The protean manifestations of IgG4-RD in gastrointestinal disorders

Disease-a-Month 61 (2015) 493–515

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The protean manifestations of IgG4-RD in gastrointestinal disorders Avik Sarkar, MD, Capecomorin S. Pitchumoni, MD, FRCP(C), MPH, MACP, MACG, AGAF

Introduction Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized fibroinflammatory condition characterized by a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, extensive fibrosis with a characteristic “storiform” pattern, and usually, elevated serum IgG4 concentrations.1–4 As a systemic disease, IgG4-RD affects many organs and systems, including the pancreaticobiliary system, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, aorta, breasts, prostate, thyroid, pericardium, and skin.1,5–9 The histopathological features bear similarities across all affected organs.1 Autoimmune pancreatitis, the IgG4-RD best known to the gastroenterologist, shares similarities in pathology with Mikulicz’s disease, retroperitoneal fibrosis, aortic aneurysms, and other IgG4-RDs. Being a newly described entity, there exists some degree of confusion regarding the diagnosis of this condition. Experts are not certain whether one can positively diagnose IgG4 disease based solely on a biopsy revealing IgG4 tissue infiltration or, on the contrary, whether one can exclude the disease due to a lack of IgG4-laden tissue. Many unrelated diseases of the past are now categorized under the spectrum of IgG4-RD based on pathophysiology. Underdiagnosis of the disease was once a problem but there is currently a growing problem of overdiagnosis. Recently, consensus criteria have helped to formulate guidelines for accurate diagnosis. In this review, we will discuss the gastrointestinal manifestations of IgG4-RD. This review should be considered an extension of other recent reviews and original articles on the subject.1,10–16

Basic science Immunoglobulins Immunoglobulins are heterodimeric proteins composed of two heavy and two light chains produced by plasma cells in response to an immunogen. Functionally, they can be separated into variable domains that bind antigens and constant domains that specify effector functions, such as activation of complement or binding to Fc receptors. The variable domains are created by http://dx.doi.org/10.1016/j.disamonth.2015.09.008 0011-5029/& 2015 Published by Mosby, Inc.

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means of a complex series of gene-rearrangement events subject to somatic hypermutation after exposure to antigens, allowing affinity maturation. Class-switch gene rearrangement of the constant regions determines which immunoglobulin (Ig) subtypes are produced in response to a particular immune challenge. Class-switching is regulated in part by the cytokines produced in response to the type and location of the immune challenge.17 There are five main classes of heavy-chain constant domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. IgG can be split into four subclasses, IgG1, IgG2, IgG3, and IgG4, each with its own biologic properties, and IgA can similarly be split into IgA1 and IgA2 (Table 1).18 IgG IgG is the predominant isotype (about 75%) in serum. The four IgG subclasses (IgG1, IgG2, IgG3, and IgG4) are monomers and have the longest serum half-life of all the immunoglobulins. IgG1 is the most abundant (450%).20 The subclasses exhibit different functional activities and only IgG1, IgG2, and IgG3 are able to fix complement. IgG1 and IgG3 antibodies are generally induced in response to protein antigens, whereas IgG2 and IgG4 antibodies are associated with polysaccharide antigens.18–20 IgG4 IgG4 accounts for less than 5% of the total IgG in healthy persons and is the least abundant IgG subclass.20 It is the only subclass that fails to fix complement and is considered to play a limited role in immune activation. In some circumstances, IgG4 has rheumatoid factor activity and can bind the Fc portion of other IgG antibodies, particularly other IgG4 molecules.1,17,20 A distinctive feature of IgG4 antibodies is a more flexible hinge region, enabling the formation of intra-chain cyclized disulfide bonds21 due to a single amino acid in the hinge, which differs between IgG1 and IgG4: a proline in IgG1 is replaced by a serine in IgG4.20 This combination has been shown to increase the susceptibility of the two-core hinge inter-heavy-chain disulfide bonds to chemical reduction,17,22 allowing the heavy chains to separate and randomly re-associate, producing a mixed population of IgG4 molecules with randomized heavy-chain and light-chain pairs and containing non-covalently linked heavy chains.17 The half-antibody exchange reaction, also referred to as Fab-arm exchange, is unique to IgG4 antibodies.17 The result is that most IgG4 molecules in circulation consist of two different Fab arms, rendering them “bi-specific” but functionally monovalent for a given antigen. In most situations, IgG4 cannot form immune complexes with antigen, as would occur with other IgG subclasses, which is the reason for the low potential for immune activation.17 The main effect of the Fab-arm exchange is perhaps the generation of monovalent, non-cross-linking (and therefore anti-inflammatory) antibodies rather than the generation of bi-specific (potentially pro-inflammatory) antibodies.20 Both IgG4 and IgE depend on interleukin (IL)-4/IL-13 for class-switching and are therefore considered to be part of the Th2 immune response.23–25 An IgG4-producing B cell can transform into an IgE-producing B cell, but not the other way around.20 Given the common reliance on the Th2 response, antigens that induce IgE also promote IgG4 responses. There are occurrences of IgG4 antibodies without IgE antibodies and this is thought to be regulated by IL-10, IL-12, and IL21, which favor IgG4 production over IgE.1,20,26 This phenomenon has been referred to as the modified Th2 response. The IgG4 response is slow, as it takes many months of repeated antigen exposure to produce adequate IL-10 before IgG4 becomes prominent.20 As a result, IgG4 may take part in immune tolerance to chronic antigenic stimulation.27 The significance of an IgG4-allergic response instead of an IgE-mediated response is unclear, as there is no definitive evidence that symptoms are caused by the IgG4 response. There is no activation of mast cells, basophils, or eosinophils by the interaction of allergen-specific IgG4 and its allergen.20 The role of IgG4 in this setting is that of a blocking antibody where it may compete with mast-cell-bound IgE for antigen binding, thereby tempering the IgE response and attenuating the allergic response.20 Another interesting characteristic of IgG4 is its tendency to interact with other immunoglobulins, most notably to the IgG rheumatoid factor.28,29 IgG4 was found to possess an intrinsic affinity for IgG

Table 1 Structure and function of immunoglobulins. General structure

Location

Complement fixing

Opsonizing

Function

IgM

Pentamer

Plasma, surface of B cells

Yes

Yes

Opsonizes antigens for destruction and fixing complement; associated with a primary immune response; used to diagnose acute exposure to an immunogen or pathogen; tends to be more polyreactive than other isotypes; rarely responsible for autoimmune disease or pathogenesis18

IgD

Monomer

Surface of B cells

No

No

Found at very low levels in the serum with a short serum halflife; function of circulating IgD is unclear because it is not known to participate in the major antibody effector mechanisms18

IgA

Monomer, dimer

Saliva, tears, breast milk, serum, and mucosa

No

No

Generally a monomer in the serum; secretory IgA (sIgA) is a dimer at the mucosa; two subclasses: IgA1 and IgA2; critical in protecting mucosal surfaces from toxins, viruses, and bacteria by means of direct neutralization or prevention of binding to the mucosal surface18,19

IgE

Monomer

Skin and tissues lining GI and respiratory tracts, serum

No

No

Present at the lowest serum concentration and has the shortest half-life; associated with hypersensitivity and allergic reactions, as well as the response to parasitic worm infections; binds with mast cells, basophils, Langerhans cells, and eosinophils18

IgG

Monomer

Serum

Yes (except IgG4)

Yes (except IgG4)

Predominant antibody; longest half-life; four subclasses; pathogenic autoantibodies tend to be drawn from the somatically mutated, high-affinity IgG population18

