ImmunoglobulinG4 (IgG4)-related disease is a recently recognized

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1 Summary IgG4-Related Cardiovascular Disorders Miyu Tajima, 1,2 MD, Ryozo Nagai, 3 MD, and Yukio Hiroi, 4 MD Immunoglobulin4 (IgG4)-related disease is a systemic inflammatory disease characterized by elevation of serum IgG4. It involves various organs such as the pancreas (autoimmune pancreatitis), lacrimal gland (Mikulicz s disease), retroperitoneum (retroperitoneal fibrosis), aorta (aortic aneurysm and aortitis), heart (constrictive pericarditis), and pseudotumors around the coronary arteries. These disorders often coexist in accordance with progression of the disease. Because IgG4-related cardiovascular disorder affects the patient s prognosis, early detection and treatment is important. Coronary CT imaging and echocardiography accidentally detect IgG4-related disorders and 18 FDG-PET imaging can identify active inflammation in the lesions. Measurement of serum IgG4 levels and tissue biopsy are necessary for diagnosis. Minor salivary gland biopsy is recommended even though 18 FDG uptake is not detected when it is difficult to obtain a biopsy specimen from IgG4-related cardiovascular lesions. The first-line treatment is high-dose corticosteroid therapy, however, relapse is often reported. Corticosteroids suppress the development of active inflammatory diseases such as aortitis, pericarditis, and pseudotumors, but already-developed lesions do not respond. A large developed aneurysm can rupture even during or after corticosteroid therapy, therefore, additional surgical treatment may be needed. Treatment of IgG4-related cardiovascular disorders might require higher doses of corticosteroids than IgG4-related extracardiovascular disorders. The adequate dose of corticosteroid, type and dose of immunosuppressant, and surgical intervention should be carefully considered on a case-by-case basis. (Int Heart J 2014; 55: ) Key words: Cardiovascular involvement, Aneurysm, Aortitis, Arteritis, Pericarditis, Pseudotumor, Rupture, Biopsy, Corticosteroid ImmunoglobulinG4 (IgG4)-related disease is a recently recognized systemic disease characterized by elevated serum IgG4 level, IgG4-positive lymphocyte infiltration mainly in exocrine tissues and causing fibrosclerotic change in various organs. 1) We recently treated an IgG4-related disease patient with systemic aneurysms and periarteritis. 2) He presented with aneurysms of the ascending aorta, lower abdominal aorta, right carotid artery, coronary arteries, bilateral subclavian arteries, celiac artery, common hepatic artery, and splenic artery. Pseudotumors around coronary arteries and in mediastinum, and pericarditis were also detected. Diagnosis of IgG4-related disease was confirmed by elevated serum IgG4 (2390 mg/dl) and abundant IgG4-positive plasmacyte infiltration in the salivary glands. He died of splenic aneurysm rupture in the sixth month of corticosteroid therapy. Herein, we review the pathology, imaging findings, and treatment of IgG4-related cardiovascular disease. All the pictures shown in this review originate from this patient with IgG4-related cardiovascular disorder, and are different from those in a previous case report. 2) History of IgG4-related disease In 1892 Johann Mikulicz reported a patient with symmetrical swelling of the lacrimal and salivary glands (Mikulicz disease). In 1961 a case of particular pancreatitis with hypergammaglobulinemia was reported 3) and in 1995 the concept of autoimmune pancreatitis (AIP) was proposed. 4) There are two clinically-different types of AIP; type 1 AIP is lymphoplasmacytic sclerosing pancreatitis, while type 2 AIP is idiopathic duct-centric pancreatitis. 5) In 2001, Type 1 AIP with elevated serum IgG4 level and abundant IgG4-positive lymphoplasmacyte infiltration in the pancreas was reported and the concept of IgG4-related disease was proposed. 6) Then, it was gradually discovered that IgG4-related disease involves inflammation and sclerosing in many other organs, 7) especially exocrine organs: 8) bile ducts, 9) lacrimal and salivary glands, 10) retroperitoneum, 11) urinary organs, 12-14) pituitary gland, 15) prostate, 16) arteries, 17-20) veins, 21-23) heart, 24-26) lung, 25,27,28) eye, 24,29) mesenterium, 30) mammary gland, 31) central nervous system, 32) esophagus, 33) stomach, 34) liver, 35) gastrointestinal tract, 36) thyroid, 37,38) nose, 39) blood, 40,41) skin, 42) and pseudotumors in various organs 9,14,25,43-48) (Table). The incidence of IgG4-related disease throughout Japan is estimated at /100,000, mainly occurring in middle-aged to elderly men. The median age of disease onset is 58 years old. The clinical symptoms are usually mild, gradually damaging various organs. 49) This disease has been referred to as several different terms by many researchers: for example, IgG4-related autoimmune disease, 50) IgG4-related sclerosing disease, 51) and IgG4-positive multi-organ lymphoproliferative From the 1 Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 2 Department of Cardiology, Sakakibara Heart Institute, Tokyo, 3 Jichi Medical University, Shimotsuke, Tochigi, and 4 Department of Cardiology, National Center for Global Health and Medicine, Tokyo, Japan. Address for correspondence: Yukio Hiroi, MD, Department of Cardiovascular Medicine, National Center for Global Health and Medicine, Toyama, Shinjukuku, Tokyo , Japan. hiroi-tky@umin.ac.jp Received for publication October 18, Accepted December 16, Released in advance online on J-STAGE June 5, All rights reserved by the International Heart Journal Association. 287

