CLINICAL REVIEW

IgG4 related Pancreatic & Biliary diseases

Hisham AL-Dhahab, MB , MRCP, FRCPC Julia Mc-Nabb Baltar, MD , FRCPC Said AL-Busafi, MD, FRCPC Alan Barkun, MDCM, MSc, FRCPC Division of Gastroenterology, McGill University and the McGill University Health Centre, Montreal, Quebec, Canada

Purpose of review Summarize important clinical aspects of IgG4 related pancreatic and biliary diseases and to review the role of IgG4 in the diagnosis of autoimmune pancreatitis and autoimmune cholangitis. Method A narrative review was carried out using PUBMED, and the following keywords were used, IgG4, IgG4 related disease, autoimmune pancreatitis, sclerosing cholangitis and autoimmune cholangitis. A total of 955 articles were retrieved, of these, 381 articles/studies contained the relevant data regarding IgG4 molecule, pathogenesis of IgG related diseases, and diagnosis, management and long term follow up for patients with autoimmune pancreatitis and autoimmune cholangitis, of the 381 articles, 66 articles were used as the main source for the review article. Abstract Autoimmune pancreatitis and autoimmune cholangitis are new clinical entities that are showing up in the horizon, and are now recognized as the pancreatico-biliary manifestations of IgG4 related diseases. The clinical importance of both diseases relies on the fact that both diseases resemble pancreatic cancer and cholangiocarcinoma closely, and since the approach to management differ in each case, it is important to review the role of IgG4 and other diagnostic modalities that aid in the diagnosis of IgG4 pancreatico-biliary diseases. IgG4 alone cant be used alone to diagnose these IgG4 related diseases, however they are useful in adjunction to other radiological and

histological features. Both diseases respond to steroids, however relapse is common, and thus long term maintenance treatment with steroids is often required. Introduction IgG4 Related Diseases (IgG4-RD) is a new clinical entity that has unique clinical, serological, radiological and pathological features with multi organ involvement. A variety of names have been suggested to describe IgG4-RD, and many different nomenclature have been used in the medical literature, IgG4-related disease , IgG4-related systemic disease , IgG4-related sclerosing disease, IgG-related systemic sclerosing disease , IgG4 syndrome and IgG4-related autoimmune disease describe the same unique condition.

Elevated concentrations of IgG4 in serum and tissue are helpful in diagnosing IgG4-RD, but neither one is a specific diagnostic marker. It is important to in cooperate the serological and tissue elevation of IgG4 with the pathological findings. Misdiagnoses of IgG4-related disease are increasingly common because of overreliance on moderate elevations of serum IgG4 concentration and the finding of IgG4-positive plasma cells in tissue [1].

The hallmark pathological features of IgG4 related diseases are a dense lymphoplasmacytic infiltrates, presence of abundant IgG4-positive plasma cells, extensive fibrosis and obliterative fibrosis. Tumorous swelling, and eosinophilia are other frequently observed features [2]. The term lymphoplasmacytic sclerosing pancreatitis (LPSP), includes the set of the first four features. [3]

Autoimmune pancreatitis and autoimmune cholangiopathy are the pancreatico-biliary manifestations of IgG4-RD, however, multiple organs can be involved in IgG4 RD, they are listed in table 1.

Table 1 : IgG4 related diseases

Organ/System Disease

Lacrimal and salivary glands Mikulicz’s disease

Kuttner’s tumour

Dacroadenitis

Lungs IgG4 pulmonary diseases

Pancreatic/biliary Autoimmune pancreatitis and autoimmune cholangiopathy

Endocrine Autoimmune hypophysitis

Reidel’s fibrosis

Diabetes Mellitus

Nervous Cranial pachymeningitis

Kidneys IgG4 related nephropathy Tubulointerstitial nephropathy Retroperitoneal fibrosis

prostitis

Lymphatic/vascular IgG4 related lymphadenopathy Castleman’s disease

Aortitis

Table 1, modified from IgG related diseases. [2, 4]

IgG4-RD can mimic various diseases, for eg autoimmune pancreatitis can be often be mistaken for pancreatic cancer, and thus it is crucial to establish the correct diagnosis since treatment is different and IgG4 related diseases are often responsive to steroids. This is

leading to a change in the practice of bilio-pancreatic specialists, and therefore warrants a timely review. Our focus on this review will be on the clinical presentation, diagnosis and overall management of autoimmune pancreatitis and autoimmune cholangitis.

