287

IgG4-Related Cardiovascular DisordersMiyu Tajima,1,2 MD, Ryozo Nagai,3 MD, and Yukio Hiroi,4 MD

Summary

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 pseu-dotumors around the coronary arteries. These disorders often coexist in accordance with progression of the disease. Be-cause 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 18FDG-PET imaging can identify active inflammation in the lesions. Measurement of serum IgG4 levels and tissue biopsy are necessary for diag-nosis. Minor salivary gland biopsy is recommended even though 18FDG uptake is not detected when it is difficult to ob-tain 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 aneu-rysm 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 extra-cardiovascular disorders. The adequate dose of corticosteroid, type and dose of immunosuppressant, and surgical inter-vention should be carefully considered on a case-by-case basis. (Int Heart J 2014; 55: 287-295)

Key words: Cardiovascular involvement, Aneurysm, Aortitis, Arteritis, Pericarditis, Pseudotumor, Rupture, Biopsy, Cor-ticosteroid

I mmunoglobulinG4 (IgG4)-related disease is a recently rec-ognized 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. Pseu-dotumors around coronary arteries and in mediastinum, and pericarditis were also detected. Diagnosis of IgG4-related dis-ease 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, im-aging 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 symmet-rical swelling of the lacrimal and salivary glands (Mikulicz’ disease). In 1961 a case of particular pancreatitis with hyper-

gammaglobulinemia 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 lymphoplasma-cytic 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 lymphoplasma-cyte 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 or-gans:8) bile ducts,9) lacrimal and salivary glands,10) retroperito-neum,11) urinary organs,12-14) pituitary gland,15) prostate,16) arter-ies,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 Ja-pan is estimated at 0.28-1.08/100,000, mainly occurring in middle-aged to elderly men. The median age of disease onset is 58 years old. The clinical symptoms are usually mild, gradu-ally 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, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. E-mail: hiroi-tky@umin.ac.jp

Received for publication October 18, 2013. Accepted December 16, 2013.Released in advance online on J-STAGE June 5, 2014.All rights reserved by the International Heart Journal Association.

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syndrome (IgG4+MOLPS).52) Japanese foremost experts in this field reached an agreement on the name “IgG4-related dis-ease (IgG4-RD)” at the IgG4 second meeting in 2010.

Pathogenesis of IgG4-related disease and aneurysm

Recently, the mechanism of IgG4-related disease has be-come more clear.53) IgG4 is the least abundant subclass of IgG antibodies (typically < 5%).54) Although its role is not well un-derstood, it is known that IgG4 sometimes elevates under IgE-mediated allergy.55) T-helper-2 (Th2) cytokines, such as inter-leukin (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 oth-er 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 al-low autoreactive CD4+ T cell infiltration in various organs. These CD4+ T cells probably activate macrophages and in-duce 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 genera-tion 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 eld-erly who have cardiac diseases other than IgG4-related dis-ease.61) A recent molecular study demonstrated CC chemokine receptor 5 (CCR5) polymorphism in chronic periaortitis, which is characterized by inflammatory abdominal aortic an-eurysm (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 de-termine 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 In-flammatory abdominal aortic aneurysm (IAAA) would be one of the most common lesions of IgG4-related disease. IgG4-re-lated 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, autoim-mune diseases like Takayasu aortitis, and other poorly under-stood diseases. However, Raparia, et al reported most IAAA immunohistochemically showed strong IgG4-positive plasma-

Table I. IgG4-Related Diseases in Various Organs

Organ Disease

Pancreas Autoimmune pancreatitis (AIP)Bile duct Sclerosing cholangitisRetroperitoneum Retroperitoneal fibrosisLacrimal gland Mikulicz’s disease (sialadenitis and

dacryoadenitis)Salivary gland Küttner tumor (sialadenitis)Urinary organs Membranous nephropathy

Tubulointerstitial nephritisSclerosing pyelitisIdiopathic segmental ureteritis

Pituitary gland HypophysitisProstate ProstatitisArteries Inflammatory aneurysm of arota and its

large branchesAortitis/arteritisPeriarteritis

Veins Obliterative phlebitis (in pancreas, sali-vary gland, and pseudotumor)

