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Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 14, 2024; 30(6): 523-526
Published online Feb 14, 2024. doi: 10.3748/wjg.v30.i6.523
Unmet needs in biomarkers for autoimmune pancreatitis diagnosis
Bao-Can Wang, Jian-Gao Fan, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
ORCID number: Bao-Can Wang (0000-0002-6288-8100); Jian-Gao Fan (0000-0001-7443-5056).
Author contributions: Fan JG conceived and outlined the manuscript; Wang BC reviewed the literature, wrote and edited the manuscript; both authors have read and approved the final version to be published.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jian-Gao Fan, MD, Professor, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China. fanjiangao@xinhuamed.com.cn
Received: December 14, 2023
Peer-review started: December 14, 2023
First decision: December 28, 2023
Revised: January 10, 2024
Accepted: January 15, 2024
Article in press: January 15, 2024
Published online: February 14, 2024

Abstract

Autoimmune pancreatitis (AIP) is a rare chronic autoimmune disorder. The diagnosis of AIP mainly depends on histopathology, imaging and response to treatment. Serum immunoglobulin 4 (IgG4) is used only as collateral evidence in diagnostic criteria for AIP because of its moderate sensitivity. Serum IgG4 levels are normal in 15%-37% of type 1 AIP and most of type 2 AIP patients. In these patients, the indeterminate imaging and histopathology may lead to the difficulty in definitive diagnosis of AIP. Therefore, discovery of new biomarkers is important for AIP diagnosis. Here, we provide some views on the progression and challenges in identifying novel serological biomarkers in AIP diagnosis.

Key Words: Autoimmune pancreatitis, Immunoglobulin G4, Biomarker, Cytokine, Autoantibody

Core Tip: Serum immunoglobulin 4 is currently the only biomarker and highly specific but moderately sensitive for diagnosis of autoimmune pancreatitis (AIP). Some cytokines and antibodies have been shown potential in AIP diagnosis.



INTRODUCTION

Autoimmune pancreatitis (AIP) is referred to as non-alcoholic destructive pancreatitis and sclerosing pancreatitis. It is a chronic pancreatitis characterized by an autoimmune inflammatory process with pancreatic swell or focal mass that responds to corticosteroid treatment. AIP was first described in 1995[1]. In 2001, elevated serum immunoglobulin 4 (IgG4) level was found as an important indicator in patients with sclerosing pancreatitis[2]. Then the International Consensus Diagnostic Criteria (ICDC) classified AIP into type 1 and type 2 in 2011[3], according to five features: Image of pancreatic parenchyma and duct, serology, other organ involvement, pancreatic histology, and response to steroid therapy. According to ICDC, more than 90% of cases are type 1 AIP, characterized by high serum IgG4 level, and IgG4-positive plasma cell infiltration in the pancreas. So, it is also known as lymphoplasmacytic sclerosing pancreatitis. Most of type 1 AIP present with the clinical signs of the systemic IgG4-related disease. Type 2 AIP is a pancreatic-specific disease, without serum IgG4 elevation, characterized by pancreatic ductal epithelium neutrophilic infiltration. So, it is also labeled as idiopathic duct-centric pancreatitis. Some of AIP patients could be diagnosed definitively, but in other patients, the clinical features including image, histopathology, IgG4 level may be not typical. Therefore, the diagnosis of AIP could not be established in all the patients using the current biomarkers[4]. New powerful biomarkers may improve the diagnosis of AIP. Some studies have shown that some cytokines and autoantibodies could be used alone or as a panel to help diagnosing AIP.

