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Corresponding author: Drs Hiroki Yagi, and Eisuke Amiya, Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel.: +81-03-3815-5411; fax: +81-3-5800-9182.
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, JapanDepartment of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, JapanAdvanced Medical Center for Heart Failure, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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.
Methods
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.
Results
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).
Conclusions
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.
Résumé
Contexte
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.
Méthodologie
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 1er janvier 2004 et le 31 décembre 2021.
Résultats
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).
Conclusions
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 (RD) is characterized by elevated serum IgG4 levels, mass formation, diffuse thickening, swelling, and fibrotic lesions due to the infiltration of IgG4-positive plasma cells. In 2001, Hamano et al. reported the first case of autoimmune pancreatitis with IgG4 infiltration.
Subsequently, findings made clear that some pathologic conditions have similar serologic and histologic features in various tissues, including endocrine and exocrine organs, lungs, skin, and kidneys, known as IgG4-RD.
IgG4-RD is generally responsive to steroid therapy; however, some patients are refractory to glucocorticoids and other immunosuppressive treatments or relapse repeatedly after temporary improvement, and the progression of fibrosis in affected organs can lead to severe functional disability.
The recent development of multidetector-row computed tomography (CT) and other imaging techniques has revealed that IgG4-RD lesions extend to cardiovascular organs, causing coronary periarteritis (CP), aortic periarteritis (AP), and pericardial thickening.
However, the factors that determine the affected sites are unknown. AP can lead to aortic aneurysm formation, which requires surgical or endovascular intervention. However, the main symptoms of IgG4-related CP include massive aneurysms or multiple ectasias and stenoses in the coronary arteries, which has no currently establishedtreatment. Therefore, predicting coronary artery events (CAEs) in patients with IgG-RD and providing appropriate early treatment are essential.
Therefore, the current study aimed to evaluate the clinical signs of patients with IgG4-RD with CP, AP, and pericardial thickening, investigate their associations with CAEs, and identify the major contributing factors to the occurrence of CAEs in patients with IgG4-RD.
Patients and Methods
Patients
We retrospectively investigated 20 consecutive patients with suspected IgG4-RD who visited our department for cardiovascular disease-related signs and symptoms (eg, chest symptoms and abnormal CT findings, electrocardiogram, and echocardiography) between January 1, 2004, and December 31, 2021. We excluded one case with an incomplete examination, and we analyzed 19 patients diagnosed with IgG4-RD. All patients had been diagnosed with IgG4-RD based on the comprehensive diagnostic criteria for IgG4-RD.
Patients with a “possible” diagnosis of IgG4-RD, without a pathologic diagnosis, were confirmed to have IgG4-RD using the classification criteria developed by the American College of Rheumatology.
IgG4-RD was diagnosed after the following diseases were ruled out: lymphoma, Castleman’s disease, Rosai-Dorfman disease, Erdheim-Chester disease, and anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV).
We analyzed the clinical characteristics of the patients, including their laboratory data, at the time of diagnosis. The patients were divided into 2 groups according to the presence or absence of CP, AP, and pericardial thickening, and whether their clinical characteristics and outcomes of CAEs. CAEs are a composite of ischemic heart disease (IHD) that requires invasive therapy—such as percutaneous coronary intervention (PCI), and coronary artery bypass surgery (CABG)—and coronary aneurysms that require treatment with aneurysmectomy after or immediately after the diagnosis of IgG4-RD. IHD is characterized by a history of acute coronary syndrome, coronary revascularization > 3 months ago, or angiographically documented coronary artery stenosis with at least 75% narrowing of the diameter according to the American Heart Association classification.
Image evaluation
All 19 patients underwent whole-body contrast-enhanced CT during diagnosis and, at the discretion of the attending physician, during the follow-up period. Experienced radiologists and cardiologists analyzed all imaging data. We performed positron emission tomography-CT on 14 patients (73.7%). AP and CP were characterized by diffuse circumferential thickening of the arterial wall (adventitia) or a soft-tissue mass around the artery with higher CT values than those of the surrounding normal peri-artery area, with lesion sites having a larger diameter than the diameter of adjacent non-lesion sites on contrast-enhanced CT.
