Autoimmune pancreatitis : from bench to bedside

Background: Decreased microbial diversity had been associated with the establishment of an environment in which pathogens could incite and sustain chronic inflammation. Metabolomic analysis of fecal samples provides insights into the gut microbiome's interaction with the host's metabolism. Autoimmune pancreatitis (AIP) is a complex immune-mediated form of chronic pancreatitis, comprising two distinct entitiesŃType 1 and Type 2Ńwith differing histological features, clinical presentations, and prognoses. AIP type 1 is a systemic disease, while type 2 is strongly associated with inflammatory bowel disease. Diagnosing AIP is challenging, relying on a set of criteria rather than a definitive diagnostic marker, and requires the exclusion of pancreatic cancer before proceeding. Management backbone are glucocorticoids, with excellent response. Relapses and often in type 1 AIP and different strategies for relapse treatment are possible including advanced therapies. Pancreatic exocrine and endocrine insufficiencies are consequences of inflammatory damage but are considered transient.

Aims: This thesis aims to enhance the scientific evidence surrounding the diagnosis, treatment, and follow-up of AIP patients by examining the relationship between pharmacological treatment and loss of pancreatic function in type 1 AIP, evaluating the outcomes of patients treated surgically and with advanced therapies, and investigating the association between type 2 AIP and IBD. Additionally, the thesis explores gut metabolic changes in AIP and identifies key metabolites associated with the disease.

Methods: The thesis comprises four epidemiological studies (Studies I-IV) and one metabolomic study (Study V) on AIP patients followed at Karolinska University Hospital in Stockholm, Sweden, from 2001-2022. The epidemiological studies are retrospective cohort studies based on medical records, with systematic reviews conducted in Studies II and IV. In Study V, fecal samples were collected from patients, and after obtaining informed consent, the samples underwent UHPLCĐ MS/MS analysis for metabolite identification.

Results: In Study I, prevalence of pancreatic exocrine insufficiency at diagnosis was 72.7% and 63.5% at follow-up. The cumulative incidence of diabetes mellitus was 17.9%, with a prevalence of diabetes mellitus at diagnosis of 32.8%. No strong association was found between pharmacological treatment and occurrence of pancreatic exocrine insufficiency and diabetes mellitus. In a multivariate analysis, only obstructive jaundice was identified as a risk factor for diabetes mellitus both at diagnosis and during follow-up. Study II showed that twelve (11.7%) of 103 patients with AIP type 1 were treated with rituximab during the study period: eight (66.7%) achieved complete and four (33.3%) partial remission. Rituximab was discontinued in one patient who developed fever and reactivation of latent tuberculosis. Altogether, eight studies with 110 AIP type-1 patients treated with rituximab were analyzed. Adverse effects ranged from 11Đ43% and the relapsefree period during follow-up ranged from 38Đ94%. Study III reported that 35 (22.0%) patients with AIP had surgery. Malignant and premalignant lesions were diagnosed in 8 (22.9%) patients for whom AIP was not the primary differential diagnosis, but in all cases, it was described as a simultaneous finding. One third of AIP type 1 patients experienced relapse in the follow up after surgery. Study IV revealed that diagnosis of inflammatory bowel disease was reported in 330 (47.8%) patients of our systematic review, whereas in 29/35 (83%) of AIP type 2 patients in our cohort. The relapse rate was 20.0% in both original and systematic analysis. Study V led to the discovery of newly identified metabolic signatures between both patient groups with enterolactone being prominent in AIP.

Conclusion: Prevalence of endocrine and exocrine insufficiency in AIP is high at diagnosis with an additional risk during follow-up despite pharmacological treatment. Obstructive jaundice is a risk factor for diabetes mellitus both at diagnosis and at follow up. Rituximab is effective in inducing and maintaining remission in relapsing AIP type 1. Surgical treatment is justified where cancer cannot be excluded, although relapse risk is not annihilated. Clinical and radiological remission of AIP type 2 is high, while the cumulative incidence of relapse is around 20%. Concomitance of inflammatory bowel disease imposes no obvious risk of a different disease course for AIP type 2.

List of scientific papers

I. Nikolic S, Maisonneuve P, Dahlman I, Lšhr JM, Vujasinovic M. Exocrine and Endocrine Insufficiency in Autoimmune Pancreatitis: A Matter of Treatment or Time?. J Clin Med. 2022;11(13):3724. Published 2022 Jun 28.
https://doi.org/10.3390/jcm11133724

II. Nikolic S, Panic N, Hintikka ES, et al. Efficacy and safety of rituximab in autoimmune pancreatitis type 1: our experiences and systematic review of the literature. Scand J Gastroenterol. 2021;56(11):1355-1362.
https://doi.org/10.1080/00365521.2021.1963837

III. Nikolic S, Ghorbani P, Pozzi Mucelli R, et al. Surgery in Autoimmune Pancreatitis. Dig Surg. 2022;39(1):32-41.
https://doi.org/10.1159/000521490

IV. Nikolic S, Lanzillotta M, Panic N, et al. Unraveling the relationship between autoimmune pancreatitis type 2 and inflammatory bowel disease: Results from two centers and systematic review of the literature. United European Gastroenterol J. 2022;10(5):496-506.
https://doi.org/10.1002/ueg2.12237

V. Dovhalyuk V, Yang F, Nikolic S et al. Differences in the Fecal Metabolome of Autoimmune Pancreatitis Patients. [Manuscript]