2 288 TAJIMA, ET AL Int Heart J July 2014 Organ Pancreas Bile duct Retroperitoneum Lacrimal gland Salivary gland Urinary organs Pituitary gland Prostate Arteries Veins Heart Lung Eye Table I. IgG4-Related Diseases in Various Organs Mesenterium Mammary gland Central nervous system Esophagus Stomach Liver Gastrointestinal tract Thyroid Nose Blood Skin Various organ (Liver, Breast, Lung, Coronary arteries, Central nerve system, Kidney, Trigeminal Nerve, Testis, Ureter, etc) Disease Autoimmune pancreatitis (AIP) Sclerosing cholangitis Retroperitoneal fibrosis Mikulicz s disease (sialadenitis and dacryoadenitis) Küttner tumor (sialadenitis) Membranous nephropathy Tubulointerstitial nephritis Sclerosing pyelitis Idiopathic segmental ureteritis Hypophysitis Prostatitis Inflammatory aneurysm of arota and its large branches Aortitis/arteritis Periarteritis Obliterative phlebitis (in pancreas, salivary gland, and pseudotumor) Constrictive pericarditis Pseudotumor Coronary artery aneurysm Interstitial pneumonia Hilar lymphadenopathy Uveitis Ocular adnexal lymphoma Sclerosing mesenteritis Mastitis Sclerosing pachymeningitis Vertebral basilar system dolichoectasia Autoimmune neurosensory hearing loss Autoimmune esophagitis Gastric ulcer IgG4 hepatopathy Swelling of papilla of Vater Riedel s thyroiditis Hashimoto s thyroiditis Chronic rhinosinusitis Schonlein-Henoch purpura Autoimmune thrombocytopenia Cutaneous pseudolymphoma Pseudotumor syndrome (IgG4+MOLPS). 52) Japanese foremost experts in this field reached an agreement on the name IgG4-related disease (IgG4-RD) at the IgG4 second meeting in Pathogenesis of IgG4-related disease and aneurysm Recently, the mechanism of IgG4-related disease has become more clear. 53) IgG4 is the least abundant subclass of IgG antibodies (typically < 5%). 54) Although its role is not well understood, it is known that IgG4 sometimes elevates under IgEmediated allergy. 55) T-helper-2 (Th2) cytokines, such as interleukin (IL)-4, IL-5, IL-6, IL-7, IL-9, and IL-13, activate IgG4 production as well as that of IgE. 56) Regulatory T (Treg) cells also induce IgG4 production by anti-inflammatory cytokines such as IL-10 and TGF-beta. 57) Thus, IgG4 could be used as a biomarker of anti-inflammation and fibrosclerosis. On the other hand, other studies suggested that IgG4 may directly act as an anti-inflammatory factor, binding to IgG1, IgG2, and IgG3 on the Fc receptors. 8,54) Decreases in IgA and IgM could cause the increase of IgG4. 58) Okazaki, et al proposed a hypothesis for the pathogenesis of autoimmune pancreatitis, one of IgG4-related disease, as follows: depletion of naive Treg cells in the periphery may allow autoreactive CD4+ T cell infiltration in various organs. These CD4+ T cells probably activate macrophages and induce further proinflammatory activation. 59) As for the role of IgG4 in cardiovascular disorders, Sakamoto, et al reported that IgG4 and soluble interleukin-2 receptors (sil2r) were high in patients with coronary artery stenosis over 50%, suggesting that IgG4-related immuno-inflammation is associated with pathogenesis of coronary atherosclerosis. 60) On the other hand, another immunohistochemical study by Stone, et al. revealed more IgG4-positive plasma cell infiltration in aortic wall of lymphoplasmacytic aortitis than in atherosclerotic aortitis. 19) This suggests that IgG4-positive plasma cells might increase as a protective response of chronic inflammatory change such as atherosclerosis, rather than play a critical role in the generation of atherosclerosis. An elevated IgG4 level is also reported to be associated with lower brain natriuretic peptide (BNP) levels and lower E/e measured by echographic examination, which both indicate good cardiac diastolic function, in the elderly who have cardiac diseases other than IgG4-related disease. 61) A recent molecular study demonstrated CC chemokine receptor 5 (CCR5) polymorphism in chronic periaortitis, which is characterized by inflammatory abdominal aortic aneurysm (IAAA) and idiopathic retroperitoneal fibrosis. 62) CCR5 is expressed in various immunocytes, especially in Th1 cells. A 32-bp deletion (delta-32) in the promoter region of CCR5 (CCR5 delta-32) gene is supposed to result in a Th2- predominant immune system. 63) It would be interesting to determine whether IgG4-related disease also has similar genetic polymorphisms, which might be involved in its etiology. The serum IgG4 level would increase in response to inflammation, but its role in cardiovascular diseases is not fully understood. Another experiment has shown that mast cells are present in media and adventitia of mouse abdominal aortic aneurysms, inducing aortic smooth muscle cell apoptosis. 64) Recently, it was suggested that tryptase, a serine protease produced by mast cells, may be involved in the development of abdominal aortic aneurysms. 65) IgG4-Related Cardiovascular Disease Aortitis/Arteritis, Inflammatory aneurysm: Abdominal aortic aneurysm (AAA)/ Thoracic aortic aneurysm (TAA)/ Coronary aneurysm/ Aneurysm of other arteries Inflammatory abdominal aortic aneurysm (IAAA) would be one of the most common lesions of IgG4-related disease. IgG4-related IAAAs are estimated to be 5% of surgical AAA and 50% of total IAAA. 66) IgG4-related inflammatory aneurysms are also reported in other large to medium-sized arteries, such as the aortic arch, 18) thoracic aorta, 67) coronary artery, 26) and other arteries. 68) Solitary aneurysm is a relatively common lesion in IgG4 related disease. Multiple aneurysms are detected in an advanced case (Figure 1). Developed aneurysms sometimes measure nearly 10 centimeters in diameter. Generally, IAAA is caused by chronic infections, autoimmune diseases like Takayasu aortitis, and other poorly understood diseases. However, Raparia, et al reported most IAAA immunohistochemically showed strong IgG4-positive plasma-