Clinical and pathological characteristics of IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis diagnosed based on experts' diagnosis.
Retroperitoneal fibrosis was diagnosed when a soft-tissue shadow was observed on the renal pelvis and ureter, or when placoid tumourous lesions were observed in the retroperitoneal region. Pericardial thickening is characterized by discontinuous pericardial thickening on contrast-enhanced CT. An echocardiogram simultaneously confirmed the absence of pericardial effusion to differentiate it from pericardial effusion.
Statistical analysis
All data were expressed as mean ± standard deviation or median with interquartile range. A 2-tailed Student t test or a Mann-Whitney U test was used for 2-group comparisons, and Fisher’s exact test was used to determine significant differences in frequency. The Kaplan–Meier method was used to construct an event-free survival curve for CAEs, and comparisons were made using the log-rank test. The endpoint of the event-free survival curve was defined as the time of revascularization or CAE-related death, and time zero was defined as the time of IgG4-RD diagnosis. The significance level was set at P < 0.05. Prism 8.0 (GraphPad, La Jolla, CA) was used to perform statistical analyses of all data.
Results
Patient characteristics in this study
Table 1 shows the characteristics of the patients included in this study at the time of diagnosis. Of the 19 patients, 15 (78.9%) were men, and the mean age of the patients was 68.1 ± 7.7 years. Tissue sampling was performed in 9 patients (47.4%), including on the submandibular gland, salivary gland, skin, extrapleural soft tissue, retroperitoneum, right infraorbital mass, and left inguinal lymph node. A total of 17 patients (89.5%) had elevated serum IgG4 levels > 135 mg/dL, and the median IgG4 level was 661.0 mg/dL (235.0-1290 mg/dL). The mean (standard deviation) C-reactive protein level and the median (interquartile range) eosinophil level, which are potential biomarkers of disease activity, were, respectively, 0.59 ± 0.81 mg/dL and 200.0 cells/μL (150.0-800.0 cells/μL). In patients with an IgG4-RD diagnosis, the diagnosis was definite in 7 patients (36.8%), probable in 2 patients (10.5%), and possible in 10 patients (52.6%), based on comprehensive diagnostic criteria for IgG4-RD.
The duration of the disease was 8.2 ± 5.4 years. We treated 14 patients (78.9%) with steroids, 4 (21.1%) with azathioprine, and 1 (5.3%) with methotrexate.
Table 1Patient characteristics at the time of diagnosis
Characteristic
Value
Age, y
68.1 ± 7.7
Sex, male
15 (78.9)
Laboratory examination
IgG4, mg/dL [11－121]
661.0 (235.0–1290.0)
IgG4 ≥ 135 mg/dL
17 (89.5)
CRP, mg/dL [0－0.3]
0.59 ± 0.81
Eosinophil, cells/μL [0%－8.5%]
200.0 (150.0–800.0)
Diagnosis
Definite/probable/possible
7 (36.8) / 2 (10.5) / 10 (52.6)
Duration of disease, y
8.2 ± 5.4
Treatment
Steroid therapy
15 (78.9)
Azathioprine
4 (21.1)
Methotrexate
1 (5.3)
Involvement of organs
Single organ
2 (10.5)
Multiorgan (≥ 2)
17 (89.5)
Cardiovascular
Aortic periarterial lesion
12 (63.2)
Coronary periarterial lesion
9 (47.4)
Pericardial thickening
5 (26.3)
Noncardiovascular
Retroperitoneal fibrosis
7 (36.8)
Eye
7 (36.8)
Salivary, parotid, and submandibular gland
5 (26.3)
Pancreas
5 (26.3)
Bone
5 (26.3)
Lymph node
4 (21.1)
Lung
4 (21.1)
Liver and biliary
2 (10.5)
Kidney
2 (10.5)
Medical history
Hypertension
16 (84.2)
Diabetes
9 (47.4)
Dyslipidemia
13 (68.4)
Smoking history
11 (57.9)
CKD
8 (42.1)
CAEs
9 (47.3)
Values are n (%), mean ± standard deviation, or median (interquartile range). Values in brackets are reference ranges in our centre.