Heart Constrictive pericarditisPseudotumorCoronary artery aneurysm

Lung Interstitial pneumoniaHilar lymphadenopathy

Eye UveitisOcular adnexal lymphoma

Mesenterium Sclerosing mesenteritisMammary gland MastitisCentral nervous system Sclerosing pachymeningitis

Vertebral basilar system dolichoectasiaAutoimmune neurosensory hearing loss

Esophagus Autoimmune esophagitisStomach Gastric ulcerLiver IgG4 hepatopathyGastrointestinal tract Swelling of papilla of VaterThyroid Riedel’s thyroiditis

Hashimoto’s thyroiditisNose Chronic rhinosinusitisBlood Schonlein-Henoch purpura

Autoimmune thrombocytopeniaSkin Cutaneous pseudolymphomaVarious organ Pseudotumor(Liver, Breast, Lung, Coro-nary arteries, Central nerve system, Kidney, Trigeminal Nerve, Testis, Ureter, etc)

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cyte infiltration in the aortic wall. IAAA may be one of the IgG4-related sclerosing diseases and not a simple inflammato-ry aneurysm.69) Ishizaka, et al suggested that IgG4 is also asso-ciated with the pathogenesis of infectious aneurysm and aorti-tis,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, ab-dominal or back pain was more commonly observed in pa-tients with non-IgG4-related IAAA than IgG4-related AAA, and low grade fever was equally associated with both inflam-matory AAAs.73) Unlike IAAAs, few patients with atheroscle-rotic 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. Su-perficial 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 adventi-tia,18) but some cases also show them in the intima in addition to the adventitia.75) Therefore, aneurysm formation might fol-low aortitis or arteritis. AAA could be attributed to a Th2-dom-inant 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 re-ported.2,75,77) Generally, aortic aneurysms, including atheroscle-rotic ones, with a large diameter (> 5.5 cm 78,79)) or high en-largement 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 aneu-rysm 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 corticos-teroid therapy may increase rupture risk by weakening the an-eurysmal wall.82)

Periaortitis/Periarteritis: Periaortitis and periarteritis are gen-erally classified as inflammatory or infectious conditions. In-flammatory periaortitis and periarteritis include giant cell ar-

teritis, Takayasu arteritis, rheumatoid arthritis, systemic lupus erythematosus (SLE), HLA-B27 associated spondyloarthropa-thies, 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 ar-tery, 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

Figure 1. IgG4-related aneurysm can develop in various arteries. Vascular echography of hepatic aneurysm with large intramural thrombus (A). Contrast-enhanced 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.

Figure 2. IgG4-related periaortitis. Contrast-enhanced CT imaging shows non-smooth thickening of soft tissue around ascending aorta.

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is hydronephrosis by ureteral encasement, is considered to be an IgG4-related disease, whereas secondary retroperitoneal fi-brosis 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 peri-arteritis.25) Cardiac and pleural effusion sometimes accompa-nies pericarditis, which could lead to a fatal outcome by caus-ing 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 diagno-sis (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 infil-tration and fibrous proliferation (Figure 5D), findings that are similar to the histological findings of idiopathic retroperitoneal fibrosis.87) Therefore, IgG4-related pseudotumors and idiopath-ic retroperitoneal fibrosis might share a common pathogenesis.

Diagnosis

Diagnostic criteria: Diagnostic criteria for IgG4-related dis-ease have been proposed by Japanese researchers.93) All of the following items are required: 1) typical tissue fibrosis or scle-rosis, 2) elevated serum IgG4 ( > 135 mg/dL), 3) histopatho-logical features including lymphocyte infiltration and signifi-cant IgG4-positive plasma cell infiltration (the ratio of IgG4-positive 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

the affected region, and there would be no characteristic fea-tures 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 abdomi-nal aortic aneurysm,68) right heart failure signs due to constric-tive 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-

Figure 3. IgG4-related pericarditis. Echocardiography (long axis view) shows epicardium with high intensity (A). CT imaging also shows thickened epi-cardium and epicardial fluid (B).

Figure 4. IgG4-related pseudotumor around coronary artery. 18FDG-PET imaging detects active inflammation in pseudotumors. Response of pseu-dotumors to corticosteroid was obvious after three months (For details to the previous case report, Tajima M, Hiroi Y, Takazawa Y, et al.2)).