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coated to a solid phase. This binding activity was located in its constant domain.30 The significance of this finding is unclear. For an exhaustive discussion on IgG4, refer to Aalberse et al.20

History Although IgG4-RD is a term coined only recently, the disease process may be traced back to 1892, when Mikulicz observed a patient with symmetrical swelling of the lacrimal, parotid, and submandibular glands, with massive infiltration of mononuclear cells.11 This presentation, termed Mikulicz’s disease, is now classified as an atypical Sjögren’s syndrome11 and may have been a manifestation of IgG4-RD. In 1991, Kawaguchi et al.31 described lymphoplasmacytic sclerosing pancreatitis with cholangitis. The concept of autoimmune pancreatitis (AIP) was proposed by Yoshida et al.32 in 1995 along with the introduction of this terminology.12 Subsequently in 2001, the elevation of IgG4 levels in the serum and tissue infiltration of IgG4-positive plasma cells in AIP was noted.33 The association between IgG4-related immune inflammation and fibrosclerotic tissue degeneration became an important pathogenic entity and was described as an IgG4-related disease spectrum8 in 2003 when AIP was included as part of the spectrum.7 An international consensus conference in 2011 detailed the clinical, laboratory, and pathological criteria for IgG4RD.12,34–37 Over the last decade, it has come to light that a constellation of diseases with similar histopathologic findings and elevated IgG4 levels exist (Table 2).1,14,35,38–41

Clinical IgG4 disease IgG4-RD encompasses several disorders described many years ago under various designations depending on the organ or system involved (e.g., Mikulicz syndrome, Riedel’s thyroiditis, retroperitoneal fibrosis).12 It is unclear whether IgG4 directly mediates the disease process or reflects a protective response induced by anti-inflammatory cytokines.17 Given the Fab-arm exchange and inability to cross-link, it is thought that IgG4 may have anti-inflammatory properties. If instead, in vivo, IgG4 is able to generate bi-specific (potentially pro-inflammatory) antibodies, this may explain the disease associations.17 Multiple immune-mediated mechanisms contribute to the fibroinflammatory process of IgG4RD. Studies on AIP have provided data on pathogenetic autoantibodies. Antibodies against lactoferrin (LF) and carbonic anhydrase (CA)-II are frequently detected in AIP.42,43 Given that LF and CA are expressed in some exocrine organs, these autoantibodies may be related to systemic manifestations of IgG4-RD. The possible involvement of Helicobacter pylori in the pathogenesis of AIP is interesting.44 Gastric H. pylori infection triggers AIP in genetically predisposed subjects via molecular mimicry between human CA-II and alphacarbonic anhydrase of H. pylori.42,45 A majority of patients with AIP have antibodies against the plasminogen-binding protein of H. pylori, which could behave as autoantibodies via molecular mimicry in genetically predisposed individuals.1,46 IgG4-RD has also been shown to involve the activation of regulatory T cells,1,47,48 which is different from the classic autoimmune conditions in which regulatory T cells are impaired.1,49 Of note is that autoantibodies of the IgG4 subclass have not been detected in patients with IgG4-RD thus far.42 In addition to IL-10, transforming growth factor β is also overexpressed in IgG4-RD, which is thought to play a crucial role in the promotion of fibrosis in this disease.1,47,50 Despite the traditional view of IgG4 as an anti-inflammatory immunoglobulin, this molecule is assumed to play a central role in certain immune-mediated conditions.1 The formation of cutaneous blisters in patients with bullous dermatoses, including pemphigus vulgaris, bullous pemphigoid, and epidermolysis bullosa acquisita, are mediated predominantly by IgG4 antibodies against an antigen.1,51,52 Pathogenic IgG4 has been implicated in other conditions, such as myasthenia gravis,53 idiopathic membranous glomerulonephritis,54 and thrombotic thrombocytopenic purpura.55 IgG4RD is not related to the above disorders and is clinically and pathologically distinct from them.

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Table 2 IgG4-related diseases. Organ

Disease

Lacrimal glands and orbit Salivary glands Heart Arteries Mediastinum Thyroid Mammary gland Lung Central nervous system Prostate Lymph node

Mikulicz syndrome, chronic sclerosing dacryoadenitis, inflammatory pseudotumor, eosinophilic angiocentric fibrosis Chronic sclerosing sialadenitis (Kuttner tumor), Mikulicz syndrome Constrictive pericarditis, pseudotumor, coronary artery aneurysm Inflammatory aortic aneurysm, periaortitis, periarteritis Sclerosing mediastinitis Hypothyroidism, Riedel’s thyroiditis, fibrosing variant of Hashimoto’s thyroiditis Sclerosing mastitis Inflammatory pseudotumor, interstitial pneumonia, eosinophilic angiocentric fibrosis Hypophysitis, sclerosing pachymeningitis Prostatitis Lymphadenopathy with Castleman disease-like features, follicular hyperplasia, interfollicular expansion by plasma cells and immunoblasts Tubulointerstitial nephritis, membranous glomerulopathy, inflammatory pseudotumor, sclerosing pyelitis, idiopathic segmental ureteritis Retroperitoneal fibrosis (Ormond’s disease), sclerosing mesenteritis

Kidney and ureter Retroperitoneum and mesentery Liver

Eyes Ears Nose Pancreas Bile duct Veins Esophagus Stomach Blood Skin Various organs

Sclerosing cholangitis involving intrahepatic ducts, inflammatory pseudotumor, portal inflammation with or without interface hepatitis, portal sclerosis, large bile duct obstruction, lobular hepatitis, canalicular cholestasis Chronic sclerosing dacryoadenitis, ocular adnexal lymphoma, extension of pseudotumor along trigeminal nerve, orbital myositis scleritis Destructive disease of middle ear Eosinophilic angiocentric fibrosis, chronic rhinosinusitis Autoimmune pancreatitis Sclerosing cholangitis Obliterative phlebitis Autoimmune esophagitis Gastric ulcer Schonlein–Henoch purpura, autoimmune thrombocytopenia Cutaneous pseudolymphoma Pseudotumor

Epidemiology The epidemiology of IgG4-RD remains unclear.1 IgG4-RD mostly affects men older than 50 years.56 The male predominance seen here contrasts with other autoimmune diseases that mimic IgG4-RD, such as Sjögren’s syndrome and primary biliary cirrhosis, all with female predominance.1,14,57 Epidemiologic studies from Japan focus on AIP, in which a prevalence of 0.8/ 100,000 and an estimated incidence of 0.2–1/100,000 were noted.14,58

Clinical manifestations of IgG4-RD IgG4-RD is a multisystem disorder with a subacute onset and no constitutional symptoms. The most common sites of involvement are the pancreas, hepatobiliary tract, salivary glands, orbits, and lymph nodes. Other sites of involvement are the retroperitoneum, aorta, mediastinum, soft tissue, skin, central nervous system, breast, kidney, prostate, lung, upper airway, and thyroid14 (Table 2). Often, it forms a mass lesion,3,14,58,59 but it also can cause diffuse or focal organ enlargement and nodular/thickened lesions, either synchronously or metachronously.11 This is due to the prominent infiltration of lymphocytes and plasmocytes with fibrosis.11,58,60,61 IgG4-RD usually comes to clinical attention due to affected organ swelling or damage. The disorder is also often identified incidentally through radiographic findings or on histopathology. Rarely, IgG4-RD causes major tissue damage and organ failure, such as

