167 (64.8) 60 (23.3) 36 (14.0) 10 (3.9) 0 0 10 (3.9) 0 1 (0.4) 1 (0.4) 1 (0.4) 1 (0.4) 0 37 (14.4) 0 0 26 (10.1) 5 (1.9)	763 (282.7) 111 (41.1) 82 (30.4) 64 (23.7) 14 (5.2) 0 1 (0.4) 14 (5.2) 0 0 1 (0.4) 1 (0.4) 0 1 (0.4) 32 (11.9) 0 0 23 (8.5)i 8 (3.0)	58.5 (28.3, 88.7) 23.7 (11.2, 36.2) -7.1 (-15.9, 1.7) -9.7 (-17.1, -2.4) -1.3 (-4.9, 2.3) 0 -0.4 (-1.1, 0.4) -1.3 (-4.9, 2.3) 0 0.4 (-0.4, 1.1) 0.0 (-1.0, 1.1) 0.0 (-1.0, 1.1) 0.4 (-0.4, 1.1) -0.4 (-1.1, 0.4) 2.5 (-3.7, 8.7) 0 0 1.6 (-3.6, 6.8) -1.0 (-3.7, 1.6)
AE – adverse event; BL - baseline; CD – Crohn’s disease; CDAI – CD activity index; ITT – intention to treat; RZB - risankizumab; PY, patient years; SES-CD, simple endoscopic score for CD; TEAE – treatment emergent AE; UST – ustekinumab; wk, week Clinical remission – CDAI < 150 Endoscopic remission - SES-CD ≤ 4 and at least a 2-point reduction versus BL and no sub score greater than 1 in any individual variable, as scored by a central reviewer blinded to treatment allocation Endoscopic response - decrease in SES-CD > 50% from BL (or for pts with isolated ileal disease and a BL SES-CD of 4, at least a 2-point reduction from BL), as scored by central reviewer Steroid-free endoscopic remission - endoscopic remission and not receiving steroids at the corresponding visit Steroid-free clinical remission - clinical remission and not receiving steroids at the corresponding visit *SEQUENCE Part 1 compared the efficacy and safety of RZB versus UST over 48 wks, while Part 2 is an ongoing open-label long-term extension to evaluate the long-term safety of RZB in pts who received RZB in Part 1 and completed wk48 visit. aCategorical variables were analyzed using Cochran-Mantel-Haenszel (CMH) test. For both the primary and secondary endpoints, the non-responder imputation while incorporating multiple imputation to handle missing data (due to COVID-19 or geopolitical conflict) was used. Primary and secondary endpoints were tested sequentially in the order specified using the CMH risk difference estimate test stratified by the number of failed anti-TNF therapies (1, > 1) and steroid use at baseline (yes, no). bITT1H population is a subset of ITT-1 population and includes approximately 50% of ITT1 subjects who have opportunity to reach wk24 by the time of the primary analysis of CDAI clinical remission at wk24; non-inferiority of RZB vs. UST cNon-inferiority test: If the lower limit of 95% confidence interval based on the CMH estimation for the risk difference between RZB and UST groups (RZB – UST) was greater than the negative of 10% noninferiority margin, then noninferiority was demonstrated for clinical remission at wk24. If non-inferiority was demonstrated for clinical remission (CDAI) at Week 24, the superiority for the endoscopic remission at Week 48 was subsequentially tested at two-sided significance level of 0.05 using the CMH test. dIntent-to-treat-1 (ITT-1) population included all randomized subjects who were randomized to RZB with the selected RZB dose (RZB 600 mg IV followed by RZB 360 mg SC) or UST and who received at least 1 dose of study drug during Part 1 of the study; superiority of RZB vs. UST eTEAEs are events that begin either on or after the first dose of UST or RZB in Part 1 and until the first dose of study drug (RZB) in Part 2 if the pt is enrolled into the Part 2 or within 140 days after the last dose administration of the study drugs (UST or RZB) in Part 1 if the pt does not participate in Part 2. Only safety data obtained before 12JUL2023 or Week 52 dosing date (the first dose date of Part 2), whichever occurred earlier, are reported here. fSA1 population includes all pts who received at least 1 dose of study drug during Part 1 of the study. gAs assessed by investigator hRZB related: 3 patients with SAEs related to RZB (anal fistula, anal abscess, campylobacter, cystitis, localized infection, genital fistula); 8 patients with SAEs related to UST (abdominal pain, anal fistula, CD, ileal stenosis, vomiting) iMACE: Major Adverse Cardiovascular Events, defined as cardiovascular death or death due to stroke, non-fatal myocardial infarction, and non-fatal stroke; extended MACE defined as MACE with hospitalization for unstable angina and coronary revascularization procedures jOpportunistic infection: RZB, oesophageal candidiasis kMalignant tumor: RZB, squamous cell carcinoma of skin; UST, anal squamous cell carcinoma iOne case of potential Hy’s Law in the UST treatment group