We investigated the distribution of organ involvement to understand this cohort better. Table 1 shows that 17 patients (89.5%) had multi-organ involvement. Regarding noncardiovascular involvement, 7 patients (36.8%) had eye involvement, such as in the lacrimal gland. A total of 5 patients (26.3%) had autoimmune pancreatitis; 5 patients (26.3%) had involvement of the salivary, parotid, and submandibular glands; 4 patients (21.1%) had involvement of the bone, lung, and lymph nodes; and 2 patients (10.5%) had involvement of the liver, biliary, and kidney. In terms of cardiovascular involvements, 9 patients (47.4%) had CP; and the affected vessel was the left anterior descending (LAD) artery in 7 patients, the left circumflex artery in 4 patients, and the right coronary artery (RCA) in 7 patients (Fig. 1). Twelve patients (63.2%) had AP complication, and the affected vessels were the ascending aorta in 6 patients, the aortic arch in 1 patient, the descending thoracic aorta in 4 patients, the abdominal aorta in 7 patients, and the iliac artery in 6 patients (Fig. 2). Seven patients (36.8%) had retroperitoneal fibrosis, 6 of whom also had AP. A total of 5 patients (26.3%) had pericardial thickening (Fig. 3). A Venn diagram (Fig. 4) shows that 4 patients (21.1%) with IgG4-RD in this study shared all 3 cardiovascular involvements, including CP, AP, and pericardial thickening.
Figure 1Contrast-enhanced computed tomography findings of IgG4-related coronary periarteritis. Thickened coronary periarterial lesions of the (A-D) left anterior descending artery (E) left circumflex artery, and (F-I) right coronary artery are shown (yellow arrowheads).
All patients had at least one risk factor for IHD, and 8 patients (42.1%) had chronic kidney disease (CKD) with a glomerular filtration rate < 60 mL/min per 1.73 m2. A total of 9 patients (47.3%) complicated CAEs after or immediately after diagnosis of IgG4-RD; 7 patients were treated with PCI or CABG for IHD, and 2 patients underwent aneurysmectomy for coronary aneurysms. Herein, 2 patients were diagnosed with IHD before they were diagnosed with IgG4-RD.
Differences in clinical features and the frequency of CAEs in patients with vs without CP
Table 2 shows evaluation of the differences in clinical characteristics of the patients with vs without CP. No differences were observed between the CP and non-CP groups in mean age, serum IgG4 levels, or frequency of hypertension, dyslipidemia, diabetes, or CKD, or smoking history. However, the frequency of incident CAEs was substantially higher in the CP group than in the non-CP group (P = 0.023; Fig. 5A ). We further examined the differences between the CP and non-CP groups in the Kaplan-Meier event-free survival curves for CAEs after diagnosis of IgG4-RD. The CP group had significantly lower event-free survival than the non-CP group (log-rank test, P = 0.008; Fig. 5B).
Table 2Clinical features of patients with vs without coronary periarteritis (CP) in IgG4-related disease
Characteristic
CP (−) (n = 10)
CP (+) (n = 9)
P
Age, y
70.7 ± 5.6
65.2 ± 8.9
0.123
Sex, male
7 (70.0)
8 (88.9)
0.582
Medical history
Hypertension
9 (90.0)
7 (77.8)
0.582
Diabetes
4 (40.0)
5 (55.6)
0.656
Dyslipidemia
6 (60.0)
7 (77.8)
0.628
Smoking history
5 (50.0)
6 (66.7)
0.645
CKD
4 (40.0)
4 (44.4)
> 0.999
Laboratory examination, mg/dL
IgG4 [11－121]
705.0 (206.5–1057.0)
383.0 (230.0–1745.0)
0.661
IgG4 ≥ 135
8 (80.0)
9 (100.0)
0.474
Diagnosis
Definite/probable/possible
5 (50.0) / 2 (20.0) / 3 (30.0)
2 (22.2) / 0 (0) / 7 (77.8)
Values are n (%), mean ± standard deviation, or median (interquartile range). Values in brackets are reference ranges in our centre.
