Introduction

Corticosteroid (CS) chronic overuse is a concern in the treatment of Crohn’s disease (CD), with adverse events and toxicities seen with the long-term use of CS resulting in increased follow-up morbidity and economic burden.^1,2 Risankizumab (RZB) is an interleukin 23 p19 inhibitor that demonstrated efficacy for the treatment of moderately to severely active CD in phase 3 trials. Here, we report the results of a post hoc analysis evaluating the ability of RZB to achieve corticosteroid-free outcomes in patients with CD enrolled in the FORTIFY open-label, long-term extension (LTE) substudy.

Aims & Methods

This analysis was designed to understand how effectively RZB can manage CD without the use of CS. The ongoing FORTIFY (NCT03105102) open-label, LTE substudy enrolled patients who entered the open-label extension trial after 52 weeks of RZB maintenance dosing. Patients received RZB 180 mg every 8 weeks, except for patients who had prior rescue therapy, who continued RZB 360 mg. Changes to CD-related CS dose were made at investigators’ discretion. Prescheduled visits occurred every 24 weeks and endoscopies every 96 weeks. Baseline CS use was per induction baseline. Outcomes assessed among the overall population and patients with baseline CS use included mean time of CS use, median CS dose, and proportion of patients who achieved CS-free (ie, no CS use at evaluation) clinical remission, assessed by average daily stool frequency and abdominal pain score (SF/APS) and Crohn’s Disease Activity Index (CDAI), endoscopic response, and endoscopic remission. Data are presented as observed for all patients and by nonresponder imputation for patients with 2 years of complete (matured) data.

Results

Of 1147 patients enrolled in the LTE study, 325 (28.3%) patients had baseline CS use. Overall, 143 of 1147 (12.5%) of patients received CS at any time during the LTE; median (IQR) time of CS use was 0.0 (0.0) days and median (IQR) CS dose was 0.0 (0.0) mg through data cutoff. Among 325 patients with baseline CS use, 79 received CS during the LTE for a median (IQR) of 138.0 (452.0) days. Among the 754 patients with 2-year matured data, 206 (27.3%) received baseline CS. For patients with 2-year matured data, CS‑free clinical remission was demonstrated at week 48 and week 96 per SF/APS (overall, 50.1%, 43.9%; with baseline CS use, 39.8%, 38.3%) and CDAI (overall, 52.5%, 45.4%; with baseline CS use, 45.1%, 40.8%). At week 96 for patients with 2-year matured data, CS-free endoscopic response was achieved by 49.5% overall and 46.6% of patients with baseline CS use; 39.7% and 32.5% achieved CS-free endoscopic remission, respectively. As observed data are also presented (Table). Overall, CS-free clinical remission and CS-free endoscopic remission were maintained from week 0 to week 96 in 62.3% and 72.2% of patients with 2-year matured data.

