Introduction

The POWER study evaluated efficacy and safety of a single intravenous (IV) re-induction ustekinumab (UST) dose vs continued UST subcutaneous (SC) treatment in Crohn’s disease (CD) patients (pts) with secondary loss of response (LoR) to standard UST maintenance therapy. Here, we present Week (W)16 pharmacokinetics, exposure–response relationships, and immunogenicity analysis.

Aims & Methods

Adult pts with moderately–severely active CD who initially responded to UST IV induction therapy per label and later experienced LoR were included. LoR was defined as CD Activity Index (CDAI) score ≥220–≤450, plus elevated C-reactive protein (>3mg/L)/faecal calprotectin (>250mg/kg), or endoscopy performed ≤3 months before baseline (W0) with active CD. At W0, randomized pts received ~6mg/kg IV UST, or SC UST 90mg, followed by SC UST 90mg dosing at W8/16. Clinical assessments occurred at W0/8/16. Serum samples evaluated UST concentration (conc) and anti-drug antibodies (ADAs) at W0/8/16 using validated assays. Clinical response (CRes) and endoscopic remission (ERem) were evaluated based on CDAI and centrally read endoscopy, respectively, at W0/8/16. Efficacy outcomes were analyzed by W0 trough conc groups (undetectable, 0.17–<0.8, 0.8–<1.3, and ≥1.3µg/mL) and conc quartile groups (QGs) at W16 using a proprietary immunoassay.

Results

Serum UST conc data were obtained from 215 pts (SC, n=107; IV, n=108) with ≥1 blood sample collected. Similar at W0, median serum UST concs at W0 (1-hour post-dose)/8/16 were higher in the IV vs SC arm (Table). Based on W16 trough concs, 63.9% (69/108) of pts were in the ≥1.3µg/mL group in the IV arm, vs 41.1% (44/107) in the SC arm. The proportion of pts with W16 CRes in the ≥1.3µg/mL group was similar between arms; more pts were in W16 ERem in the IV vs SC arm. By W16 quartile analysis, CRes was numerically higher in the IV vs SC arm in QG1 and 4. More IV arm pts achieved ERem in QG4 vs QG1; a small number of pts in SC arm achieved ERem independent of QGs. Incidence of UST ADAs through W16 was low (SC, n=2; IV, n=0; 0.93% overall).

Conclusion

Although, IV re-induction resulted in higher serum concs and proportions of pts with high (≥1.3µg/mL) trough conc at W16; there did not appear to be an exposure-response relationship for CRes. However, quartile analysis showed a relationship between increased exposure in the IV arm and differences in ERem. This observation is consistent with the notion that pts with secondary LoR may benefit from single-dose re-induction.

Disclosure

S. Schreiber has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Fresenius, Galapagos/Gilead, Hikma, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist, ProventionBio, Takeda, and Theravance Biopharma. S. Lee served as a consultant for Applied Molecular Transport, Arena, Boehringer Ingelheim, Bridge Biotherapeutics, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Cornerstones Health, Eli Lilly and Company, Janssen, KCRN Research, Samsung Bioepis, and UCB; and received research grants from AbbVie, AbGenomics, Arena, Celgene, Janssen, Salix, Takeda, and UCB. C.J. van der Woude received grant support from Falk Benelux, Ferring, and Pfizer; received speaker fees from AbbVie, Takeda, Ferring, Dr Falk Pharma, and Pfizer; and served as a consultant for Janssen. I Marín-Jiménez has served as a consultant, advisory member, speaker or has received research funding from Abbvie, Chiesi, Faes Farma, Dr Falk Pharma, Ferring, Gebro Pharma, Hospira, Janssen, MSD, Otsuka Pharmaceutical, Pfizer, Shire, Takeda, Tillots, and UCB Pharma. D. Wolf has received honoraria as a speaker, consultant and/or advisory board member from AbbVie, Arena, Celgene/Bristol Myers Squibb, Janssen, Pfizer, and Takeda. E. Schnoy has received personal fees from AbbVie, Bristol Myers Squibb, Celltrion Healthcare, Dr Falk Pharma, Galapagos/Gilead, I-Mab, Janssen, Lilly, Pfizer, Pharmacosmos, Takeda, and Tillotts Pharma. B. Salzberg served as a consultant for Johnson and Johnson, and has received honoraria as a speaker from AbbVie, Bristol Myers Squibb, and Johnson & Johnson. M. Nazar is an employee of Janssen-Cilag Polska Sp. z o.o. and has restricted stocks. C. Busse, W. Langholff, C Gasink, T. Baker, B. Godwin and Adedokun O.J. report employment with/funding by Janssen Research & Development, LLC, a wholly owned subsidiary of Johnson & Johnson, and stock ownership in Johnson & Johnson. B. Feagan received grant/research support from AbbVie Inc., Amgen Inc., AstraZeneca/MedImmune Ltd., Atlantic Pharmaceuticals Ltd., Boehringer Ingelheim, Celgene Corporation, Celltech, Genentech Inc./Hoffmann-La Roche Ltd., Gilead Sciences Inc., GlaxoSmithKline (GSK), Janssen Research & Development LLC., Pfizer Inc., Receptos Inc./Celgene International, Sanofi, Santarus Inc., Takeda Development Center Americas Inc., Tillotts Pharma AG, and UCB; was a consultant for Abbott/AbbVie, AdMIRx Inc., Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport Inc., Aptevo Therapeutics, Asta Pharma, AstraZeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Galapagos, Galen/Atlantica, GiCare Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD Inc., Intact Therapeutics, Johnson & Johnson/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestlé, Nextbiotix, Novo Nordisk, ParImmune, Parvus Therapeutics Inc., Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Qu Biologics, Rebiotix, Receptos, Roche/Genentech, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd., and Zyngenia; was a member of the speakers’ bureau for Abbott/AbbVie, Johnson & Johnson/Janssen, Lilly, Takeda, Tillotts, and UCB Pharma; a member of the scientific advisory board for Abbott/AbbVie, Allergan, Amgen, AstraZeneca, Atlantic Pharma, Avaxia Biologics Inc., Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Galapagos, Genentech/Roche, Johnson & Johnson/Janssen, Merck, Nestlé, Novartis, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG, and UCB Pharma; and was a Senior Scientific Officer for Robarts Clinical Trials Inc.

