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Diagnostic Approach to the Complexity of IgG4-Related Disease

      Abstract

      IgG4-related disease (IgG4-RD) is a systemic disease characterized by the infiltration of IgG4-bearing plasma cells and, more importantly, distinctive histopathological features: storiform fibrosis, obliterative phlebitis, a lymphoplasmacytic infiltrate, and mild-to-moderate tissue eosinophilia. The diagnostic approach is complex and relies on the coexistence of various clinical, laboratory, and histopathological findings, none of which is pathognomonic in and of itself. IgG4-related disease should be suspected in patients presenting with unexplained enlargement or swelling of 1 or more organs or tissue organs. Four laboratory abnormalities often provide initial clues to the diagnosis of IgG4-RD: peripheral eosinophilia, hypergammaglobulinemia, elevated serum IgE levels, and hypocomplementemia. Elevated serum IgG4 levels provided critical information in identifying the first cases of IgG4-RD, but recent studies have reported substantial limitations to the measurement of serum IgG4 concentrations, precluding reliance on serum IgG4 concentrations for diagnostic purposes. In contrast, new studies have suggested a promising role of flow cytometry studies in the diagnosis and longitudinal management of IgG4-RD. Demonstration of the classic histopathological features of IgG4-RD remains crucial to diagnosis in most cases, and biopsy proof is preferred strongly by most disease experts before the initiation of treatment. Of note, the multiorgan nature of IgG4-RD was first established in 2003. This review intends to provide most recent knowledge about the clinical, laboratory, radiological, and pathological characteristics of IgG4-RD that may guide the physician to establish an early diagnosis. We searched PubMed and MEDLINE for relevant articles published between January 1, 2000, and November 1, 2014, using the search terms IgG4 and IgG4-related.

      Abbreviations and Acronyms:

      CT (computed tomography), GN (glomerulonephropathy), HPF (high-power field), IgG4-RD (IgG4-related disease), IgG4-RKD (IgG4-related kidney disease), MRI (magnetic resonance imaging)
      Article Highlights
      • First identified in the initial years of the 21st century as a unified disorder, IgG4-related disease (IgG4-RD) is a multiorgan entity that integrates numerous conditions formerly considered unrelated, single-organ diseases.
      • Serum IgG4 levels were initially thought to be a key diagnostic feature of IgG4-RD, but recent evidence has de-emphasized the value of elevated serum IgG4 levels.
      • The key to diagnosis is immunohistochemical demonstration of tissue infiltration by IgG4-bearing plasma cells and morphological evidence of lymphoplasmacytic infiltrates, storiform fibrosis, and obliterative phlebitis.
      • Although the heterogeneous clinical, laboratory, and histological presentation affecting a wide range of organ systems means that the diagnostic approach may be complex, IgG4-RD should be clinically suspected in patients presenting with unexplained enlargement or swelling of 1 or more organs or tissues.
      • The more clinical, laboratory, imaging, and pathological red flags the patient presents, the greater the likelihood of a diagnosis of IgG4-RD.
      • New research suggests a promising role of flow cytometry analysis in the diagnosis and longitudinal management of IgG4-RD.
      IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disease characterized by the infiltration of IgG4-bearing plasma cells into affected organs and tissues. Many patients also have a marked elevation in the serum concentrations of IgG4.
      • Stone J.H.
      • Zen Y.
      • Deshpande V.
      IgG4-related disease.
      This disease was first identified in the initial years of the 21st century by Japanese investigators.
      • Mahajan V.S.
      • Mattoo H.
      • Deshpande V.
      • Pillai S.S.
      • Stone J.H.
      IgG4-related disease.
      • Stone J.H.
      IgG4-related disease: nomenclature, clinical features, and treatment.
      It was recognized initially in patients with sclerosing pancreatitis—now known as type 1 (IgG4-related) autoimmune pancreatitis—who were found to have the same histopathological features in extrapancreatic organs as in the pancreas, thus heralding a multiorgan disease. Since 2003, the disease has been reported in nearly every organ.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      The diagnosis of IgG4-RD now provides context for various single organ syndromes that once seemed highly disparate. Examples of this are Riedel thyroiditis, Küttner tumor (sclerosing sialadenitis of the submandibular gland), Mikulicz disease (simultaneous lacrimal, parotid, and submandibular gland involvement), and Ormond disease (retroperitoneal fibrosis). The epidemiology of this disease has not been explored in detail, although nearly 80% of patients have been reported from Japan, with a mean age of approximately 60 years at diagnosis and with a male predominance.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      Although the clinical presentations are protean and the natural history is variable, many organ system manifestations of IgG4-RD can quickly lead to the failure of vital organs such as pancreas, liver and biliary tree, kidneys, or aorta.
      Few data exist on the diagnostic approach to patients with suspected IgG4-RD. This review addresses current knowledge about the diagnosis of IgG4-RD, focusing on the clinical, laboratory, radiological, and pathological features that may facilitate an early diagnosis of this complex disease. The authors searched PubMed and MEDLINE for potentially relevant articles published from January 1, 2000, through November 1, 2014, using the search terms IgG4 and IgG4-related. Searches were boosted by examining references of identified articles, and articles judged relevant were selected for full-text review. We selected publications since 2000, because it was not until 2003 that the multiorgan nature of IgG4-RD was unearthed.

      Clinical Suspicion

      The signs and symptoms of IgG4-RD at presentation are diverse and may be divided into general and organ-specific signs and symptoms.

       General Signs and Symptoms

      IgG4-related disease usually presents subacutely, and most patients do not appear at first to be severely ill (ie, constitutional symptoms such as hectic fevers or other features suggesting infection or sepsis are absent). Some patients lose a substantial amount of weight (eg, 10-25 lb); however, the period over which the weight is lost is many months, and many weeks elapse before patients realize that they are ill. Most reports have focused on describing the organs involved and not on the signs and symptoms that led ultimately to diagnosis. Only 2 small series including a total of 53 patients with systemic IgG4-RD reported detailed signs and symptoms at diagnosis.
      • Ebbo M.
      • Daniel L.
      • Pavic M.
      • et al.
      IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry.
      • Chen H.
      • Lin W.
      • Wang Q.
      • et al.
      IgG4-related disease in a Chinese cohort: a prospective study.
      The main general symptoms included asthenia in 14 patients (26%), weight loss in 11 (21%), and fever in 4 (8%).

