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Unraveling the relationship between autoimmune pancreatitis type 2 and inflammatory bowel disease: Results from two centers and systematic review of the literature

Abstract Introduction The relationship between autoimmune pancreatitis (AIP) type 2 and inflammatory bowel disease (IBD) has been established and previously described within International Consensus Diagnostic Criteria. However, it is unknown if the presence of IBD changes the natural disease course of AIP type 2. Our aim was to investigate the association between AIP type 2 and IBD as well as to systematically summarize all the existing evidence in the literature. Methods Electronic medical record analysis was conducted in two centers (in Stockholm, Sweden, and Milan, Italy; records dated between January 2001 and June 2021). Additionally, we conducted a systematic review of the literature. Results A total of 35 patients (18 females, 51.4%) fulfilled the diagnostic criteria of AIP type 2 and were included in the study. A diagnosis of IBD was established in 29 patients (82.8%), ulcerative colitis in 17 (58.6%) and Crohn's disease in 11 (37.9%). Median follow‐up was 54 months. AIP patients with IBD commonly presented with abdominal pain and/or acute pancreatitis at diagnosis, the latter was prevailing in concomitant and later IBD onset. These patients more frequently used steroids, but there were no differences in relapse rates. Concomitant onset of IBD was associated with the development of diabetes mellitus. There were no cases of colon or pancreatic malignancy during follow‐up. In our systematic analysis, a total of 693 AIP type 2 patients were included from 24 single‐center retrospective studies and 8 multicenter retrospective studies. A diagnosis of IBD was reported in 330 (47.8%) patients. Relapse rate was 20.0%. Conclusions Clinical and radiological remission of AIP type 2 was high, while the cumulative incidence of relapse is around 20%. Our results show that concomitance of IBD imposes no obvious risk of a different disease course for AIP type 2.


INTRODUCTION
Autoimmune pancreatitis (AIP) is a unique form of pancreatic inflammation that often causes chronic pancreatitis with consequent pancreatic exocrine insufficiency (PEI) and endocrine insufficiency. 1,2 To date, histopathological observations have identified two AIP subtypes: lymphoplasmacytic sclerosing pancreatitis, also called AIP type 1, and idiopathic duct-centric chronic pancreatitis, or AIP type 2. 3 The former belongs to the IgG4-related disease spectrum, being its most prevalent manifestation in the digestive system, characterized by fibrotic lesions rich in IgG4 + plasma cells. 2,4 Hence, multiple other organ involvement (OOI), positive IgG4 serology in the majority of patients and a significant relapse rate after treatment are typical AIP type 1 features. 4 In contrast, AIP type 2 is less frequent, unrelated to IgG4 and associated with a lower risk of relapse after treatment. 5,6 Involvement of organs typically described in type I AIP is not observed in AIP type 2, where inflammatory bowel diseases (IBD) are more commonly described 5 and acknowledged within the International Consensus Diagnostic Criteria (ICDC). Indeed, the presence of IBD in patients with imaging evidence for AIP suggests a probable AIP type 2 diagnosis. 3 Definite AIP type 2 diagnosis still requires either histologically confirmed idiopathic duct-centric pancreatitis or the presence of IBD and positive glucocorticoid (GC) trial. 3 Overlooking a diagnosis of IBD in the setting of AIP-type-2associated pancreatic exocrine insufficiency may not be infrequent as both diseases can present with diarrhea and abdominal discomfort. 7 Moreover, there is a certain amount of similarity and overlap between both initial IBD and AIP treatment (GC, azathioprine), 2,8,9 so the choice of AIP treatment might be influenced by the synchronous IBD, and vice versa. More importantly, IBD concurrent with AIP might hypothetically lead to a broadening of the available treatment options since a recent report described the successful use of tumor necrosis factor (TNF) inhibitors in AIP type 2 patients with and without concomitant IBD. 10 While the prevalence of IBD in different types of pancreatitis [11][12][13] and the influence of AIP on the natural disease course of IBD 14

Inclusion and exclusion criteria
The patient selection process is outlined in Figure 1. All patients with a definite or probable diagnosis of AIP type 2 according to ICDC were included in the study. 3 Patients diagnosed before publication of the ICDC (2011) were retrospectively reviewed by two senior pancreatologists per center to ensure a correct diagnosis when the diagnosis was not based on histology. Patients with AIP type 1 and AIP not otherwise specified (NOS) were excluded. Follow-up was defined as the time from the AIP diagnosis until the last contact with the patient. Patients followed for less than 6 months were excluded from the long-term outcomes analysis.

Definition of exposure and outcomes
Exposure was defined as the diagnosis of IBD according to the European Crohn's and Colitis Organization (ECCO) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR) joint collaborative guidelines. 15 Exposure was classified in a sub-analysis according to IBD onset in relation to AIP. IBD in relation to the date of AIP diagnosis was subclassified as: before AIP diagnosis