In total, 520 pts were randomized and assessed for efficacy: RZB (N=255) and UST (N=265). The proportion of pts who completed the study was numerically higher with RZB (89.4%) vs UST (74.0%). The two primary endpoints of the study were met. At wk24, in half of the patients enrolled, clinical remission rates were 58.6% (75/128) for RZB and 39.5% (54/137) for UST (Δ18.4 [6.6-30.3], non-inferiority met with the pre-defined margin of 10%) (Table). At wk48, endoscopic remission rates were 31.8% (81/255) for RZB and 16.2% (43/265) for UST (Δ15.6% [8.4-22.9], P<0.0001 for superiority). RZB was superior to UST for all secondary endpoints (all P<0.0001). Exposure adjusted adverse event (AE) rates (Events [E/100PYs]) were comparable between RZB (879 [341.2]) and UST (763 [282.7]). Rates of serious AEs and AEs leading to study drug discontinuation were numerically higher with UST than RZB (Table). Rates of serious infections and hepatic events were similar between treatment groups, with no serious hepatic events with RZB. Two cases of malignancy were reported (one in each treatment arm). There was one event of adjudicated MACE with UST. There were no deaths.

Conclusion

In pts with moderate to severe CD who failed anti-TNF therapy, RZB demonstrated non-inferiority to UST in achieving wk24 clinical remission, superiority in achieving wk48 endoscopic remission, and superiority for achieving all secondary endpoints. The safety profiles of RZB and UST were consistent with previously published results.