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destructive bone lesions mimicking granulomatosis with polyangiitis or tumors in the sinuses, head, and middle ear, although less-aggressive lesions are typical in most organs. Allergic conditions such as bronchial asthma, allergic rhinitis, and chronic sinusitis are frequently associated with IgG4-RD, and peripheral blood eosinophilia and elevated serum IgE concentrations are often found.51,62,63 Rheumatoid factor and low titers of antinuclear antibodies are present in many cases.51 Elevated serum IgG levels with hypocomplementemia and an increased erythrocyte sedimentation rate due to hypergammaglobulinemia may be seen. The serum C-reactive protein levels are usually normal.51 Diagnosis Since it is a new entity, the diagnostic criteria for IgG4-RD are just evolving and multiple criteria currently exist. The diagnosis of IgG4-RD is generally based on a combination of features that include clinical parameters, imaging, serology, histopathology, and immunohistochemistry.1,34,36,37,64 Multifocal involvement, particularly synchronous or metachronous involvement of two or more sites such as the pancreas, biliary tract, salivary gland, kidney, and lung, is suggestive of IgG4-RD.64 Histopathology, the gold standard for the diagnosis of IgG4-RD, shows three major features, dense lymphoplasmacytic inflammation, storiform-type fibrosis, and obliterative phlebitis. However, there are organ-based variations in the histopathology of this disease.37,64,65 Other associated features are phlebitis without obliteration of the lumen and eosinophilia, although neither is sensitive nor specific for the diagnosis.37 In most cases, a definitive diagnosis of IgG4-RD requires the presence of two of the three major histological features (Fig. 1). In the majority of cases, these include a dense lymphoplasmacytic infiltrate and storiform-type fibrosis. According to an international symposium held in 2011, the diagnosis of IgG4-RD requires both an appropriate histological appearance and increased numbers of IgG4-positive plasma cells (or an elevated IgG4:IgG ratio) in tissue.37 The typical finding is an abundant IgG4-positive cell infiltration with Z40% of IgG-positive plasma cells being IgG4; in other words, the IgG4/total IgG ratio in tissue is 40.4.51 Cutoff values for the absolute number of IgG4-positive plasma cells per high-power field (HPF) within a given organ vary according to the specific organ.37 A characteristic feature of IgG4-RD is an elevated serum IgG4 concentration (Z135 mg/dL) or a serum IgG4/IgG ratio in the peripheral blood of Z8%.51,66 Serum IgG4 levels of 2- or 3-fold above the upper limit of normal are unusual outside the context of IgG4-RD. It should be noted that the IgG4 concentration can be normal in up to 40% of cases with biopsy-proven IgG4-RD.67 Furthermore, increased serum IgG4 and elevated numbers of IgG4-positive plasma cells in tissue have not been shown to be specific for IgG4-RD. Vasculitides, rheumatoid arthritis, pancreatic cancer, and other conditions may show elevated values.51,68 Given the absence of a more specific biomarker, it is recommended to use morphological features as the basis for the diagnosis of IgG4-RD.37 In 2011, an “All Japan IgG4 Team,” with the aim to draft comprehensive diagnostic criteria for IgG4-RD51 (Table 3), proposed three major items 51,69 (1) single or multiple organs involved with diffuse or localized swelling, masses, nodules, and/or hypertrophic lesions; (2) elevated serum IgG4 levels (Z 135 mg/dL); and (3) histopathologic features that include marked lymphocytic and plasma cell infiltration and fibrosis, with IgG4-positive plasma cell infiltration (IgG4/IgGpositive cell ratio of Z40% and IgG4-positive plasma cells exceeding 10/HPF). Based on these criteria, patients can be classified into the categories of definite, probable, or possible IgG4-RD.51 There is a need for better guidelines to avoid over- and underdiagnosis.

Gastrointestinal-associated IgG4-RD Autoimmune pancreatitis (AIP) AIP has been frequently characterized by serum IgG4 elevations and various extrapancreatic lesions,70 which are seen in 49–80% of cases (Table 4).14

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Fig. 1. Diagnostic algorithm for IgG4-RD.51

The extrapancreatic lesions associated with AIP, such as sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis, show infiltration of abundant IgG4-positive plasma cells.38,39,61,70 Both the pancreatic and extrapancreatic lesions of AIP respond well to steroid

Table 3 Guidelines for diagnosis of IgG4-RD (proposed by the Research Program for Intractable Disease of Japan’s Ministry of Health, Labor and Welfare, G4 team).58 Clinical features highly suggestive of IgG4-RD Symmetrical swelling of lacrimal, parotid, or submandibular glands Autoimmune pancreatitis Inflammatory pseudotumor Retroperitoneal fibrosis Suspicion of Castleman disease

Laboratory features highly suggestive of IgG4-RD Serum IgG4 4 135 mg/dL Tissue IgG4-positive cells/tissue IgG-positive cells 4 40%

Clinical features suggestive of IgG4-RD Unilateral swelling of at least one lacrimal, parotid, or submandibular gland Orbital pseudotumor Sclerosing cholangitis Prostatitis Hypertrophic pachymeningitis Interstitial pneumonitis Interstitial nephritis Thyroiditis Hypophysitis Inflammatory aneurysm

Laboratory features suggestive of IgG4-RD Hypergammaglobulinemia of unknown origin Hypocomplementemia or existence of immune complex Increase of IgE or eosinophils Tumefactive lesions or lymph node swelling detected by gallium scan or fluoro-D-glucose positron emission tomography (FDG-PET)

500

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Frequency (%)

Hilar lymphadenopathy Extrapancreatic bile duct Lacrimal and salivary gland Kidney Hypothyroidism Pulmonary complications Retroperitoneal fibrosis

80.4 73.9 39.1 30 22.2 13.3 12.5

therapy.2,70,72 Validated criteria for the diagnosis of AIP, such as histology, imaging, serology, other organ involvement and response to therapy (HISORt) criteria (Table 5) include the histological parameter of “abundant” IgG4-positive plasma cells on immunostaining (typically defined as 410 IgG4-positive plasma cells per HPF).73,74 In 2011, international consensus diagnostic criteria for AIP were proposed69 (Table 6). On 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), abnormal FDG uptake has been observed in various extrapancreatic lesions.75,76 Infiltration of many IgG4-positive plasma cells detected in the gastric and colonic mucosa and major duodenal papilla of patients with AIP cannot be diagnosed as gastrointestinal lesions involved in IgG4-RD because none of the following is observed in these lesions: a mass-like formation, dense fibrosis, or obliterative phlebitis.15 Serum IgG4 levels and immunostaining with anti-IgG4 antibody are useful in making the diagnosis.70 Hypergammaglobulinemia has been reported with a frequency ranging from 37% to 76%.28,82 Levels of autoimmune antibodies, including antinuclear antibody, anti-smooth muscle antibody, rheumatoid factor, and pancreatic secretory trypsin inhibitor may all be elevated in patients with AIP.28,82 It is not known if the formation of these antibodies results from a pathogenetic event or whether they represent an associated epiphenomenon of AIP.1,28,60,83

Type I AIP Type 1 AIP is the most common subtype, especially in Japan and Korea.31,33,39 It is known as lymphoplasmacytic sclerosing pancreatitis (LPSP) due to its rich IgG4 plasma cell and lymphocytic infiltrations noted in the pancreas and other organs. This is the only form of AIP that is associated with extrapancreatic involvement, which can be found in 60% of patients.84 Type 1 AIP is the pancreatic manifestation of IgG4-RD,34,36 mostly affecting middle-aged and elderly men (mean age of 59–68 years) and at a male/female ratio of 4–7.5/1. It is characterized by mild abdominal symptoms, usually Table 5 The HISORt criteria for diagnosis of AIP.73,77 Category

Criteria

Histology (at least one)