3 Vol 55 No 4 IGG4-RELATED CARDIOVASCULAR DISORDERS 289 Figure 1. IgG4-related aneurysm can develop in various arteries. Vascular echography of hepatic aneurysm with large intramural thrombus (A). Contrastenhanced CT of common hepatic aneurysm (B, arrow) and splenic aneurysm (C, arrow) with large thrombi. The maximum diameter of common hepatic aneurysm is 8.6 cm. cyte infiltration in the aortic wall. IAAA may be one of the IgG4-related sclerosing diseases and not a simple inflammatory aneurysm.69) Ishizaka, et al suggested that IgG4 is also associated with the pathogenesis of infectious aneurysm and aortitis,70) based on a case of infectious aortitis with IgG4-positive plasmacyte infiltration.71) Etiologically, inflammatory thoracic aortic aneurysm is prevalent in old females while IAAA and retroperitoneal fibrosis are prevalent in old males, although they have similar histological features.72) As for symptoms, abdominal or back pain was more commonly observed in patients with non-igg4-related IAAA than IgG4-related AAA, and low grade fever was equally associated with both inflammatory AAAs.73) Unlike IAAAs, few patients with atherosclerotic AAA would present these symptoms.74) They might be caused by adhesion to an organ adjacent to an inflammatory AAA, such as duodenum, left renal vein, and the ureters. Superficial aneurysm can be detected as a pulsatile mass. Most cases of IgG4-related aneurysm and aortitis show IgG4-positive cell and eosinophil infiltration in the adventitia,18) but some cases also show them in the intima in addition to the adventitia.75) Therefore, aneurysm formation might follow aortitis or arteritis. AAA could be attributed to a Th2-dominant immune response. Th2 cells may cause vascular smooth muscle cell apoptosis, which may develop an aneurysm.76) Proximal large arteries have many vascular smooth muscle cells in order to tolerate high blood pressure. This may be the reason why aneurysms develop mainly in large arteries. Aneurysm rupture IgG4-related aneurysm rupture is often reported.2,75,77) Generally, aortic aneurysms, including atherosclerotic ones, with a large diameter (> 5.5 cm 78,79)) or high enlargement rate (> 0.5 cm/year 80)) have a high risk of rupture. Rapidly growing intraluminal thrombosis is also reported to increase the rupture risk of AAA.81) Although corticosteroid therapy is the first-line treatment for IgG4-related disease, IgG4-related aortic aneurysm rupture can occur during or after corticosteroid therapy.2) Kasashima, et al reported that aneurysm rupture significantly occurred more frequently in patients with non-igg4-related IAAA than in atherosclerotic AAA or IgG4-related IAAA.73) On the other hand, Tang, et al. had a different opinion, suggesting that the thickened inflammatory aneurysmal wall protects itself from rupture risk and corticosteroid therapy may increase rupture risk by weakening the aneurysmal wall.82) Periaortitis/Periarteritis: Periaortitis and periarteritis are generally classified as inflammatory or infectious conditions. Inflammatory periaortitis and periarteritis include giant cell ar- Figure 2. IgG4-related periaortitis. Contrast-enhanced CT imaging shows non-smooth thickening of soft tissue around ascending aorta. teritis, Takayasu arteritis, rheumatoid arthritis, systemic lupus erythematosus (SLE), HLA-B27 associated spondyloarthropathies, ANCA associated vasculitides, Behcet disease, Cogan syndrome, relapsing polychondritis, sarcoidosis, and isolated aortitis such as IgG4-related aortitis or arteritis.83) While most inflammatory aortitis or arteritis associated with rheumatologic disorders appears commonly in large arteries such as the aorta and aortic arch, IgG4-related periaortitis and periarteritis are found in various large to medium-sized arteries; for example, the abdominal aorta, iliac artery, thoracic aorta, coronary artery, renal artery and mesenteric artery.2,63) Histopathological analysis shows inflammatory infiltrates mostly in the adventitia in IgG4-related periaortitis/periarteritis, while they are seen in the medial layer in giant cell arteritis and in the medial layer to adventitia in Takayasu arteritis and SLE-associated arteritis.84) Periaortitis and periarteritis could be detected by CT imaging, showing non-smooth thickening of soft tissue around arteries (Figure 2).18FDG-PET will show FDG uptake at the lesion if it has active periarterial inflammation.20) Pericarditis: IgG4-positive plasma cell infiltration into the pericardium would cause IgG4-related constrictive pericarditis, possibly presenting right heart failure in an advanced case.24) Mediastinal fibrosis and idiopathic retroperitoneal fibrosis can be associated with patients with IgG4-related pericarditis.85,86) Idiopathic retroperitoneal fibrosis, the main symptom of which

4 290 TAJIMA, ET AL Int Heart J July 2014 Figure 3. IgG4-related pericarditis. Echocardiography (long axis view) shows epicardium with high intensity (A). CT imaging also shows thickened epicardium and epicardial fluid (B). is hydronephrosis by ureteral encasement, is considered to be an IgG4-related disease, whereas secondary retroperitoneal fibrosis is caused by drugs, malignancy, infection, radiotherapy, and surgery.87-89) Retroperitoneal fibrosis sometimes coexists with sclerosing pancreatitis.90) These fibrosclerotic lesions might share a common pathogenesis with periaortitis or periarteritis.25) Cardiac and pleural effusion sometimes accompanies pericarditis, which could lead to a fatal outcome by causing respiratory insufficiency.85) Echocardiography can detect it as highly echogenic thickening of the pericardium and cardiac effusion (Figure 3A). CT imaging is also of help in the diagnosis (Figure 3B). Pseudotumors around coronary arteries: Pseudotumors can develop around a coronary artery as well as in other organs (Figures 4 and 5).25) A coronary artery with a pseudotumor can have an aneurysmal change at the site.2,25,91) It is sometimes found by chance because of the complication of myocardial ischemia.92) It can be easily found by CT imaging, especially by coronary CT scan.18fdg-pet imaging shows FDG uptake at the lesion, which indicates the coronary artery has an active inflammation (Figure 4) and significantly responds to steroid therapy. This pseudotumor consists of lymphoplasmacyte infiltration and fibrous proliferation (Figure 5D), findings that are similar to the histological findings of idiopathic retroperitoneal fibrosis.87) Therefore, IgG4-related pseudotumors and idiopathic retroperitoneal fibrosis might share a common pathogenesis. Figure 4. IgG4-related pseudotumor around coronary artery. 