DIAGNOSTIC ROLE OF IG4 IN AIP

Many studies have shown that serum IgG4 level was elevated in AIP patients. This provides the solid data for using elevation of serum IgG4 as diagnostic biomarker for AIP in clinical practice. However, the sensitivity and specificity of IgG4 varied among these studies, which may be attributed to discrepant patient population, diagnostic criteria, race/region, and year of study before and after 2011. Among these factors, cut-off point has been studied by several researchers. In a meta-analysis of 13 studies including 594 patients, the pooled sensitivity of serum IgG4 for the diagnosis of AIP was 0.72 [95% confidence interval (CI): 0.68-0.75] when cut-off value was set at 130 to 140 mg/dL, specificity was 0.93 (95%CI: 0.92-0.95), diagnostic odds ratios was 51.37 (95%CI: 23.20-113.74), and area under the curve was 0.91 (95%CI: 0.87-0.95). When cut-off value was set at two folds of upper limit of normal level (260-280 mg/dL), the specificity increased to 0.98, while the sensitivity decreased to 43%[5]. In addition, elevated serum IgG4 level at the time of glucocorticoid cessation was an independent predictor of AIP relapse (hazard ratio: 4.511)[6]. In type 2 AIP, serum IgG4 levels are usually normal[7]. These suggested that IgG4 has poor correlation with type 2 AIP. Based on these data, serum IgG4 is a useful biomarker for diagnosing tyoe 1 AIP, but its sensitivity is not high.

In the recent issue of the World Journal of Gastroenterology, Zhou et al[8] showed that elevated serum IgG4 and IgA levels were associated with a more active immune system and higher relapse rates in AIP. Their study suggested that IgG4 could be combined with other markers to evaluate the disease activity and treatment efficacy, and monitor relapse. Even if the specificity of serum IgG4 for AIP is high, slight increase of serum IgG4 could be observed in other diseases, such as pancreatic cancer, cholangiocarcinoma, primary sclerosing cholangitis[9]. Therefore, more biomarkers are needed for AIP diagnosis. The new biomarkers may be used alone or together with IgG4.

NEW SEROLOGICAL BIOMARKERS IN AIP

Recently, great progresses have been made in understanding the abnormality of immune networks. Different types of immune cells, including dendritic cells, monocytes, T cell subgroups, B cells, were found to be involved in the pathogenesis of AIP by producing cytokines. Serum κ, λ free light chain, interleukin (IL)-5, IL-6, IL-33, soluble IL-2 receptor, interferon (IFN)-α[10-15] were significantly changed in patients with AIP. It is worth mentioning that the serum concentrations of IFN-α and IL-33 produced by dendritic cells significantly increased in the patients with active AIP, and decreased after induction of remission. The specificities of serum levels of IFN-α and IL-33 were 91.7% and 83.3%, respectively, and the sensitivity of IFN-α and IL-33 were 85.7% each. Serum levels of IFN-α and IL-33 correlated better with disease activity than that of IgG4. This study suggests that the serum concentrations of IFN-α and IL-33 have the potential to be the biomarkers for type 1 AIP diagnosis[15]. But confirmation from more studies and patients are needed.

Multiple autoantibodies secreted by plasma cells have been found in the sera of patients with AIP, such as anti-carbonic anhydrases I (anti-CA I), anti-CA II[16], anti-lactoferrin[17], antibodies against plasminogen-binding protein[18]. These studies have shown that AIP is an autoimmune-mediated disease. But the role of these autoantibodies in the diagnosis of AIP is still undetermined. Recently, three newly identified antibodies, anti-amylase α[19], anti-laminin 511[20], and anti-prohibition[21] have shown moderate to high accuracy for AIP diagnosis in some small sample studies. Annexin A11[22] and galectin-3[23] antibodies were identified specifically in the sera of patients with AIP screened by mass spectrometry.

All these findings about autoantibodies provide the possibility for identifying the new diagnostic biomarkers for AIP. However, more studies including more patients are required to verify the sensitivity and specificity of autoantibodies as useful biomarkers for AIP.

CONCLUSION

Although there are accepted diagnostic criteria for AIP, many patients cannot be diagnosed definitively because their clinical features are not typical. Histopathology is an important examination for diagnosis. Serum IgG4 is the only biomarker for AIP diagnosis in clinical practice, but it is only used collaterally because of its moderate sensitivity. Therefore, discovery of new biomarkers for AIP diagnosis is highly needed. The published literatures have shown that some cytokines and autoantibodies have the potential to be developed as diagnostic biomarker for AIP.

Since AIP is a rare disease, the number of cases in published papers is limited and almost all the studies were single-center retrospective study, a collaborative group can be set up in the future to collect more AIP cases for further research. Firstly, IgG4 may be combined with one more biomarker or as a panel, together with imaging, histopathology and therapy response, to classify AIP more precisely. Secondly, efforts should be made to find new autoantibodies with higher sensitivity and specificity for better diagnosing and monitoring AIP.