(1) Periductal lymphoplasmacytic infiltrate with obliterative phlebitis and storiform fibrosis (2) Lymphoplasmacytic infiltrate with storiform fibrosis showing abundant (Z10 cells/HPF) IgG4-positive cells Typical: diffusely enlarged gland with delayed enhancement; diffusely irregular, attenuated main pancreatic duct Others: Focal pancreatic mass/enlargement; focal pancreatic duct stricture; pancreatic atrophy; pancreatic calcification; pancreatitis Elevated serum IgG4 level Hilar/intrahepatic biliary strictures, persistent distal biliary stricture, parotid/lacrimal gland involvement, mediastinal lymphadenopathy, retroperitoneal fibrosis Resolution of pancreatic/extrapancreatic manifestation with steroid therapy

Pancreatic imaging

Serology Other organ involvement Response to steroids

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Table 6 International consensus diagnostic criteria for type 1 AIP.69,78 Feature

Typical

Indeterminate/suggestive

Pancreatic imaging —parenchyma

Diffuse enlargement with delayed enhancement without low-density mass, ductal dilatation, or duct cutoff ERCP: long (4 1/3 length of the main pancreatic duct) or multiple strictures without marked upstream dilatation IgG4 4 2 times upper limit of normal value Any one of a or b: (a) Histology of extrapancreatic organs showing any three of the following:

Segmental/focal enlargement with delayed enhancement

Pancreatic imaging —duct Serology Other organ involvement

(i) Marked lymphoplasmacytic infiltration with fibrosis and without granulocytic infiltration (ii) Storiform fibrosis (iii) Obliterative phlebitis (iv) Abundant (4 10 cells/HPF) IgG4positive cells

Histology of pancreas

Response to steroid therapy

(b) Typical radiological evidence of at least one of the following: (i) Segmental/multiple proximal or proximal and distal bile duct strictures (ii) Retroperitoneal fibrosis LPSP (core biopsy/resection) with at least 3 features: (i) Periductal lymphoplasmacytic infiltrate without granulocytic infiltration (ii) Obliterative phlebitis (iii) Storiform fibrosis (iv) Abundant (4 10 cells/HPF) IgG4positive cells Rapid (o2 weeks) radiologically demonstrable resolution or marked improvement in pancreatic or extrapancreatic manifestations

ERCP: segmental/focal narrowing without marked upstream dilatation (duct size o 5 mm) IgG4 1–2 times upper limit of normal value Any one of a or b: (a) Histology of extrapancreatic organs, including endoscopic biopsies of bile duct, showing both of the following: (i) Marked lymphoplasmacytic infiltration without granulocytic infiltration and (ii) Abundant (4 10 cells/HPF) IgG4positive cells (b) Physical or radiological evidence of at least one of the following: (i) Symmetrically enlarged salivary/ lacrimal glands (ii) Radiologic evidence of renal involvement described in association with AIP LPSP (core biopsy) with any 2 features: (i) Periductal lymphoplasmacytic infiltrate without granulocytic infiltration (ii) Obliterative phlebitis (iii) Storiform fibrosis (iv) Abundant (4 10 cells/HPF) IgG4positive cells Rapid (o2 weeks) radiologically demonstrable resolution or marked improvement in pancreatic or extrapancreatic manifestations

ERCP: endoscopic retrograde cholangiopancreatography.

without acute attacks of pancreatitis. Imaging studies typically show enlargement of the pancreas, predominantly at the pancreatic head, diffuse enlargement of the pancreas with a capsule-like lowdensity rim, narrowing of the pancreatic duct, and painless obstructive jaundice that may mimic adenocarcinoma of the pancreas. Systemic symptoms are rare, and new-onset type II diabetes mellitus and steatorrhea are seen in some cases.14,60,83 Endoscopic retrograde cholangiopancreatography (ERCP) shows irregular narrowing of the pancreatic duct with mimicry of pancreatic cancer clinically and radiographically. Serum IgG4 elevations are apparent in 80% of patients with type 1 AIP. There is response to steroid therapy but clinical recurrence is common.14,60,84–86

Type 2 AIP Type 2 AIP was proposed by American and European pathologists based on histological examination of the resected pancreatic glands from patients with chronic non-alcoholic pancreatitis. Type 2 is more common in younger patients, with 16% exhibiting underlying inflammatory bowel disease.78,84 In contrast to type 1, type 2 requires histological confirmation because clinical, serological, and imaging findings alone are not sufficient for diagnosis. Type

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2 AIP remains underdiagnosed because of the diagnostic need for histological confirmation.84 The pancreas is often infiltrated by various types of immune cells, including CD4-positive T cells and granulocytes.28,87 The most distinctive characteristic is the granulocytic epithelial lesion (GEL), which often presents with destruction and obliteration of the pancreatic duct.88,89 The non-IgG4-RD autoimmune forms of pancreatitis are associated with neutrophilic infiltrates and epithelioid cell granulomas, both of which are generally inconsistent with the diagnosis of IgG4RD.14,90,91 Serum IgG4 elevations are uncommon and there is no extrapancreatic manifestation, no presence of autoantibodies, and no other organ involvement. Type 2 AIP is also steroidresponsive and clinical recurrence is very rare (Table 7). Esophageal disease Our knowledge of IgG4-related esophageal disease is limited to a few case reports (Table 8). A recent study95 has shown a non-stricturing esophageal IgG4 entity, eosinophilic esophagitis (EoE), which had been postulated to be an IgE-mediated phenomenon, given the eosinophil, mast cell, IL-5, and IL-13 involvement and the frequent presence of high serum IgE and atopy.96 The involvement of IgE in EoE came into doubt recently with a study revealing that some otherwise-typical adult eosinophilic esophagitis patients lack mucosal mast cell IgE.95,97 Abundant IgG4 antibodies to the common trigger foods were present in most eosinophilic esophagitis subjects,95 suggesting that EoE may not be IgE-mediated, given the failure of omalizumab, abundant tissue IgG4, and elevated serum IgG4.95 The three case reports on esophageal IgG4 disease had distinct masses or strictures, whereas examination of the esophagus in EoE revealed widespread, shallow lamina propria fibrosis.95 Typical IgG4-related diseases involve storiform fibrosis, obliterative phlebitis, and significant elevation of serum IgG4. EoE is likely an IgG4-associated disease rather than part of IgG4-RD.95 IgG4-related gastric disease The stomach is not usually involved in IgG4-RD, but there have been case reports of possible gastric involvement (Table 9). Infiltration of IgG4-positive plasma cells was observed in the gastric mucosa in 33–47% of AIP patients.2,15,105–107 However, neither dense fibrosis nor obliterative phlebitis was observed. With

Table 7 Type 1 and type 2 AIP.28,58,79–81

Age Prevalence Gender Serum IgG4 levels Histology IgG4 immunostain Granulocytic epithelial lesions Abdominal pain Obstructive jaundice Other organ involvement (OOI) Ulcerative colitis Steroid response Relapse

Type 1 AIP

Type 2 AIP

Sixth decade Asia 4 US, Europe Male predominance Elevated Lymphoplasmacytic sclerosing pancreatitis (LPSP) Abundant Absent

Fourth decade Europe 4 US 4 Asia Equal Normal Idiopathic duct centric pancreatitis (IDCP) Rare Present

Rare Often Sclerosing cholangitis, sclerosing sialadenitis, retroperitoneal fibrosis, others Rare Responsive High rate

Common Often Unrelated to OOI

Often Responsive Rare

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Table 8 Case reports of IgG4-related esophageal disease. References

Case

Histology

Meets criteria for IgG4-RD?