       Organ-Specific Signs and Symptoms

      The classic feature of IgG4-RD is a tumefactive lesion in 1 or more organs. Of the 832 reported cases in which the number of organs affected was detailed,
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      approximately 40% of the patients had single-organ involvement—usually with a tumefactive lesion—at the time of their description. In the 2 aforementioned small series,
      • Ebbo M.
      • Daniel L.
      • Pavic M.
      • et al.
      IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry.
      • Chen H.
      • Lin W.
      • Wang Q.
      • et al.
      IgG4-related disease in a Chinese cohort: a prospective study.
      organ-specific symptoms at diagnosis included abdominal pain in 21 patients (40%), sicca features in 8 (15%), respiratory symptoms in 7 (13%), pruritus in 7 (13%), and diarrhea in 3 (6%). Sentinel signs, that is, findings that on further evaluation led directly to the diagnosis, included salivary gland swelling in 22 patients (42%), lymphadenopathy in 22 (42%), jaundice in 12 (23%), lacrimal gland swelling in 14 (26%), hepatomegaly in 3 (6%), and splenomegaly in 2 (4%).
      The presenting features of IgG4-RD vary substantially according to the specific specialty evaluating the patient first. Gastroenterologists are more likely to encounter patients with jaundice, pruritus, and mild abdominal discomfort resulting from autoimmune pancreatitis or IgG4-related sclerosing cholangitis. Ophthalmologists are more likely to be referred patients with lacrimal gland swelling or other orbital lesions. Nephrologists may be called to evaluate patients with renal dysfunction caused by tubulointerstitial nephritis or, rarely, nephrotic range proteinuria associated with IgG4-related membranous glomerulonephropathy (GN). Although rheumatologists are perhaps most likely to encounter patients with major salivary gland enlargement because this disease feature often raises the spectrum of Sjögren syndrome, these specialists may also be consulted in the setting of multiorgan disease.
      Multiorgan disease is sometimes easier to identify at diagnosis because patients appear more ill, yet multiorgan disease can evolve metachronously, adding 1 organ at a time, over months or even years, thereby achieving a subtle presentation.
      • Stone J.H.
      • Zen Y.
      • Deshpande V.
      IgG4-related disease.
      As mentioned earlier, involvement of major organs may lead to organ failure.

      Laboratory Abnormalities

       Routine Tests

      Routine laboratory tests such as complete blood cell counts and biochemical profiles often provide nonspecific indications of organ involvement that require further investigation. In particular, abnormalities of liver function tests that suggest biliary obstruction should focus diagnostic efforts on the pancreas and biliary tree, whereas elevated serum creatinine levels or proteinuria may signal renal disease. Mild-to-moderate peripheral eosinophilia is found in 34% of patients (Table 1), but this finding is quite nonspecific and does not guide the physician to a specific organ that can be targeted for biopsy.
      Table 1Main Laboratory Abnormalities and Immunological Features Detailed in the Main Series (n>10) of Patients With IgG4-Related Disease
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      ,
      Values are presented as n/N (%) or as otherwise indicated, with n = number of cases with the feature, and N = number of cases in which the feature was detailed.
      Elevated C-reactive protein levels33/182 (18)
      Eosinophilia74/219 (34)
      Serum IgG levels (mg/dL)
       >1800313/510 (61)
       Mean of individual values (n=192)2589.17 (range, 611-9470)
      Range of mean IgG values (26 studies) (mg/dL)
       <18004/26 (15)
       1800-360020/26 (77)
       3601-50002/26 (8)
      Serum IgG4 levels (mg/dL)
       >1351586/1883 (84)
       Mean of individual values (n=192)769.42 (range, 15-4020)
      Range of mean IgG4 values (42 studies) (mg/dL)
       <1351/42 (2)
       135-2704/42 (10)
       271-5408/42 (19)
       541-108024/42 (57)
       >10805/44 (11)
      Mean serum IgG4/total IgG ratio (%)39.92 (range, 25-86)
      Serum IgE levels >360 IU/mL96/165 (58)
      Autoantibodies and complement
       Antinuclear antibodies168/524 (32)
       Rheumatoid factor50/255 (20)
       Anti-Ro/SSA antibodies14/249 (6)
       Anti-La/SSB antibodies0/249 (0)
       Low complement levels80/220 (36)
      a Values are presented as n/N (%) or as otherwise indicated, with n = number of cases with the feature, and N = number of cases in which the feature was detailed.
      Elevated C-reactive protein levels were reported in 23% of cases.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      Even in the setting of multiorgan disease, elevation in serum C-reactive protein concentrations is, however, generally modest and is less pronounced than is elevation in the erythrocyte sedimentation rate.

       Serum IgG4 Levels

      Although most patients with IgG4-RD have elevated serum IgG4 concentrations, the range varies widely. A serum IgG4 level of greater than 135 mg/dL (to convert to mmol/L, multiply by 0.0259), the upper limit of normal for many reference laboratories, was reported in 1586 of 1883 patients (84%) for whom such data were detailed.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      The mean serum IgG4 level, reported individually in 349 cases, was 769 mg/dL, ranging between 15 and 4020 mg/dL (Table 1). Of the nearly 40 studies in which the mean IgG4 level was reported,
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      more than half reported a mean value that was 4 to 6 times higher than the upper limit of normal. Only 5 studies reported a mean serum IgG4 concentration more than 6 times the upper limit of normal, and only 4 had mean values between 135 and 270 mg/dL (ie, a maximum of 2 times higher than the cutoff).
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      Some studies also measured the IgG4/total IgG ratio, which is usually less than 5%. The mean ratio found in these studies was 40%, ranging from 25% to 86%.
      • Takahashi H.
      • Yamamoto M.
      • Tabeya T.
      • et al.
      The immunobiology and clinical characteristics of IgG4 related diseases.
      • Ohta N.
      • Kurakami K.
      • Ishida A.
      • et al.
      Clinical and pathological characteristics of IgG4-related sclerosing sialadenitis.
      The frequency of serum IgG4 concentration elevation in cohorts of patients with IgG4-RD may be affected profoundly by the manner in which potential patients of the cohort were identified originally. Two studies from 1 major referral center illustrate this point. When cases were sought by querying the hospital laboratory database about the number of patients with abnormally high serum IgG4 concentration measurements, the sensitivity of an elevated serum IgG4 concentration for the diagnosis of IgG4-RD was estimated to be 90%.
      • Carruthers M.N.
      • Khosroshahi A.
      • Augustin T.
      • Deshpande V.
      • Stone J.H.
      The diagnostic utility of serum IgG4 concentrations in IgG4-related disease.
      However, when histopathological proof of IgG4-RD was the main criterion for cohort entry (ie, potential patients entered the cohort through the pathology department rather than through serological testing), just over half of the patients with biopsy-proven disease were found to have elevated serum IgG4 concentrations before treatment.
      • Wallace Z.S.
      • Deshpande V.
      • Mattoo H.
      • Mahajan V.S.
      • Kulikova M.
      • Pillai S.
      • Stone J.H.
      IgG4-related disease: baseline clinical and laboratory features in 125 patients with biopsy-proven disease.
      Several major points should be drawn from contrasting studies from the same center. First, elevated serum IgG4 levels by themselves have a low specificity (60%) and a low positive predictive value (34%) for the diagnosis of IgG4-RD.
      • Carruthers M.N.
      • Khosroshahi A.
      • Augustin T.
      • Deshpande V.
      • Stone J.H.
      The diagnostic utility of serum IgG4 concentrations in IgG4-related disease.
      Second, a large proportion of patients with biopsy-proven, clinically validated IgG4-RD have normal serum IgG4 levels, even before beginning treatment.
      • Wallace Z.S.
      • Deshpande V.
      • Mattoo H.
      • Mahajan V.S.
      • Kulikova M.
      • Pillai S.
      • Stone J.H.
      IgG4-related disease: baseline clinical and laboratory features in 125 patients with biopsy-proven disease.
      Therefore, reliance on serum IgG4 concentration elevation for diagnosis is certain to lead to substantial underdiagnosis. Finally, in patients with elevated serum IgG4 levels, the range of values is extremely wide.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      Factors contributing to such IgG4 response variability remain poorly defined. Nevertheless, although current diagnostic criteria of IgG4-RD recommend the measurement of serum IgG4 levels, most patients with this disease may often be identified by high serum IgG4 concentrations and can be diagnosed in combination with other components such as imaging and histology.
      • Mahajan V.S.
      • Mattoo H.
      • Deshpande V.
      • Pillai S.S.
      • Stone J.H.
      IgG4-related disease.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      Therefore, rigorous clinicopathologic correlation is required to ensure that the disease is neither overdiagnosed nor underdiagnosed on the basis of serum IgG4 values.
      Serum IgG4 concentration tends to correlate with the number of organs involved: the greater the number of organs affected, the higher the serum concentration.
      • Carruthers M.N.
      • Khosroshahi A.
      • Augustin T.
      • Deshpande V.
      • Stone J.H.
      The diagnostic utility of serum IgG4 concentrations in IgG4-related disease.
      In addition, elevated serum IgG4 concentrations appear to identify a subset of IgG4-RDs that are more “inflammatory” as compared with normal serum IgG4 levels. That is, patients with elevated serum IgG4 concentrations denote a large subset of patients with IgG4-RD whose disease is characterized by more extensive organ involvement, high inflammatory markers, low complement levels, and (possibly) greater refractoriness to treatment as compared with patients with normal IgG4 levels.
      • Matsubayashi H.
      • Sawai H.
      • Kimura H.
      • et al.
      Characteristics of autoimmune pancreatitis based on serum IgG4 level.
      • Wallace Z.S.
      • Mattoo H.
      • Carruthers M.
      • et al.
      Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations.
      • Kawa S.
      • Ito T.
      • Watanabe T.
      • et al.
      The utility of serum IgG4 concentrations as a biomarker.
      • Kaji R.
      • Takedatsu H.
      • Okabe Y.
      • et al.
      Serum immunoglobulin G4 associated with number and distribution of extrapancreatic lesions in type 1 autoimmune pancreatitis patients.
      In a study of patients with autoimmune pancreatitis, Matsubayashi et al
      • Matsubayashi H.
      • Sawai H.
      • Kimura H.
      • et al.
      Characteristics of autoimmune pancreatitis based on serum IgG4 level.
      reported a higher frequency of certain symptoms (eg, jaundice) and number of extrahepatic lesions together with a large size of pancreatic lesions in patients with higher IgG4 levels.
      A potential pitfall in serum-based diagnosis is related to the technique used for measuring IgG4 levels. Some nephelometry assays are susceptible to the prozone or “hook” effect, which leads to spuriously low reports of the “antigen” being measured (IgG4 in this case). This prozone effect is more likely to occur when conditions of large antigen excess exist. Falsely low measurements of serum IgG4 concentrations were reported in 26% of patients in 1 study because of the prozone effect.
      • Khosroshahi A.
      • Cheryk L.A.
      • Carruthers M.N.
      • Edwards J.A.
      • Bloch D.B.
      • Stone J.H.
      Brief Report: spuriously low serum IgG4 concentrations caused by the prozone phenomenon in patients with IgG4-related disease.
      This error in measurement can be circumvented by performing appropriate dilutions, which allow for the reagent antibody to remain in excess of the antigen of interest. Newer assays designed to detect higher serum IgG4 concentrations have the potential to prevent this problem in the future.