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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 de-creased 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 ex-amination, vascular echography is recommended at first for detailed examination of an aortic aneurysm. Even after CT im-aging finds an aortic aneurysm, vascular echography is appro-priate for the evaluation of aneurysm size, intramural throm-bus, and blood flow inside the aneurysm (Figure 1A).Echocardiography Echocardiography is performed for de-tailed 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-re-lated lesions,96) including pericarditis, pseudotumors, aortitis/arteritis and aneurysms, even if they have no inflammatory change. Recently, IgG4-cardiovascular disease might be de-tected 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 ster-oid therapy. 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 18FDG-PET with respect to spatial resolution and signal-to-noise ratio in diagnostic imaging of IgG4-related disease.98) It is some-times difficult to differentiate between IgG4-related disease

67

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 coro-nary branch exhibits a tumor-like appearance (C). Hematoxylin-eosin staining specimen indicates tumor-forming periarteritis with mild to moderate infil-tration of plasmacytes and lymphocytes, and fibrous proliferation with prominent hyalinization (F).

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and sarcoidosis when gallium accumulation is detected in hilar and mediastinal lymph nodes.99)

FDG-PET 18FDG-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 corticoster-oid has not been proved yet,100) our case of IgG4-related sys-temic aneurysms would suggest that lesions with no FDG up-take do not respond to corticosteroid therapy.2) Generally, persistent uptake of FDG during corticosteroid therapy is con-sidered to be a continuation of active inflammation, which in-dicates an increase of future relapse. Since its image resolution is higher than that of 67Ga scintigraphy, 18FDG-PET would be most helpful for choosing a biopsy site and evaluating the ther-apeutic 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 thera-py.101)

Biopsy: The diagnostic criteria of IgG4-related disease in-clude IgG4-positive plasmacyte infiltration in specific organs, such as the lacrimal glands, salivary glands, pancreas, and ret-roperitoneum. It is recommended that biopsy of involved or-gans where active inflammation is suggested by CT, 18FDG-PET or 67Ga 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 pa-tients, which sometimes preceded AIP.102-104) 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 dis-ease,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 18FDG PET scan on patients with IgG4-related cardiovascu-lar disease, detecting the site with active inflammation, and then obtaining a safe biopsy from the extra-cardiovascular le-sion. 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 inflam-mation by suppressing lymphocyte activation, which is expect-ed to prevent further development of inflammatory lesions, in-cluding aortitis/arteritis and aneurysm. The effect of corticosteroid therapy could be confirmed by decrease in se-rum 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 in-flammatory aneurysms, while largely-developed aneurysms might have slight or no inflammation detected by 18FDG-PET.2)

18

Reduction of a periarterial pseudotumor and thinning arterial wall by corticosteroid therapy might increase the risk of aneu-rysm 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 dis-ease are still unclear. Generally, high-dose corticosteroid thera-py is started, tapered over a few months, and then a mainte-nance 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 2.5 - 5 mg/day have been recommended before,107) but it can relapse on this regi-men.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 corti-costeroid 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 cor-ticosteroid 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 as-sociated with a higher serum IgG4 level than other IgG4-relat-ed diseases.

Considering a case of developed IgG4-related systemic aneurysms under low-dose corticosteroid therapy (7.5 - 20 mg/day, equal to 0.15 - 0.33 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 cardio-vascular disease.2) An initial dose of 20 mg/day was reported to be effective at diminishing the aortic wall thickness,68) howev-er, we are not sure if it is sufficient for systemically-developed aneurysms. It is necessary to find an appropriate dose of ster-oid 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, inter-stitial pneumonia, cardiac damage, and renal failure.112)

Surgery/Endovascular Treatment: Generally, surgical opera-tion or endovascular treatment is prophylactically recommend-ed for a large aortic aneurysm (diameter: > 5.5 cm, or enlarge-ment 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 periopera-tive complications, and higher morbidity and mortality after open repair for inflammatory AAA compared with atheroscle-rotic 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 periopera-tive complications than open repair, but it is not able to sup-press inflammation around inflammatory AAA to the extent of

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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 treat-ment.

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.

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