18FDG-PET imaging detects active inflammation in pseudotumors. Response of pseudotumors to corticosteroid was obvious after three months (For details to the previous case report, Tajima M, Hiroi Y, Takazawa Y, et al.2)). Diagnosis Diagnostic criteria for IgG4-related disease have been proposed by Japanese researchers.93) All of the following items are required: 1) typical tissue fibrosis or sclerosis, 2) elevated serum IgG4 ( > 135 mg/dl), 3) histopathological features including lymphocyte infiltration and significant IgG4-positive plasma cell infiltration (the ratio of IgG4positive plasma cells to IgG-positive plasma cells > 40% and > 10 IgG4-positive plasma cells/hpf). In cases with 1) and 2), or 1) and 3), there is a possibility of IgG4-related disease.94) Physical examination: Clinical manifestation will depend on Diagnostic criteria: the affected region, and there would be no characteristic features of IgG4-related cardiovascular disease. Examples of chief complaints associated with IgG4-related cardiovascular disease are as follows: pulsatile mass and low grade fever due to various inflammatory aneurysms, back pain due to abdominal aortic aneurysm,68) right heart failure signs due to constrictive pericarditis,24) and hoarseness (recurrent nerve palsy) due to aortic arch aneurysm.20) Laboratory findings: IgG4-related disease is accompanied by the following features: elevated systemic inflammatory mark-

5 Vol 55 No 4 IGG4-RELATED CARDIOVASCULAR DISORDERS 291 Figure 5. IgG4-related pseudotumor around coronary artery. Coronary CT imaging shows pericoronary pseudotumor as a thickening of soft tissue around coronary arteries (A, left anterior descending branch; B, right coronary artery). At autopsy, the macroscopic transverse section of the left circumflex coronary branch exhibits a tumor-like appearance (C). Hematoxylin-eosin staining specimen indicates tumor-forming periarteritis with mild to moderate infiltration of plasmacytes and lymphocytes, and fibrous proliferation with prominent hyalinization (F). ers, such as white blood cell count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR),66) elevation of IgG, IgG4, IgE,93,95) and soluble IL-2 receptor (sil2r);60) and decreased albumin-globulin (A/G) ratio. CRP and ESR are useful markers for the inflammatory activity of IgG4-related disease. A low A/G ratio reflects overproduction of immunoglobulin; therefore it is useful for simplified screening and follow-up of IgG4 related disease patients. Most of these laboratory data will normalize after appropriate steroid treatment, but some markers may remain higher than normal, including IgG, IgG4, and IgE. Imaging tests: Vascular echography Echography is noninvasively performed at the bedside. If a pulsatile mass is palpable on physical examination, vascular echography is recommended at first for detailed examination of an aortic aneurysm. Even after CT imaging finds an aortic aneurysm, vascular echography is appropriate for the evaluation of aneurysm size, intramural thrombus, and blood flow inside the aneurysm (Figure 1A). Echocardiography Echocardiography is performed for detailed examination of cardiac structural abnormalities such as pericarditis, cardiac effusion, coronary aneurysm, a pseudotu- mor around a coronary artery, and myocardial damage (Figure 3A). It is also important to evaluate cardiac function because these cardiac complications could deteriorate diastolic and systolic function. CT imaging Contrast-enhanced CT detects various IgG4-related lesions,96) including pericarditis, pseudotumors, aortitis/ arteritis and aneurysms, even if they have no inflammatory change. Recently, IgG4-cardiovascular disease might be detected by chance because coronary CT is frequently performed on patients who may have ischemic heart disease and do not present any symptoms of IgG4-related disease (Figure 5). CT is also useful for follow-up of an IgG4-related inflammatory lesion and evaluation of disease activity during and after steroid therapy. 67 Ga scintigraphy 67Gallium (Ga) scintigraphy demonstrates gallium uptake in pulmonary hila, pancreas, salivary gland, lacrimal gland, and periaortic lesions in IgG4-related disease patients.97) 67Ga scintigraphy is superior to 18FDG-PET in terms of availability and inexpensiveness, but is inferior to 18FDGPET with respect to spatial resolution and signal-to-noise ratio in diagnostic imaging of IgG4-related disease.98) It is sometimes difficult to differentiate between IgG4-related disease

6 292 TAJIMA, ET AL Int Heart J July 2014 and sarcoidosis when gallium accumulation is detected in hilar and mediastinal lymph nodes. 99) 18 FDG-PET 18 FDG-PET can detect IgG4-related lesions as long as they have active inflammation (Figure 4). Although the relationship between the initial high intensity of FDG uptake in the IgG4-related lesion and its good response to corticosteroid has not been proved yet, 100) our case of IgG4-related systemic aneurysms would suggest that lesions with no FDG uptake do not respond to corticosteroid therapy. 2) Generally, persistent uptake of FDG during corticosteroid therapy is considered to be a continuation of active inflammation, which indicates an increase of future relapse. Since its image resolution is higher than that of 67 Ga scintigraphy, 18 FDG-PET would be most helpful for choosing a biopsy site and evaluating the therapeutic effect, but not always. 96) IgG4-related patients treated only by rituximab without corticosteroid might demonstrate stable FDG uptake, although they responded well to the therapy. 