Lopes et al.92

23-year-old man with chronic dysphagia due to esophageal strictures; patient underwent esophagectomy; serum IgG4 level not drawn; no other manifestations of IgG4-RD 63-year-old man with chronic dysphagia; found on endoscopy to have a non-traversable, friable, fibrotic stricture in the midesophagus; underwent esophagectomy due to concern for malignancy; serum IgG4 level postoperatively found to be mildly elevated but the patient did not have any other IgG4-RD manifestations 63-year-old woman with progressive dysphagia; found to have esophagitis dissecans superficialis with chronic strictures; patient also had primary biliary cirrhosis, Sjögren disease, Raynaud disease, and asthma

Submucosal tumor with fibroblastic spindle cell proliferation; immunohistochemistry revealed significant IgG4-positivity

Possible

Biopsy with IgG4-positive plasma cells; transmural chronic fibrosing inflammation with abundant plasma cell infiltration, lymphoid follicles, and stromal sclerosis; immunostaining revealed many IgG4-positive plasma cells

Yes

Thickening of the esophageal wall with complete absence of squamous mucosa associated with lamina propria sclerosis and muscularis mucosae hypertrophy; few inflammatory cells, mainly lymphocytes and plasma cells, found in the lamina propria, associated with sclerosis; few IgG4-positive cells in the sections

Possible

Lee et al.93

Dumas-Campagna et al.94

respect to gastric disease, AIP is a risk factor for a high prevalence of chronic gastric ulceration, which is independent of H. pylori infection status.106,108 Although not recognized in the nomenclature,35 case reports indicate that gastric lesions as part of IgG4-RD may be possible and may present as chronic ulcerations or pseudotumor formation in patients with AIP. As mentioned previously, the finding of IgG4-positive plasma cells in the mucosa alone cannot be diagnosed as a gastrointestinal lesion involved in IgG4-RD because none of the following are observed in these lesions: a mass-like formation, dense fibrosis, or obliterative phlebitis.15

IgG4-related major duodenal papillary disease The major duodenal papilla is a conduit between the duodenum and the pancreatobiliary system and occasionally reflects underlying pancreatobiliary disorders.109 In AIP, the major and minor papillae are endoscopically abnormal (41–65% of patients),109–112 abundant infiltration of IgG4-positive plasma cells is detected in biopsy specimens from the major papilla (53–80% of patients),109–111,113 and the major papilla is frequently swollen.114 Steroid therapy has been shown to reverse the histological findings.110–112 In the international diagnostic criteria for AIP,69 positive IgG4 immunostaining in the major papilla was added as a histological criterion of extrapancreatic organs, and ampullary biopsy was regarded as an adjunctive method for the diagnosis of AIP. Chari et al.115 also revised their HISORt criteria and added positive IgG4 immunostaining in the ampulla as a supportive diagnostic criterion. There is 100% specificity of IgG4 immunostaining of the major duodenal papilla in distinguishing AIP from other pancreatobiliary diseases, especially with regard to

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Table 9 Case reports of IgG4-related gastric disease. References

Case

Histology

Meets criteria for IgG4-RD?

Fujita et al.98

77-year-old man with chronic gastric ulcers complicated by upper stomach stricture despite H. pylori eradication and treatment with proton pump inhibitor; serum IgG4 twice the upper limit; no systemic disease

Intense infiltration of IgG4 plasma cells

Did not meet pathologic criteria for IgG4-RD due to superficial biopsies and no other systemic disease; stricture may signal fibrosis so possibly IgG4-RD

Frydman et al.99

65-year-old man with Rouxen-Y reconstruction and an inflammatory mass in the stomach remnant with evidence of fistulization via the diaphragm into the pericardium; serum IgG4 620 mg/dL; no systemic disease

Chronic gastric ulcer with extensive fibrosis; multiple IgG4-positive plasma cells in the fibrous stroma with an IgG4:IgG ratio of 4 40%

Yes

Rollins et al.100

75-year-old woman with 5 cm gastric body mass; mass resected; no serum IgG4 measured; no systemic disease

Fibrous stroma of abundant dense eosinophilic material and prominent inflammatory cell infiltrate; abundant infiltration of IgG4-positive plasma cells

Yes; likely IgG4-related pseudotumor within the stomach

Baez et al.101

58-year-old man with history of AIP with UGI symptoms; EGD: diffusely thickened and nodular gastric mucosa; serum IgG4 level within normal range but gastric lesion improved after steroid therapy

Abundant infiltration of IgG4positive plasma cells

No, although only superficial gastric biopsies were obtained; likely AIPassociated gastric disease

Na et al.102

56-year-old man with anorexia, nausea, and abdominal discomfort; EGD: 8 mm gastric nodule; lesion removed by endoscopic submucosal dissection; no history of systemic inflammatory disorder and laboratory testing unremarkable

Marked submucosal fibrosis with storiform pattern; diffuse lymphoplasmacytic infiltrate and occasional eosinophils; abundant infiltration of IgG4-positive plasma cells

Yes

Bateman et al.103

73-year-old woman with anemia; EGD: non-healing 30 mm firm ulcer in lesser curve of stomach; resected due to concern for malignancy

Marked submucosal fibrosis with a partly storiform pattern; prominent lymphoid aggregates; prominent IgG4-positive plasma cells within the inflammatory infiltrate

Yes

Kim do et al.104

Two women (aged 59 and 54) with subepithelial lesions; underwent laparoscopic wedge resection; no evidence of OOI; serum IgG4 within normal limits

Abundant fibrous stroma and many lymphoid follicles; storiform fibrous bands; abundant infiltration with IgG4-positive plasma cells

Suggestive of IgG4related sclerosing disease of stomach

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pancreatobiliary malignancies.109,113 Although infiltration of IgG4-positive cells in the pancreases of patients with pancreatic cancer has been reported,116 positive IgG4 immunostaining of the major duodenal papilla has not been found in such patients.113,117 IgG4 immunostaining of duodenal papilla offers the highest sensitivity (52%) and accuracy (73%) in supporting the diagnosis of AIP among eight different sites (pancreas, stomach, duodenum, duodenal papilla, colon, liver, bile duct, and minor salivary gland).118