Statistical analysis
Data is expressed as median and interquartile range (IQR) for numerical data, or percentages for categorical data. The comparison of data was undertaken using appropriate non-parametric statistical tests, for categorical data the chi-square or Fisher's exact test, for numerical data the Mann-Whitney U test or Kruskal-Wallis test.
Univariable and multivariable analyses were performed to identify possible predictors for relapse, based on a Cox-proportional hazards regression model. Hazard ratios (HR) were expressed with 95% confidence intervals (CI 95%). The analysis was performed using IBM SPSS Statistics 28. A p-value <0.05 (two-sided) was considered statistically significant.  Table S1 and search strategy in Table S2. Eligibility assessment was performed by screening the titles and, subsequently, the abstracts and full articles.
This was undertaken by three independent reviewers (SN, ML, NP).
All disagreements were resolved by MV and JML. Review articles, editorials, conference reports, comments on other studies, animal studies, non-English-language articles, book sections and theses, overlapping articles and articles that did not contain individual data on the prevalence of IBD in patients with AIP type 2 were excluded.
When the results of a single study were reported in more than one publication, only the most recent or complete data was included in the analysis. Using a "snowball method", additional articles were identified by hand-searching the reference lists of all the articles retrieved to identify potentially relevant studies. The same above-mentioned inclusion criteria were then applied. Studies in which a distinction between AIP type 1 and type 2 was not made were excluded. The proportions of patients having IBD subtypes, definite AIP diagnosis and certain treatment options were calculated by referring to the total number of patients in the respective study. The quality of the studies was assessed according to a checklist based on a modified version of the Newcastle-Ottawa quality assessment scale, with a score ranging 0-9. The selection process of articles for the review is summarized in Figure 2.

Study selection
Our primary search identified 260 titles. After the removal of duplicate articles, 178 studies remained. We excluded 103 articles because they were not consistent with our inclusion criteria. Finally, 75 studies were included in a qualitative synthesis and the full text of each one was reviewed to establish eligibility for quantitative analysis. After reviewing these articles, 43 more were excluded due to insufficient data related to IBD or AIP subtype. Thirty-two studies fulfilled the inclusion criteria and were selected for the systematic review ( Figure 2). The characteristics and key findings of the included studies are reported in the (Table S4).

DISCUSSION
AIP type 2 is a specific entity within the pancreatic diseases spectrum. 34 In this work, we aimed to examine the salient features in AIP type 2 patients from a large dual-center cohort, with a special focus on the relationship with IBD occurrence. The existing evidence in the literature on this subject was also systematically evaluated.
The prevalence of IBD in our study was 82.8%, whereas the systematic review analysis reveals a prevalence of 47.8%.
AIP patients with IBD were more likely to have acute pancreatitis (not statistically significant) and abdominal pain at presentation.
The prevalence of acute pancreatitis in our cohort was similar to that identified from the systematic review of the literature, 45.2% versus 45.7%. 10,21,22,24,25,[27][28][29]48 Hart et al. 24 observed a higher prevalence of acute pancreatitis in patients with concurrent IBD, which was also the case in our cohort (Table 1), but the difference was not statistically significant in our study. Moreover, AIP patients with either IBDc or IBDa were more likely to present with acute pancreatitis (Table 2).
Interestingly, IBDa patients complained about weight loss significantly more often than those in the IBDc or IBDb groups. Thus, it may be important to consider the concomitant presence of IBD and AIP in patients with non-typical clinical course.
In contrast to the findings of the systematic review, in our study GC treatment was the most prevalent therapy choice (74.3% vs. 29.2%), in comparison to surgery (20% vs. 28.8%) and watchful waiting (11.4% vs. 15.5%). 1,13,14,[18][19][20]22,23,25,27,28,[30][31][32][33]40,42 This observation is probably due to the generally higher proportion of IBD in our cohort. Consequently, surgery was significantly more prevalent as a treatment method in AIP type 2 patients without IBD, while steroids were used in AIP type 2 patients with IBD. We noted a trend towards a significant association between the onset of IBD and GC treatment for AIP in the IBDc and IBDa groups. The use of AZA is commonly considered in the setting of both AIP and IBD-related maintenance therapy. Yet, the risk of AZA-induced acute pancreatitis is significant, occurring in up to 7% of AZA-exposed patients. 49 Biologic drugs, including TNF inhibitors, form a central part of the IBD armamentarium. Recently, Lorenzo et al. 10  We observed a significantly higher prevalence of PEI at diagnosis in IBDc patients. 55 At last contact with patients, that difference was no longer significant due to PEI recovery in 3 patients.
This might be explained by the dilution effect of diarrhea on fecal elastase-1 (FE1) concentration that is, falsely low FE1 values. 56 Interestingly, the opposite was observed in DM prevalence-it was significantly higher at the last contact. We believe that it is crucial to regard IBD as a reason for malabsorption syndrome and diarrhea in AIP patients, and especially vice versa. The risk of cancer seems to be low, as we detected no pancreatic or colon cancer during follow-up.
Our work does not come without limitations. Besides the obvioussmall sample size due to AIP type 2 being an orphan disease-the retrospective nature of the study might have affected data retrieval. Despite these limitations, our work is based on the cohorts of two centers highly skilled in the management of pancreatic diseases.
According to the systematic review we performed, this is the first paper exploring the influence of IBD on AIP-related outcomes.
In conclusion, there was no obvious association between IBD and relapse or remission in AIP type 2. The prevalence of both clinical and radiological remission was very high, while the cumulative incidence of relapse was around 20%. Remarkably, IBD represents a common bystander that should be actively investigated and managed in a multidisciplinary approach. However, IBD does not seem to be a risk factor for a more aggressive AIP type 2 natural course. Potentially common pathogenetic pathways and effective treatment strategies for both diseases should be explored in further studies.