101) Biopsy: The diagnostic criteria of IgG4-related disease include IgG4-positive plasmacyte infiltration in specific organs, such as the lacrimal glands, salivary glands, pancreas, and retroperitoneum. It is recommended that biopsy of involved organs where active inflammation is suggested by CT, 18 FDG- PET or 67 Ga scintigraphy be performed in order to make a rapid diagnosis of IgG4-related disease. Our case of IgG4-related multiple systemic aneurysms presented abundant IgG4-positive plasmacyte infiltration in the salivary gland. 2) Although the frequency of abnormal salivary gland findings in IgG4-related cardiovascular disorders is not yet known, swelling of the salivary gland with dense IgG4- positive plasmacyte infiltration is seen in 20-25% of AIP patients, which sometimes preceded AIP ) Considering the high incidence of abnormal salivary gland findings in AIP, we expect that IgG4-related cardiovascular disease is frequently associated with salivary gland disorders as well. There have been some cases of needle biopsy of pseudotumors around a coronary artery for a definite diagnosis of IgG4-related disease, 105) but it is usually difficult to obtain a biopsy specimen from IgG4-related cardiovascular diseases unless a surgical operation is performed. Therefore, we recommend performing an 18 FDG PET scan on patients with IgG4-related cardiovascular disease, detecting the site with active inflammation, and then obtaining a safe biopsy from the extra-cardiovascular lesion. The salivary gland is a good candidate biopsy site even if no imaging test has proven the presence of active inflammation in the gland. Treatment Steroid Therapy: Steroid therapy is well recognized as the first-line therapy for IgG4-related disease. It reduces inflammation by suppressing lymphocyte activation, which is expected to prevent further development of inflammatory lesions, including aortitis/arteritis and aneurysm. The effect of corticosteroid therapy could be confirmed by decrease in serum IgG4, 102) IgG and IgE levels; decreases in inflammatory markers, such as ESR, CRP and sil2r; and improvement of inflammatory lesions on CT or PET imaging. On the other hand, it is not able to shrink the size of an already-developed aneurysm. 2,68) Active inflammation occurs only in the early inflammatory aneurysms, while largely-developed aneurysms might have slight or no inflammation detected by 18 FDG-PET. 2) Reduction of a periarterial pseudotumor and thinning arterial wall by corticosteroid therapy might increase the risk of aneurysm rupture, therefore, careful follow-up during corticosteroid therapy or endovascular aneurysm repair after corticosteroid therapy is recommended. 25,82,106) The therapeutic corticosteroid doses for IgG4-related disease are still unclear. Generally, high-dose corticosteroid therapy is started, tapered over a few months, and then a maintenance dose is administered for several years. For AIP, one of the IgG4-related disorders, an initial oral prednisolone dose of 0.6 mg/kg/day and a maintenance dose of mg/day have been recommended before, 107) but it can relapse on this regimen. 108) Following treatment with an initial dose of 1 mg/kg/ day, 10% of AIP patients can also experience a post-treatment recurrence. 109) Although no study has examined the risk factors of corticosteroid resistance or relapse after corticosteroid therapy in IgG4-related cardiovascular disorders, a retrospective study with 459 AIP patients showed that persistent elevation of IgG4 level is related to corticosteroid resistance or relapse after corticosteroid therapy. 110) Another multivariate analysis with 20 AIP patients revealed that serum IgG4 level at diagnosis was not related to the response to corticosteroid therapy. 111) It is also unknown whether IgG4-related cardiovascular disorder is associated with a higher serum IgG4 level than other IgG4-related diseases. Considering a case of developed IgG4-related systemic aneurysms under low-dose corticosteroid therapy ( mg/ day, equal to mg/kg/day of prednisolone), at least 7.5 mg/day of prednisolone for a maintenance dose would be needed to prevent further development of IgG4-related cardiovascular disease. 2) An initial dose of 20 mg/day was reported to be effective at diminishing the aortic wall thickness, 68) however, we are not sure if it is sufficient for systemically-developed aneurysms. It is necessary to find an appropriate dose of steroid that can adequately suppress inflammation and does not render the aortic wall too thin. Immunosuppressant: Azathioprine, mycophenolate mofetil, and bortezomib have also been tried although their efficacies have not been proven yet. Therapy with rituximab, an anti- CD20 antibody, could be effective in recurrent cases, but it has negative side effects such as bone marrow suppression, interstitial pneumonia, cardiac damage, and renal failure. 112) Surgery/Endovascular Treatment: Generally, surgical operation or endovascular treatment is prophylactically recommended for a large aortic aneurysm (diameter: > 5.5 cm, or enlargement rate: > 0.5 cm/year). Some AAAs will turn out to be IAAA after surgery by pathological examination, including IgG4-related IAAAs. 113) Stone, et al reported more perioperative complications, and higher morbidity and mortality after open repair for inflammatory AAA compared with atherosclerotic AAA. 114) The IgG4-related aneurysm wall is thickened and adheres to the surrounding tissue, so a surgical approach to an IgG4-related aneurysm would be difficult technically. Therefore, AAAs should be assessed based on whether or not they are inflammatory before surgical treatment. IAAA might be treated initially with medication. Surgical treatment would be considered for very large aneurysms when the inflammation is reduced. Endovascular aneurysm repair has fewer perioperative complications than open repair, but it is not able to suppress inflammation around inflammatory AAA to the extent of