Introduction

Coexistence of bile acid diarrhoea (BAD) and microscopic colitis (MC) has been described (1), and treating this with sequestrants could reduce the need for budesonide. Fasting plasma 7α-hydroxy-4-cholesten-3-one (C4) values >46 ng/mL are specific for BAD but sensitivity is only 47% (37-57%) compared with tauroselcholic [75-Se]
acid (SeHCAT) retention <10% (2). C4 values between 33 and 46 are in a diagnostic grey zone. Budesonide directly affects the bile acid homeostasis making the temporal relation between treatment and testing important. Fortunately, unlike SeHCAT testing, C4 may be sampled immediately when a patient presents with a flare of MC.

Aims & Methods

To assess the prevalence of coexisting BAD in patients with active MC.
Consequtive patients with MC and a flare fulfilling the Hjortswang diarrhoea criteria (≥3 stools or ≥1 watery stool per day) and a negative test for infectious diarrhoea were included. Patients were treated with budesonide 9 mg once daily for 6 weeks. Clinical assessment, Bristol stool charts, and fasting C4 were obtained at baseline, during the last treatment week and 4 weeks after end of treatment. Remission was defined as a daily mean of <1 watery bowel movement and <3 total bowel movements [EudraCT: 2019-002762-12].

Results

49 patients were included; 26 (53%) with collagenous colitis. Mean age was 60 (range 55-70) years, 22% current smoker, none on NSAIDs. Six (12%; 95%CI: 5–25%) of 49 patients had BAD diagnosed by C4. Another 3 patients had grey zone C4 values. Mean C4 did not change during budesonide treatment, 22 and 23 ng/mL at baseline and at week 6, respectively. SeHCAT was performed outside the study in 26 patients of whom 3 had retention of <10% and 6 of <15%. The mean total number of stools per day declined from baseline 7.9 to 1.9 and watery stools from 3.7 to 0.3 during budesonide treatment. Remission was obtained in 45. Twenty-nine had relapsed four weeks after end of budesonide treatment, 5 of 6 (83%; 95%CI: 36–100%) with MC and BAD, and 24 of 43 (56%; 95%CI: 40–71%) with MC and not BAD.

Conclusion

During an inflammatory flare of MC, 12% (5–25%) had C4-defined BAD. However, C4 only identifies about half of patients with BAD compared with the diagnostic gold standard SeHCAT, meaning about 25% of patients with MC could have coexisting BAD. Screening for BAD may have merit in MC patients with relapse of diarrhoea after budesonide treatment.

References

1 Bjørnbak C, Engel PJH, Nielsen PL, Munck LK. Microscopic colitis: clinical findings, topography, and persistence of histopathological subgroups. Aliment Pharmacol Ther. 2011, 34: 1225-34.
2. Borup C, Vinter-Jensen L, Jørgensen SPG, Wildt S, Graff J, Gregersen T, Zaremba A, Andersen TB, Nøjgaard C, Timm HB, Lamazière A, Rainteau D, Hansen SH, Rumessen JJ, Munck LK. Prospective comparison of diagnostic tests for bile acid diarrhoea. Aliment Pharmacol Ther. 2024; 59: 39-50.

Disclosure

Budesonide was donated for study use by Tillotts Pharma as an unrestricted scientific grant. Tillotts Pharma had no influence on the planning, conduct, or reporting of the study.

Introduction

Although chronic alcohol consumption has progressively decreased in recent years, a third of people over 15 years declare at least one episode of excessive use every month, which ranks Romania on second position, with a rate of 35%, far above the average registered in the EU (20%). Therefore, Romania has one of the highest incidence rates of alcohol-related liver cirrhosis, which has become a major public health problem. This study aimed to investigate the prevalence of liver fibrosis in the asymptomatic alcohol-consuming population.

Aims & Methods

The study aimed to evaluate the relationship between advanced liver fibrosis measured by transient elastography, laboratory parameters, and the amount of alcohol consumed depending on non-modifiable risk factors such as age and gender. Between January 2022 and December 2022, we examined patients with day hospitalization in the Institute of Gastroenterology and Hepatology in Iasi, without liver history, who admitted a moderate or high consumption (women <7 versus >7 drinks/week; men <14 versus >14 drinks/week) for at least one year. The classification of the fibrosis stage by transient elastography was adjusted according to transaminase values. The results were analyzed by univariate analysis and logistic regression to establish models of prediction.

Results

The study included 689 patients with an average age of 49.32±14.31 years, a proportion of 63.7% represented by men. Advanced fibrosis (³ F3) was detected in 19.30% of the examined patients, predominantly in men (14.1%) and patients over 55 years old (12.5%). Excessive alcohol consumption is associated 2 times more with advanced fibrosis in women (OR=5.08; CI 95%: 3.45-9.50, p<0,001) and the group under 40 years old (OR=6.29; CI 95%: 1.67-9.43, p<0,001) compared to men (OR=2.27; CI 95%: 1.76-3.81, p=0,012) respectively patients over 55 years old (OR=3.21; CI 95% : 2.28-4.45 p<0,001). Using logistic regression, it was demonstrated that there was a strong correlation between advanced fibrosis, excessive alcohol consumption, low serum albumin level and the reduction of triglycerides in men (R² Nagelkerke = 0.854; p<0.001) supplemented with the reduction of cholesterol in the age group 40-55 years (R² Nagelkerke = 0.785; p<0.001), respectively of ferritin in those over 55 years old (R² Nagelkerke = 0.804; p<0.001). The association of excessive alcohol consumption, age, low levels of albumin, LDL-cholesterol and C-reactive protein generated a significant predictive model (R² Nagelkerke = 0.784; p<0.001) for female patients.

Conclusion

Screening using transient elastography represents an approach that could provide early diagnosis of advanced liver fibrosis in an asymptomatic population, with the possibility to prevent the evolution of ALD and the development of complications of cirrhosis.

Introduction

Pancreatic serous cystic neoplasms, benign lesions with distinct histologic appearance and very low malignant potential, represent 1-2% of pancreatic cysts.¹ Microcystic serous cystadenoma (SCA) is the most common subtype.² It may have a solid appearance on cross sectional imaging, which is only diagnostic in 50% of cases.³ In the absence of characteristic features on imaging, EUS-guided fine-needle aspiration (FNA) is the next diagnostic method of choice for large microcystic SCAs. However, cytology is often inconclusive and usually enough fluid is not attainable for chemistry analysis.⁴ Previous case series have shown that fine-needle biopsy (FNB) may be an effective method for diagnosing SCAs⁴; however, these studies were limited in patient number. We present a case series of 23 patients who underwent FNB for the diagnosis of suspected microcystic SCAs.

Aims & Methods

A single-center retrospective review of the electronic health record was performed on patients who underwent EUS to evaluate a solitary pancreatic lesion on cross sectional imaging. If EUS imaging was suggestive of a microcystic lesion and fluid aspiration was expected to be non-diagnostic or not feasible due to the small cystic components, the decision was made to pursue an FNB intraoperatively. FNB was performed on all patients using a 22-gauge fork tip biopsy needle, using either a transgastric or transduodenal approach. The acquired tissue was placed in formalin, underwent standard histologic handling, and was reviewed by an expert gastrointestinal pathologist. SCAs were diagnosed histologically by tight acinar tubules bordered by cuboidal cells with clear cytoplasms and round nuclei.

Results

A total of 23 patients were included (18 female). The mean age was 69.5 ± 12.2 years and the mean cyst size in its largest diameter was 33.3 ± 14 (range of 8-60mm). Seven of the lesions were in the tail, 8 in the body, and 8 in the head/genu. Histological diagnosis of SCA was established in 78% (18/23) of the lesions and no further surveillance or imaging was recommended for these patients. A mean number of 1.4 ± 0.63 (range of 1-3 passes) of passes were obtained. In one of the patients, only one pass was obtained due to intra-lesional bleeding after initial needle puncture. The patient did not require admission or any further intervention. There were no other adverse events noted, including bleeding and/or pancreatitis.

Conclusion

Our case series demonstrates that EUS-guided FNB is a safe and feasible method for diagnosing microcystic SCAs, despite previous literature suggesting high intraprocedural bleeding. This may be a cost-effective approach, since after the diagnosis is confirmed, follow-up imaging and surveillance is not needed. This may also prevent unnecessary surgical intervention in cases of larger lesions where EUS-guided FNA was non-diagnostic.

References

1. Kimura W, Moriya T, Hirai I, et al. Multicenter study of serous cystic neoplasm of the Japan pancreas society. Pancreas. 2012;41(3):380-387. doi:10.1097/MPA.0b013e31822a27db
2. Reid MD, Choi HJ, Memis B, et al. Serous Neoplasms of the Pancreas. American Journal of Surgical Pathology. 2015;39(12):1597-1610. doi:10.1097/PAS.0000000000000559
3. Tseng JF, Warshaw AL, Sahani D V, Lauwers GY, Rattner DW, Fernandez-del Castillo C. Serous cystadenoma of the pancreas: tumor growth rates and recommendations for treatment. Ann Surg. 2005;242(3):413-419; discussion 419-21. doi:10.1097/01.sla.0000179651.21193.2c
4. Manfrin E, Perini C, Di Stefano S, et al. Pseudo solid-appearing pancreatic serous microcystic adenomas: Histologic diagnosis with the EUS core biopsy fork-tip needle. Endosc Ultrasound. 2019;8(5):334-341. doi:10.4103/eus.eus_11_19

Disclosure

No conflict of interest to disclose.

Introduction

Hypertriglyceridemia is a well-established cause of acute pancreatitis, representing up to 35% of all etiologies. The risk of developing acute pancreatitis increases progressively with serum triglyceride (TG) levels over 500 mg/dL. The degree of TG elevation is also associated to the severity of hypertriglyceridemia-induced pancreatitis (HTGP). Besides general measures, it has been suggested from observation studies that, in selected patients, insulin and plasmapheresis may have a role in the management of this condition.

Aims & Methods

We present an observational retrospective study of patients diagnosed with severe HTGP treated with plasmapheresis (PX) in an Intensive Care Unit (ICU) between January 2013 and March 2023.

Results

Of the 19 patients included in this study, 89% were men (n=17) and the mean age of presentation was 41 ± 7 years. Around 90% of patients were obese with a mean body mass index (BMI) of 29 ± 3 kg/m². The average APACHE II score was 9±7 and most patients did not require organ support (n=16, 84%). All the selected patients had severe hypertriglyceridemia at admission (1225 to 4700 mg/dL) and underwent PX within 48h of ICU admission. Levels of TG were measured before and after each plasmapheresis. 68% of patients needed only one treatment to reduce TG to a value below 500 mg/dL (n=13), 26% needed two treatments (n=5) and 5% needed four (n=1). A total of 27 PX were conducted. The average decrease in TG levels per treatment was 67% and 74% with the first treatment. The mean volume exchanged was 3683 mL ± 859 mL, and the most used replacement solutions were albumin/crystalloid (n=12, 44%) and albumin alone (n=11, 41%). The technique was interrupted mainly due to elevated transmembrane pressure (n=11, 40%). There were no PX interruptions due to complications related to the patient. Although heparin was used in all patients for anticoagulation, no hemorrhagic complications were associated to the technique. Hypotension occurred in 7% of plasmapheresis and was solved with crystalloid administration . The mean ICU length of stay was 7+11 days and the mean hospital length of stay was 17+21 days. The hospital mortality was 5% (n=1).

Conclusion

PX proved to be successful in lowering TG levels in HTGP. One to two plasma exchanges effectively reduced the serum TG level. There was a low rate of procedure-related complications. However, having no comparison with standard treatments, the impact of this technique on the patients’ clinical outcomes is still uncertain. Further prospective randomized clinical studies are needed to outline an efficient treatment for the management of HTGP.

References

Padmanabhan, A et al, “Guidelines on the Use of Therapeutic Apheresis in Clinical Practice”, J Clin Apher. 2019;34:171–354.
Banks PA, “Practice guidelines in acute pancreatitis.”, Am J Gastroenterol. 2006;101(10):2379)
Rawla, P. “Hypertriglyceridemia-induced pancreatitis: updated review of current treatment and preventive strategies”, Clin J Gastroenterol. 2018 Dec;11(6):441-448.
Faria, R. et al, “Therapeutic Plasmapheresis: Seven Year Experience of an Intensive Care Unit in Portugal”, Acta Med Port 2022 Mar;35(3):176-183
Stefanutti, C. et al, “Severe Hypertriglyceridemia-Related Acute Pancreatitis”, Therapeutic Apheresis and Dialysis 2013; 17(2):130–137