References

1. Stelara Label [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125261s161lbl.pdf

Disclosure

Laurent Peyrin-Biroulet: Fees: Galapagos, AbbVie, Janssen, Genentech, Alimentiv, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index, Sandoz, Celgene, Biogen, SamsungBioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSEImmunotherapeutics, Enthera, Theravance, Pandion, Gossamer, Viatris, ThermoFisher, ONOPharma, Mopac, Cytoki, Morphic, Prometheus, Applied MolecularTransport; J. Casey Chapman: Consultant: AbbVie, Medtronic; Advisory Board: AbbVie, Pfizer, Takeda; Speaker: AbbVie, BMS, Janssen, Pfizer, Takeda; Jean-Frederic Colombel: Grants: AbbVie, Janssen, Takeda, BMS; Speaking fees: AbbVie, Takeda; Consultant: AbbVie, Amgen, AnaptysBio, Allergan, Arena, BI, BMS, Celgene, Celltrion, Lilly, Ferring, Galmed, GSK, Genentech (Roche), Janssen, Kaleido, Immunic, IterativeScopes, Merck, Landos, Microba Life Science, Novartis, Otsuka, Pfizer, ProtagonistTherapeutics, Sanofi, Takeda, TiGenix, Vifor; Stock options: IntestinalBiotechDevelopment; Flavio Caprioli: Consultant: AbbVie, MSD, Takeda, Janssen, Roche, Celgene, BMS, Galapagos, Gllead, Pfizer, Mundipharma, Galapagos, Biogen; Speaker: AbbVie, Ferring, Takeda, AllergyTherapeutics, Janssen, Pfizer, Biogen; Research grants: Giuliani, Sofar, MSD, Takeda, AbbVie; Geert D’Haens: Advisor: AbbVie, Ablynx, ActiveBiotechAB, AgomabTherapeutics, Alimentiv, Allergan, Alphabiomics, Amakem, Amgen, AMPharma, AppliedMolecularTherapeutics, Arena, AstraZeneca, Biogen, BMS, BI, Celltrion, DSMPharma; Echo, Engene, Exeliom, Ferring, Dr Falk, Galapagos, Genentech/Roche, Gilead, GSK, Gossamerbio, Immunic, J&J, Kintai, Lilly, Lument, Lycera, Medtronic, MSD, MitsubishiTanabe, NovoNordisk, Otsuka, Pfizer, Photopill, ProciseDx, Prodigest, Progenity, Prometheus/Nestlé, Protagonist, RedHill, SamsungBioepis, Sandoz, Seres, Setpoint, Shire, Takeda, Teva, Tillotts, Topivert, Versant, Vifor. Marc Ferrante: Grants: AbbVie, Amgen, Biogen, EG, Janssen, Pfizer, Takeda, Viatris; Consultant: AbbVie, Agomab, BI, Celgene, Celltrion, Lilly, Janssen-Cilag, Medtronic, MSD, Pfizer, Regeneron, SamsungBioepis, Sandoz, Takeda, ThermoFisher; Speaker: AbbVie, Amgen, Biogen, BI, Falk, Ferring, Janssen-Cilag, Lamepro, MSD, Pfizer, Sandoz, Takeda, Truvion, Viatris; Stefan Schreiber: Consultant: AbbVie, Amgen, Arena, BMS, BI, Celltrion, Dr Falk, Ferring, Fresenius, Galapagos, Genentech, Gilead, GSK, IMAB-Biopharma, Janssen, Lilly, Merck, Novartis/Sandoz, Pfizer, Protagonist, Takeda, Theravance. Raja Atreya: Speaker, consultant, or grants: AbbVie, Amgen, Arena, Biogen, BI, BMS, Cellgene, Celltrion, DrFalk, Galapagos, Gilead, InDex, Janssen-Cilag, Lilly, MSD, Novartis, Pandion, Pfizer, Roche, SamsungBioepis, Takeda, Viatris; Silvio Danese: Consultant: AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, AthosTherapeutics, Biogen, BI, Celgene, Celltrion, Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, J&J, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, and Vifor; Lecture fees: Abbvie, Amgen, Dr Falk, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda. James O. Lindsay: Consultant/advisory board: AbbVie, AtlanticHealthcare, BMS, Celgene, Celltrion, Lilly, Ferring, Galapagos, Gilead, GSK, Janssen, MSD, Napp, Pfizer, Shire, Takeda, Vifor; Speaker fees/sponsorship: AbbVie, Ferring, Janssen, MSD, Napp, Norgine, Pfizer, Shire, Tillotts, Takeda; Grants: AbbVie, Gilead, Pfizer, Shire, Takeda; Peter Bossuyt: Grants: AbbVie, Amgen, Janssen, Mundipharma, Mylan, Pfizer; Speaker: AbbVie, Celltrion, Janssen, Pfizer, Takeda; Advisory Board: AbbVie, Arena, BMS, Hospira, Janssen, Lilly, Merck, Mundipharma, PentaxMedical, Pfizer, PSI CRO, Roche, Sandoz, Takeda; Britta Siegmund: Consultant: AbbVie, Arena, BI, BMS, Celgene, Falk, Galapagos, Janssen, Lilly, Pfizer, Prometheus, Takeda; Speaker’s fees: AbbVie, CEDServiceGmbH, Falk, Ferring, Janssen, Novartis, Pfizer, Takeda; Peter Irving: Grants/ Fees: Janssen, MSD,Takeda; Personal fees: AbbVie, Arena, Dr. Falk, Lilly, Ferring, Genentech, Hospira, Pfizer, Pharmacosmos, SamsungBioepis, Sandoz, Shire, Tillotts, TopiVert, VHsquared, Vifor, WarnerChilcott. Remo Panaccione: Consultant: AbbVie, Abbott, Alimentiv, Amgen, Arena, AstraZeneca, BMS, BI, Celgene, Celltrion, Cosmos, Eisai, Elan, Ferring, Galapagos, Genentech, Gilead, GSK, Janssen, Lilly, Merck, Mylan, Oppilan, Pandion, Pfizer, Progenity, Protagonist, Roche, Sandoz, Satisfai, Schering-Plough, Shire, Sublimity, Theravance, UCB, Takeda; Speaker: AbbVie, Arena, Celgene, Ferring, Gilead, Janssen, Lilly, Merck, Pfizer, Roche, Sandoz, Shire, and Takeda; Grants: AbbVie, Ferring, Janssen, Pfizer, Takeda; Advisory board: AbbVie, Amgen, Arena, BMS, Celgene, Celltrion, Ferring, Galapagos, Genentech, Gilead, GSK, Janssen, Lilly, Merck, Mylan, Oppilan, Pandion, Pfizer, Sandoz, Shire, Sublimity, Takeda, Theravance. Marla Dubinsky: Consultant: AbbVie, Arena, BMS, Celgene, Lilly, Genentech, Gilead, Janssen, Pfizer, Prometheus, Takeda; Founder/shareholder Trellus Health.
Ezequiel Neimark, Kori Wallace, Toni Anschutz, Kristina Kligys, W Rachel Duan, Valerie Pivorunas, Xiu Huang, Sofie Berg, Lei Shu: AbbVie full-time employees; may own AbbVie stock or options.