7 Vol 55 No 4 IGG4-RELATED CARDIOVASCULAR DISORDERS 293 open repair. The true natural course of inflammatory AAA is not yet fully understood and it is difficult to say whether it has a better prognosis than atherosclerotic AAA even after treatment. Surgical treatment might be chosen in cases of a ruptured aneurysm, but the prognosis is not good. 75) It might be more difficult to perform in an IgG4-related aneurysm than in an atherosclerotic aneurysm, due to adhesion of intra-abdominal organs. Coil embolization of the artery could be considered to stop the bleeding after an aneurysm rupture. References 1. Sato Y, Notohara K, Kojima M, Takata K, Masaki Y, Yoshino T. IgG4-related disease: Historical overview and pathology of hematological disorders. Pathol Int 2010; 60: (Review) 2. Tajima M, Hiroi Y, Takazawa Y, et al. Immunoglobulin G4-related multiple systemic aneurysms and splenic aneurysm rupture during steroid therapy. Hum Pathol 2014; 45: Sarles H, Sarles JC, Muratore R, Guien C. Chronic inflammatory sclerosis of the pancreas -- an autonomous pancreatic disease? Am J Dig Dis 1961; 6: Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci 1995; 40: (Review) 5. Matsubayashi H, Sawai H, Kimura H, et al. Characteristics of autoimmune pancreatitis based on serum IgG4 level. Dig Liver Dis 2011; 43: Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001; 344: Kawa S, Okazaki K, Kamisawa T, Shimosegawa T, Tanaka M. Japanese consensus guidelines for management of autoimmune pancreatitis: II. Extrapancreatic lesions, differential diagnosis. J Gastroenterol 2010; 45: Okazaki K, Uchida K, Koyabu M, Miyoshi H, Takaoka M. Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease. J Gastroenterol 2011; 46: (Review) 9. Zen Y, Harada K, Sasaki M, et al. IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Am J Surg Pathol 2004; 28: Yamamoto M, Harada S, Ohara M, et al. Clinical and pathological differences between Mikulicz s disease and Sjögren s syndrome. Rheumatology(Oxford) 2005; 44: Zen Y, Sawazaki A, Miyayama S, Notsumata K, Tanaka N, Nakanuma Y. A case of retroperitoneal and mediastinal fibrosis exhibiting elevated levels of IgG4 in the absence of sclerosing pancreatitis (autoimmune pancreatitis). Hum Pathol 2006; 37: Watson SJ, Jenkins DA, Bellamy CO. Nephropathy in IgG4-related systemic disease. Am J Surg Pathol 2006; 30: Yoneda K, Murata K, Katayama K, et al. Tubulointerstitial nephritis associated with IgG4-related autoimmune disease. Am J Kidney Dis 2007; 50: Joo M, Chang SH, Kim H, Lee KC, Ro JY. Idiopathic segmental ureteritis, misdiagnosed as ureteral cancer preoperatively: a case report with literature review. Pathol Int 2010; 60: (Review) 15. Wong S, Lam WY, Wong WK, Lee KC. Hypophysitis presented as inflammatory pseudotumor in immunoglobulin G4-related systemic disease. Hum Pathol 2007; 38: Nishimori I, Kohsaki T, Onishi S, et al. IgG4-related autoimmune prostatitis: two cases with or without autoimmune pancreatitis. Intern Med 2007; 46: Kasashima S, Zen Y, Kawashima A, et al. Inflammatory abdominal aortic aneurysm: close relationship to IgG4-related periaortitis. Am J Surg Pathol 2008; 32: Ishida M, Hotta M, Kushima R, Asai T, Okabe H. IgG4-related inflammatory aneurysm of the aortic arch. Pathol Int 2009; 59: Stone JH, Khosroshahi A, Deshpande V, Stone JR. IgG4-related systemic disease accounts for a significant proportion of thoracic lymphoplasmacytic aortitis cases. Arthritis Care Res (Hoboken) 2010; 62: Takahashi M, Shimizu T, Inajima T, et al. A case of localized IgG4-related thoracic periarteritis and recurrent nerve palsy. Am J Med Sci 2011; 341: Kanno A, Satoh K, Kimura K, et al. Autoimmune pancreatitis with hepatic inflammatory pseudotumor. Pancreas 2005; 31: Kitagawa S, Zen Y, Harada K, et al. Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis(küttner s tumor). Am J Surg Pathol 205; 29: Zen Y, Kitagawa S, Minato H, et al. IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung. Hum Pathol 2005; 36: Sugimoto T, Morita Y, Isshiki K, et al. Constrictive pericarditis as an emerging manifestation of hyper-igg4 disease. Int J Cardiol 2008; 130: e Matsumoto Y, Kasashima S, Kawashima A, et al. A case of multiple immunoglobulin G4-related periarteritis: a tumorous lesion of the coronary artery and abdominal aortic aneurysm. Hum Pathol 2008; 39: Ikutomi M, Matsumura T, Iwata H, et al. Giant tumorous legions(correction of legions) surrounding the right coronary artery associated with immunoglobulin-g4-related systemic disease. Cardiology 2011; 120: Takato H, Yasui M, Ichikawa Y, et al. Nonspecific interstitial pneumonia with abundant IgG4-positive cells infiltration, which was thought as pulmonary involvement of IgG4-related autoimmune disease. Intern Med 2008; 47: Yamamoto H, Yasuo M, Nomura Y, et al. IgG4-related airway involvement which developed in a patient receiving corticosteroid therapy for autoimmune pancreatitis. Intern Med 2011; 50: Cheuk W, Yuen HK, Chan AC, et al. Ocular adnexal lymphoma associated with IgG4+ chronic sclerosing dacryoadenitis: a previously undescribed complication of IgG4-related sclerosing disease. Am J Surg Pathol 2008; 32: Chen TS, Montgomery EA. Are tumefactive lesions classified as sclerosing mesenteritis a subset of IgG4-related sclerosing disorders? J Clin Pathol 2008; 61: Cheuk W, Chan AC, Lam WL, et al. IgG4-related sclerosing mastitis: description of a new member of the IgG4-related sclerosing diseases. Am J Surg Pathol 2009; 33: Cho HK, Lee YJ, Chung JH, Koo JW. Otologic manifestation in IgG4-related systemic disease. Clin Exp Otorhinolaryngol 2011; 4: Lopes J, Hochwald SN, Lancia N, Dixon LR, Ben-David K. Autoimmune esophagitis: IgG4-related tumors of the esophagus. J Gastrointest Surg 2010; 14: (Review) 34. Fujita T, Ando T, Sakakibara M, Hosoda W, Goto H. Refractory gastric ulcer with abundant IgG4-positive plasma cell infiltration: a case report. World J Gastroenterol 2010; 16: Umemura T, Zen Y, Hamano H, Kawa S, Nakanuma Y, Kiyosawa K. Immunoglobin G4-hepatopathy: association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis. Hepatology 2007; 46: Unno H, Saegusa H, Fukushima M, Hamano H. Usefulness of endoscopic observation of the main duodenal papilla in the diagnosis of sclerosing pancreatitis. Gastrointest Endosc 2002; 56: Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V, Stone JH. Riedel s thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res (Hoboken) 2010; 62:

