**2. Definition, classification, and histology**

The concept of autoimmune pancreatitis was introduced by Yoshida in 1995 [9] and accepted worldwide. The majority of cases initially described came from Asia, but later on the disease was recognized in the whole world. With the exponentially growing information, two different forms were distinguished: the type 1 or lymphoplasmacytic sclerosing pancreatitis (LPSP) and the type 2 or idiopathic duct-centric pancreatitis. Type 1 has been dominant in the whole world and represents the most frequent digestive manifestation of a systemic fibroinflammatory IgG4-related disease. Its histology is characteristic: the association of storiform fibrosis, obliterative phlebitis, and marked lymphoplasmacytic infiltration are unique, and the immunohistology can be the final proof, demonstrating the presence of more than 40% of IgG4-positive lymphocytes as compared to the whole number of IgG-positive cells. Details of the autoimmune reaction are well described, but the whole process is not known. Circulating plasmablasts are present in increased number in the active phase of the disease and decrease rapidly with the treatment [11]. Interaction of T- and B lymphocytes has been demonstrated. Th2 reaction and regulator T-cell activation are part of the process, resulting from one part in an increase of interleukins 4, 5, and 13 with a consecutive increase of eosinophils and serum IgE and from the other part increased IL-10 production, lymphoplasmacytes, and fibroblast proliferation, with an increased IgG4 level. As these diseases are recognized as IgG4-related, one could expect IgG4 lymphoplasmacytes as key factors inducing the immune reaction and organ damage. However, the characteristics of the IgG4 subclass do not permit complement activation or immune complex formation. Both IgG4 and IgG1 obtained from an active AIP patient, when injected separately, induced pancreatic damage in experimental design. However, when injected simultaneously, IgG4 was rather protective and reduced the IgG1-induced pancreatic damage [12]. Based on these experimental data, IgG1 subclass seems to be more active in producing damage, and the local increase of IgG4 cells and elevated serum IgG4 level seems to be rather a consequence. In type 2, AIP has a clearly different histology. The fibrosis is important, but not storiform, phlebitis/venulitis is rare, and if present, it is not obliterative. The essential finding is infiltration by neutrophil leucocytes, forming the typical granulocytic epithelial lesion (GEL), with duct cell damage. Similar lesions can also be observed in pancreatic lobules. While lymphoplasmacytic infiltration can exist, IgG4-positive cells are rare. A unique finding in type 2. AIP is the presence of IL-8 around the ductal cells, in particular in the damaged pancreatic ducts. IL-8 is a chemotactic factor for neutrophils, and its high expression is in line with the formation of granulocytic epithelial lesions [13]. In addition, similar accumulation of IL-8 was described in the damaged mucosa of ulcerative colitis but not in other types of colitis. This finding points out a similarity in pathomechanism of these diseases as a possible explanation of the well-known association.

#### **2.1 Autoantibodies: serology**

Several autoantibodies were described in AIP, against carbonic anhydrase [14] and amylase [15], but they do not have any demonstrated role in the initiation of the autoimmune process. A cross-reaction was found against a protein of *Helicobacter*, the plasminogen-binding protein [16], but its role in the pathogenesis of AIP was not confirmed. Unspecific autoantibodies, as antinuclear and anti-DNA, can also be present. A variety of autoantibodies have been found in the sera of patients with AIP, but none of these autoantibodies appear to be disease specific. The serum IgG4 level has been found elevated in a variable proportion of confirmed type 1 AIP cases. Sensitivity above 80% was published in some papers, while others found only

**95**

**4. Diagnosis**

**Table 1.**

**4.1 Clinical symptoms**

*Autoimmune Pancreatitis: Clinical Presentation and Therapy*

our clinical practice, even considering a lower cutoff value.

**3. Epidemiology and clinical characteristics**

<50% [17]. On the contrary, IgG4 can be elevated even in some cases of pancreatic cancer. Once increased, the serum IgG4 level is a useful marker in confirming the diagnosis of AIP type 1, but a normal value does not exclude AIP. Unfortunately, no specific test exists even for the diagnosis of AIP type 1, and type 2 is not accompanied by laboratory alterations. In our experience [18], we found IgG4 > 135 mg% in 80% of confirmed AIP type 1 cases but in none of 20 NOS undetermined cases, while several of these patients, if not the majority of them, were probably seronegative type 1. It means that the real diagnostic performance was far less than 80% in

AIP is increasingly recognized. For example, 900 cases were known in Japan in 2002 [19]; 2790 in 2007 [20]; and 5745 in 2011 [21]. The calculated prevalence was 4.6/100,000, while the incidence 1.4/100,000/yr. Experiences from different regions of the world have been increasingly published; the annual number of papers increased exponentially from 39 in 2000 to 935 in 2017, as found in PubMed Central. We also observed a marked increase in the diagnosis of AIP in Chile [18]. However, the worldwide increase in the frequency of this disease is probably mainly due to its better recognition rather than a-so-important increase in incidence. The more frequent type 1 AIP is part of a systemic IgG4- related disease. A male dominance has been observed; about two thirds of patients are men. The average age is above 50 years. However, there are also women in considerable number. The pancreatic affection is frequently associated with manifestation of the same disease in other organs. Recurrence in the pancreas or in other organs is relatively frequent in this form. Type 2 AIP has been described later, but it is also recognized with a growing frequency. No gender difference was described, and the disease affects young people; the mean age is no more than 30 years. The only associated disease is inflammatory bowel disease (IBD), mainly ulcerative colitis, which can occur simultaneously with the pancreatitis or any other period, before or after the AIP. This form of pancreatitis seldom recurs (**Table 1**)