Table. Corticosteroid-free Clinical and Endoscopic Outcomes With Risankizumab at Week 96 in the Overall Population and in Patients With Baseline Corticosteroid Use
AO, as observed; CDAI, Crohn’s Disease Activity Index; NRI, nonresponder imputation; SES-CD, Simple Endoscopic Score for Crohn’s Disease; SF/APS, stool frequency/abdominal pain score. aOnly patients with 2-year matured data are included in NRI analysis. SF/APS clinical remission: Average daily SF ≤ 2.8 and not worse than baseline value and average daily APS ≤ 1 and not worse than baseline value. CDAI clinical remission: CDAI < 150. Endoscopic response: Decrease in SES-CD > 50% from baseline as scored by a central reviewer. Endoscopic remission: SES-CD ≤ 4 and at least a 2-point reduction vs baseline and no subscore greater than 1 in any individual variable, as scored by a central reviewer.
	NRIa								AO
	Overall				Baseline corticosteroid use				Overall				Baseline corticosteroid use
Endpoint	Pooled, n/N (%) [95% CI]	180mg, n/N (%) [95% CI]	360mg, n/N (%) [95% CI]	Pooled, n/N (%) [95% CI]		180mg, n/N (%) [95% CI]	360mg, n/N (%) [95% CI]	Pooled, n/N (%) [95% CI]		180mg, n/N (%) [95% CI]	360mg, n/N (%) [95% CI]	Pooled, n/N (%) [95% CI]		180mg, n/N (%) [95% CI]	360mg, n/N (%) [95% CI]
Corticosteroid-free SF/APS clinical remission	331/754 (43.9) [40.4, 47.4]	281/577 (48.7) [44.6, 52.8]	50/177 (28.2) [21.6, 34.9]	79/206 (38.3) [31.7, 45.0]		64/156 (41.0) [33.3, 48.7]	15/50 (30.0) [17.3, 42.7]	334/493 (67.7) [63.6, 71.9]		283/400 (70.8) [66.3, 75.2]	51/93 (54.8) [44.7, 65.0]	79/135 (58.5) [50.2, 66.8]		64/109 (58.7) [49.5, 68.0]	15/26 (57.7) [38.7, 76.7]
Corticosteroid-free CDAI clinical remission	342/754 (45.4) [41.8, 48.9]	285/577 (49.4) [45.3, 53.5]	57/177 (32.2) [25.3, 39.1]	84/206 (40.8) [34.1, 47.5]		72/156 (46.2) [38.3, 54.0]	12/50 (24.0) [12.2, 35.8]	343/460 (74.6) [70.6, 78.5]		285/369 (77.2) [73.0, 81.5]	58/91 (63.7) [53.9, 73.6]	84/129 (65.1) [56.9, 73.3]		72/104 (69.2) [60.4, 78.1]	12/25 (48.0) [28.4, 67.6]
Corticosteroid-free endoscopic response	373/754 (49.5) [45.9, 53.0]	303/577 (52.5) [48.4, 56.6]	70/177 (39.5) [32.3, 46.8]	96/206 (46.6) [39.8, 53.4]		74/156 (47.4) [39.6, 55.3]	22/50 (44.0) [30.2, 57.8]	374/535 (69.9) [66.0, 73.8]		303/425 (71.3) [67.0, 75.6]	71/110 (64.5) [55.6, 73.5]	96/143 (57.1) [59.4, 74.8]		74/114 (64.9) [56.2, 73.7]	22/29 (75.9) [60.3, 91.4]
Corticosteroid-free endoscopic remission	299/754 (39.7) [36.2, 43.1]	251/577 (43.5) [39.5, 47.5]	48/177 (27.1) [20.6, 33.7]	67/206 (32.5) [26.1, 38.9]		55/156 (35.3) [27.8, 42.8]	12/50 (24.0) [12.2, 35.8]	299/535 (55.9) [51.7, 60.1]		251/425 (59.1) [54.4, 63.7]	48/110 (43.6) [34.4, 52.9]	67/143 (46.9) [38.7, 55.0]		55/114 (48.2) [39.1, 57.4]	12/29 (41.4) [23.5, 59.3]

​

Conclusion

Long-term use of RZB in patients with moderately to severely active CD may achieve CS-free clinical remission, endoscopic response, and endoscopic remission. Additionally, a majority of patients did not add CS during the LTE. Thus, RZB may be used to support the reduction of CS in patients with CD.

References

1. Lichtenstein GR, et al. Am J Gastroenterol. 2018;113(4):481-517.
2. Walter E, et al. Bone. 2018;108:44-54.

Disclosure

ID has received consultation fees, research grants, or honoraria from AbbVie, Altman, Arena Pharmaceuticals, Athos, Celgene/Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Ferring, Galapagos, Genentech, Gilead, Iterative Scopes, Janssen, Lilly, Pfizer, Prometheus, Sandoz, Sangamo, Sublimity, Takeda. She is a shareholder in Gutreat and Harp Diagnostics.
SS has been a consultant for AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion Healthcare, Dr Falk Pharma, Ferring, Fresenius, Galapagos, Genentech, Gilead, GlaxoSmithKline, IMAB-Biopharma, Janssen, Lilly, Merck, Novartis/Sandoz, Pfizer, Protagonist, Takeda, Theravance, and Ventyx.
GD’H has served as a consultant and/or received speaker fees from AbbVie, Alimentiv, AstraZeneca, Biora (Progenity), Boehringer Ingelheim, Bristol Myers Squibb, Celltrion Healthcare, Cytoki Pharma, Ferring, Galapagos, GlaxoSmithKline, Gossamer Bio, Immunic, InDex Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Lilly, Pfizer, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Takeda, Tillotts, and Ventyx Biosciences.
MD has been a consultant for AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Gilead, Janssen, Lilly, Merck, Pfizer, Prometheus, Takeda, and UCB. She has received research grants from AbbVie, Janssen, and Prometheus.
JL has received consulting fees from AbbVie, honoraria from Janssen, and served as a consultant for GlaxoSmithKline and Takeda.
JCC has been a consultant and advisor for AbbVie, Janssen, Medtronic, Pfizer, and Takeda.
SMF, YZ, KK, JZ, and AS are employees of AbbVie and may hold AbbVie stock or stock options.
PB has received research grants from AbbVie, Amgen, Celltrion, Mylan, Pfizer, and Takeda; lecture fees from AbbVie, Celltrion, Janssen, Lilly, and Takeda; and consulting fees from AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros.
AbbVie funded this study and participated in the study design, study research, data collection, analysis, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship.
AbbVie and authors thank all trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Jory Fleischauer, PharmD, of JB Ashtin, and funded by AbbVie.

Introduction

Acute severe colitis (ASC) is a medical-surgical emergency that can occur at any time during the course of chronic inflammatory bowel disease. It most commonly affects UC.

Aims & Methods

Aims: The aim of our work is to describe the particularities of GCA management during Crohn's disease (CD).
Materials and methods: This is a retrospective descriptive and analytical study spread over a 5-year period from January 2018 to January 2023. All patients who developed GAC during the course of Crohn's disease, whether inaugural or progressive, were included in our study.Data collected included age, sex, Crohn's disease location and phenotype, Lichtiger score before and after coticotherapy, second-line treatment, and use of surgery. SPSS 2.0 software was used for the statistical study. A binary logistic regression model was used for univariate analysis.

Results

Of the 424 IBD cases, 267 were being followed for Crohn's disease, of whom 38 (14.2%) patients presented with GAC. Mean age was 44.21 ±12.7 years (range 19-72 years). The F/H sex ratio was 1.9 (25 women to 13 men).The location of Crohn's disease was pancolic in 28 patients, ileocolic in 9, and ileocolic with high involvement in 1 patient. GCA was inaugural in 10 patients (26.3%), and complicated known Crohn's disease in 28 patients (73.7%). The mean Lichtiger score calculated at D0 was 11.84±1.8. The mean CRP value on admission was 89.8±47. Mean albumin was 27.9±3.6. Emergency abdomino-pelvic CT scans showed no complications such as colectasis, perforation or abscess in our series. All patients received IV methylprednisolone corticosteroids at a dose of 0.8 mg/kg/d, not to exceed 40 mg/d, with close clinico-biological monitoring. 21 patients (55.2%) were corticosensitive. The mean Lichtiger score calculated at D5 in corticosensitive patients was 8.7, with a mean CRP value at D3 of 36.8±12.

In univariate analysis, CRP >45 (on admission) and hypoalbuminemia were predictive factors for failure of IV corticosteroid therapy, with [OR=3.2 [1.3-5.2]; p=0.0005] and [OR = 1.31 [1.015-7,] p=0.002] respectively.Of the 17 (44.8%) cortico-resistant patients, 3 (7.9%) received emergency second-line treatment with Infliximab, and 15 (39.47%) underwent subtotal colectomy with ileostomy. Of these patients, one was scheduled after failure of second-line treatment. Good outcome was noted in 36 patients (94.7%). 2 cases of death (5.3%) were reported postoperatively. On discharge, 23 patients (63.9%) were treated with immunosuppressive agents or 13 (36.1%) with biotherapy.

Conclusion

Acute severe colitis can reveal or complicate Crohn's disease at any stage of its evolution. Management must be urgent, and requires medical-surgical coordination. The first-line medical treatment is intravenous corticosteroid therapy. Colectomy should be discussed at every stage of management.

Introduction

New methods are urgently needed to detect pancreatic ductal adenocarcinoma (PDAC) at an earlier stage to improve outcomes.^{1, 2} We have previously reported six protein N-glycosylation traits (NGTs) and further grouped these into three biologically distinct ones to discriminate PDAC patients from healthy controls with an area under the curve (AUC) of 0.81-0.88.³ A subsequent longitudinal study revealed glycosylation differences up to 50 months prior to diagnosis, indicating potential for early detection.⁴ However, external validation is needed to determine accuracy of this biomarker panel. Moreover, it is unknown whether this panel can differentiate PDAC in a diverse group that resembles clinical practice better. Therefore, this study aims to validate the biomarker panel in a heterogeneous cohort.

Aims & Methods

Protein N-glycans in prospectively collected plasma samples from Mayo Clinic were analyzed by mass spectrometry at the Leiden University Medical Center using a semi-automated preparation protocol.⁵ Glycosylation profiles were determined and compared between PDAC cases and controls. The control group consisted of imaging-confirmed pancreatic disease-negative controls and individuals with benign pancreatic diseases, including (non)-mucinous cysts and pancreatitis. Logistic regression was performed to calculate odds ratios (ORs) for the six previously reported protein NGTs. Additionally, AUC, sensitivity and specificity were calculated to determine the accuracy of the three biologically distinct NGTs (antennarity (CA4), sialylation (A3F0L), and fucosylation (CFa)) in discriminating PDAC cases from controls.