8 294 TAJIMA, ET AL Int Heart J July Kojima M, Hirokawa M, Kuma H, et al. Distribution of IgG4- and/or IgG-positive plasma cells in Hashimoto s thyroiditis: an immunohistochemical study. Pathobiology 2010; 77: Moteki H, Yasuo M, Hamano H, Uehara T, Usami S. IgG4-related chronic rhinosinusitis: a new clinical entity of nasal disease. Acta Otolaryngol 2011; 131: Tamai R, Hasegawa Y, Hisano S, Miyake K, Nakashima H, Saito T. A case of IgG4-related tubulointerstitial nephritis concurrent with Henoch-Schönlein purpura nephritis. Allergy Asthma Clin Immunol 2011; 7: Saeki T, Ito T, Youkou A, et al. Thrombotic thrombocytopenic purpura in IgG4-related disease with severe deficiency of AD- AMTS-13 activity and IgG4 autoantibody against ADAMTS-13. Arthritis Care Res(Hoboken) 2011; 63: Cheuk W, Lee KC, Chong LY, Yuen ST, Chan JK. IgG4-related sclerosing disease: a potential new etiology of cutaneous pseudolymphoma. Am J Surg Pathol 2009; 33: Zen Y, Kasahara Y, Horita K, et al. Inflammatory pseudotumor of the breast in a patient with a high serum IgG4 level: histologic similarity to sclerosing pancreatitis. Am J Surg Pathol 2005; 29: Zen Y, Kitagawa S, Minato H, et al. IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung. Hum Pathol 2005; 36: Bruneval P. Coronary artery pseudotumor: IgG4-related disease versus localized castleman disease. Hum Pathol 2009; 40: Shoji S, Nakano M, Usui Y. IgG4-related inflammatory pseudotumor of the kidney. Int J Urol 2010; 17: Katsura M, Morita A, Horiuchi H, Ohtomo K, Machida T. IgG4- related inflammatory pseudotumor of the trigeminal nerve: another component of IgG4-related sclerosing disease? AJNR Am J Neuroradiol 2011; 32: E Bösmüller H, von Weyhern CH, Adam P, Alibegovic V, Mikuz G, Fend F. Paratesticular fibrous pseudotumor--an IgG4-related disorder? Virchows Arch 2011; 458: Umehara H, Okazaki K, Masaki Y, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol 2012; 22: (Review) 50. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003; 38: Kamisawa T. IgG4-related sclerosing disease. Intern Med 2006; 45: Masaki Y, Dong L, Kurose N, et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis 2009; 68: Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012; 366: (Review) 54. Aalberse RC, Stapel SO, Schuurman J, Rispens T. Immunoglobulin G4: an odd antibody. Clin Exp Allergy 2009; 39: (Review) 55. Robinson DS, Larché M, Durham SR. Tregs and allergic disease. J Clin Invest 2004; 114: (Review) 56. Jeannin P, Delneste Y, Lecoanet-Henchoz S, Gretener D, Bonnefoy JY. Interleukin-7 (IL-7) enhances class switching to IgE and IgG4 in the presence of T cells via IL-9 and SCD23. Blood 1998; 91: Meiler F, Klunker S, Zimmermann M, Akdis CA, Akdis M. Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors. Allergy 2008; 63: Taguchi M, Kihara Y, Nagashio Y, Yamamoto M, Otsuki M, Harada M. Decreased production of immunoglobulin M and A in autoimmune pancreatitis. J Gastroenterol 2009; 44: Okazaki K, Uchida K, Koyabu M, Miyoshi H, Takaoka M. Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease. J Gastroenterol 2011; 46: (Review) 60. Sakamoto A, Ishizaka N, Imai Y, Nagai R. Serum levels of IgG4 and soluble interleukin-2 receptor in patients with abdominal and thoracic aortic aneurysm who undergo coronary angiography. Atherosclerosis 2012; 221: Sakane K, Shibata K, Fujita SI, et al. Association between serum immunoglobulin G4 concentration and cardiac function among elderly cardiology inpatients. Geriatr Gerontol Int in press 62. Boiardi L, Vaglio A, Nicoli D, et al. CC chemokine receptor 5 polymorphism in chronic periaortitis. Rheumatology(Oxford) 2011; 50: Vaglio A, Pipitone N, Salvarani C. Chronic periaortitis: a largevessel vasculitis? Curr Opin Rheumatol 2011; 23: 1-6. (Review) 64. Sun J, Sukhova GK, Yang M, et al. Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. J Clin Invest 2007; 117: Zhang J, Sun J, Lindholt JS, et al. Mast cell tryptase deficiency attenuates mouse abdominal aortic aneurysm formation. Circ Res 2011; 108: Kasashima S, Zen Y. IgG4-related inflammatory abdominal aortic aneurysm. Curr Opin Rheumatol 2011; 23: (Review) 67. Kasashima S, Zen Y, Kawashima A, et al. A clinicopathologic study of immunoglobulin G4-related sclerosing disease of the thoracic aorta. J Vasc Surg 2010; 52: Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related periaortitis and periarteritis: CT findings in 17 patients. Radiology 2011; 261: Raparia K, Molina CP, Quiroga-Garza G, Weilbaecher D, Ayala AG, Ro JY. Inflammatory aortic aneurysm: possible manifestation of IgG4-related sclerosing disease. Int J Clin Exp Pathol 2013; 6: Ishizaka N, Sohmiya K, Miyamura M, et al. Infected aortic aneurysm and inflammatory aortic aneurysm--in search of an optimal differential diagnosis. J Cardiol 2012; 59: (Review) 71. Kanemitsu S, Shimono T, Nakamura A, Yamamoto K, Wada H, Shimpo H. Molecular diagnosis of nonaneurysmal infectious aortitis. J Vasc Surg 2011; 53: 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. Int J Clin Exp Pathol 2013; 6: Kasashima S, Zen Y, Kawashima A, Endo M, Matsumoto Y, Kasashima F. A new clinicopathological entity of IgG4-related inflammatory abdominal aortic aneurysm. J Vasc Surg 2009; 49: Nitecki SS, Hallett JW Jr, Stanson AW, et al. Inflammatory abdominal aortic aneurysms: a case-control study. J Vasc Surg 1996; 23: Qian Q, Kashani KB, Miller DV. Ruptured abdominal aortic aneurysm related to IgG4 periaortitis. N Engl J Med 2009; 361: Henderson EL, Geng YJ, Sukhova