       Polyclonal Hypergammaglobulinemia

      Hypergammaglobulinemia (total serum IgG levels >1800 mg/dL) was reported in 313 of 510 cases (61%). The mean serum IgG level detailed individually in 192 cases was 2589 mg/dL, ranging between 611 and 9470 mg/dL (Table 1). Most studies reported a mean of serum IgG levels between 1800 and 3600 mg/dL.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      Although serum IgE levels were elevated in 96 (58%) of 165 patients included in 10 studies,
      • Ebbo M.
      • Daniel L.
      • Pavic M.
      • et al.
      IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry.
      • Chen H.
      • Lin W.
      • Wang Q.
      • et al.
      IgG4-related disease in a Chinese cohort: a prospective study.
      • Li Y.
      • Nishihara E.
      • Hirokawa M.
      • Taniguchi E.
      • Miyauchi A.
      • Kakudo K.
      Distinct clinical, serological, and sonographic characteristics of Hashimoto’s thyroiditis based with and without IgG4-positive plasma cells.
      • Moteki H.
      • Yasuo M.
      • Hamano H.
      • Uehara T.
      • Usami S.
      IgG4-related chronic rhinosinusitis: a new clinical entity of nasal disease.
      • Sato Y.
      • Inoue D.
      • Asano N.
      • et al.
      Association between IgG4-related disease and progressively transformed germinal centers of lymph nodes.
      • Della Torre E.
      • Mattoo H.
      • Mahajan V.S.
      • Carruthers M.
      • Pillai S.
      • Stone J.H.
      Prevalence of atopy, eosinophilia, and IgE elevation in IgG4-related disease.
      • Matsui S.
      • Hebisawa A.
      • Sakai F.
      • et al.
      Immunoglobulin G4-related lung disease: clinicoradiological and pathological features.
      • Sato Y.
      • Takeuchi M.
      • Takata K.
      • et al.
      Clinicopathologic analysis of IgG4-related skin disease.
      • Hirano K.
      • Tada M.
      • Sasahira N.
      • et al.
      Incidence of malignancies in patients with IgG4-related disease.
      • Sogabe Y.
      • Ohshima K.
      • Azumi A.
      • et al.
      Location and frequency of lesions in patients with IgG4-related ophthalmic diseases.
      a recent study reported the presence of serum monoclonal bands in patients with IgG4-RD due to the relatively restricted migration of polyclonal IgG4, which may form a characteristic focal band bridging the β and γ fraction in serum protein electrophoresis.
      • Jacobs J.F.
      • van der Molen R.G.
      • Keren D.F.
      Relatively restricted migration of polyclonal IgG4 may mimic a monoclonal gammopathy in IgG4-related disease.

       Autoantibodies

      No specific autoantibody has been described consistently in patients with IgG4-RD, but the finding of nonspecific antibodies common to other immune-mediated conditions is common.
      The prevalence of serum positive antinuclear antibody and rheumatoid factor in patients with IgG4-RD, for example, is nearly 30% and 20%, respectively (Table 1). Most positive antinuclear antibody and rheumatoid factor assays are associated with low serum titers. Identification of more specific autoantibodies such as anti-Ro/SSA, anti–double stranded DNA, or anti–neutrophil cytoplasmic antibodies is highly unusual, however, and should suggest the presence of another condition, such as Sjögren syndrome, systemic lupus erythematosus, or granulomatosis with polyangiitis, respectively. In contrast, hypocomplementemia was reported in 115 of 281 patients (41%) in whom the test was done.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      Hypocomplementemia is a particularly common finding in patients with IgG4-related kidney disease (IgG4-RKD). The precise mechanisms for this association remain to be defined. Although, in theory, IgG4 does not bind complement effectively,
      • Davies A.M.
      • Rispens T.
      • Ooijevaar-de Heer P.
      • et al.
      Structural determinants of unique properties of human IgG4-Fc.
      immune complexes composed of other immunoglobulin subclasses that bind the complement more effectively (eg, IgG1 and IgG3) may account for this finding.

