Characteristics and prognosis of IgG4-related periaortitis/periarteritis: A systematic literature review

doi:10.1016/j.autrev.2019.102354

Autoimmunity Reviews

Volume 18, Issue 9, September 2019, 102354

https://doi.org/10.1016/j.autrev.2019.102354 Get rights and content

Abstract

Objective

Immunoglobulin G4 (IgG4)-related disease is a systemic chronic fibroinflammatory disease that can affect almost every organ of the body. IgG4-related periaortitis/periarteritis is a newly recognized subset of IgG4-related disease, and its characteristics and prognosis remain unclear. We investigated the clinical characteristics and prognosis of IgG4-related periaortitis/periarteritis.

Methods

We performed a systematic literature review of IgG4-related periaortitis/periarteritis. Additionally, we have summarized the characteristics and prognosis of IgG4-related coronary arteritis.

Results

We investigated 248 patients with IgG4-related periaortitis/periarteritis. All studies reported the condition in elderly patients, and male predominance was observed. The infra-renal abdominal aorta and iliac arteries were the most commonly affected sites. Most reports showed the serum C-reactive protein elevation in this disease entity, in contrast to non-vascular IgG4-related disease. Based on radiological findings observed in 27 patients with IgG4-related coronary arteritis, vasculitic lesions were classified into 3 types: stenotic (67% of patients), aneurysmal (42%), and diffuse wall thickening type (92%). Serum IgG4 level, but not C-reactive protein level, was associated with the number of affected organs in IgG4-related coronary arteritis. Corticosteroid treatment with or without cardiac surgery or percutaneous coronary intervention was effective in most patients with IgG4-related coronary arteritis; however, 33% of patients showed an unfavorable clinical course including disease progression, relapse, or death. Pre-treatment stenosis and/or aneurysms were associated with progression of stenosis or aneurysm after corticosteroid treatment.

Conclusion

Most clinical characteristics were similar between the IgG4-related periaortitis/periarteritis and the non-vascular IgG4-related disease groups; however, serum C-reactive protein level elevation was observed only in the former. Although corticosteroid treatment was effective, this disease can be life-threatening secondary to myocardial infarction, aortic dissection, and aneurysmal rupture. Pre-treatment evaluation of stenosis or aneurysms is important for predicting progression of stenosis or aneurysm after corticosteroid treatment.

Introduction

Immunoglobulin G4 (IgG4)-related disease is a chronic fibroinflammatory disease characterized by serum IgG4 elevation, as well as histopathological changes including massive infiltration of IgG4-positive plasma cells at the affected sites and storiform fibrosis [1,2]. Recent advances in understanding the pathogenesis of this disease reveal the role of disease-associated T cell subsets and innate immune responses such as T-follicular helper cells [[3], [4], [5], [6]], cytotoxic CD4 T cells [7], T helper type 2 and regulatory T cells [8,9], plasmablasts [10], and alternatively activated macrophages [11,12].

Various organs such as the orbits, lacrimal and salivary glands, the lungs, pancreas, the biliary tract, kidneys, retroperitoneum, mediastinal tissue, as well as lymph nodes and blood vessels are affected [1,2,13,14]. In untreated cases, the affected organs become dysfunctional secondary to enlargement and severe fibrosis. Despite the introduction of B-cell depletion therapy as a promising approach, corticosteroids remain the mainstay of therapy [2]. The high rates of relapse during corticosteroid tapering [16] and various adverse effects associated with prolonged corticosteroid use are problematic. Comorbidities and polypharmacy in elderly patients, who are predisposed to this disease, tend to exaggerate this risk.

Periaortitis or periarteritis is a critical clinical manifestation of IgG4-related disease that occurs in 10%–30% of patients [17], and may present as an isolated manifestation or as a component of systemic organ involvement. The 2012 revised International Chapel Hill Consensus Conference Nomenclature on Vasculitides proposed IgG4-related disease as a potential cause of aortitis [18]. This condition affects not only the aorta but also medium-sized arteries, such as the coronary, carotid, pulmonary, splenic, mesenteric and iliac arteries [17]. IgG4-related periaortitis/periarteritis can cause life-threatening complications such as aortic aneurysm rupture and arterial stenosis; however, details of the clinical characteristics, prognosis, and optimal treatment remain unclear owing to the rarity of this condition.

