Clinical Case Summary

A 40-year-old male came to our emergency department referring worsening jaundice, mental status deterioration, epigastric pain and anorexia over the past week. Four weeks earlier he presented odynophagia, myalgias, and hand pruritus but didn’t seek medical attention.
Patient’s clinical background included cognitive impairment due to peripartum anoxia and type 2 Diabetes Mellitus. At admission, he had elevated liver enzymes (R value=2,7), coagulopathy (INR 1.3), pancreatic enzymes >3 times the upper normal level and hyperbilirubinemia (mostly conjugated).
The CT-scan revealed pancreatic tail globosity, diffuse abdominal and retroperitoneal peri-centimetric lymph nodes and excluded biliary lithiasis.
After common causes of acute hepatitis and pancreatitis were ruled out, and since patient was at risk of acute liver failure despite supportive treatment, a liver biopsy was performed. Autoimmune hepatitis, drug-induced liver injury or lymphoproliferative disease were held as potential differentials. Hepatitis E Virus (HEV) RNA was then found and genotyped in the serum (genotype 3). HEV infection was assumed as the cause for both hepatitis and pancreatitis. Histological pattern was inconclusive and epidemiological source wasn’t found.

HEV infection paradigm has changed and is now considered an endemic zoonotic infection in most high-income countries (Portuguese seroprevalence is 16.3%)¹. Infection occurs due to ingestion of undercooked pig or boar meat and should be suspected in every acute hepatitis, mostly with a cholestatic pattern.
The setting of acute HEV hepatitis complicated with acute pancreatitis (AP) is uncommon². AP usually starts after a median of 10 days of jaundice onset³. Literature only reports association between AP and HEV caused by genotype 1 from Southeast Asia^{3 4}, and genotype 3 was only related to gallstone-related pancreatitis, according to current knowledge⁵. This might be the first form of HEV genotype 3 infection with hepatitis and pancreatitis.

References

1. Nascimento MSJ, Pereira SS, Teixeira J, et al. A nationwide serosurvey of hepatitis E virus antibodies in the general population of Portugal. Eur J Public Health 2018;28(4):720-24. doi: 10.1093/eurpub/ckx213 [published Online First: 2017/12/14]
2. Debnath P, Datta AK, Chakraborty U, et al. Acute viral hepatitis E complicated with acute pancreatitis in an immunocompetent adult. BMJ Case Rep 2021;14(2) doi: 10.1136/bcr-2020-239684 [published Online First: 2021/02/06]
3. Haffar S, Bazerbachi F, Garg S, et al. Frequency and prognosis of acute pancreatitis associated with acute hepatitis E: A systematic review. Pancreatology 2015;15(4):321-6. doi: 10.1016/j.pan.2015.05.460 [published Online First: 2015/06/08]
4. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol 2018;68(6):1256-71. doi: 10.1016/j.jhep.2018.03.005 [published Online First: 2018/04/04]
5. Karlsson M, Norder H, Bergstrom M, et al. Hepatitis E virus genotype 3 is associated with gallstone-related disease. Scand J Gastroenterol 2019;54(10):1269-73. doi: 10.1080/00365521.2019.1666163 [published Online First: 20190925]

Clinical Case Summary

A 70-year-old patient with diabetes mellitus and cholecystectomy performed six months earlier was admitted to the emergency department for generalized abdominal pain, hyporexia and weight loss.
An abdominal CT scan showed a solid-cystic pancreatic lesion suggestive of mucinous neoplasia, together with peritoneal nodules in the right paracolic gout. In view of the suspicion of malignancy, an echoendoscopy with fine needle aspiration puncture (EUS-FNA) was performed, identifying an irregular lesion with heterogeneous and hypovascular ultrastructure in the pancreatic neck-body and a discrete dilatation of the main pancreatic duct. Finally, the histological study didn´t show neoplastic cells.
Suddenly the patient experienced a clinical worsening with severe pain and high fever. Laboratory tests showed a progressive increase in C-reactive protein and leukocytosis with left shift. In a control CT scan, a reduction in the size of the pancreatic lesion is observed, together with an increase in the peritoneal lesions which present a polyglobulated contour, hypercapillary margins and rarefaction of the surrounding fat. These finding suggesting the presence of peritoneal abscesses secondary to dropped gallstones. After broad-spectrum antibiotic therapy, the intra-abdominal abscesses improved radiologically, but the collection persisted in the right posterior pararenal space which was drained under ultrasound control with subsequent disappearance of fever and normalization of analytical parameters.
Dropped gallstones occur in approximately 7% of cholecystectomies. The secondary granulomatous reaction in paucisymptomatic patients can simulate peritoneal tumor processes in imaging tests, being one of the adverse effects described in relation to this pathology. In our case, the concomitant presence of peritoneal lesions together the pancreatic lesion oriented the initial case as a malignant process; however, the patient's evolution were key to the final diagnosis.