      Imaging Studies

      Cross-sectional imaging studies using computed tomography (CT) or magnetic resonance imaging (MRI) play an important diagnostic role. Organ lesions of IgG4-RD frequently lead to the finding of organ enlargement or frank pseudotumors on CT. These same lesions usually generate low signal intensity on T2-weighted MRI.
      • Toyoda K.
      • Oba H.
      • Kutomi K.
      • et al.
      MR imaging of IgG4-related disease in the head and neck and brain.
      • Fujita A.
      • Sakai O.
      • Chapman M.N.
      • Sugimoto H.
      IgG4-related disease of the head and neck: CT and MR imaging manifestations.
      Some studies have suggested a potential diagnostic role of 18F-fluorodeoxyglucose positron emission tomography/CT .
      • Taniguchi Y.
      • Ogata K.
      • Inoue K.
      • Terada Y.
      Clinical implication of FDG-PET/CT in monitoring disease activity in IgG4-related disease.
      • Nguyen V.X.
      • De Petris G.
      • Nguyen B.D.
      Usefulness of PET/CT imaging in systemic IgG4-related sclerosing disease: a report of three cases.
      A recent study identified a more extensive disease using positron emission tomography/CT in nearly 70% of cases in comparison with the standard evaluation (ie, physical examination, ultrasonography, and CT).
      • Zhang J.
      • Chen H.
      • Ma Y.
      • et al.
      Characterizing IgG4-related disease with (18)F-FDG PET/CT: a prospective cohort study.
      Positron emission tomography/CT may be more sensitive than conventional imaging studies to detect some specific organ involvements such as major salivary glands, lymph nodes, or vascular involvement but less sensitive for small-sized lesions or brain and kidney involvement.
      • Ebbo M.
      • Grados A.
      • Guedj E.
      • et al.
      Usefulness of 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography for staging and evaluation of treatment response in IgG4-related disease: a retrospective multicenter study.

       Pancreatic and Biliary Tract Involvement

      The pancreas is among the most commonly affected organs in IgG4-RD. Abdominal CT often shows pancreatic enlargement, more frequently focal (56%) than diffuse (44%).
      • Matsubayashi H.
      • Sawai H.
      • Kimura H.
      • et al.
      Characteristics of autoimmune pancreatitis based on serum IgG4 level.
      • Ghazale A.
      • Chari S.T.
      • Zhang L.
      • et al.
      Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy.
      Focal lesions can easily be confused with malignant pancreatic neoplasms. The morphology of the pancreas is often described as sausage-shaped when the enlargement is diffuse. Edema around the rim of the organ leads to enhancement. Pancreatic atrophy—either diffuse or distal—has also been reported.
      • Ghazale A.
      • Chari S.T.
      • Zhang L.
      • et al.
      Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy.
      • You M.W.
      • Kim J.H.
      • Byun J.H.
      • et al.
      Relapse of IgG4-related sclerosing cholangitis after steroid therapy: image findings and risk factors.
      Uncommon radiological findings are those of acute pancreatitis (inflammation and edema), a normal-size gland with diffusely decreased enhancement, and a normal pancreatic appearance on imaging.
      • Ghazale A.
      • Chari S.T.
      • Zhang L.
      • et al.
      Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy.
      Biliary strictures caused by the inflammation of the bile ducts are the key sign in imaging studies of IgG4-related sclerosing cholangitis. These have been classified according to their cholangiographic location into 4 types: type 1, stricture localized to the distal common bile duct; type 2, stricture involving the intrahepatic bile ducts; type 3, strictures involving both the hilar and distal common bile ducts; and type 4, strictures of only hilar bile ducts.
      • Nakazawa T.
      • Ohara H.
      • Sano H.
      • Ando T.
      • Joh T.
      Schematic classification of sclerosing cholangitis with autoimmune pancreatitis by cholangiography.
      Type 1 strictures—those localized to the distal common bile duct—are the most common. Three studies including 428 patients found that types I, II, III, and IV patterns were present in 66%, 15%, 13%, and 11% of patients, respectively.
      • Nakazawa T.
      • Naitoh I.
      • Hayashi K.
      • et al.
      Diagnostic criteria for IgG4-related sclerosing cholangitis based on cholangiographic classification.
      • Ohara H.
      • Nakazawa T.
      • Kawa S.
      • et al.
      Establishment of a serum IgG4 cut-off value for the differential diagnosis of IgG4-related sclerosing cholangitis: a Japanese cohort.
      • Tanaka A.
      • Tazuma S.
      • Okazaki K.
      • Tsubouchi H.
      • Inui K.
      • Takikawa H.
      Nationwide survey for primary sclerosing cholangitis and IgG4-related sclerosing cholangitis in Japan.
      A recent study reported that although the presence of continuous stricture in the bile ducts, gallbladder involvement, and single-wall common bile duct thickness greater than 2.5 mm may help differentiate IgG4-RD from other inflammatory biliary diseases, the location and length of common bile duct stricture were less useful.
      • Tokala A.
      • Khalili K.
      • Menezes R.
      • Hirschfield G.
      • Jhaveri K.S.
      Comparative MRI analysis of morphologic patterns of bile duct disease in IgG4-related systemic disease versus primary sclerosing cholangitis.

       Salivary Gland Involvement

      Major salivary glands enlargement is a common hallmark of IgG4-RD, with the submandibular glands being more commonly affected than the parotid glands. Some studies using ultrasound studies to characterize glandular involvement of IgG4-RD have revealed multiple hypoechoic areas in enlarged glands as the foremost finding.
      • Takagi Y.
      • Nakamura H.
      • Origuchi T.
      • et al.
      IgG4-related Mikulicz’s disease: ultrasonography of the salivary and lacrimal glands for monitoring the efficacy of corticosteroid therapy.
      Asai et al
      • Asai S.
      • Okami K.
      • Nakamura N.
      • et al.
      Localized or diffuse lesions of the submandibular glands in immunoglobulin G4-related disease in association with differential organ involvement.
      reported 2 patterns in submandibular glands, namely, localized tumor-forming and diffuse focal involvement. With regard to MRI studies, main reported features are well-defined, iso/hypointense T2-weighted MRI lesions, with homogeneous enhancement without vascular occlusion or compression signs.
      • Katsura M.
      • Mori H.
      • Kunimatsu A.
      • et al.
      Radiological features of IgG4-related disease in the head, neck, and brain.

       Ocular Involvement

      Ocular CT imaging studies disclosed not only a predominant involvement of lachrymal glands (often bilateral) but also involvement of other tissues including trigeminal nerve branches (frontal, supraorbital, or infraorbital nerves), extraocular muscles (orbital myositis), orbital fat tissue, eyelids, and nasolacrimal duct or bones comprising part of the orbit.
      • Wallace Z.S.
      • Deshpande V.
      • Stone J.H.
      Ophthalmic manifestations of IgG4-related disease: single-center experience and literature review.
      Ocular adnexal lesions exhibited well-defined margins, isoattenuation on precontrast CT studies, T1-isointense and T2-hypointense MRI lesions with a homogeneous internal architecture, enhancement patterns, and bone remodeling without destruction.
      • Song Y.S.
      • Choung H.K.
      • Park S.W.
      • Kim J.H.
      • Khwarg S.I.
      • Jeon Y.K.
      Ocular adnexal IgG4-related disease: CT and MRI findings.

       Pulmonary Involvement

      CT pulmonary lesions have been classified into 4 types: (1) thickening of bronchovascular bundles and interlobular septa (20 cases); (2) solid nodules resembling primary lung cancer (19 cases); (3) interstitial involvement (3 cases); and (4) round-shaped ground-glass opacities resembling bronchioloalveolar carcinoma (1 case).
      • Matsui S.
      • Hebisawa A.
      • Sakai F.
      • et al.
      Immunoglobulin G4-related lung disease: clinicoradiological and pathological features.
      • Inoue D.
      • Zen Y.
      • Abo H.
      • et al.
      Immunoglobulin G4-related lung disease: CT findings with pathologic correlations.
      Pleural effusions are unusual and seldom dominate the clinical picture, but pronounced pleural thickening is not uncommon. Hilar and/or mediastinal lymphadenopathy accompanies most cases of pulmonary disease.