In this study, we reviewed the published literature describing IgG4-related periaortitis/periarteritis and summarized the clinical characteristics and prognosis of this disease.

Section snippets

Materials and methods

We performed a careful search of the literature published in English in the PubMed database using the following Medical Subject Heading terms: “IgG4-related periaortitis”, “IgG4-related periarteritis”, “IgG4-related inflammatory aortic aneurysm”, “IgG4-related coronary artery”, or “IgG4-related coronary arteritis” from the inception dates until March 27, 2019. Two investigators (MA and YK) independently screened the identified articles based on their relevance to the topic. Disagreements were

Literature search

We initially identified 142 potentially relevant articles of which 108 were excluded based on the aforementioned inclusion/exclusion criteria (5 non-English articles, 30 unrelated to IgG4-related periaortitis/periarteritis or coronary arteritis, 20 with insufficient clinical information, 17 single case reports describing periaortitis, 7 basic research articles, and 29 reviews). Eventually, 7 articles were included in the study for IgG4-related periaortitis/periarteritis, 24 articles for

Discussion

In this study, we observed that the clinical characteristics of IgG4-related periaortitis/periarteritis or coronary arteritis were essentially similar to those observed in patients with non-vascular IgG4-related disease. However, serum C-reactive protein elevation was typically observed in patients with IgG4-related periaortitis/periarteritis in contrast to non-vascular IgG4-related disease. The infra-renal abdominal aorta and iliac arteries were the most commonly affected sites in patients

Conclusion

Most clinical characteristics were similar between the IgG4-related periaortitis/periarteritis and the non-vascular IgG4-related disease groups, but serum C-reactive protein level elevation was unique only in the IgG4-related periaortitis/periarteritis. IgG4-related coronary arteritis was classified into 3 types: stenotic, aneurysmal, and diffuse wall thickening type. Although corticosteroid treatment was effective, this disease can be life-threatening secondary to myocardial infarction, aortic

Funding support

None.

Disclosure statement

The authors have no conflict of interest to declare.