IgG4-related sclerosing cholangitis (IgG4-SC) IgG4-SC, also known as IgG4 cholangiopathy, IgG4-sclerosing cholangitis, or autoimmune cholangitis, can involve any part of the biliary system from the intrahepatic to the extrahepatic bile ducts. IgG4-SC must be differentiated from primary sclerosing cholangitis (PSC) and from a hilar pseudotumorous mass that resembles hilar cholangiocarcinoma.119,120 The diagnosis relies on a combination of serological, histological, and radiological features. In 95% of cases, IgG4-SC predominantly affects large intrahepatic and extrahepatic bile ducts, resembling PSC.4 Smallduct IgG4 cholangiopathy has also been described.121 IgG4-SC usually presents with obstructive jaundice secondary to a pancreatic head mass, as an inflammatory pseudotumor secondary to associated AIP, or as biliary strictures.4 Incidental discovery of IgG4-SC during workup for other IgG4-related conditions, such as sialadenitis, retroperitoneal fibrosis, and kidney lesions, may occur. Weight loss or new-onset diabetes mellitus are other potential symptoms.42 More than 80% of patients with IgG4-SC show elevation of serum hepatobiliary enzymes, of total bilirubin in cases of obstructive jaundice, and of serum IgG4 levels.33,122,123 Elevation of serum IgG4 levels is, however, not specific to IgG4-SC, and can also be seen in other diseases, including PSC and cholangiocarcinoma. A small proportion of PSC patients with elevated serum IgG4 can have more severe liver disease with a shorter time to liver transplantation.124 However, IgG4-SC can be differentiated from other hepatobiliary diseases by the magnitude of the elevation.122,123,125 Other sensitive, but not specific, markers for IgG4-SC include hypergammaglobulinemia (observed in 50% of patients), high IgG (60–70%), antinuclear antibody (40–50%) and rheumatoid factor (20%) levels, and eosinophilia (15–25%).4,42,43,126 IgG4-SC is part of the spectrum of IgG4-RD and can occur concurrently with other diseases of the spectrum. Intense lymphoplasmacytic infiltrations and high levels of IgG4 are observed in the bile ducts of patients with IgG4-SC.127 IgG4-SC involves a massive infiltration of IgG4positive plasma cells, storiform fibrosis, and/or obliterative phlebitis in the bile duct wall and is histologically known as lymphoplasmacytic sclerosing cholangitis (LPSC).36,88,119,122,123 The involvement is mainly in the submucosa of the bile duct wall, whereas the epithelium is intact.123,128 Circular and symmetrical thickening of the bile duct wall is observed123 in the entire duct, including both stenotic and non-stenotic areas.88,129 The pathophysiology is not completely known but there is upregulation of the Th2 response, which, as mentioned previously, is not common in autoimmune disease.47 This Th2 type of response is typical for the pathogenesis of allergic disorders such as bronchial asthma and atopic dermatitis.47 Interleukin-10 and transforming growth factor, a powerful inducer of fibrogenesis, are the main cytokines overexpressed in IgG4-SC.4 More than 90% of patients with IgG4-SC also have type 1 AIP. The diagnosis of IgG4-SC can be made when biliary strictures are associated with a confirmed diagnosis of AIP. The diagnosis of IgG4-SC without associated AIP can be challenging, as it must be differentiated from PSC (Table 10). The Japanese study group for IgG4-SC proposed the clinical diagnostic criteria for IgG4-SC (Table 11).122 Patients with IgG4-SC have significantly higher than normal levels of IgG4 as well as increased IgG4-positive plasma cell staining in various tissues.130 The mainstay of therapy is steroids, with relapses treated with immunomodulators such as azathioprine or mycophenolate mofetil, after initiating steroids for the first relapse.4,131 Rituximab has also been used.132 Biliary stenting is also useful in cases with suboptimal clinical response.127 If lesions do not respond to steroids, re-evaluation to rule out malignancy should be performed.

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Table 10 IgG4-SC vs. PSC.4 Feature

PSC

IgG4-SC

Age Obstructive jaundice Biliary strictures

Young to middle-aged Marked Band-like strictures with beaded and pruned-tree appearance No No Yes Yes

Older Less severe Segmental strictures (distal CBD)

Associated AIP IgG4-RD IBD association Risk of cholangiocarcinoma

Yes Yes Rarely associated with type 2 AIP Rare; can mimic

IgG4-related cholecystitis Diffuse lymphoplasmacytic acalculous cholecystitis was described in 1998133–135 after the gallbladders in PSC-related cholecystitis patients were found to have a histologic triad of diffuse, mucosal-based, plasma-cell-rich inflammatory infiltrates. Typical gallbladder findings in AIP have been increasingly recognized, and about one-quarter of AIP gallbladders show a dense and diffuse lymphoplasmacytic infiltrate. Transmural lymphoplasmacytic inflammatory infiltrates, extramural inflammatory nodules, tissue eosinophilia, phlebitis, and increased tissue IgG4 are all seen more frequently in the gallbladders of patients with AIP. These findings are not specific, because some of these features can be seen in PSC and pancreatic adenocarcinoma.105,134 In one report, the majority (60%) of gallbladders in type 1 AIP contained moderate or marked inflammatory infiltrates and lymphoid nodules, frequencies similar to PSC but significantly higher than in chronic cholelithiasis and benign non-LPSP pancreatic disease.135 The inflammatory pathology of the gallbladder is frequently associated with type 1 AIP and it is part of the spectrum of biliary tract disease, rather than a simple reflection of the pancreatitis itself. Kamisawa et al.134 proposed the term “sclerosing cholecystitis” after their study revealed that thickening of the gallbladder wall with IgG4-positive plasma cell infiltrates is an extrapancreatic manifestation of AIP. Table 11 The Japanese clinical diagnostic criteria of 2012 for IgG4-SC.123 Diagnostic Items (1) Biliary tract imaging reveals diffuse or segmental narrowing of the intrahepatic and/or extrahepatic bile duct associated with thickening of the bile duct wall (2) Hematological examination reveals elevated serum IgG4 concentrations (Z135 mg/dL) (3) Coexistence of AIP, IgG4-related dacryoadenitis/sialadenitis, or IgG4-related retroperitoneal fibrosis (4) Histopathological examination shows: (a) Marked lymphocytic and plasmacytic infiltration and fibrosis (b) Infiltration of IgG4-positive plasma cells: 4 10 IgG4-positive plasma cells/HPF (c) Storiform fibrosis (d) Obliterative phlebitis Optional: effectiveness of steroid therapy when malignancy is ruled out Diagnosis Definite diagnosis 1 þ 3 1 þ 2 þ 4a þ 4b 4a þ 4b þ 4c 4a þ 4b þ 4d Probable diagnosis 1 þ 2 þ optional Possible diagnosis 1 þ 2

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Deshpande et al.136 evaluated gallbladders from AIP patients and compared them with gallbladders from the two diseases that are most likely to be clinically and radiologically mistaken for AIP: pancreatic ductal adenocarcinoma (PDAC) and PSC. A moderate to marked mucosal-based mononuclear infiltrate was seen in AIP (55%), PSC (45%), and PDAC (100%) gallbladders.105,136 Extramural inflammatory infiltrates were observed in 41% of AIP gallbladders, compared with 0% and 4% of the PSC and PDAC gallbladders, respectively. Additional significant findings were phlebitis in AIP (41%) and PDAC (22%) and increased inflammatory nodules in AIP (27%) vs. PDAC (4%). The elevated number of IgG4-positive plasma cells and an elevated IgG4/IgG plasma cell ratio in the AIP gallbladders support the hypothesis that gallbladder involvement is an extrapancreatic manifestation of this systemic disease.136 A small number of IgG4-related cholecystitis cases have been reported (Table 12). IgG4-related diseases of the gallbladder mimic gallbladder cancer, and given the findings that have been reported, IgG4-related cholecystitis may be part of IgG4-RD. IgG4-related autoimmune hepatitis/IgG4-related hepatopathy Confusion exists regarding autoimmune hepatitis (AIH), as it may be IgG4-related or nonIgG4-related.140 IgG4-related AIH is defined as having definite AIH according to the International Autoimmune Hepatitis Group (IAIHG) scoring system, serum IgG4 concentration of Z135 mg/dL, Table 12 Case reports of IgG4-related cholecystitis. References

Case

Histology

Meets criteria for IgG4-RD?