       Renal Involvement

      Intrarenal disease has been described in 13% of patients who reported systemic involvement at presentation.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      CT imaging has revealed kidney abnormalities in nearly 70% of patients with IgG4-RKD.
      • Saeki T.
      • Kawano M.
      • Mizushima I.
      • et al.
      The clinical course of patients with IgG4-related kidney disease.
      Most common findings are multiple low-density lesions with T2 hypointensity, diffusion restriction, and a progressive enhancement pattern in more than half of the cases, followed by diffuse renal swelling (typically bilateral) and diffuse thickening of the renal pelvis wall.
      • Saeki T.
      • Kawano M.
      • Mizushima I.
      • et al.
      The clinical course of patients with IgG4-related kidney disease.
      • Raissian Y.
      • Nasr S.H.
      • Larsen C.P.
      • et al.
      Diagnosis of IgG4-related tubulointerstitial nephritis.
      Solitary nodules or cysts have rarely been reported. Renal atrophy is infrequently found at diagnosis, but it has been reported in nearly half of the cases during follow-up, even in those patients who appeared to respond well to glucocorticoid treatment.
      • Saeki T.
      • Kawano M.
      • Mizushima I.
      • et al.
      The clinical course of patients with IgG4-related kidney disease.

       Retroperitoneal Involvement

      Retroperitoneal fibrosis has been reported in 13% of patients presenting systemic IgG4-RD.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      CT findings have documented the primary locations of retroperitoneal masses as periaortic (83%) and peri-iliac (67%), even though pericaval, presacral, retrovesicular, and perirectal locations also occur.
      • Khosroshahi A.
      • Carruthers M.N.
      • Stone J.H.
      • et al.
      Rethinking Ormond’s disease: “idiopathic” retroperitoneal fibrosis in the era of IgG4-related disease.
      One third of patients have concomitant hydronephrosis, more commonly unilateral. Intra-abdominal, inguinal, and axillary lymphadenopathy is common in the setting of IgG4-related retroperitoneal fibrosis. Furthermore, aortitis is a common finding in imaging studies (periaortitis, aortic dilatation, and aneurysms).

       Central Nervous System Involvement

      Involvement of the central nervous system has been reported infrequently. Hypertrophic pachymeningitis has been identified by localized or diffuse thickening of the cranial or spinal cord dura mater, with imaging studies commonly disclosing either linear dural thickening or a bulging mass.
      • Inoue D.
      • Zen Y.
      • Sato Y.
      • et al.
      IgG4-related perineural disease.
      Destructive bone involvement has been reported in isolated cases, affecting the bones of the orbit or the temporal, maxillary, or mastoid bones, and cranial nerves are often involved in adjacent tumor masses. Involvement of the hypophysis is rare. MRI studies typically reveal enlargement of the anterior pituitary and thickening of the pituitary stalk.

      Histopathological Approach

      Histopathological analysis of specimens from the organ involved remains the diagnostic cornerstone of IgG4-RD. Needle biopsies are generally useful in excluding malignancies but often provide insufficient quantities of tissue to confirm a diagnosis of IgG4-RD.
      • Deshpande V.
      • Zen Y.
      • Chan J.K.
      • et al.
      Consensus statement on the pathology of IgG4-related disease.

       Morphological Data

      The key morphological features of IgG4-RD are dense lymphoplasmacytic infiltrates, fibrosis with a storiform pattern, obliterative phlebitis, and (often) eosinophilic infiltration.
      • Raissian Y.
      • Nasr S.H.
      • Larsen C.P.
      • et al.
      Diagnosis of IgG4-related tubulointerstitial nephritis.
      Table 2 summarizes the prevalence of the chief histopathological features.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      Storiform fibrosis, eosinophilic infiltration, and obliterative phlebitis were found in 78%, 51%, and 40% of cases, respectively. Confident pathological diagnosis requires the presence of at least 2 of these major histological features and careful clinicopathologic correlation. In contrast, the presence of epithelioid cell granulomas, other features of granulomatous inflammation, and the finding of a prominent neutrophil infiltrate are all highly atypical of IgG4-RD and must trigger consideration of other diagnoses.
      • Deshpande V.
      • Zen Y.
      • Chan J.K.
      • et al.
      Consensus statement on the pathology of IgG4-related disease.
      IgG4-related disease is analogous to sarcoidosis in 1 fundamental way: regardless of the organ involved, the same histopathological features are found throughout all involved organs.
      Table 2Main Pathological Features Detailed in the Main Series (n>10) of Patients With IgG4-Related Disease
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      ,
      HPF = high-power field.
      ,
      Values are presented as n/N (%) or as otherwise indicated, with n = number of cases with the feature, and N = number of cases in which the feature was detailed.
      Histopathological features
       Lymphocytic infiltration509/511 (100)
       Fibrosis238/305 (78)
       Storiform fibrosis56/76 (74)
       Phlebitis136/317 (43)
       Obliterative phlebitis124/306 (41)
       Eosinophilia130/257 (51)
       Follicular lymphoid formation98/204 (48)
       Germinal centers31/59 (53)
      No. of IgG4+ cells per HPF
       Mean of individual values (n=57)117.6 (range, 1-396)
      Range of mean IgG4+ cells per HPF (11 studies)
       10-301/11 (9)
       31-502/11 (18)
       51-1001/11 (9)
       101-2004/11 (36)
       >2003/11 (27)
      IgG4+/total IgG+ cell ratio (%)
       Mean of individual values (n=139)57.84 (range, 0-100)
       Ratio used in 9 studies
      >30%6/9 (67)
      >40%2/9 (22)
      >50%1/9 (11)
      a HPF = high-power field.
      b Values are presented as n/N (%) or as otherwise indicated, with n = number of cases with the feature, and N = number of cases in which the feature was detailed.
      Subtle variations in histopathological findings exist between some organs.
      • Deshpande V.
      • Zen Y.
      • Chan J.K.
      • et al.
      Consensus statement on the pathology of IgG4-related disease.
      As an example, typical storiform fibrosis is rare in lacrimal, parotid, and minor salivary glands and in interstitial lung disease, whereas obliterative phlebitis is reported more frequently in the pancreas and submandibular glands than in the parotid/lacrimal glands, lymph nodes, or kidneys.
      • Deshpande V.
      • Zen Y.
      • Chan J.K.
      • et al.
      Consensus statement on the pathology of IgG4-related disease.