GK, Whittemore AD, Knox J, Libby P. Death of smooth muscle cells and expression of mediators of apoptosis by T lymphocytes in human abdominal aortic aneurysms. Circulation 1999; 99: Trinidad-Hernandez M, Duncan AA. Contained ruptured paravisceral aortic aneurysm related to immunoglobulin G4 aortitis. Ann Vasc Surg 2012; 26: 108.e Elefteriades JA. Natural history of thoracic aortic aneurysms: indications for surgery, and surgical versus nonsurgical risks. Ann Thorac Surg 2002; 74: S United Kingdom Small Aneurysm Trial Participants. Long-term outcomes of immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med 2002; 346: Choke E, Cockerill G, Wilson WR, et al. A review of biological factors implicated in abdominal aortic aneurysm rupture. Eur J Vasc Endovasc Surg 2005; 30: (Review) 81. Stenbaek J, Kalin B, Swedenborg J. Growth of thrombus may be a better predictor of rupture than diameter in patients with abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2000; 20: Tang T, Boyle JR, Dixon AK, Varty K. Inflammatory abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2005; 29:

9 Vol 55 No 4 IGG4-RELATED CARDIOVASCULAR DISORDERS 295 (Review) 83. Gornik HL, Creager MA. Aortitis. Circulation 2008; 117: (Review) 84. Pacini D, Leone O, Turci S, et al. Incidence, etiology, histologic findings, and course of thoracic inflammatory aortopathies. Ann Thorac Surg 2008; 86: Sakamoto A, Nagai R, Saito K, et al. Idiopathic retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pericarditis--retrospective analysis of 11 case histories. J Cardiol 2012; 59: Bahler C, Hammoud Z, Sundaram C. Mediastinal fibrosis in a patient with idiopathic retroperitoneal fibrosis. Interact Cardiovasc Thorac Surg 2008; 7: (Review) 87. Corradi D, Maestri R, Palmisano A, et al. Idiopathic retroperitoneal fibrosis: clinicopathologic features and differential diagnosis. Kidney Int 2007; 72: Laco J, Podhola M, Kamarádová K, et al. Idiopathic vs. Secondary retroperitoneal fibrosis: a clinicopathological study of 12 cases, with emphasis to possible relationship to IgG4-related disease. Virchows Arch 2013; 463: Vaglio A, Salvarani C, Buzio C. Retroperitoneal fibrosis. Lancet 2006; 367: (Review) 90. Hamano H, Kawa S, Ochi Y, et al. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet 2002; 359: Urabe Y, Fujii T, Kurushima S, Tsujiyama S, Kihara Y. Pigs-in-ablanket coronary arteries: a case of immunoglobulin G4-related coronary periarteritis assessed by computed tomography coronary angiography, intravascular ultrasound, and positron emission tomography. Circ Cardiovasc Imaging 2012; 5: Tanigawa J, Daimon M, Murai M, Katsumata T, Tsuji M, Ishizaka N. Immunoglobulin G4-related coronary periarteritis in a patient presenting with myocardial ischemia. Hum Pathol 2012; 43: Masaki Y, Kurose N, Umehara H. IgG4-related disease: a novel lymphoproliferative disorder discovered and established in Japan in the 21st century. J Clin Exp Hematop 2011; 51: (Review) 94. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), Mod Rheumatol 2012; 22: Okazaki K, Uchida K, Miyoshi H, Ikeura T, Takaoka M, Nishio A. Recent concepts of autoimmune pancreatitis and IgG4-related disease. Clin Rev Allergy Immunol 2011; 41: (Review) 96. Nguyen VX, De Petris G, Nguyen BD. Usefulness of PET/CT imaging in systemic IgG4-related sclerosing disease. A report of three cases. JOP 2011; 12: Ishii S, Shishido F, Miyajima M, Sakuma K, Shigihara T, Kikuchi K. Whole-body gallium-67 scintigraphic findings in IgG4-related disease. Clin Nucl Med 2011; 36: Nakatani K, Nakamoto Y, Togashi K. Utility of FDG PET/CT in IgG4-related systemic disease. Clin Radiol 2012; 67: (Review) 99. Tsushima K, Tanabe T, Yamamoto H, et al. Pulmonary involvement of autoimmune pancreatitis. Eur J Clin Invest 2009; 39: Nakajo M, Jinnouchi S, Fukukura Y, Tanabe H, Tateno R. The efficacy of whole-body FDG-PET or PET/CT for autoimmune pancreatitis and associated extrapancreatic autoimmune lesions. Eur J Nucl Med Mol Imaging 2007; 34: Ebbo M, Grados A, Guedj E, et al. 18F-FDG PET/CT for staging and evaluation of treatment response in IgG4-related disease: a retrospective multicenter study. Arthritis Care Res (Hoboken) 2014; 66: Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003; 38: Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol 2006; 41: (Review) 104. Hamano H, Arakura N, Muraki T, Ozaki Y, Kiyosawa K, Kawa S. Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. J Gastroenterol 2006; 41: Kusumoto S, Kawano H, Takeno M, et al. Mass lesions surrounding coronary artery associated with immunoglobulin G4-related disease. J Cardiol Cases 2012; 5: e Puchner S, Bucek RA, Loewe C, et al. Endovascular repair of inflammatory aortic aneurysms: Long-term results. AJR Am J Roentgenol 2006; 186: Kamisawa T, Takuma K, Hara S, et al. Management strategies for autoimmune pancreatitis. Expert Opin Pharmacother 2011; 12: (Review) 108. Tabata T, Kamisawa T, Takuma K, et al. Serial changes of elevated serum IgG4 levels in IgG4-related systemic disease. Intern Med 2011; 50: Pezzilli R, Cariani G, Santini D, et al. Therapeutic management and clinical outcome of autoimmune pancreatitis. Scand J Gastroenterol 2011; 46: Kamisawa T, Shimosegawa T, Okazaki K, et al. Standard steroid treatment for autoimmune pancreatitis. Gut 2009; 58: Kubota K, Iida H, Fujisawa T, et al. Clinical factors predictive of spontaneous remission or relapse in cases of autoimmune pancreatitis. Gastrointest Endosc 2007; 66: Khosroshahi A, Stone JH. Treatment approaches to IgG4-related systemic disease. Curr Opin Rheumatol 2011; 23: (Review) 113. Sakata N, Tashiro T, Uesugi N, et al. IgG4-positive plasma cells in inflammatory abdominal aortic aneurysm: the possibility of an aortic manifestation of IgG4-related sclerosing disease. Am J Surg Pathol 2008; 32: Stone WM, Fankhauser GT, Bower TC, et al. Comparison of open and endovascular repair of inflammatory aortic aneurysms. J Vasc Surg 2012; 56: