Clinical Case Summary

A 29 year old women was diagnosed with Crohn’s disease with ileocolonic involvement and a penetrating behaviour (Montreal classification A2L3B3). After the pre imunosupression workup we proposed the patient to start Infliximab (IFX) with a dosage of 5 mg/kg.
During the first infusion the patient referred sudden visual impairment. There were no visible inflamation of the sclera, conjunctiva or peri orbital area. The patient reported no pain and there were no signs of ophthalmoparesis. We stopped the infusion immediately and asked for an urgent observation by Ophtalmology. Although the fundoscopic examination didn’t detect any abnormalities, there was a significant decrease in the visual acuity of the left eye.
The patient regained full visual acuity the day after the event. We decided to switch the biologic therapy to Ustekinumab. The patient was reevaluated in the outpatient clinic two weeks after discharge, she maintained full visual acuity and showed significant improvement of her symptoms.
IFX is a generally well tolerated drug, participating in the therapeutic approach of a wide variety of autoimmune conditions. Despite its favorable safety profile, IFX is associated with rare paradoxical adverse events that correspond to the development or exacerbation of an inflammatory condition during IFX therapy. Ocular adverse events represent part of this group of complications known as paradoxical adverse events. In the literature we can find reports of: uveitis, optic neuritis, endophthalmitis and orbital apex syndrome.
We report a case of a paradoxical adverse event manifested as a transitory sudden asymmetric loss of visual acuity.
From our research, this is the first report in the literature of transitory visual loss due to IFX. We intend to publish this case to further amplify the medical knowledge regarding the therapy with this drug and better inform both patients and physicians regarding the potential advserse events of IFX.

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) is recognized as a foundational procedure within the realm of interventional gastroenterology. Nevertheless, a significant amount of hands-on experience is required to achieve proficiency in this procedure, particularly with regard to the performance of sophisticated therapeutic maneuvers. Access to authentic training cases remains limited, while the use of cadaveric or live animal models presents distinct ethical, logistical and financial challenges (1). The advent of 3D printing technology paved the way for the development of advanced medical simulators. This study utilized computer-aided design and fused deposition modeling techniques to engineer an ERCP simulator that is both anatomically accurate and enables the training of trainee physicians in the intricate procedures of their chosen discipline (2). The simulator's modular design allows it to replicate a spectrum of papillary conditions, enabling targeted training in anatomies that are resistant to cannulation, as well as high-risk procedures like precut sphincterotomy and fistulotomy.

Aims & Methods

The design process for the ERCP simulator employed accessible parametric modeling software. Fabrication of the primary structural components, including the pancreas, the duodenum, and the bile ducts, were undertaken using polylactic acid (PLA) filament, a material that is both widely accessible and economical, thereby ensuring adequate rigidity and durability. The interchangeable papillary components were produced using flexible thermoplastic polyurethane (TPU) 95A filament, selected for its elasticity and capacity to be readily incised during procedures such as endoscopic sphincterotomy (EST). This allowed for easy exchangeability and facilitated the acquisition of skills by novice endoscopists. This process were selected on the basis of accessibility, user-friendly interface and cost-effectiveness, enabling replication in diverse settings. The biliary and pancreatic ductal lumens were meticulously calibrated to represent a range of procedural difficulty, with internal diameters that closely mirrored real anatomical variations.

Results

The simulator exhibited a high degree of anatomical and biomechanical fidelity, featuring a structurally stable duodenal framework and a flexible papillary interface. The simulator accurately reproduced tactile feedback experienced by gastroenterologists during ERCP, thereby validating its efficacy as a training tool. Furthermore, the simulator was enabled meticulous rehearsal of EST through sphincterotomy incisions and facilitated fistulotomy simulation using an elastomeric papilla structure. The simulator's design is both cost-effective and easily replicable, making it a valuable asset for continuing education and training in this field (3,4).

Conclusion

The ERCP simulator, fabricated using 3D printing technology, can be regarded as both technologically advanced and economically efficient for a number of complex procedures. These encompass endoscopic sphincterotomy, precut techniques, fistulotomy and stent placement. The simulator's design, featuring a modular papillary system, was crafted to provide a structured and progressive learning environment for novice users as well as experienced endoscopists. The simulator's cost-effectiveness, ease of scaling up and potential for wide dissemination signify a paradigm shift in ERCP education, facilitating proficiency acquisition in complex interventional endoscopy with greater efficiency and safety. Further investigations are needed for the simulator in ERCP training.

References

1. Lee S, Ahn JY, Han M, Lee GH, Na HK, Jung KW, et al. Efficacy of a three-dimensional-printed training simulator for endoscopic biopsy in the stomach. Gut and liver. 2017;12(2):149.
2. Zhang Y, Chen L, Hu B. Advances of 3D printing in gastroenterology and where it might be going. International Journal of Bioprinting. 2023;9(6):0149.
3. Lee DS, Ahn JY, Lee GH. A newly designed 3-dimensional printer-based gastric hemostasis simulator with two modules for endoscopic trainees (with video). Gut and Liver. 2019;13(4):415.
4. Bundy JJ, Weadock WJ, Chick JFB, Srinivasa RN, Patel N, Johnson E, et al. Three-dimensional printing facilitates creation of a biliary endoscopy phantom for interventional radiology-operated endoscopy training. Current Problems in Diagnostic Radiology. 2019;48(5):456-61.

Introduction

Identifying patient populations and factors associated with long-term treatment response can enable personalised management strategies in ulcerative colitis (UC). Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active UC.

Aims & Methods

Our aim was to identify patient subgroups with distinct response trajectories based on changes in combined rectal bleeding subscore (RBS) and stool frequency subscore (SFS) over time. In this post hoc analysis of etrasimod-treated patients from the ELEVATE UC 52 trial, PRO2 (SFS+RBS) was assessed to identify unique disease response trajectories, with further evaluation of the Week 52 achievement of primary and secondary endpoints. Additionally, a composite of objective and subjective disease activity measures, previously used in trajectory modelling, was assessed as comprehensive disease control (CDC). CDC was defined as meeting all the following criteria by Week 52: complete treatment (up to Week 50), clinical remission, RBS and SFS =0, endoscopic subscore =0/1, complete Mayo score ≤2, histological remission (Geboes score <2 or Robarts Histopathology Index <3), and C-reactive protein and/or faecal calprotectin within normal range. Longitudinal k-means was used to analyse PRO2 disease activity data as individual time-series connected datasets. Response-trajectory groups (TGs) were related to maintenance outcomes and baseline clinical characteristics. We evaluated the clinical relevance of grouping patients this way by assessing the proportions achieving key endpoints and their association with baseline demographics.

Results

Among the cohort of 283 etrasimod-treated UC patients, five TGs were identified (Table). 57% of the super-responders who achieved CDC were clustered in TGs C and E, characterised by rapid response and sustained clinical remission (TG C: 34/51 patients, TG E: 25/44 patients). Baseline characteristics of these patients included lower baseline disease activity, as measured by histology and Mayo score components. In TGs B and D, clinical remission was achieved by 31.7% and 34%, respectively, with clinical response achievement of 48.3% (29/60) and 53.2% (25/47). In TG E, symptomatic improvement according to PRO2 continued beyond Week 12.

Conclusion

Trajectory modelling allows the identification of distinct phenotypic subgroups among UC patients responding to a targeted therapy, highlighting heterogeneity often masked when analysed as a single population or clinical trial. Notably, a subset of etrasimod patients demonstrated super-fast and fast response dynamics, associated with higher rates of clinical remission and CDC. This may provide an important utility for therapeutic choice and patient management under therapy. Further studies across different modes of action are ongoing to validate these results and identify similarities and differences across patient populations and treatment effects.

Disclosure

VS is an employee of Pfizer Inc.
JCW is an employee and shareholder of Pfizer Inc.
CWL has served as a speaker for AbbVie, Dr Falk, Ferring, Hospira, Janssen, MSD, Pfizer Inc, Shire, Takeda, and Warner-Chilcott; has served as a consultant for AbbVie, Dr Falk, Gilead, GSK, Hospira, Iterative Scopes, Janssen, MSD, Oshi Health, Pfizer Inc, Pharmacosmos, Takeda, Topivert, Trellus Health, and Vifor Pharma; and has received research funding from AbbVie and Gilead.
SJ is an employee of Pfizer Inc.
WN is an employee and shareholder of Pfizer Inc.
SS has received lecture/speaker fees from AbbVie, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Falk, Fresenius, Janssen, MSD, Pfizer Inc, Takeda. Consultancy/advisory fees: AbbVie, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Falk, Fresenius, Gilead Sciences, IMAB, Janssen, MSD, Mylan, Pfizer Inc, Protagonist, Provention Bio, Takeda, Theravance and Ventyx Biopharma.

Introduction

Previous studies reported a positive correlation between serum and tissue drug levels in IBD receiving intravenous (IV) infliximab (IFX) therapy, except in those with severely inflamed tissue (1). Tissue drug levels in patients with IBD receiving SC IFX have not yet been investigated. We aimed to compare both the serum and tissue drug levels between SC and IV IFX maintenance therapy in IBD patients.

Aims & Methods

Any IBD patients under maintenance therapy with SC or IV stable doses IFX who underwent a colonoscopy for routine follow-up were eligible. Patient and disease characteristics, as well as clinical and endoscopic activity were recorded. Clinical activity was defined by high activity score (CDAI or pMAYO score) with at least one elevated biomarker (fecal calprotectin >250 mg/g, serum CRP >5 mg/L). Endoscopic disease activity was categorized as absent (normal), low (mild inflammation), moderate (friability, aphthoid lesions), or severe (ulcerations), as reported by the endoscopist blinded to the results of serum and tissue drug levels. Two biopsies were taken from the same location (either the most active area or randomly if no endoscopic lesion), and tissue and serum IFX levels were measured simultaneously in a centralized manner blinded to clinical and endoscopic disease activity. Frozen biopsy specimens were treated with the Bio-Plex® Cell Lysis Kit after tissue cutting and homogenates were sonicated at 4°C (Omni Ruptor 205). Tissue extracts were then frozen at -80°C prior drug measurements (iTrack10; Theradiag).

Results

Thirty-five patients were enrolled (CD in 65%, Sex ratio 1.4, 14 % with clinically and 57 % with endoscopically active disease, and 23 under SC IFX therapy). The characteristics of both IV and SC IFX groups were comparable, except for drug dose intensification in 90% of those treated with IV IFX group and 5% in the SC IFX cohort (p < 0.001). In patient in endoscopic remission, tissue levels were undetectable or very low for both IV and SC IFX therapy. Serum and tissue drug levels were significantly higher in the SC IFX cohort compared with the IV IFX group (22 mg/mL vs 9 mg/mL for serum; p < 0.001 and 25 mg/g vs 10 mg/g for tissue; p = 0.002, respectively). A moderate correlation was found between serum and tissue drug levels for both IV and SC IFX therapy (Spearman r = 0.42; p = 0.014 and r = 0.43; p = 0.001, respectively). Tissue drug levels increased gradually in patients with minimal or moderate endoscopic activity and were lower in those with severe endoscopic activity for both IV and SC IFX groups (p < 0.001). Tissue drug levels remained significantly higher in minimal or moderate endoscopically active disease in SC compared with IV route of IFX administration. The two independent factors associated with drug tissue levels > 14 mg/g (median levels) were the SC IFX route (OR: 2.25, 95% CI = [1.19–2.23]; p = 0.001) and the serum IFX levels (OR: 1.63, 95% CI = [1.19–2.23]; p = 0.002). A serum IFX level greater than 16.1 mg/mL was highly predictive of a tissue drug level > 14 mg/g tissue (Se: 0.94, Spe: 0.94, PPV: 0.94, NPV: 0.94, and Accuracy = 94.3%).

Conclusion

Serum and tissue drug levels are positively correlated in IBD patients under IV and SC maintenance IFX therapy. Interestingly, drug levels were higher both in serum and tissue in patients under SC IFX compared with IV IFX and tissue drug levels gradually increased in minimally to moderately inflamed intestine but were lower or undetectable in more severe inflamed areas.

References

1. Yarur AJ, et al. The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study. Gut 2016; 65: 249-255.