       Immunohistochemical Studies

      Immunohistochemical studies with IgG4 and IgG staining represent an important part of the pathological diagnosis of IgG4-RD.
      • Stone J.H.
      • Zen Y.
      • Deshpande V.
      IgG4-related disease.
      Tissue infiltration by IgG4+ plasma cells is a strong characteristic of IgG4-RD, but does not constitute a sine qua non finding for diagnosis because, as noted, an impressively long list of other diagnoses can be associated with tissue-infiltrating IgG4+ plasma cells.
      • Deshpande V.
      • Zen Y.
      • Chan J.K.
      • et al.
      Consensus statement on the pathology of IgG4-related disease.
      In addition, in some cases, there is a paucity of infiltrating IgG4+ plasma cells and the diagnosis is based on the morphologic appearance.
      • Mahajan V.S.
      • Mattoo H.
      • Deshpande V.
      • Pillai S.S.
      • Stone J.H.
      IgG4-related disease.
      • Deshpande V.
      • Zen Y.
      • Chan J.K.
      • et al.
      Consensus statement on the pathology of IgG4-related disease.
      Semiquantitative analysis of IgG4 immunostaining helps distinguish IgG4-RD from other conditions. Various cutoff values ranging from more than 10 to more than 50 IgG4+ plasma cells per high-power field (HPF) have been proposed. The mean number of IgG4+ cells per HPF detailed in 57 cases was 118 (ranging from 1 to 396).
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      In 11 studies in which the mean number of IgG4+ plasma cells per HPF was detailed, a mean value of more than 100 was found in more than half of the cases, ranging from 13 to 229.
      • Matsui S.
      • Hebisawa A.
      • Sakai F.
      • et al.
      Immunoglobulin G4-related lung disease: clinicoradiological and pathological features.
      • Sato Y.
      • Takeuchi M.
      • Takata K.
      • et al.
      Clinicopathologic analysis of IgG4-related skin disease.
      • Wallace Z.S.
      • Deshpande V.
      • Stone J.H.
      Ophthalmic manifestations of IgG4-related disease: single-center experience and literature review.
      • Khosroshahi A.
      • Carruthers M.N.
      • Stone J.H.
      • et al.
      Rethinking Ormond’s disease: “idiopathic” retroperitoneal fibrosis in the era of IgG4-related disease.
      • Kitagawa S.
      • Zen Y.
      • Harada K.
      • et al.
      Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Küttner’s tumor).
      • Kamisawa T.
      • Nakajima H.
      • Egawa N.
      • Funata N.
      • Tsuruta K.
      • Okamoto A.
      IgG4-related sclerosing disease incorporating sclerosing pancreatitis, cholangitis, sialadenitis and retroperitoneal fibrosis with lymphadenopathy.
      • Geyer J.T.
      • Ferry J.A.
      • Harris N.L.
      • et al.
      Chronic sclerosing sialadenitis (Küttner tumor) is an IgG4-associated disease.
      • Yoo J.J.
      • Park J.J.
      • Kang E.H.
      • et al.
      Risk factors for the recurrence of IgG4-related sclerosing disease without autoimmune pancreatitis.
      • Go H.
      • Kim J.E.
      • Kim Y.A.
      • et al.
      Ocular adnexal IgG4-related disease: comparative analysis with mucosa-associated lymphoid tissue lymphoma and other chronic inflammatory conditions.
      • Agaimy A.
      • Weyand M.
      • Strecker T.
      Inflammatory thoracic aortic aneurysm (lymphoplasmacytic thoracic aortitis): a 13-year-experience at a German Heart Center with emphasis on possible role of IgG4.
      • Suzuki M.
      • Nakamaru Y.
      • Akazawa S.
      • et al.
      Nasal manifestations of immunoglobulin G4-related disease.
      Most patients in whom this feature was detailed had more than10 IgG4+ cells per HPF (498 of 538 [93%]) (Table 2). A critical point in interpreting the number of IgG4+ plasma cell counts within tissues is that the cutoff for a “positive” number varies according to the specific tissue. Guidelines have been suggested in an international consensus report.
      • Deshpande V.
      • Zen Y.
      • Chan J.K.
      • et al.
      Consensus statement on the pathology of IgG4-related disease.
      Measurement of the IgG4+ plasma cell/total IgG+ plasma cell ratio may be useful, especially in cases in which fibrosis predominates. In the 6 studies in which the ratio was detailed, 3 used a minimum ratio of 30%, 1 used 40%, and 2 used 50%.
      • Chen H.
      • Lin W.
      • Wang Q.
      • et al.
      IgG4-related disease in a Chinese cohort: a prospective study.
      • Ohta N.
      • Kurakami K.
      • Ishida A.
      • et al.
      Clinical and pathological characteristics of IgG4-related sclerosing sialadenitis.
      • Inoue D.
      • Zen Y.
      • Abo H.
      • et al.
      Immunoglobulin G4-related lung disease: CT findings with pathologic correlations.
      • Kubota T.
      • Moritani S.
      • Katayama M.
      • Terasaki H.
      Ocular adnexal IgG4-related lymphoplasmacytic infiltrative disorder.
      • Kiyama K.
      • Kawabata D.
      • Hosono Y.
      • et al.
      Serum BAFF and APRIL levels in patients with IgG4-related disease and their clinical significance.
      • Takano K.
      • Keira Y.
      • Seki N.
      • et al.
      Evaluation of submandibular versus labial salivary gland fibrosis in IgG4-related disease.
      The mean IgG4+ plasma cell/total IgG+ plasma cell ratio per HPF specified in 139 cases was 58%, ranging from 0% to 100% (Table 2). A major example of the utility of the IgG4+ plasma cell/total IgG+ plasma cell ratio is in retroperitoneal fibrosis, a condition in which the fibrotic nature of the disease is frequently so dominant at the time of diagnosis that the lymphoplasmacytic infiltrate present early in this condition is sparse by the time the patient comes to medical attention. Finding high numbers of IgG4+ plasma cells per HPF is unlikely in this setting. In such cases, the IgG4+ plasma cell/total IgG+ plasma cell ratio can be useful in suggesting the diagnosis. If there are only 10 plasma cells per HPF but 90% of them are IgG4+, the diagnosis of IgG4-related retroperitoneal fibrosis is tenable if other pathological and clinical features consistent with this diagnosis are present.

       Unusual Case of the Kidney

      IgG4-related kidney disease represents an unusual exception to the pathology of IgG4-RD in that at least 2 types of lesions are found in this organ. Renal biopsy disclosed tubulointerstitial nephritis in 110 of 115 biopsy-proven cases of IgG4-RKD (96%). Such cases of tubulointerstitial nephritis include all the classic histopathological features and immunostaining findings found in other organs affected by IgG4-RD, namely, a lymphoplasmacytic infiltrate, storiform fibrosis, common presence of moderate tissue eosinophilia, and occasional presence of obliterative phlebitis. However, biopsies also disclosed concomitant glomerular lesions in 22% of cases in 1 study.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      Glomerular lesions included various pathologies: membranous GN (n=7), Henoch-Schönlein GN/IgA nephropathy (n=4), focal and segmental endocapillary proliferative GN (n=2), membranoproliferative GN (n=1), mesangial proliferative GN (n=1), and other GN not otherwise specified (n=3).
      • Saeki T.
      • Kawano M.
      • Mizushima I.
      • et al.
      The clinical course of patients with IgG4-related kidney disease.
      • Cornell L.D.
      IgG4-related kidney disease.
      • Yamaguchi Y.
      • Kanetsuna Y.
      • Honda K.
      • et al.
      Characteristic tubulointerstitial nephritis in IgG4-related disease.
      Alexander et al
      • Alexander M.P.
      • Larsen C.P.
      • Gibson I.W.
      • et al.
      Membranous glomerulonephritis is a manifestation of IgG4-related disease.
      recently reported 9 additional patients with membranous GN. Membranous GN secondary to IgG4-RD is a disorder distinct from idiopathic membranous GN, which is characterized by the deposition of immunoglobulin, predominantly IgG4, along the glomerular-basement membrane epithelial surface, and is associated with antibodies directed against the phospholipase A2 receptor.
      • Beck Jr., L.H.
      • Bonegio R.G.
      • Lambeau G.
      • et al.
      M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.
      The presence of both tubulointerstitial nephritis and various glomerular lesions in patients with IgG4-RD strongly suggests the possibility of different pathophysiological mechanisms in these manifestations of renal disease. Further investigation is required to elucidate them.