The IgG4 Molecule

Immunoglobulin G4 (IgG4) is the least common of the 4 subclasses of IgG, it constitutes only 3% to 6% of the entire IgG fraction. It is present at mean concentrations of 0.35 – 0.51 mg/ml. Unlike the other IgG subclasses, the concentration of IgG4 varies greatly among healthy people. IgG4 levels generally range from less than 10 mcg/ml to 1.4 mg/ml, with levels over 2 mg/ml noted in a few individuals, and levels generally higher in men and older individuals.[5]

IgG4 seems to play a significant role in atopic reactions, such as eczema, bronchial asthma, and bullous skin lesions. IgG4 is also a protective blocking antibody in allergen-induced IgE-mediated reactions seen in parasitic infestation. [6]

IgG4, in contrast to the other IgG subclasses, does not activate complement and has a low affinity for target antigens. IgG4 activation is driven by T-helper cell 2 cytokines.

The pathophysiology of IgG4 related diseases are not typical for autoimmune disorders like rheumatoid arthritis, but rather IgG4 antibodies undergo ‘half-antibody exchange’, also referred to as fragment antigen-binding (Fab)–arm exchange. The disulfide bonds between the heavy chains of the IgG4 molecule are unstable, dissociations of the noncovalent bonds permit the chains to separate and recombine randomly, such that asymmetric antibodies with two different antigen-combining sites are formed. The resulting bispecific (functionally monovalent) IgG4 molecules are unable to cross- link antigens, thereby losing the ability to form immune complexes seen in classical autoimmune diseases.[1]

The driving force behind IgG4 production is not fully understood, especially that most cytokines found to be involved in promoting or enhancing IgG4 production have similar effects on IgE production. It

is unclear whether IgG4 directly mediates the disease process in IgG4-RD or reflects a protective response induced by anti-inflammatory cytokine.[3] There is limited evidence that Helicobacter pylori may be the inciting antigen behind IgG mediation.[7, 8]

These mechanisms may underlie many of the clinical presentations of IgG4 related diseases of which we will discuss in turn, autoimmune pancreatitis and autoimmune cholangitis.

Autoimmune Pancreatitis

Autoimmune pancreatitis [AIP], even though a rare disease, has recently gained a lot of attention due to its distinctive clinical and pathological features, which may mimic pancreatic cancer. There are two types of autoimmune pancreatidites: type 1 AIP, more common and associated with multi-system organ IgG4 diseases, and type 2 AIP, which tends be pancreatic specific.

1- Classification of autoimmune pancreatitis and

general presentations:

a- Type 1 AIP : Type 1 AIP is the most common subtype, especially in Japan and Korea. It affects elderly patients, usually in the seventh decade, and is also known as lymphoplasmacytic sclerosing pancreatitis due to its rich IgG4 plasma cell and lymphocytic infilteration of the pancreas and other organs. This is the only AIP form that is associated with extra pancreatic involvement which can be found in 60% of patients, indeed AIP type 1 is the pancreatic manifestation of a more generalized IgG4 related disease. Serum IgG4 elevations are seen in 80% of patients with type 1 AIP. This subtype responds to steroids, however, clinical recurrence is common.[9, 10] b-Type 2 AIP : Type 2 AIP is more common in younger patients, and 16% will have underlying inflammatory bowel disease.[11] Contrarily to Type 1, Type 2 AIP requires histological diagnosis since clinical, serological and imaging findings alone are not sufficient for diagnosis. Associated serum IgG4 elevations are uncommon, and there are no

extra pancreatic manifestations. This subtype is also steroid responsive and clinical recurrence is very rare. This type of AIP is under diagnosed because of the need for histological confirmation. Table 2 : Comparison between type 1 and type 2 Autoimmune pancreatitis Feature Type 1 AIP Type 2 AIP

Age Elderly Young

Clinical presentation

Painless jaundice Obstructive jaundice +/- acute pancreatitis

Histology 1-Periductal lymphoplasmacytic infiltrate

2- storiform fibrosis

3-obliterative phlebitis

Characteristic granulocytic epithelial lesion

Serum IgG Elevated (80% cases)

normal

IgG4 related diseases

Yes No

Association with IBD

Rare Yes 16%

Response to steriods

Yes Yes

Relapse Common Rare

Modified from table 1, differences between type 1 AIP and type 2 AIP [9] 2- Clinical presentation of autoimmune

pancreatitis :