Feely et al.137

Three cases of IgG4-related cholecystitis presenting as biliary malignancy with symptoms of gallbladder disease; radiographic studies suggesting malignant gallbladder neoplasms; cholecystectomy performed

Marked fibrosis and inflammation of the gallbladder, composed predominantly of lymphocytes, plasma cells, and occasional eosinophils; IgG4/IgG ratio 68%/81%

Yes

Leise et al.105

76-year-old man with right upper quadrant abdominal pain; non-visualization of the gallbladder on HIDA scan, suggesting cholecystitis; patient eventually underwent open cholecystectomy; mild serum IgG4 elevation

Acute and chronic cholecystitis surrounded by mixed inflammation and fibrosis; follicular cholecystitis with transmural lymphoid nodules, storiform fibrosis, and lymphocytic phlebitis; 20 IgG4-positive plasma cells/HPF

Yes

Memon et al.138

16-year-old boy with abdominal pain, biliary duct dilatation, hepatitis, elevated serum IgG4 to 4080 mg/dL; found to have autoimmune hepatitis (AIH) by liver biopsy and serology; underwent cholecystectomy

Diffuse lymphoplasmacytic acalculous cholecystitis with IgG4-positive plasma cells in liver and gallbladder specimens

Maybe; unclear if this is related to underlying AIH

Shin et al.139

58-year-old man with history of stomach cancer, status post subtotal gastrectomy, with right upper quadrant pain; imaging concerning for gallbladder cancer; underwent cholecystectomy

Diffuse, transmural, acute, and chronic inflammation with multifocal lymphoid follicles and diffuse fibrosis; extensive infiltration of plasma cells; 15 IgG4positive plasma cells/HPF

Yes

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and immunostaining of IgG4 showing infiltration of Z 10/HPF IgG4 plasma cells in the portal tract141; however, consensus diagnostic criteria have yet to evolve. IgG4-related AIH140–142 accounts for 3% of cases of type 1 AIH in the Japanese population.42,141 Marked plasma cell infiltration and lobular hepatitis, portal inflammation, infiltration of B cells, T cells, and plasma cells are noted.140 Steroid therapy is effective in preventing relapses in the IgG4 group. Whether this entity is truly a part of IgG4-RD is uncertain since none of the AIH patients studied have shown other manifestations of IgG4-RD.143 Given that the patients with IgG4-related AIH had high serum IgG4 and abundant infiltration of IgG4-bearing plasma cells in the liver, Umemura et al.141 proposed that this disease entity should be considered IgG4-RD rather than AIH. They further proposed that AIH patients with pancreatic abnormalities should be excluded from the diagnosis of IgG4-related AIH, because a prior study showed that interface hepatitis was found in 24% of patients with AIP141,144 and overall liver injury is observed in 60–70% of AIP cases, although the cause of liver injury is not always clear.39 In these cases, patients should be considered to have AIP with histological damage in the liver instead of IgG4-related hepatopathy.141,143 The differences between IgG4related AIH and IgG4-related hepatopathy are as follows: patients with IgG4-related AIH have a much higher degree of IgG4-bearing plasma cell infiltration in the liver, compared not only with classical AIH, but also with AIP; obvious giant cell change and rosette formation; and lack of bile duct damage or loss.141 IgG4-related colonic disease The colon is typically not a site of disease in IgG4-RD; however, there have been many reports of IgG4-positive plasma cells in the colon, most notably in patients with inflammatory bowel disease (IBD) and in AIP.2,39 It has been suggested that pancreatitis is an extraintestinal manifestation of IBD.145,146 In one study,147 6% of patients with proven AIP had a diagnosis of IBD, compared to a prevalence of 0.4–0.5% in the general population, potentially implying a 12– 15-fold increase in risk. This finding of IgG4-positive cells on colon biopsy suggests that IBD may represent an extrapancreatic manifestation of AIP. Still, in those with AIP and IBD, it is unclear whether IBD is an associated immune-mediated disease or a true extrapancreatic manifestation of AIP.147,148 Ulcerative colitis (UC) is typically not associated with type 1 AIP, although infiltration of IgG4-positive plasma cells is sometimes detected in the colonic mucosa of UC patients.149 There have been case reports that show possible colon involvement as part of IgG4-RD.150–152 Cases of possible colonic IgG4-RD without other lesions, such as AIP or UC, are rare, but as described in the case reports, solitary colonic lesions causing pseudotumor formation or extension of lesions from other areas are possible. IgG4-associated pouchitis IgG4-associated pouchitis was first described in 2011 and attributed to the association of AIP with IBD.147 There are no defined diagnostic criteria as of yet, but studies have utilized elevated serum IgG4 levels and/or tissue with IgG4-positive plasma cells (4 10/HPF). The initial report of IgG4-associated pouchitis described a UC patient with ileal pouch–anal anastomosis (IPAA) with pouchitis associated with elevated serum IgG4 and a mucosal biopsy showing strong cytoplasmic immunoreactivity in IgG4-positive plasma cells (4 10/HPF).153 IgG4-mediated autoimmunity may be a contributing factor for chronic antibiotic-refractory pouchitis (CARP).154 In a follow-up study of consecutive symptomatic patients with ileal pouches, the prevalence of elevated serum IgG4 was 8% and it was found that patients with elevated serum IgG4 were more likely to have CARP.154 Overall, 29% of symptomatic patients had abnormal IgG4 plasma cell infiltration (410/HPF) on pouch biopsy. It is not clear if any of the cases of IgG4-associated pouchitis represent an ileal pouch manifestation of IgG4-RD.74 None of the currently reported cases of pouchitis with elevated IgG4 meet the IgG4-RD diagnostic criteria,1,34,36,37,64 although

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some cases associated with PSC have been reported153,154; however, it remains unclear if these cases were truly PSC or IgG4-SC. Serum IgG4 elevation may be a useful biological marker of an increased risk for CARP.74 However, it is apparent that elevated IgG4 serology does not reliably correspond to increased IgG4-positive cell infiltration in the ileal pouch.74,154

Management No clear guidelines exist with regard to the management of IgG4-RD. The prominence of IgG4-expressing plasma cells may imply corticosteroid sensitivity as well as responsiveness to therapy targeting B cells, analogous to the case with AIP.74 Currently, our management plan is guided by the experience of experts in the field, mostly focused on AIP. There is unanimous opinion that remission can be achieved with steroid therapy, although recurrence may occur.12,155 Spontaneous remission may also occur. Wakabayashi et al.156 showed that without steroid therapy, 50% of patients with AIP in the no-treatment group had resolution of narrowed main pancreatic duct and common bile duct, and these patients typically had low serum IgG4 concentrations at baseline, had no obstructive jaundice or diabetes mellitus, and showed focal rather than diffuse pancreatic swelling.157 Those who did not have spontaneous resolution had bile duct strictures with increased serum levels of cholestatic enzymes. In the group that received steroids, pancreas size decreased or returned to normal in all 21 patients and these patients were subsequently followed for up to 32 months. Relapse appeared in 3 patients within 8 months while on a maintenance steroid dose of 2.5–5 mg/day, while one patient had a relapse after cessation of maintenance therapy for 2 years.156 In a large, retrospective, multicenter study at 17 referral centers in Japan, Kamisawa et al.158 evaluated steroid therapy in 563 AIP patients, with 82% receiving steroid treatment and achieving a remission rate of 98%, compared to 74% without steroid treatment. Maintenance steroid treatment was given to 82% of 459 steroid-treated patients, and treatment was stopped in 104 patients. The relapse rate of patients with AIP on maintenance treatment was 23%, compared to 34% in those who stopped maintenance treatment. From the start of treatment, 56% relapsed within 1 year and 92% within 3 years. Of the relapsed patients, 93% received steroid re-treatment, which was effective in 97% of them. As mentioned previously, type 1 AIP is more likely than type 2 to have disease relapse after steroid therapy. According to the Japanese Consensus Guidelines for AIP,159 the indications for steroid therapy in AIP patients are symptoms such as obstructive jaundice, abdominal pain, and back pain, and the presence of symptomatic extrapancreatic lesions. Impaired pancreatic endocrine or exocrine function improved in some AIP patients after treatment.160 The Japanese recommendation for initial oral prednisolone dose for induction of remission is 0.6 mg/kg/day,158,159 which is administered for 2–4 weeks and then gradually tapered. The Mayo Clinic protocol starts with 40 mg/day for 4 weeks, tapering by 5 mg/week to complete a course of 11 weeks.78,161,162 The Japanese criteria for tapering involves decreasing the dose by 5 mg every 1–2 weeks based on changes in clinical manifestations, biochemical blood tests, and repeated imaging. The dose is tapered to a maintenance dose over a period of 2–3 months159 but some patients are continued on steroids for over 3 years.158 Markers for relapse include markedly elevated serum IgG4 levels and the presence of bile duct stenosis.158,163 Kamisawa et al.158 also found that 69% of relapsed patients during maintenance treatment had re-elevation of serum IgG4 levels; this may be useful for predicting or detecting relapse earlier. Elevations of IgG4 and the immune complex determined by the monoclonal rheumatoid factor method was associated with the recurrence of AIP in one study.164 Re-initiating or increasing the steroid dose is effective for treating AIP relapses. Administration of immunomodulatory drugs and anti-TNF-α therapy is considered for AIP patients who prove resistant to steroid therapy.159 The Mayo Clinic evaluated 116 patients with type 1 AIP with disease relapse, and relapse-free survival was similar in those treated with steroids plus immunomodulators compared to those treated with steroids alone; about 50% of