      Flow Cytometry

      Blood plasmablast concentrations may be superior to serum IgG4 concentrations for the diagnosis of IgG4-RD and offer important possibilities to follow disease activity in the longitudinal evaluation of patients. Untreated patients with IgG4-RD have a marked elevation in blood plasmablast concentrations.
      • Wallace Z.S.
      • Mattoo H.
      • Carruthers M.
      • et al.
      Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations.
      • Mattoo H.
      • Mahajan V.S.
      • Della-Torre E.
      • et al.
      De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease.
      Plasmablasts can be identified through flow cytometry analysis of peripheral blood, gating on cells that are CD19lowCD38+CD20CD27+.
      • Wallace Z.S.
      • Mattoo H.
      • Carruthers M.
      • et al.
      Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations.
      Of note, increased plasmablasts showing CD19+CD38+CD20CD27+ cells in IgG4-RD are also expressed as CD19lowCD38+CD20CD27+ cells.
      • Wallace Z.S.
      • Mattoo H.
      • Carruthers M.
      • et al.
      Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations.
      Interestingly, plasmablasts share some surface markers with human regulatory B cells.
      • Mattoo H.
      • Mahajan V.S.
      • Della-Torre E.
      • et al.
      De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease.
      In several phenotypes of regulatory B cells, CD19+CD24hiCD38hi B cells is one of them, including these plasmablasts,
      • Blair P.A.
      • Noreña L.Y.
      • Flores-Borja F.
      • et al.
      CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients.
      which suggests that increased plasmablasts may be regulatory B cells.
      Concentrations of IgG4+ plasmablasts can also be determined by flow cytometry.
      • Wallace Z.S.
      • Mattoo H.
      • Carruthers M.
      • et al.
      Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations.
      Early studies of flow cytometry in IgG4-RD suggest that circulating plasmablasts are highly elevated even in patients with normal serum IgG4 concentrations. In addition, elevation in plasmablasts appears to decline sharply with therapy and rise again during disease flares. Therefore, plasmablast counts are a potentially useful biomarker for diagnosis, for assessing the response to treatment, and for determining the appropriate time for retreatment. Additional studies of plasmablasts are required, particularly prospective investigations that focus on IgG4+ plasmablasts, the relation of these cells’ concentration to disease activity, and the ability of increases in their concentrations to predict disease relapses.

      Differential Diagnosis

      The first diagnostic challenge is to differentiate whether the clinical picture owes to IgG4-RD or to malignancy, especially when the disease affects a single organ and is either diagnosed unexpectedly in pathological specimens or identified incidentally on radiological studies. It is essential to differentiate single-organ IgG4-RD from pancreatic cancer, cholangiocarcinoma, lung adenocarcinoma, prostate cancer, and lymphoma. Similarly, multiorgan IgG4-RD may mimic lymphoma or a metastatic cancer, with manifestations of weight loss, other constitutional symptoms, and lymphadenopathy.
      Some laboratory abnormalities may help differentiate IgG4-RD from other systemic infiltrative diseases, including eosinophilia, hypergammaglobulinemia, elevated serum IgE levels, hypocomplementemia, and, especially, elevated levels of IgG4. None of these features is pathognomonic of IgG4-RD, however, and even elevated IgG4 levels have been reported in a wide range of diseases (Table 3).
      • Kaji R.
      • Takedatsu H.
      • Okabe Y.
      • et al.
      Serum immunoglobulin G4 associated with number and distribution of extrapancreatic lesions in type 1 autoimmune pancreatitis patients.
      • Yamamoto M.
      • Takahashi H.
      • Tabeya T.
      • et al.
      Risk of malignancies in IgG4-related disease.
      • Tabata T.
      • Kamisawa T.
      • Takuma K.
      • et al.
      Serum IgG4 concentrations and IgG4-related sclerosing disease.
      • Tabata T.
      • Kamisawa T.
      • Takuma K.
      • et al.
      Serial changes of elevated serum IgG4 levels in IgG4-related systemic disease.
      • Terzin V.
      • Földesi I.
      • Kovács L.
      • Pokorny G.
      • Wittmann T.
      • Czakó L.
      Association between autoimmune pancreatitis and systemic autoimmune diseases.
      • Mavragani C.P.
      • Fragoulis G.E.
      • Rontogianni D.
      • Kanariou M.
      • Moutsopoulos H.M.
      Elevated IgG4 serum levels among primary Sjögren’s syndrome patients: do they unmask underlying IgG4-related disease?.
      In addition, limitations about its test characteristics preclude reliance on measurements of serum IgG4 levels for the purpose of diagnosis.
      Table 3Differential Diagnosis in Patients With Suspected IgG4-Related Disease Associated With Elevated Serum IgG4 Levels
      • Yamamoto M.
      • Takahashi H.
      • Tabeya T.
      • et al.
      Risk of malignancies in IgG4-related disease.
      • Tabata T.
      • Kamisawa T.
      • Takuma K.
      • et al.
      Serum IgG4 concentrations and IgG4-related sclerosing disease.
      • Tabata T.
      • Kamisawa T.
      • Takuma K.
      • et al.
      Serial changes of elevated serum IgG4 levels in IgG4-related systemic disease.
      • Terzin V.
      • Földesi I.
      • Kovács L.
      • Pokorny G.
      • Wittmann T.
      • Czakó L.
      Association between autoimmune pancreatitis and systemic autoimmune diseases.
      • Mavragani C.P.
      • Fragoulis G.E.
      • Rontogianni D.
      • Kanariou M.
      • Moutsopoulos H.M.
      Elevated IgG4 serum levels among primary Sjögren’s syndrome patients: do they unmask underlying IgG4-related disease?.
      • Umehara H.
      • Okazaki K.
      • Masaki Y.
      • et al.
      Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.
      DiseaseNo. of patients testedNo. of patients with serum IgG4 levels >135 mg/dLPercentage of patients with IgG4 levels >135 mg/dL
      Sjögren syndrome284227.7
      Pancreatic cancer15385.2
      Systemic lupus erythematosus1221713.9
      Rheumatoid arthritis831214.5
      Biliary tract cancer6446.2
      Chronic pancreatitis4524.4
      Systemic sclerosis4436.8
      Liver cirrhosis2229.1
      Chronic hepatitis2114.8
      Castleman disease16743.7
      Hypereosinophilic syndrome16212.5
      Interstitial lung disease12433.3
      Behçet disease10110
      Eosinophilic granulomatosis with polyangiitis7571.4
      Asthma7114.3
      Inflammatory myopathies6116.7
      Antiphospholipid syndrome5120
      Mixed connective tissue disease500
      Microscopic polyangiitis5120
      Healthy controls7711.3
      SI conversion factor: To convert mg/dL values to mmol/L, multiply by 0.0259.
      With respect to infiltration by IgG4+ cells, multiple clinical entities can be associated with elevated numbers of IgG4+ plasma cells in tissue (Table 4). Yet these conditions lack the characteristic histopathological features of IgG4-RD.
      • Deshpande V.
      • Zen Y.
      • Chan J.K.
      • et al.
      Consensus statement on the pathology of IgG4-related disease.
      For this reason, the presence of the classic histopathological features is actually of greater utility than immunostaining studies for IgG4 positivity in plasma cells. Clinicopathologic correlation is essential to making a diagnosis of IgG4-RD, however, even in the presence of typical histopathological features. The clinician must answer this critical question: Do these pathological findings make sense within the patient’s clinical context? Red flags for the diagnosis of IgG4-RD are shown in Table 5.
      Table 4Differential Diagnosis in Patients With Suspected IgG4-Related Disease Associated With Tissue Infiltration by IgG4+ Cells
      Vasculitis
       Eosinophilic granulomatous with polyangiitis (Churg-Strauss)
       Granulomatosis with polyangiitis (Wegener)
       Hypocomplementemic urticarial vasculitis
      Hematological malignancy
       Castleman disease
       Extranodal marginal zone B-cell lymphoma
       Follicular lymphoma
       Angioimmunoblastic lymphoma
      Solid-organ neoplasms
       Pancreatic cancer
       Lung cancer
       Sarcoma
      Infections
       Pulmonary abscess
       Epstein-Barr virus–related lymphadenopathy
       Aortitis caused by chronic Staphylococcus aureus infection
      Digestive diseases
       Inflammatory bowel disease
       Diverticulitis
      Other systemic diseases
       Rheumatoid arthritis (synovium and lymph nodes)
       Histiocytosis (Rosai-Dorfman disease)
      Table 5Red Flags for the Diagnosis of IgG4-Related Disease
      Epidemiological features
       Middle-aged men
       Patients from Southeast Asian countries
      Clinical findings
       Tumefactive lesion in ≥1 organs
       Abdominal symptoms
       Orbital swelling
       Renal dysfunction
       Salivary gland swelling
       Lymph node enlargement
      Laboratory abnormalities
       Eosinophilia
       Elevated IgE levels
       Hypergammaglobulinemia
       Monoclonal band
       Hypocomplementemia
       IgG4 levels >135 mg/dL
      Imaging findings
       Solitary or multiple nodules/masses
       Enlarged organs
       Homogeneous lesions with well-defined margins
       Enhancement/thickening patterns
       T2-weighted hypointense lesions on magnetic resonance imaging
      Histopathological findings
       Lymphocytic infiltration
       Storiform fibrosis
       Obliterative phlebitis
       Eosinophilic infiltration
      Immunohistochemical findings
       IgG4+ cells per high-power field >10
       IgG4+/total IgG+ cell ratio >40%
      Flow cytometry findings
       Increased circulating plasmablasts (CD19lowCD38+CD20CD27+)
      The more features of different subsets the patient presents, the greater the probability of a diagnosis of IgG4-related disease.