Introduction

Filgotinib (FIL) is an oral, once-daily, Janus kinase 1 preferential inhibitor. We evaluated the safety of FIL in Crohn’s disease (CD) in the DIVERSITY1 study and compared it with previously reported FIL safety data in ulcerative colitis (UC) from the SELECTION study.¹

Aims & Methods

The phase 3 double-blind, placebo-controlled DIVERSITY1 trial (NCT02914561) randomized adults aged 18–75 years with moderately to severely active CD 1:1:1 to receive FIL 200 mg (FIL200), FIL 100 mg (FIL100) or placebo (PBO) once daily for 10 weeks in Induction (IND) Study A (biologic-naive and biologic-experienced) or B (biologic-experienced). FIL-treated patients who met either co-primary endpoint (clinical remission or endoscopic response) at week 10 were rerandomized 2:1 to receive their IND dose or PBO in the Maintenance (MNT) Study to week 58. Safety and tolerability were assessed throughout the study in all patients who received at least one dose of FIL or PBO within each study part. The SELECTION (NCT02914522) study evaluated the same FIL doses as DIVERSITY1.¹ Proportions of patients with treatment-emergent adverse events (TEAEs), serious TEAEs and AEs of special interest were compared between DIVERSITY1 (CD) and SELECTION (UC). Efficacy data have been reported elsewhere.^1,2

Results

In CD IND studies A and B, 707 and 665 patients respectively, were randomized to receive FIL200 (n=223; n=204), FIL100 (n=245; n=230) or PBO (n=239; n=231). In the MNT Study, FIL200-induced patients received FIL200 (n=118) or PBO (n=56), FIL100-induced patients received FIL100 (n=105) or PBO (n=56) and PBO-induced patients received PBO (n=146). Safety outcomes in CD and UC IND studies are reported in the Table. In the MNT studies, infection rates ranged from 25.5–33.9% and 22.6–35.1% in CD and UC, respectively; serious infections were reported in nine patients (1.9%) with CD and eight patients (1.2%) with UC. In the MNT studies, malignancy (excluding non-melanoma skin cancer) was reported in one FIL100-FIL100-treated patient (1.0%; lung metastases) with CD, and in one FIL200-FIL200-treated patient (0.5%; malignant melanoma) and one FIL100-FIL100-treated patient (0.6%; colon cancer) with UC. Venous thromboembolism (VTE) was reported in one FIL200-FIL200-treated patient (0.8%) with CD and one PBO-PBO-treated patient (1.1%) with UC in the MNT studies. Major adverse cardiovascular events (MACE) were reported in one patient (0.4%; IND Study B FIL100) with CD and five patients with UC (IND PBO [n=1; 0.4%]; FIL200-FIL200 [n=2; 1.0%], FIL100-FIL100 [n=1; 0.6%]; PBO-PBO [n=1; 1.1%]). No deaths were reported in DIVERSITY1; two deaths were reported in SELECTION, but neither was considered related to treatment by the investigator.

Table. Summary of safety outcomes in the DIVERSITY1 and SELECTION IND studies.

Conclusion

FIL treatment was well tolerated. FIL showed a safety profile in CD that was generally consistent with that in UC, and no new safety signals were observed.¹ The numbers of malignancy, VTE and MACE events for FIL were low in CD and UC clinical trials.¹

References

1. Feagan BG et al. Lancet 2021;397:2372–84.
2. Vermeire S et al. Abstract submitted to the United European Gastroenterology Week, 14–17 October 2023, Copenhagen, Denmark.

Disclosure

SS reports personal fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos/Gilead, Hikma Pharmaceuticals, I-Mab, Janssen Pharmaceuticals, Morphic, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Sandoz/Hexal, Takeda, Theravance Biopharma and UCB.
SV reports grants from AbbVie, Galapagos, Johnson & Johnson, Pfizer and Takeda; consulting and/or speaker fees from AbbVie, AbolerIS Pharma, Agomab, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia Biologics, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead, GSK, Hospira, IMIDomics, Janssen Pharmaceuticals, Johnson & Johnson, Eli Lilly, Materia Prima, MiroBio, Morphic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillotts Pharma and Zealand Pharma.
DTR reports personal fees from AbbVie, AltruBio, Biomica, Boehringer Ingelheim, Bristol Myers Squibb, Celgene/Syneos, Dizal Pharmaceuticals, Eli Lilly, Galenpharma/Atlantica, Gilead Sciences, GSK, InDex Pharmaceuticals, Janssen Pharmaceuticals, Pfizer, Prometheus Laboratories, Reistone Biopharma, Roche/Genentech, Takeda and TECHLAB; and grants from Takeda.
SD reports personal fees from AbbVie, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen Pharmaceuticals, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB and Vifor.
RM declares no competing interests.
XR reports personal fees from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Eli Lilly, Galapagos, Janssen Pharmaceuticals, MSD, Pfizer, Takeda and Theradiag.
PK is an employee of Gilead Sciences Inc.
PvH reports consulting fees from AOP Health, Aspen, Astellas Pharma, Galapagos and Sanofi; and employment by Janssen, MSD and Schering-Plough.
TM, RB and F-OLB are employees and shareholders of Galapagos NV.
MW has received grants or contracts from AbbVie, Alfresa Pharma, EA Pharma, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Takeda and Zeria Pharmaceutical; consulting fees from AbbVie, EA Pharma, Eli Lilly Japan, Gilead Sciences, Nippon Boehringer Ingelheim and Takeda Pharmaceutical; and honoraria from Celltrion Healthcare, EA Pharma, Eli Lilly Japan, Gilead Sciences, Janssen Pharmaceuticals, JIMRO, Kissei Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Pfizer Japan, Takeda Pharmaceutical and Zeria Pharmaceutical.
The DIVERSITY1 study was sponsored by Galapagos NV (Mechelen, Belgium). Gilead Sciences Inc. (Foster City, CA, USA) was a collaborator for the study.
Medical writing support for the development of this abstract was provided by Michelle Antoni, PhD, of PharmaGenesis London, London, UK, and was funded by Galapagos NV.