Footnotes

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: China

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Day AS, New Zealand S-Editor: Wang JJ L-Editor: A P-Editor: Yuan YY

References
1.  Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci. 1995;40:1561-1568.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1044]  [Cited by in F6Publishing: 1070]  [Article Influence: 36.9]  [Reference Citation Analysis (0)]
2.  Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa K. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732-738.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2026]  [Cited by in F6Publishing: 1799]  [Article Influence: 78.2]  [Reference Citation Analysis (0)]
3.  Shimosegawa T, Chari ST, Frulloni L, Kamisawa T, Kawa S, Mino-Kenudson M, Kim MH, Klöppel G, Lerch MM, Löhr M, Notohara K, Okazaki K, Schneider A, Zhang L; International Association of Pancreatology. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40:352-358.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1050]  [Cited by in F6Publishing: 952]  [Article Influence: 73.2]  [Reference Citation Analysis (0)]
4.  Umehara H, Okazaki K, Kawa S, Takahashi H, Goto H, Matsui S, Ishizaka N, Akamizu T, Sato Y, Kawano M; Research Program for Intractable Disease by the Ministry of Health, Labor and Welfare (MHLW) Japan. The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD. Mod Rheumatol. 2021;31:529-533.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 69]  [Cited by in F6Publishing: 159]  [Article Influence: 53.0]  [Reference Citation Analysis (0)]
5.  Lee SC, Yang CH, Chang CT, Yu KH. Diagnostic Utility of Serum IgG4 in Autoimmune Pancreatitis: An Updated Comprehensive Systematic Review and Meta-analysis. J Clin Gastroenterol. 2022;56:810-817.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 3]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
6.  Kiyoshita Y, Ishii Y, Serikawa M, Hanada K, Sasaki T, Fujimoto Y, Yamaguchi A, Hirao K, Noma B, Minami T, Okazaki A, Yukutake M, Mouri T, Tsuboi T, Tatsukawa Y, Nakamura S, Hirano T, Ikemoto J, Saeki S, Tamura Y, Miyamoto S, Furukawa M, Nakmura K, Yamashita Y, Iijima N, Oka S. Relapse rate and predictors of relapse after cessation of glucocorticoid maintenance therapy in type 1 autoimmune pancreatitis: a multicenter retrospective study. BMC Gastroenterol. 2023;23:295.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
7.  Ikeura T, Manfredi R, Zamboni G, Negrelli R, Capelli P, Amodio A, Caliò A, Colletta G, Gabbrielli A, Benini L, Okazaki K, Vantini I, Frulloni L. Application of international consensus diagnostic criteria to an Italian series of autoimmune pancreatitis. United European Gastroenterol J. 2013;1:276-284.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 38]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
8.  Zhou GZ, Zeng JQ, Wang L, Liu M, Meng K, Wang ZK, Zhang XL, Peng LH, Yan B, Pan F. Clinical characteristics and outcome of autoimmune pancreatitis based on serum immunoglobulin G4 level: A single-center, retrospective cohort study. World J Gastroenterol. 2023;29:5125-5137.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
9.  Caba O, Diéguez-Castillo C, Martínez-Galán J, González-Cebrián I, Jiménez-Luna C. Serum biomarkers for the differentiation of autoimmune pancreatitis from pancreatic ductal adenocarcinoma. World J Gastrointest Oncol. 2023;15:268-275.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
10.  Ikemune M, Uchida K, Tsukuda S, Ito T, Nakamaru K, Tomiyama T, Ikeura T, Naganuma M, Okazaki K. Serum free light chain assessment in type 1 autoimmune pancreatitis. Pancreatology. 2021;21:658-665.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
11.  Yamamoto M, Takano K, Kamekura R, Suzuki C, Ichimiya S, Himi T, Nakase H, Takahashi H. Stage classification of IgG4-related dacryoadenitis and sialadenitis by the serum cytokine environment. Mod Rheumatol. 2018;28:1004-1008.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 5]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
12.  Tsukuda S, Ikeura T, Ito T, Nakamaru K, Masuda M, Hori Y, Ikemune M, Yanagawa M, Tanaka T, Tomiyama T, Yamaguchi T, Ando Y, Uchida K, Fukui T, Nishio A, Terasawa R, Tanigawa N, Okazaki K. Clinical implications of elevated serum interleukin-6 in IgG4-related disease. PLoS One. 2020;15:e0227479.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 6]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
13.  Furukawa S, Moriyama M, Miyake K, Nakashima H, Tanaka A, Maehara T, Iizuka-Koga M, Tsuboi H, Hayashida JN, Ishiguro N, Yamauchi M, Sumida T, Nakamura S. Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease. Sci Rep. 2017;7:42413.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 71]  [Article Influence: 10.1]  [Reference Citation Analysis (0)]
14.  Matsubayashi H, Uesaka K, Kanemoto H, Asakura K, Kakushima N, Tanaka M, Kimura H, Ono H. Soluble IL-2 receptor, a new marker for autoimmune pancreatitis. Pancreas. 2012;41:493-496.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 13]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
15.  Minaga K, Watanabe T, Hara A, Kamata K, Omoto S, Nakai A, Otsuka Y, Sekai I, Yoshikawa T, Yamao K, Takenaka M, Chiba Y, Kudo M. Identification of serum IFN-α and IL-33 as novel biomarkers for type 1 autoimmune pancreatitis and IgG4-related disease. Sci Rep. 2020;10:14879.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 19]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
16.  Kino-Ohsaki J, Nishimori I, Morita M, Okazaki K, Yamamoto Y, Onishi S, Hollingsworth MA. Serum antibodies to carbonic anhydrase I and II in patients with idiopathic chronic pancreatitis and Sjögren's syndrome. Gastroenterology. 1996;110:1579-1586.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 150]  [Cited by in F6Publishing: 157]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
17.  Jin CX, Hayakawa T, Kitagawa M, Ishiguro H. Lactoferrin in chronic pancreatitis. JOP. 2009;10:237-241.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Detlefsen S, de Vos JD, Tanassi JT, Heegaard NHH, Fristrup C, Schaffalitzky de Muckadell OB. Value of anti-plasminogen binding peptide, anti-carbonic anhydrase II, immunoglobulin G4, and other serological markers for the differentiation of autoimmune pancreatitis and pancreatic cancer. Medicine (Baltimore). 2018;97:e11641.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 14]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
19.  Sánchez Castañón M, Zuliani V, Amodio A, Campagnola P, Granato A, Gabbrielli A, Benini L, López Hoyos M, Frulloni L. Role of Amylase-α2A Autoantibodies in the Diagnosis of Autoimmune Pancreatitis. Pancreas. 2015;44:1078-1082.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 7]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
20.  Shiokawa M, Kodama Y, Sekiguchi K, Kuwada T, Tomono T, Kuriyama K, Yamazaki H, Morita T, Marui S, Sogabe Y, Kakiuchi N, Matsumori T, Mima A, Nishikawa Y, Ueda T, Tsuda M, Yamauchi Y, Sakuma Y, Maruno T, Uza N, Tsuruyama T, Mimori T, Seno H, Chiba T. Laminin 511 is a target antigen in autoimmune pancreatitis. Sci Transl Med. 2018;10.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 103]  [Cited by in F6Publishing: 111]  [Article Influence: 22.2]  [Reference Citation Analysis (0)]
21.  Du H, Shi L, Chen P, Yang W, Xun Y, Yang C, Zhao L, Zhou Y, Chen G. Prohibitin Is Involved in Patients with IgG4 Related Disease. PLoS One. 2015;10:e0125331.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 45]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
22.  Hubers LM, Vos H, Schuurman AR, Erken R, Oude Elferink RP, Burgering B, van de Graaf SFJ, Beuers U. Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease. Gut. 2018;67:728-735.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 63]  [Article Influence: 10.5]  [Reference Citation Analysis (0)]
23.  Perugino CA, AlSalem SB, Mattoo H, Della-Torre E, Mahajan V, Ganesh G, Allard-Chamard H, Wallace Z, Montesi SB, Kreuzer J, Haas W, Stone JH, Pillai S. Identification of galectin-3 as an autoantigen in patients with IgG(4)-related disease. J Allergy Clin Immunol. 2019;143:736-745.e6.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 85]  [Article Influence: 14.2]  [Reference Citation Analysis (0)]