Introduction

One in four patients experiencing a first episode of non-gallstone-related acute pancreatitis (AP) will develop recurrent disease. Recurrent episodes of AP or acute-on-chronic pancreatitis (CP) lead to decreased quality of life and disease progression. Aside from addressing the underlying cause of pancreatitis (which is sometimes impossible), effective measures to prevent recurrence are lacking. Meta-analyses of randomized controlled trials and epidemiological and cohort studies indicate that statins may provide protection against the development of initial AP.

Aims & Methods

The SIMBA study is a triple-blind, randomized, placebo-controlled, parallel-group multicenter trial. Patients with non-biliary recurrent acute pancreatitis (AP) or acute flares of chronic pancreatitis (CP) (at least two episodes in the last 12 months) were randomized to receive either simvastatin 40 mg daily or a placebo and followed up for 1 year. The sample size was calculated to be 144 patients, but slow recruitment prompted an interim analysis. The primary aim was to compare the recurrence of AP or acute flares in CP (RAP/AF).

Results

Eighty-three patients were included from 22 centers from Spain and 1 from India. The median age was 54 years, and 49 (59%) were men. Sixty-one (73.5%) patients had AP and 22 (26.5%) CP. Thirty-nine (47%) patients received placebo and 44 (53%) simvastatin. The median follow-up was 262 months. During follow-up, there were 12 (30.8%) RAP/AF in the placebo group and 15 (34.1%) in the simvastatin group (p 0.747, intention-to-treat analysis). Nor were there significant differences in the Kaplan-Meier curve (p=0.543). These results did not change when analyzing the patients who had finished treatment (per-protocol analysis) or when analyzing AP and CP separately.

Conclusion

Simvastatin does not appear to protect against recurrent episodes of acute pancreatitis or acute-on-chronic pancreatitis.