**Type 1 (LPSP) Type 2 (IDCP)**

Sex Male dominance (two to three times) No difference Age After fifth decade Young people, <30 Dominant symptom Jaundice Pain, mild pancreatitis

Response to steroids Quick, complete Quick, complete Relapse >30% Rare, <10% *LPSP, lymphoplasmacytic sclerosing pancreatitis; IDCP, idiopathic duct-centric pancreatitis.*

Associated diseases IgG4-related organ involvement Inflammatory bowel disease

Serum IgG4 level Frequently increased (50–80%) Normal

*Clinical characteristics of two types of autoimmune pancreatitis.*

The clinical manifestation of AIP is variable and non-specific. The most frequent symptom is painless jaundice due to compression of intrapancreatic

*DOI: http://dx.doi.org/10.5772/intechopen.83349*

*Autoimmune Pancreatitis: Clinical Presentation and Therapy DOI: http://dx.doi.org/10.5772/intechopen.83349*

*Chronic Autoimmune Epithelitis - Sjogren's Syndrome and Other Autoimmune Diseases...*

of these diseases as a possible explanation of the well-known association.

Several autoantibodies were described in AIP, against carbonic anhydrase [14] and amylase [15], but they do not have any demonstrated role in the initiation of the autoimmune process. A cross-reaction was found against a protein of *Helicobacter*, the plasminogen-binding protein [16], but its role in the pathogenesis of AIP was not confirmed. Unspecific autoantibodies, as antinuclear and anti-DNA, can also be present. A variety of autoantibodies have been found in the sera of patients with AIP, but none of these autoantibodies appear to be disease specific. The serum IgG4 level has been found elevated in a variable proportion of confirmed type 1 AIP cases. Sensitivity above 80% was published in some papers, while others found only

The concept of autoimmune pancreatitis was introduced by Yoshida in 1995 [9] and accepted worldwide. The majority of cases initially described came from Asia, but later on the disease was recognized in the whole world. With the exponentially growing information, two different forms were distinguished: the type 1 or lymphoplasmacytic sclerosing pancreatitis (LPSP) and the type 2 or idiopathic duct-centric pancreatitis. Type 1 has been dominant in the whole world and represents the most frequent digestive manifestation of a systemic fibroinflammatory IgG4-related disease. Its histology is characteristic: the association of storiform fibrosis, obliterative phlebitis, and marked lymphoplasmacytic infiltration are unique, and the immunohistology can be the final proof, demonstrating the presence of more than 40% of IgG4-positive lymphocytes as compared to the whole number of IgG-positive cells. Details of the autoimmune reaction are well described, but the whole process is not known. Circulating plasmablasts are present in increased number in the active phase of the disease and decrease rapidly with the treatment [11]. Interaction of T- and B lymphocytes has been demonstrated. Th2 reaction and regulator T-cell activation are part of the process, resulting from one part in an increase of interleukins 4, 5, and 13 with a consecutive increase of eosinophils and serum IgE and from the other part increased IL-10 production, lymphoplasmacytes, and fibroblast proliferation, with an increased IgG4 level. As these diseases are recognized as IgG4-related, one could expect IgG4 lymphoplasmacytes as key factors inducing the immune reaction and organ damage. However, the characteristics of the IgG4 subclass do not permit complement activation or immune complex formation. Both IgG4 and IgG1 obtained from an active AIP patient, when injected separately, induced pancreatic damage in experimental design. However, when injected simultaneously, IgG4 was rather protective and reduced the IgG1-induced pancreatic damage [12]. Based on these experimental data, IgG1 subclass seems to be more active in producing damage, and the local increase of IgG4 cells and elevated serum IgG4 level seems to be rather a consequence. In type 2, AIP has a clearly different histology. The fibrosis is important, but not storiform, phlebitis/venulitis is rare, and if present, it is not obliterative. The essential finding is infiltration by neutrophil leucocytes, forming the typical granulocytic epithelial lesion (GEL), with duct cell damage. Similar lesions can also be observed in pancreatic lobules. While lymphoplasmacytic infiltration can exist, IgG4-positive cells are rare. A unique finding in type 2. AIP is the presence of IL-8 around the ductal cells, in particular in the damaged pancreatic ducts. IL-8 is a chemotactic factor for neutrophils, and its high expression is in line with the formation of granulocytic epithelial lesions [13]. In addition, similar accumulation of IL-8 was described in the damaged mucosa of ulcerative colitis but not in other types of colitis. This finding points out a similarity in pathomechanism

**2. Definition, classification, and histology**

**94**

**2.1 Autoantibodies: serology**

<50% [17]. On the contrary, IgG4 can be elevated even in some cases of pancreatic cancer. Once increased, the serum IgG4 level is a useful marker in confirming the diagnosis of AIP type 1, but a normal value does not exclude AIP. Unfortunately, no specific test exists even for the diagnosis of AIP type 1, and type 2 is not accompanied by laboratory alterations. In our experience [18], we found IgG4 > 135 mg% in 80% of confirmed AIP type 1 cases but in none of 20 NOS undetermined cases, while several of these patients, if not the majority of them, were probably seronegative type 1. It means that the real diagnostic performance was far less than 80% in our clinical practice, even considering a lower cutoff value.