      Diagnostic Criteria

      The diagnostic approach is heterogeneous, and the first proposed sets of criteria centered on specific organs rather than IgG4-RD as a whole. The best examples of organ-specific criteria are those created for IgG4-related pancreatitis, sclerosing cholangitis, kidney disease, and major salivary gland disease. In 2012, Umehara et al
      • Umehara H.
      • Okazaki K.
      • Masaki Y.
      • et al.
      Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.
      proposed a set of criteria for the diagnosis of systemic IgG4-RD designed to be used independently of the predominant organ involvement but exclusively focused on IgG4-related diagnostic tests (in particular elevated serum levels and immunohistochemical studies). The sensitivity and specificity of these criteria remain untested.
      We have found a wide heterogeneity of the diagnostic criteria used in the main studies.
      • Brito-Zerón P.
      • Ramos-Casals M.
      • Bosch X.
      • Stone J.H.
      The clinical spectrum of IgG4-related disease.
      Thus, a significant percentage of studies did not specify the criteria used, and a large percentage used organ-specific criteria, with only 15 using the Umehara criteria,
      • Umehara H.
      • Okazaki K.
      • Masaki Y.
      • et al.
      Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.
      including clinical, serological, and histopathological criteria. In these studies, 82% of patients fulfilled all 3 of the Umehara criteria and were therefore classified as having definitive IgG4-RD, whereas only 7% were classified as probable disease (ie, fulfillment only of clinical and serological criteria).

      Conclusion

      IgG4-related disease is an increasingly recognized systemic disease in adults, with a heterogeneous clinical, laboratory, and histological presentation affecting a wide range of organ systems. The diagnostic approach is complex and should include not only IgG4-related tests (serum levels of IgG4 and immunohistochemical studies) but also an extensive evaluation of the patient’s condition including epidemiological, clinical, laboratory, imaging, and typical pathological features; the more features of different subsets the patient presents, the greater the probability of a diagnosis of IgG4-RD (Figure). Therefore, a compatible clinical and laboratory picture together with elevated serum IgG4 levels and a highly suggestive histopathological setting, including both classical features and immunohistochemical studies, should be considered the ideal scenario for a solid diagnosis of IgG4-RD. This diagnostic approach is common to other complex systemic diseases such as sarcoidosis or adult hemophagocytic syndrome (hemophagocytic lymphohistiocytosis).
      • Ramos-Casals M.
      • Brito-Zerón P.
      • López-Guillermo A.
      • Khamashta M.A.
      • Bosch X.
      Adult haemophagocytic syndrome.
      Flow cytometry will probably play an increasingly important role in the future in diagnosing IgG4-RD.
      Figure thumbnail gr1
      FigureDiagnostic algorithm in IgG4-related disease: sequential diagnostic approach integrating clinical suspicion and IgG4-specific diagnostic tests. HPF = high-power field; MRI = magnetic resonance imaging.
      Advances in the understanding of IgG4-RD are likely to alter the optimal diagnostic approach in the future. With respect to serum IgG4 levels, which were identified as the key feature in identifying the first cases of IgG4-RD, recent studies
      • Carruthers M.N.
      • Khosroshahi A.
      • Augustin T.
      • Deshpande V.
      • Stone J.H.
      The diagnostic utility of serum IgG4 concentrations in IgG4-related disease.
      • Khosroshahi A.
      • Cheryk L.A.
      • Carruthers M.N.
      • Edwards J.A.
      • Bloch D.B.
      • Stone J.H.
      Brief Report: spuriously low serum IgG4 concentrations caused by the prozone phenomenon in patients with IgG4-related disease.
      have reported some significant limitations of their measurement and clinical interpretation, suggesting that the role of serum IgG4 levels in making the diagnosis should be de-emphasized compared with the prominence it has held in the initial years of the description of IgG4-RD. Elevated IgG4 levels in other diseases should be carefully evaluated to rule out potential misdiagnosis or even a possible coexistence of 2 diseases. With regard to histopathological studies and IgG4 tissue immunostaining, abnormal results are the most reliable diagnostic tools at this time, though they are not pathognomonic and may show significant variations depending on the organ whose biopsy was performed, the time of disease evolution (early vs advanced disease), or the therapies administered. Experience is a key factor in interpreting the pathological findings in IgG4-RD.
      This review illustrates the complex approach to the diagnosis of IgG4-RD. The body of the available evidence relies predominantly on a small series of cases, with a high degree of heterogeneity, especially with respect to the lack of a homogeneous organ-by-organ diagnostic approach. Greater understanding of the etiopathogenic mechanisms for the role of IgG4 in organ damage, identification of new disease markers with greatest sensitivity and specificity rates, and, especially, active multidisciplinary collaboration promoting a standardized set of classification criteria, well-designed and internationally validated, which include the main features that help differentiate IgG4-RD from other diseases, will improve the diagnostic approach of this emerging and as yet little-known systemic disease.

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