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patients treated with immunomodulators either did not respond to therapy or relapsed on fulldose immunosuppression despite a period of remission.87 In a multicenter, international analysis of long-term outcomes in AIP, steroids were the most commonly used treatment for managing disease relapse in type 1 AIP, inducing remission in 95% of 210 subjects.165 Steroidsparing agents, including azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, 6-mercaptopurine, and cyclophosphamide, have also been used successfully in induction.165–167 B-cell depletion with rituximab, a monoclonal antibody directed against the CD20 antigen on B lymphocytes, was found to be an effective treatment for both immunomodulator-resistant and steroid-intolerant patients.87 One study in which four patients were treated revealed that serum IgG4 concentrations declined by a mean of 65% within 2 months of rituximab administration. All four patients had clinical improvement within 1 month of therapy. The other IgG subclasses remained stable.168 In a follow-up report, 10 patients with steroid- and DMARD (Disease-modifying antirheumatic drug) -refractory IgG4-RD (failed prednisone, azathioprine, 6-mercaptopurine, methotrexate, and mycophenolate mofetil) all achieved remission with rituximab.169 A multicenter study of the efficacy and prescription modalities of rituximab in IgG4-RD is under way12 (ClinicalTrials.gov: noNCT01584388). Bortezomib, a drug typically used to treat multiple myeloma, is a proteasome inhibitor with cytotoxicity against plasma cells. There is a report of successfully treating a patient with recurrent pulmonary infiltration with IgG4 plasma cells, thought to be a possible IgG4-RD.170 We may summarize the treatment recommendations as follows. Treatment is initiated with oral prednisolone at 40 mg daily and tapering begins after 2–4 weeks of therapy, which is when clinical improvement is expected.10 Therapy may be continued over a period of several months. Steroid-sparing agents such as azathioprine, mycophenolate mofetil, or methotrexate may be added while reducing the dose of steroids. Other medications found to be of benefit in refractory cases include cyclophosphamide, fludarabine, bortezomib, and rituximab.

Future directions Integrated PET/CT with 18F-FDG as the tracer provides metabolic information about the entire body.75 This imaging modality may be used to assess both infectious and non-infectious inflammatory conditions.75,171 A prospective cohort study was designed to investigate the efficacy of 18F-FDG PET/CT in characterizing IgG4-RD and evaluating the response to steroidbased treatment.75 It was concluded that whole-body 18F-FDG PET/CT can provide a comprehensive view of the organs/tissues involved in IgG4-RD, and can detect a larger number of lesions than conventional imaging methods, such as ultrasonography and CT. Moreover, this method is valuable for early response monitoring to achieve personalized treatment of the disease. A rapid, significant response to steroid-based therapy may also help verify the diagnosis and exclude possible malignancies. Therefore, 18F-FDG PET/CT is a useful tool that has the potential to uncover more details and provide a better understanding of IgG4-RD. Additional biomarkers for the diagnosis and follow-up of IgG4-RD patients are an area of future investigation. Recent studies172,173 suggest that circulating plasmablasts may be useful biomarkers.10

Conclusion IgG4, which comprises less than 5% of the total serum immunoglobulins, has assumed importance recently in light of an IgG4 disease that is characterized by a systemic fibroinflammatory disorder that may affect virtually every organ and responds to steroid therapy. IgG4-RD is a multisystem disease and as such, it is an important diagnostic consideration for multiple specialties. As a relatively new entity, there is considerable enthusiasm associated with the lack of unanimity with regard to its diagnosis. Overdiagnosis is becoming nearly as common as underdiagnosis, and better diagnostic criteria are welcomed to avoid diagnostic

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confusion. Also, errors in estimation of IgG4 can be avoided with more sensitive techniques. Ultimately, a better understanding of the pathophysiology of the disease will allow for a more tailored management strategy and possibly new treatment options. References 1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366(6):539–551. 2. Kamisawa T, et al. Gastrointestinal findings in patients with autoimmune pancreatitis. Endoscopy. 2005;37(11): 1127–1130. 3. Khosroshahi A, Stone JH. A clinical overview of IgG4-related systemic disease. Curr Opin Rheumatol. 2011;23(1): 57–66. 4. Hisham Al-Dhahab, McNabb-Baltar Julia, Said Al-Busafi, Alan N Barkun. Immunoglobulin G4-related pancreatic and biliary diseases. Can J Gastroenterol Hepatol. 2013;27(9):523–530. 5. Cornell LD. IgG4-related kidney disease. Semin Diagn Pathol. 2012;29(4):245–250. 6. Ferry JA, Deshpande V. IgG4-related disease in the head and neck. Semin Diagn Pathol. 2012;29(4):235–244. 7. Tan TJ, et al. Extrapancreatic findings of IgG4-related disease. Clin Radiol. 2014;69(2):209–218. 8. Terumi Kamisawa NF, Hayashi Yukiko, Eishi Yoshinobu, et al. Hitoshi Nakajima A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38(10):982–984. 9. Zen Y, Kasashima S, Inoue D. Retroperitoneal and aortic manifestations of immunoglobulin G4-related disease. Semin Diagn Pathol. 2012;29(4):212–218. 10. Pieringer H, et al. IgG4-related disease: an orphan disease with many faces. Orphanet J Rare Dis. 2014;9:110. 11. Okazaki K, et al. Recent advances in the concept and pathogenesis of IgG4-related disease in the hepato-biliopancreatic system. Gut Liver. 2014;8(5):462–470. 12. Palazzo E, Palazzo C, Palazzo M. IgG4-related disease. Joint Bone Spine. 2014;81(1):27–31. 13. Stone JH, et al. IgG4-related disease. Int J Rheumatol. 2013;2013:532612. 14. Guma M, Firestein GS. IgG4-related diseases. Best Pract Res Clin Rheumatol. 2012;26(4):425–438. 15. Koizumi S, et al. 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Localization of an Fc-binding reactivity to the constant region of human IgG4. Implications for the pathogenesis of rheumatoid arthritis. J Immunol. 1995;155(10):5057–5063. 30. Rispens T, et al. Human IgG4 binds to IgG4 and conformationally altered IgG1 via Fc–Fc interactions. J Immunol. 2009;182(7):4275–4281. 31. Kawaguchi K, et al. Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas. Hum Pathol. 1991;22(4):387–395. 32. Yoshida K, et al. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci. 1995;40(7):1561–1568. 33. Hamano H, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344 (10):732–738. 34. Umehara H, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21–30. 35. Stone JH. 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