The true incidence of AIP is unknown. The best estimates so far come from studies of patients who were presumed to have pancreatic cancer and underwent resection, but the resection specimen showed AIP. AIP was the diagnosis in approximately 3% to 5% of such patients.[12] AIP presents with painless obstructive jaundice ,75% in type 1 AIP and 50% in type 2 AIP , often associated with anorexia and weight loss, similar to pancreatic adenocarcinoma involving the pancreatic head, and this is one of the main reasons why often autoimmune pancreatitis is mistaken as pancreatic cancer. [13, 14] Acute attacks of pancreatitis are rare presentations of autoimmune pancreatitis. Chronic abdominal pain with narcotic dependency is not a feature of AIP, however a proportion of patients can develop chronic pancreatitis AIP accounted for 4-6% of all chronic pancreatitis.[15] Diabetes mellitus and exocrine insufficiency can precede the diagnosis of AIP, or may herald the onset of AIP, or may develop as consequence of steroid therapy during the maintenance phase of AIP treatment , or interestingly may resolve after steroid treatment.[16] Patients may present with signs and symptoms reflecting other organ involvement or other autoimmune disorders, such as sjogrens syndrome, SLE and PBC.[17]

3- Diagnosis: A constellation of serological, radiological, pathological, and evidence of other organ involvement, in the case of type 1 AIP, is required for diagnosis. These various clinical parameters were incorporated into a number of diagnostic criteria. a-Role of IgG4: Elevated IgG4 levels have been observed in atopic disorders, parasitic infections, skin bullous disorders, and rarely in autoimmune disorders such as rheumatoid arthritis, primary biliary cirrhosis and Sjögren’s syndrome. About 5% of normal population and 10% of pancreatic cancer patients have serum IgG4 elevations (>140 mg/dl). [18] Therefore serum IgG4 alone cannot be used as a sole marker to differentiate between autoimmune pancreatitis and pancreatic adenocarcinoma; indeed since autoimmune pancreatitis is rare, an elevated serum IgG4 in patient with a low pretest probability of having AIP reflects a false positive result.[19] Both serum IgG4 and

total IgG were studied in the diagnosis of AIP. Compared with IgG4 alone, the combined measurements of serum IgG4 and total IgG may increase the sensitivity for diagnosing AIP. A prospective study examined combined IgG4 and total IgG in 82 patients. The sensitivity of combined measurements of total IgG and IgG4 for AIP was 68.3% significantly higher than that of IgG4 alone, 52.5% . The specificity of combined measurement of total IgG and IgG4 was 95.5%, and it was not significantly different from that of IgG4 alone ,99.1%.[20] Hamano and his colleagues found that serum IgG4 was elevated significantly in autoimmune pancreatitis but not in ordinary chronic pancreatitis or other autoimmune disorders. They used a cutoff value for serum IgG4 concentrations of 135 mg /dl which resulted in high rates of diagnostic accuracy (97 percent), sensitivity (95 percent), and specificity (97 percent) in the differentiation of autoimmune pancreatitis from pancreatic cancer. Total serum IgG was also slightly elevated in autoimmune pancreatitis. Serum IgG, serum IgG4, and the IgG4/IgG ratio decreased significantly in 12 of 20 patients with autoimmune pancreatitis following a four week course therapy of steroids, in addition to improvements in symptomatology and imaging findings.[21] These findings suggest that IgG is a direct response to the presence of an antigen implicating that AIP is a closely related autoimmune disorder, however given the small power in this study, insufficient conclusions can be drawn as to whether or not IgG can be used to monitor response to steroid therapy. A systematic review and meta-analysis conducted by Morsolli et al. showed that serum IgG4 was a good marker to distinguish AP from pancreatic cancer and other autoimmune diseases. However, pooling the results together showed heterogeneous specificities, sensitivities and odd ratios, probably due to the different diagnostic criteria used to define AIP. The role of IgG4 in monitoring response to treatment after four weeks of steroid therapy, was also examined in these studies, and it seems to be efficacious in patients with high levels of IgG4 pre-treatment.[22]

20% of patients with AIP exhibit low levels of serum IgG4, an entity known as serum negative IgG4 autoimmune pancreatitis, probably representing the type 2 AIP. This group was also responsive to treatment, and less likely to relapse. This was more common in : females, patients presenting with acute pancreatitis , segmental pancreatic body and/or tail swelling, and lack of extra pancreatic

organ involvement.[23]