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Citation Excerpt :
Corticosteroids remain the mainstay therapeutic option in IgG4-RD despite the associated side-effects of prolonged exposure and high risk of relapse within one year after the taper 45,91. However, there are concerns about potential for rapid aneurysm enlargement and rupture with prolonged steroid therapy 49,92-94. Immunosuppressants and biologics are promising as steroid-sparing agents and in patients with steroid-refractory disease 95-98.
Inflammatory abdominal aortic aneurysms (IAAAs) are a variant involving a distinct immunoinflammatory process, with nearly one half believed to be associated with IgG4-related disease (IgG4-RD).
MEDLINE and Google Scholar searches were conducted for English-language publications relevant to inflammatory aortic aneurysms from January 1970 onward. The search terms included inflammatory aortic aneurysms, aortitis, periaortitis, IgG4-related disease, and retroperitoneal fibrosis. Relevant studies were selected for review based on their relevance.
Morphologically, IAAAs are characterized by a thickened aneurysm wall often displaying contrast enhancement and elevated metabolic activity on fluorine-18 fluorodeoxyglucose-positron emission tomography imaging. A strong association exists with perianeurysmal and retroperitoneal fibrosis. Although the rupture risk appears lower with IAAAs than with noninflammatory abdominal aortic aneurysms (AAAs), the currently recommended diameter threshold for operative management is the same. Open repair has been associated with increased morbidity compared with noninflammatory AAAs, and a retroperitoneal approach or minimal dissection transperitoneal approach has been recommended to avoid duodenal and retroperitoneal structural injuries. Endovascular aneurysm repair has been increasingly used, especially for patients unfit for open surgery. It is important to exclude an infectious etiology before the initiation of immunosuppressive therapy or operative repair. Multimodality imaging follow-up is critical to monitor disease activity and secondary involvement of retroperitoneal structures by the associated fibrotic process. Maintenance of immunosuppressive therapy will be needed postoperatively for most patients with active systemic disease, especially those with IgG4-RD and those with persistent symptoms. Additional interventions aimed at ureteral decompression could also be required, and lifelong follow-up is mandatory.
Preoperative multimodality imaging is a diagnostic cornerstone for assessment of the disease extent and activity. IgG4-RD is an increasingly recognized category of IAAAs, with implications for tailoring adjunctive medical therapy. Open surgical repair remains the procedure of choice, although endovascular aneurysm repair is increasingly being offered. Maintenance immunosuppressive therapy can be offered according to the disease activity as assessed by follow-up imaging studies.
Coronary Periarteritis and Pericardial Thickening Could Be Predictors for Coronary Artery Events Complicated by IgG4-Related Disease
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IgG4-related disease (IgG4-RD) is a systemic disease characterized by serum IgG4 upregulation, massive infiltration of IgG4-positive plasma cells, and storiform fibrosis, which results in nodules or thickening of the involved organs. Cardiologists have recently recognized that IgG4-RD can be complicated by coronary artery events (CAEs); however, the mechanisms and clinical characteristics of this phenomenon are unknown. We evaluated the clinical signs of patients with coronary periarteritis (CP), aortic periarteritis (AP), and pericardial thickening, which are complications of IgG4-RD, to determine the contributing factors.
We retrospectively examined 19 patients with IgG4-RD who attended or consulted a cardiologist in our department at the University of Tokyo Hospital between January 1, 2004, and December 31, 2021.
The frequency of CAEs was significantly higher in the CP group than in the non-CP group. Furthermore, the CP group had significantly lower event-free survival than the non-CP group (log-rank test, P = 0.008). However, the frequency of incidents and event-free survival for CAEs after IgG4-RD diagnosis did not differ significantly between the AP and non-AP groups. Although no statistically significant difference was present between the frequency of CAEs for those with vs without pericardial thickening, the group with pericardial thickening had significantly worse event-free survival than the group without pericardial thickening (log-rank test, P = 0.017).
The incidence and clinical course of CAEs complicated by IgG4-RD could be predicted by identifying CP and pericardial thickening in IgG4-RD but not AP.
La maladie liée aux immunoglobulines de type G4 (ML-IgG4) est une maladie généralisée caractérisée par une augmentation du taux sérique d’IgG4, par une infiltration massive de plasmocytes exprimant les IgG4 et par une fibrose storiforme, qui produit des nodules ou un épaississement des organes touchés. Les cardiologues ont récemment reconnu que la ML-IgG4 peut être compliquée par des événements coronariens; les mécanismes et caractéristiques cliniques de ce phénomène demeurent cependant inconnus. Nous avons évalué les signes cliniques chez des patients atteints de périartérite coronarienne (PC), de périaortite (PA) et d’épaississement du péricarde, des complications de la ML-IgG4, pour tenter d’établir les facteurs contributifs.
Nous avons examiné de manière rétrospective les dossiers de 19 patients atteints de ML-IgG4 qui ont été admis à notre service de l’Hôpital de l’Université de Tokyo ou qui ont consulté un cardiologue du service entre le 1^er janvier 2004 et le 31 décembre 2021.
La fréquence des événements coronariens était significativement plus élevée dans le groupe PC que dans les autres groupes. Par ailleurs, le groupe PC avait une survie sans événement significativement plus courte que les autres groupes (test logarithmique par rangs; p = 0,008). En outre, la fréquence des événements coronariens et la survie sans événement coronarien après un diagnostic de ML-IgG4 ne variaient pas de manière significative entre le groupe PA et les autres groupes. Bien qu’aucune différence statistiquement significative n’ait été constatée quant à la fréquence des événements coronariens entre les patients présentant un épaississement du péricarde et les autres patients, le premier groupe affichait une survie sans événement significativement plus courte que l’autre (test logarithmique par rangs; p = 0,017).
L’incidence et le déroulement clinique des événements coronariens compliqués par la ML-IgG4 pouvaient être anticipés dans les cas de ML-IgG4 en présence de PC et d’un épaississement du péricarde, mais pas de PA.
IgG4-related disease as a variable-vessel vasculitis: A case series of 13 patients with medium-sized coronary artery involvement
2023, Seminars in Arthritis and Rheumatism
IgG4-related disease (IgG4-RD) is a systemic autoimmune fibroinflammatory disease that can affect multiple organ systems. Although large-vessel vasculitis is a well-recognized manifestation of IgG4-RD, this condition is generally not regarded as a vasculitis. We aimed to describe coronary artery involvement (CAI), a vascular distribution about which little is known in IgG4-RD.
Patients with IgG4-related CAI were identified from a large, prospective IgG4-RD cohort. CAI was confirmed by imaging evidence of arterial or periarterial inflammation in any coronary artery. We extracted details regarding demographics, features of IgG4-RD, and manifestations of CAI.
Of 361 cases in the cohort, 13 (4%) patients had IgG4-related CAI. All were male and all had highly-elevated serum IgG4 concentrations, with a median value of 955 mg/dL (interquartile range [IQR]: 510–1568 mg/dL; reference: 4–86 mg/dL). Median disease duration at the time of CAI diagnosis was 11 years (IQR: 8.23–15.5 years). Extensive disease in the coronary arteries was the rule: all three major coronary arteries were involved in 11 patients (85%). The coronary artery manifestations included wall thickening or periarterial soft tissue encasement (85%), stenosis (69%), calcification (69%), and aneurysms or ectasia (62%). Five patients (38%) had myocardial infarctions, 2 (15%) required coronary artery bypass grafting, and 2 (15%) developed ischemic cardiomyopathy.
Coronary arteritis and periarteritis are important manifestations of IgG4-RD, which should be regarded as a variable-vessel vasculitis that is among the most diverse forms of vasculitis known. Potential complications of CAI include coronary artery aneurysms, myocardial infarction, and ischemic cardiomyopathy.
Successful treatment of IgG4-related disease with tocilizumab monotherapy
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Current Evidence in the Diagnosis and Management of Coronary Arteritis Presenting as Acute Coronary Syndrome
2023, Current Problems in Cardiology
Coronary arteritis is a rare but life-threatening cause of coronary artery disease and could manifest as acute coronary syndrome in clinical scenarios. Coronary arteritis could occur in the setting of systematic vasculitis or being isolated. Most of these patients were lacking of conventional risk factors in atherosclerotic cardiovascular disease. Diagnosis of coronary arteritis still be difficult and often be delayed. Clinicians should take in account of comprehensive factors including the evidence of muti-organ involvement (mainly by symptoms, physical examination and radiology imaging findings) and specific laboratory test results. For the treatment of coronary arteritis, systematic drug therapy (i.e., corticosteroid and immunosuppressive therapy) combined with revascularization were applied in the most cases. However, problems of frequently in-stent restenosis and recurrent myocardial infarction still needed to be solved. It is still unclear whether revascularization is efficient and safe for these patients, and the strategy to prevent restenosis and re-ischemia still needs to be studied in the future. In this study, we reviewed the specific clinical manifestations, laboratory results, imaging findings, diagnosis criteria and therapeutic strategies for patients with coronary arteritis presented as acute coronary syndrome.
The levels of IL-1β and soluble IL-1 receptors in patients with IgG4-related periaortitis/periarteritis
2022, Advances in Medical Sciences
IgG4-related disease (IgG4-RD) is a chronic fibrotic inflammatory and an immune-mediated disease characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system, and its pathogenesis and characteristics remain unclear.
The inflammatory cytokine IL-1β is involved in a variety of cellular activities including inflammation, fibrosis, and angiogenesis. The present study compared the levels of the inflammatory cytokine IL-1β and two soluble IL-1 receptors, IL-1R1 and IL-1R2, between IgG4-RD patients with and without IgG4-related periaortitis/periarteritis.
The patients with IgG4-related periaortitis/periarteritis (n = 38), those without (n = 66) and healthy (n = 33) were recruited to measure cytokines of IL-1β and soluble receptors (sIL-1R1 and sIL-1R2) in sera by ELISA assay.
Serum IgG4 was significantly higher in patients with periaortitis/periarteritis compared to non-periaortitis/periarteritis (p = 0.0074), while serum IL-1β was significantly lower in patients with periaortitis/periarteritis (p = 0.00037).
The three groups did not show significant difference in sIL1-R1, while sIL-1R2 in the periaortitis/periarteritis and healthy group was higher than in the group without periaortitis/periarteritis (p = 0.00001).
The characteristic changes in IL-1β, sIL-1R1, and sIL-1R2 levels in IgG4-RD patients with and without IgG4-related periaortitis/periarteritis may indicate an active phase of the inflammatory process in these diseases.

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ReviewCharacteristics and prognosis of IgG4-related periaortitis/periarteritis: A systematic literature review

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Materials and methods

Literature search

Discussion

Conclusion

Funding support

Disclosure statement

Lancet

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Review
Characteristics and prognosis of IgG4-related periaortitis/periarteritis: A systematic literature review