Results

We included 232 individuals, of whom 42 (18.1%) were diagnosed with PDAC, and 190 (81.9%) served as controls. Among controls, 59 (31.1%) were pancreatic disease-negative and 131 (68.9%) had benign pancreatic diseases. Median age of PDAC cases and controls was 71.7 (IQR=14.5) and 65.5 years (IQR=17.6), respectively. Among PDAC cases, 19 (45.2%) were female, and 106 (52.2%) among controls. The BMI in PDAC cases and controls was equal (26.8 (IQR=7.0) and 26.6 (IQR=7.6), respectively). Table 1 shows ORs for the six NGTs and PDAC. The AUC for the three biologically distinct traits was 0.77 (95% CI: 0.69-0.86), with a sensitivity of 0.81 (95% CI: 0.69-0.93) and specificity of 0.70 (95% CI: 0.64-0.76). When comparing PDAC cases to pancreatic disease-negative controls, the AUC was 0.83 (95% CI: 0.74-0.92), with a sensitivity of 0.79 (95% CI: 0.64-0.90) and specificity of 0.80 (95% CI: 0.69-0.90).

Table 1: The odds ratios for six glycosylation traits distinguishing pancreatic ductal adenocarcinoma cases from a heterogeneous cohort, including pancreatic disease-negative and benign pancreatic diseases controls. A subanalysis was performed for disease-negative controls. The Bonferroni correction was used to account for multiple testing.
Abbreviations: PDAC= pancreatic ductal adenocarcinoma, CI= confidence interval.
	PDAC compared to Heterogeneous cohort		PDAC compared to pancreatic disease-negative cohort
Variables	Odds ratio (95% CI)	P-value	Odds ratio (95% CI)	P-value
CA2	0.90 (0.85-0.95)	<0.001	0.86 (0.79-0.93)	0.001
CA4	1.59 (1.30-1.97)	<0.001	2.08 (1.49-3.10)	<0.001
CFa	1.76 (1.28-2.47)	0.004	3.40 (1.86-7.15)	0.002
A3F0L	0.91 (0.84-0.97)	0.043	0.82 (0.72-0.91)	0.005
A3F0E	1.17 (1.07-1.29)	0.004	1.37 (1.18-1.64)	0.001
A3FE	1.90 (1.39-2.66)	0.001	2.58 (1.69-4.23)	<0.001

Conclusion

Distinctive NGTs from plasma protein differentiate PDAC from non-PDAC in a diverse group, consisting of cystic pancreatic diseases and pancreatitis. This panel holds potential for future early detection methods.

References

1. Klatte DCF, Wallace MB, Löhr M, Bruno MJ, van Leerdam ME. Hereditary pancreatic cancer. Best Pract Res Clin Gastroenterol. 2022;58-59:101783.
2. Goggins M, Overbeek KA, Brand R, Syngal S, Del Chiaro M, Bartsch DK, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020;69(1):7-17.
3. Vreeker GCM, Hanna-Sawires RG, Mohammed Y, Bladergroen MR, Nicolardi S, Dotz V, et al. Serum N-Glycome analysis reveals pancreatic cancer disease signatures. Cancer Med. 2020;9(22):8519-29.
4. Levink IJM, Klatte DCF, Hanna-Sawires RG, Vreeker GCM, Ibrahim IS, van der Burgt YEM, et al. Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals. Pancreatology. 2022;22(4):497-506.
5. Vreeker GCM, Nicolardi S, Bladergroen MR, van der Plas CJ, Mesker WE, Tollenaar R, et al. Automated Plasma Glycomics with Linkage-Specific Sialic Acid Esterification and Ultrahigh Resolution MS. Anal Chem. 2018;90(20):11955-61.

Introduction

The interleukin 36 (IL-36) family includes the agonists IL-36α, IL-36β, IL-36γ, which activate the NF-κB pathway and the natural antagonist IL-36RA, which inhibits IL-36 signaling. While missense mutations in the gene encoding IL-36RA (IL36RN) are associated with severe skin inflammation, their role in Crohn’s disease (CD) is currently unknown. Therefore, we here investigated if IL36RN mutations contribute to inflammation in CD and whether IL-36 signaling might represent a potential drug target for personalized therapy.

Aims & Methods

Mutations in IL36RN were identified by whole exome sequencing (WES) followed by targeted Sanger sequencing. Peripheral blood mononuclear cells (PBMCs) of affected patients were analyzed by mass cytometry and serum cytokines were measured by ELISA. Identified IL36RN mutations were characterized by overexpression experiments and functional assays. Clinical and molecular responses of one IL-36RN mutant patient to combined treatment with spesolimab and certolizumab pegol was assessed by fecal calprotectin, endoscopy and mass cytometry at week 0 and 12 of treatment.

Results

In a cohort of 86 ulcerative colitis patients, 244 CD patients and 45 healthy controls, we identified 4 CD patients with heterozygous missense mutations in IL36RN (IL-36RA S113L, IL-36RA P76L and IL-36RA L133I). In the patient carrying the IL-36RA S113L variant, we detected elevated serum levels of IL-18 and IL-23, as well as an increased frequency of TH17 cells in PBMCs, suggesting an overactivation of the IL-36 pathway. Overexpression experiments showed that IL-36RA S113L causes decreased expression of IL-36RA, resulting in increased IL-36 signaling. The patient was therefore treated with 1200 mg of the IL-36R blocking antibody spesolimab every 4 weeks and 200 mg of certolizumab pegol biweekly on the basis of an Out Of Scope request. This approach resulted in reduced intestinal inflammation and a reduction in the frequency of pro-inflammatory myeloid cells in PBMCs.

Conclusion

In this study, we show that pathogenic IL36RN mutations are present in a subset of CD patients and that blocking IL-36 signaling may represent a personalized therapeutic approach for this rare subset of patients in whom conventional biologic therapies have failed.
Disclaimer: Boehringer Ingelheim was given the opportunity to review the abstract for medical and scientific accuracy as well as intellectual property considerations in relation to the potential mention of BI substances.
Boehringer Ingelheim had no role in the design, analysis or interpretation of the results in this study.
Spesolimab was made available on the basis of an out of scope request. Boehringer Ingelheim was given the opportunity to review this abstract as a courtesy.

Disclosure

Britta Siegmund has served as consultant for Abbvie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; Speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité).

Introduction

Obefazimod is an investigational, oral, once-daily (od), small molecule which enhances expression of microRNA-124 and is currently in phase 3 clinical trials for the treatment of patients with moderately to severely active ulcerative colitis (UC) [1]. Obefazimod demonstrated efficacy and safety in patients with UC at week-8 in a placebo-controlled, Phase 2b induction trial and in the subsequent open-label maintenance (OLM) study [2]. Here we present results for effects of obefazimod induction on histologic and combined histologic and endoscopic outcomes at week 8.

Aims & Methods

Patients with a modified Mayo score of 5-9 and a centrally read Mayo endoscopy subscore ≥2 at induction baseline were randomized 1:1:1:1 to receive either obefazimod 25mg, 50mg or 100mg od or placebo. Rectal or sigmoidal biopsies were collected during endoscopy at baseline and week 8 to evaluate treatment effect on histopathology scores utilizing the Geboes Index. Histologic improvement (Geboes histologic score ≤3.1), and histo-endoscopic mucosal improvement (Geboes histologic score ≤3.1 + Mayo endoscopy subscore of 0 or 1 with no friability; HEMI) were evaluated at week 8.

Results

Of the 252 patients randomized (with a mean age of 41.2 years; 41.3% female; mean UC disease duration of 8.05 years), 188 received obefazimod treatment, and 64 were administered a placebo. Baseline demographics, disease characteristics and histologic activity were consistent across treatment groups. The proportion of patients with histologic improvement at week 8 was 43% among obefazimod-treated patients (all doses) and 31% among those receiving placebo (Table 1). The proportion of patients with endoscopic improvement at week 8 was 35% among obefazimod-treated patients (all doses) and 13% among those receiving placebo. The proportion of obefazimod-treated patients who achieved HEMI at week 8 was greater than placebo-treated patients (27% vs 13%, respectively). Consistently positive histological outcomes were observed when evaluating all three obefazimod induction doses individually compared to placebo (Table 1).

Table 1: Histologic and combined histologic and endoscopic outcomes at week 8

1: Histological improvement: Neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system (ie, Geboes histologic score ≤3.1); 2: Endoscopic improvement: endoscopic sub-score ≤1; 3: Histo-endoscopic mucosal improvement: A combination of histologic improvement (ie, Geboes histologic score ≤ 3.1) and endoscopic improvement (Mayo endoscopy subscore of 0 or 1 with no friability).

Conclusion

In this Phase 2b induction trial, patients with moderately to severely active UC treated with obefazimod experienced clinically meaningful improvements in histologic and combined histologic and endoscopic outcomes at week 8.

References

1. Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-1697
2. Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022; 7: 1024-1035.

Disclosure

Bruce E Sands has served as a consultant or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, AgomAb, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead Sciences, Genentech, Glaxo SmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kalyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, Viela Bio, and stock options from Ventyx Biosciences.
Séverine Vermeire has received grants from AbbVie, J&J, Pfizer, Takeda and Galapagos; SV has received consulting and/or speaking fees from: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma.
Laurent Peyrin-Biroulet has received grants from Celltrion, Fresenius Kabi, Takeda; LPB has served as a consultant or received speaker’s fees from Abbvie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, Connect Biopharm , Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilea, Gossamer Bio, GSK, Hac Pharm, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopa, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vifor, Vectivbio, Ventyx, Ysopia.
Silvio Danese has served as consultant or received speaker’s fees from AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim.
Parambir Dulai received speaker’s fees from Abbvie, Abivax, Adiso, Bristol Meyer Squibb, Geneoscopy, GSK, Janssen, Lilly, Pfizer, Takeda.
Herbert Tilg has served as a consultant or received speaker’s fees from Abbvie, Abivax, Dr Falk Pharma, ferring, Galapagos, Microbiotica, MSD, Pfizer, Takeda.
Britta Siegmund has served as consultant for Abbvie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; Speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité).

Introduction

The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) published an update of its guideline in 2021, in which vancomycin or fidaxomicin replaced metronidazole as the preferred first-line treatment option for non-severe Clostridioides difficile infection (CDI). This decision was controversially discussed since outcome data in this particular patient group remains limited. The IBIS study aimed to close this evidence gap.

Aims & Methods

The IBIS multicentre cohort enrolled patients with an index episode of CDI between August 2017 and September 2020. The primary endpoint was event-free survival (EFS), defined as response to treatment with metronidazole or vancomycin within ten days of initiation, absence of recurrence and death from any cause up to 90 days post-treatment. A Cox proportional hazards model with inverse probability of treatment weighting was used to investigate the comparative effectiveness of this outcome. Additionally, subgroup analyses were performed based on severe and non-severe infections.

Results

​Of the 489 patients included, 118 (24%) received initial treatment with metronidazole and 371 (76%) with vancomycin. Of these, 78/118 (66.1%) and 247/371 (66.6%), respectively, responded to treatment within ten days, neither developed a recurrence nor died within 90 days and thus achieved the outcome of EFS. In the subgroup of non-severe infections, 74/293 patients (25.3%) received metronidazole, and 219/293 (74.7%) received vancomycin. Of these, 33/74 (44.6%) metronidazole patients and 150/219 (68.5%) vancomycin patients survived event-free. The Cox proportional hazards model revealed differences in EFS for the overall population and both sub-groups (reference metronidazole: all severity levels: hazard ratio [HR] 0.46, [95% Cl 0.33-0.65]; non-severe: HR 0.39; [95% Cl 0.24-0.60]; severe: HR 0.52; [95% Cl 0.28-0.95]).

Conclusion

Our analysis confirms current changes in guidelines, as it supports the superiority of vancomycin compared to metronidazole across all severity levels.

References

1. Khanna S, Pardi DS. The growing incidence and severity of Clostridium difficile infection in inpatient and outpatient settings. Expert Review of Gastroenterology & Hepatology. 2010;4(4):409-16.
2. van Prehn J, Reigadas E, Vogelzang EH, Bouza E, Hristea A, Guery B, et al. European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clinical Microbiology and Infection. 2021;27:1-21.
3. McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.
4. Manthey CF, Epple H-J, Keller K-M, Lübbert C, Posovszky C, Ramharter M, et al. S2k-Leitlinie Gastrointestinale Infektionen der Deutschen Gesellschaft für
5. Zar FA, Bakkanagari SR, Moorthi KMLST, Davis MB. A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile–Associated Diarrhea, Stratified by Disease Severity. Clinical Infectious Diseases. 2007;45(3):302-7.
6. Debast SB, Bauer MP, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases: Update of the Treatment Guidance Document for Clostridium difficile Infection. Clinical Microbiology and Infection. 2014;20:1-26.