Other autoantibodies have been examined in patients with AIP, but none have been found to be specific. Antibodies to Carbonic Anhydrase and Lactoferrin are most frequently detected in AIP (54% and 73%, resp.) [24] Serum ANA and RF add no additional discriminatory value.[20]

b-Imaging : A pancreas protocol abdominal CT is rapidly becoming the imaging modality of choice to diagnose AIP. Imaging findings that are diagnostic or highly suggestive of AIP include a diffusely enlarged pancreas with featureless borders and delayed enhancement with or without a capsule-like rim. [25] In contrast, findings that are highly suggestive, or diagnostic, of pancreatic cancer include a low density mass, dilatation and/or cutoff of the pancreatic duct, and distal pancreatic atrophy. MRI imaging reveals focal or diffuse pancreatic enlargement that is hypo-intense in T1-weighted MRI images and slightly hyper-intense in T2-weighted images. As with CT, a capsule-like hypo-intense rim can be observed in T2-weighted MRI images. MRCP can show multiple intrahepatic strictures and strictures of CBD. [26]

c-Endoscopy in AIP : An international multicenter study has identified 4 specific endoscopic retrograde cholangiopancreatography (ERCP) features of AIP that are useful to distinguish between AIP and pancreatic cancer: (1) a long (>1/3 the length of the pancreatic duct) stricture, (2) lack of upstream dilatation from the stricture (<5 mm), (3) multiple strictures, and (4) side branches arising from the stricture site. [27] ERCP is generally recommended when CT scan /MRI pancreas findings are atypical for AIP. In addition to biliary stenting to relieve biliary obstruction and cytology brushings from biliary strictures, obtaining ampullary biopsies can be useful in diagnosing AIP. Kamisawa et al, first reported that ampullary biopsies demonstrating IgG4 positive infiltration, defined as more than ten cells per high power fieldIgG4 cells per high power field with positive IgG4 staining was sensitive and specific for AIP. ( 52% to 80% and 89% to 100%, respectively). [28]

Endoscopic ultrasound (EUS) examination and EUS-fine needle aspiration is highly recommended because it has excellent negative

predictive value and can detect a small pancreatic mass not visible on a CT scan. It is also the most reliable tool for excluding pancreatic cancer while avoiding pancreatic resection. There are no pathognomonic EUS findings of AIP, plus these findings can be seen in a variety of pancreatic disorders, hence EUS alone can not be used as the sole diagnostic modality. The EUS features of AIP include a diffusely hypoechoic pancreatic swelling and/or a focal hypoechoic swelling in the head of the pancreas with associated pancreatic duct narrowing. [29] Another finding suggestive of AIP is common bile duct dilatation with a thickened wall. The thickening of the bile duct wall in AIP shows some unique features: it is homogeneous, with an echo-poor intermediate layer and hyper-echoic outer and inner layers called “sandwich-pattern” wall. The wall may reach 5 millimeters in thickness. [30]

Other EUS parenchymal and ductal changes were described in AIP and include: hyperechoic foci, hyperechoic strands , lobularity, cysts, and shadowing calcifications. The ductal features, includes dilation, irregularity, or hyperechoic duct margins, and visible side branches are EUS features seen in chronic pancreatitis in general. Portal vein or superior mesenteric involvement should not preclude the diagnosis of AIP. Although EUS-FNA is sufficient for diagnosing pancreatic cancer, EUS-Tru cut biopsy (EUS-TCB) is essential for the histologic diagnosis of AIP, especially type 2 AIP where histological diagnosis is crucial. However EUS-TCB may not be available due to the lack of expertise.

d-Histopathological features : Although histopathological features are considered the gold standard for the diagnosis of AIP, there is a lack of consensus regarding the histopathological diagnostic criteria for this disease. The inflammatory response is usually focal to the head of the pancreases, and diffuse involvement has been described, but is rare. The reasons behind this focal distribution in AIP are still unclear. In addition AIP, differs from the other forms of pancreatitis such as alcoholic and hereditary pancreatitis, in the lack of pseudocyst formation. Intraductal calcifications are absent, and if they occur they tend to develop later in the advanced stages. The pathological features of both AIP types, include : periductal lymphoplasmacytic infiltrate and inflammatory cellular stroma. It is the intense lymphoplasmacytic infilteration around the ducts that lead to

narrowing of the pancreatic duct as well as the bile ducts. In the advanced stages extensive lobular fibrosis and vein occlusion by the lymphocytic infiltration leads to storiform fibrosis, obliterative phlebitis which are the distinguishing features of type 1 AIP. Granulocytic epithelial lesions are pathognomonic for type 2 AIP. Acinar neutrophilic infiltrate is another unique to type 2 AIP. [31]These features were diagnosed and validated in a study conducted by pathologists on 40 resected pancreases from patients with AIP. The significance of the IgG4-positive plasma cells as a pathognomonic and/or diagnostic marker remains to be elucidated. In the study conducted above, IgG4 staining was not used, and IgG4 abundant plasma cells were seen in non-AIP cases. Because of the patchy distribution of the IgG4 cells , the sensitivity may be lowered. [32] Previously, because EUS-FNA samples were scanty pathologists recommend tru-cut biopsy for histopathological diagnosis. However, a recent retrospective study assessing EUS guided FNA ,using the 22 gauge needle provided adequate samples for histopathological diagnosis. [33]

e- Diagnostic classifications: There exist various diagnostic criteria to diagnose autoimmune pancreatitis. The most commonly used are the Mayo clinic HISORt revised criteria, (see table 3). The diagnosis of AIP when one histological criteria, imaging, serology, other organ involvement and response to steroids are met.

Table 3: The Mayo clinic HISORt criteria for the diagnosis of AIP

Modified from table 1 Mayo clinic HISORt criteria for the diagnosis of autoimmune pancreatitis [34]

Diagnostic criteria Findings

Histology (at least one should be met)

imaging(parenchymal and ductal )

1. Peri-ductal lymphoplasmacytic infiltrate with obliterative phlebitis and storiform fibrosis

2. Lymphoplasmacytic infiltrate with storiform fibrosis showing abundant (10 cells/HPF) IgG4-positive cells

1. Typical: diffusely enlarged gland with delayed enhancement; diffusely irregular, attenuated main pancreatic duct.

2. Others: focal pancreatic mass/enlargement; focal pancreatic duct stricture; pancreatic atrophy; pancreatic calcification; or pancreatitis

Serology Elevated IgG4

Other Organ involvement Extrapancreatic manifestations

Response to steroids Resolution of pancreatic and extrapancreatic manifestations with steroid therapy

The Asian diagnostic criteria developed by Japanese and Korean experts for AIP rely on imaging [ERCP+/- MRCP] as an essential part of the diagnosis of AIP [35]. The diagnosis is established when criterion I : imaging showing diffuse or focal pancreatic enlargement, in addition to diffuse/or focal pancreatic duct narrowing with or without CBD strictures and one of the other two criteria are met, which are serology IgG4 elevation or presence of autoantibodies(criterion 2)and histology(criterion3), or when the histology shows the presence of lymphoplasmacytic sclerosing pancreatitis in the resected pancreas. Response to steroid therapy is optional. [35]

The International Consensus Diagnostic Criteria (ICDC) was recently developed in an attempt to unify both diagnostic criteria sets. Typical diagnosis of AIP type 1 can be made using a combination of non-invasive and invasive criteria, and in selected cases after a trial of steroid therapy. See table 4.

Table 4: The International Consensus Diagnostic Criteria for AIP

Feature Typical Indeterminate/suggestive

Pancreatic imaging

Diffuse enlargement with delayed enhancement without low-density mass, ductal dilatation or duct cutoff

ERCP: Long (>1/3 length of the main pancreatic duct) or multiple strictures without marked upstream dilatation

Segmental/focal enlargement with delayed enhancement

ERCP: Segmental/focal narrowing without marked upstream dilatation (duct size <5 mm)

IgG4 IgG4 >2 X upper limit of normal value

IgG4 1–2 X upper limit of normal value

Histology (Core biopsy/resection):

at least 3 features

i. Periductal lymphoplasmacytic infiltrate without granulocytic infiltration

ii. Obliterative phlebitis ��� iii. Storiform fibrosis ���

iv. Abundant (>10 cells/hpf) IgG4 positive cells

(Core biopsy):

any 2 features

i. Periductal lymphoplasmacytic infiltrate without granulocytic infiltration

ii. Obliterative phlebitis ���

iii. Storiform fibrosis ��� iv. Abundant (>10 cells/hpf) IgG4 positive cells

Response to steroids

Rapid (<2 wk) radiological resolution or marked improvement in pancreatic or extra-pancreatic manifestations

Rapid (<2 wk) radiological resolution or marked improvement in pancreatic or extra-pancreatic manifestations

Modified from table 2 criteria for diagnosis of type 1 AIP [36]

4-How to differentiate AIP from pancreatic

cancer :

A retrospective study was conducted to compare mass associated AIP from pancreatic cancer using various clinical, serological, radiological, as well as histological features. A capsule-like rim on CT, a skipped lesion of MPD on ERCP or MRCP, gamma-globulin > 2 g/dl, other organ involvement (extrapancreatic biliary stricture, salivary gland swelling and retroperitoneal fibrosis) and ruling out pancreatic cancer by histopathological findings of EUS-FNA showed 100% specificity for mass-forming AIP. Other findings including: IgG4 > 280 mg/dl (98%), IgG > 1800 mg/ dl (97%), maximal diameter of upstream MPD<5mm on MRCP(95%), and IgG4> 135 mg/dl (94%), showed over 90% specificity for mass-forming AIP.[37] In order to avoid misdiagnosing autoimmune pancreatitis as pancreatic cancer, a number of differentiating features have been suggested. [34] See table 5

TABLE 5: Features to consider when attempting differentiating AIP from pancreatic cancer

modified from table 4 : clinical pearls to avoid misdiagnosing AIP [34]

An algorithm to help differentiate inflammatory mass forming AIP from pancreatic cancer

Feature Clue

Epidemiology

AIP is rare, less common than pancreatic cancer

Diagnostic criteria Use the Mayo and other diagnostic criteria mentioned earlier to help diagnose AIP and differentiate it from malignant disease.

Serology

* Serum IgG4 levels are elevated in 5% of healthy individuals, 10% of those with pancreatic cancer, and 6% of those with chronic pancreatitis—an increased IgG4 level is therefore not specific for AIP.

*Conversely, elevated serum IgG4 levels can decrease in patients with pancreatic cancer inappropriately treated with corticosteroids

Trial of steroid therapy *All focal pancreatic masses should be sampled before initiation of corticosteroids.

*Before initiating corticosteroids, a clinical parameter ie symptomatology, serology, radiology must be identified to follow for an objective response during treatment.

*Corticosteroids often cause subjective improvement in symptoms even in patients without AIP.

*Corticosteroid response in AIP is generally seen within 2–4 weeks. If no objective response is documented within 4 weeks, the diagnosis is unlikely to be AIP.

Painless  jaundice  and  weight  and  pancreatic  cancer  is  suspected  

 

Features  typical  for  

AIP  

Pancreatic  cancer  work  up  ie  

positive  cytology  on  EUS-­‐FNA  or  brushings  via  

ERCP  

-­‐IgG4  elevated  -­‐  Other  organ  involvement  -­‐Histology  supportive  of  AIP  

Treat  as  Pancreatic  cancer  

Diagnostic  criteria  supportive  of  AIP  

Treat  as      AIP  

-­‐Consider  EUS-­‐Tru  cut  biopsy  -­‐consider  surgical  resection  since  pancreatic  cancer  is  highly  suspected  

CT  Pancreas  protocol  

YES   NO  

NO   YES  

YES  NO  

YES  

NO  

Algorithm 1: modified from fig 6, differentiating AIP from pancreatic cancer[9]

5-Management of autoimmune pancreatitis:

Both types of AIP respond to steroids. Remission or response of AIP can be classified into 5 categories: (1) symptomatic, (2) serologic, (3) radiologic, (4) histological, and (5) functional. [38] Symptomatic remission refers to resolution of symptoms of obstructive jaundice and/or pain, usually within 2-3 weeks of initiating steroids. Serologic remission is defined as the normalization of the serum IgG or IgG4 level with steroid therapy. Serum IgG4 concentration does not always return to the normal levels even though radiologic remission is achieved. [39] Radiologic remission refers to the resolution of typical enlargement of the pancreas and irregular narrowing of the main pancreatic duct. Both serological and radiological remission takes several weeks to months to achieve suggesting the need for maintenance therapy. Histological remission has been shown to accompany clinical remission in several reports, but histological examination is not usually conducted to evaluate the remission in the clinical field. Functional remission is defined as restoration of exocrine and/or endocrine function of the pancreas.

The most common induction treatment protocol used is prednisone 40mg/day for four weeks [40], although a lower dose can be used. There was no difference in complete remission between patients treated with 40 mg/d and those treated with 30 mg/d in 2 Japanese studies.[38] The exact duration for maintenance remission therapy needs to be investigated, however the recommended maintenance remission dose is 5mg of prednisone per day that should be given for a total of 6 months, after discussing the benefit/risk ratio of prolonged steroid treatment and related complication to such therapy, including osteoporosis and avascular necrosis of the hip. [41] All AIP patients should be treated. [42, 43] Indeed, in the multicenter survey of steroid therapy for AIP, the remission rate of AIP patients was significantly higher in patients who received steroid therapy than in those not given steroid therapy ( 94% versus 74%, p < 0.01).[44, 45]. The relapse rate of patients with AIP was significantly lower in those who received steroid therapy compared to those not given steroid therapy

(24% versus 42%, p < 0.01). The relapse rate with maintenance therapy was significantly lower than those patients who stopped maintenance therapy (23% versus34%). In the United states and United Kingdom, where no maintenance therapy was given, relapse rates of patients treated with steroid varied between 38 and 60% .[45, 46]. The exact role immunomodulator drugs such as azathioprine and myco-phenolate mofetil has not been fully established; however, it should be reserved for patients who experience several relapses or for those who are intolerant or resistant to steroid therapy.[38, 46] Recently in a small cohort of ten patinets, Rituximab was found to be effective in the treatment of steroid intolerant or immunomodulator resistant AIP in 10 patients. During a median follow up of 47months, 44% of patients with type 1AIP experienced relapses. These were treated with steroids or steroid plus an immunomodulator; the relapse free survival until the second relapse was similar in both groups. Patients who were refractory or intolerant to immunomodulator therapy, 45% of cases, were treated with Rituximab, an induction dose of 375mg/m2 every week for 4 weeks followed by repeat infusion every 2-3 months for 24 months; 84% of patients achieved remission with no relapses on maintenance therapy.[47]

The role of endoscopy in the management of AIP focuses on relieving biliary obstruction from biliary strictures using metal or plastic stents in cases with associated autoimmune sclerosing cholangitis, who present with obstructive jaundice, and also in cases which pancreatic adenocarcinoma still remains a possibility [48, 49]

For many years because of its resemblance to pancreatic adenocarcinoma and lack of knowledge of AIP and iGg4 , surgery was the only treatment for AIP. Abraham et al. have reported that, out of 442 Whipple resections, 11 (2.5%) cases were chronic AIP. With a pancreatic head mass, a pancreaticoduodenectomy (Whipple resection) was the surgery of choice. Distal and total pancreatectomies were also performed for distal lesions [40, 50]. No subsequent pharmacotherapy was carried once the diagnosis was made, and recurrences were reported after surgical resection.[51] 6- Long term outcomes / complications of

autoimmune pancreatitis :

• Relapse : Disease relapse is more common in type 1 AIP. The majority of relapses occur within the first 3 years of initiating medical treatment. Proximal bile duct strictures, diffuse pancreatic swelling and incomplete remission during maintenance therapy are the major predictors of disease relapse in AIP. [38]

• Pancreatic insufficiency: endocrine insufficiency manifested as diabetes mellitus was reported in 26% to 78% of patients with AIP. Several studies have shown improvement of diabetes post treatment of AIP whereas one study showed worsening glucose control after treatment. [11] Pancreatic stone formation occurs in 19% of AIP patients. The repeated attacks of acute relapsing pancreatitis may lead to pancreatic duct obstruction resulting in stasis of pancreatic secretions and subsequent stone formation. [52]

• Risk of malignancy: Because both AIP and pancreatic cancer are rare, it is difficult to estimate the prevalence of pancreatic cancer in AIP, however, Kamisawa et al. observed high frequency of KRAS mutation in the pancreaticobiliary region of AIP patients. They hypothesized that long term inflammmation induces fibrotic changes that leads to KRAS mutation. In a cohort study, prevalence of pancreatic intraepithelial neoplasia PIN was examined in resected pancreatic specimens of AIP. It was similar if not higher than those with chronic pancreatitis patients, suggesting that AIP may be a risk factor for pancreatic cancer. [53] There are few reports of solid malignancies as well as lymphoproliferative disorders in AIP but the exact relationship is not known. [54] A recent cohort retrospective study was conducted to examine the relationship between AIP and various cancer risks. The study showed that patients with AIP have a higher risk of cancers, highest risk is during the first three years of diagnosis, The relative risk of cancer among AIP patients was 4.9. The lack of relapse of AIP following treatment of coexisting cancers, may suggest that AIP may develop as a paraneoplastic phenomena. [55]

IgG4 Cholangiopathy

Introduction :

IgG4 cholangiopathy or IgG4- sclerosing cholangitis or autoimmune cholangiopathy can involve any part of the biliary system ranging from intrahepatic and extrahepatic bile ducts, mimicking sclerosing cholangitis to pseudotumourous hilar lesions, mimicking cholangiocarcinoma. Most cases of IgG4 cholangiopathy are associated with autoimmune pancreatitis. The diagnosis can be challenging in those without evidence of AIP, and relies on a combination of serological, histological and radiological features. It is important to distinguish IgG4 cholangiopathy from PSC since both treatment is different in each case.

IgG4 cholangiopathy predominantly affects large intrahepatic and extrahepatic bile ducts, resembling the classical PSC; this is the form of AIC noted in 95%, and is further discussed below. Small duct IgG4 cholangiopathy, similar to small duct PSC, has also been described in the literature. A prospective study showed that small duct IgG4 cholangiopathy, defined as evidence of bile duct damage with >10 IgG4 + plasma cell/ HPF, was present in 26% of patients with IgG4 cholangiopathy. These patients also exhibit a higher incidence of intrahepatic strictures on cholangiographic images. [56] IgG4 autoimmune hepatitis, which is found in 3% of patients with type 1 autoimmune hepatitis has recently been described and may represent part of the spectrum of IgG4 cholangiopathies.

Pathogenesis:

IgG4 cholangiopathy is part of the spectrum of IgG4-RD. As a result there is considerable overlap between AIP and IgG4 cholangiopathy, since both conditions tend to occur concurrently. There is intense lymphoplasmocystic infiltrations and high levels of IgG4 observed in the bile ducts of patients with IgG4 cholangiopathy. [57] There is upregulation of T- helper 2 (Th-2) cells, which is surprisingly uncommon in autoimmune disorders. [58] IL-10 and transforming growth factor (TGF), a powerful inducer of fibrogenesis are the main cytokines that are overexpressed in IgG4 cholangiopathy. The exact autoantigen behind IgG4 production still remains to be identified.

Clinical Features:

IgG4 cholangiopathy may be asymptomatic and diagnosed incidentally during the work up of other IgG4 RD ie retroperitoneal fibrosis, or because of abnormal routine liver enzyme tests. IgG4 cholangiopathy usually presents with obstructive jaundice secondary to a pancreatic head mass, as an inflammatory pseudotumor secondary to associated AIP, or from biliary strictures. New onset diabetes mellitus and weight loss are other reported symptoms.

Elevated serum IgG4 levels are the most specific indicator. Other sensitive but not specific markers include hyper γ- globulinemia (observed in 50% of patients), hyper IgG (60– 70%), antinuclear antibodies (40–50%), rheumatoid factor (20%), and eosinophilia (15–25%). [59]

Diagnosis:

Over 90% of cases of IgG4 cholangiopathy are associated with AIP. The diagnosis of IgG4 cholangiopathy can be made when biliary strictures are associated with a confirmed diagnosis of AIP, using the previously described diagnostic criteria mentioned earlier. The diagnosis of IgG4 cholangiopathy without associated AIP can be quite challenging, it can resemble Primary Scleorsing cholangitis (PSC) (table 6), and should be also considered in the differential diagnosis of hilar strictures. [60] IgG4 alone cannot elucidate the diagnosis. Indeed patients with IgG4 cholangiopathy can initially present with normal IgG4 levels, but will have subsequent elevated levels during follow-up, so repeating IgG4 testing may be required to confidently exclude the diagnose of IG4 cholangiopathy in a patient presenting with a PSC-like picture. [61] IgG4 levels were measured in 116 patients with different pancreatic and biliary diseases. Thirty-six percent of patients with PSC had elevated levels of IgG4. [62] However IgG4 levels were significantly higher amongst IgG4 cholangiopathy patients. These patients also expressed higher IgG4 positive plasma cell staining in various tissues. [63] TheIgG4 plasma cell infiltration was also more severe in the liver biopsies of patients with IgG4 cholangioptahy. [64]. The table below illustrates the predominant clinical differences between IgG4 cholangiopathy and PSC.

Table 6: Differences between PSC and IgG4 cholangiopathy

Feature PSC IgG4 cholangiopathy

Age Young-middle age Older

Obstructive jaundice

Marked Less severe

Biliary strictures Band like strictures with beaded and pruned tree appearance

Segmental strictures (distal CBD)

Associated autoimmune pancreatitis

No Yes

IgG4 related diseases

No Yes

IBD association yes Rarely seen in association with type 2 AIP

Risk of cholangiocarcinoma

yes Rare (with limited data)

Modified from table comparison between PSC and autoimmune cholangiopathy [57] [65]

Management:

As with AIP, the mainstay of therapy is steroids, [66] consisting in an initial dose of prednisolone 40mg orally daily for at least four weeks,

followed by slow tapering down of 5mg per week over 6 months. Relapses are treated with immune modulators such as Azathioprine 2-2.5mg/kg or mycophenolate mofetil 750 mg po twice daily, after initiating steroids for the first relapse. In addition biliary stenting with brushings should be considered in cases where suboptimal clinical response is achieved. [57] As most patients with IgG4 cholangiopathy have associated AIP, other management issues are as described above.

Summary:

The recent recognition of autoimmune pancreatitis and autoimmune cholangitis has become increasingly common. IgG4 alone cannot be used to confidently diagnose or exclude these clinical entities. A number of various and evolving diagnostic criteria have been developed to aid in the diagnosis. The mainstay of treatment is steroids and/or immune modulators in cases of relapse or cases refractory or resistant to steroids. Both clinical conditions should be included in the differential diagnosis of pancreatic cancer and hilar cholangiocarcinoma.

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