Figure 5Correlation between coronary periarteritis (CP) and coronary artery events (CAEs) complicated by IgG4-related disease (IgG4-RD). (A) The frequencies of CAEs in patients with vs without CP are presented as numbers and were compared using Fisher’s exact test. (B) The Kaplan-Meier analysis was performed to assess the differences in the event-free survival for CAEs after the diagnosis of IgG4-RD with vs without CP, and the log-rank test was used to compare the distributions of the event-free survival for CAEs. ∗P < 0.05.
Differences in clinical features and the frequency of CAEs in patients with vs without AP
Table 3 shows the differences in clinical characteristics of patients with vs without AP, among patients with IgG4-RD. We did not find significant differences between the AP and non-AP groups in the mean age, serum IgG4 levels, frequency of hypertension, dyslipidemia, diabetes mellitus, or CKD, or smoking history. Furthermore, no significant differences in the concomitant frequency of CP or the frequency of CAEs were observed between the AP and non-AP groups (Fig. 6, A and B ). We examined the differences between the AP and non-AP groups in the Kaplan-Meier event-free survival curves for CAEs after diagnosis of IgG4-RD. We found no significant difference between the AP and non-AP groups in event-free survival for CAEs (log-rank test, P = 0.156; Fig. 6C).
Table 3Clinical features of patients with vs without aortic periarteritis (AP) in IgG4-related disease
Characteristic
AP (−) (n = 7)
AP (+) (n = 12)
P
Age, y
69.1 ± 7.1
67.5 ± 8.2
0.666
Sex, male
6 (85.7)
9 (75.0)
> 0.999
Medical history
Hypertension
5 (71.4)
11 (91.7)
0.523
Diabetes
4 (57.1)
5 (41.6)
0.650
Dyslipidemia
3 (42.9)
10 (83.3)
0.129
Smoking history
5 (71.4)
6 (50.0)
0.633
CKD
1 (14.3)
7 (58.2)
0.147
Laboratory examination, mg/dL
IgG4 [11－121]
979.0 (205.0–1950.0)
341.0 (240.0–816.0)
0.340
IgG4 ≥ 135
6 (85.7)
11 (91.7)
> 0.999
Diagnosis
Definite/probable/possible
4 (57.1) / 1 (14.3) / 2 (28.6)
3 (25.0) / 1 (8.3) / 8 (66.7)
Retroperitoneal fibrosis
1 (14.3)
6 (50.0)
0.173
Values are n (%), mean ± standard deviation, or median (interquartile range). Values in brackets are reference ranges in our centre.
Figure 6Correlation between aortic periarteritis (AP) and coronary artery events (CAEs) complicated by IgG4-related disease (IgG4-RD). (A) The concomitant frequencies of coronary periarteritis (CP) in patients with vs without AP are presented as numbers and were compared using Fisher’s exact test. (B) The frequencies of incident CAEs in patients with vs without AP are presented as numbers and were compared using Fisher’s exact test. (C) The Kaplan-Meier analysis was performed to assess the differences in the event-free survival for CAEs after the diagnosis of IgG4-RD with vs without AP, and the log-rank test was used to compare the distributions of the event-free survival for CAEs. n.s., not significant.
Differences in clinical features and frequency of CAEs between patients with vs without pericardial thickening
Table 4 shows the differences in clinical characteristics between patients with vs without pericardial thickening. No significant differences were observed in the mean age, serum IgG4 levels, frequency of hypertension, dyslipidemia, diabetes, or CKD, or smoking history between the groups with vs without pericardial thickening. However, the concomitant frequency of CP was significantly higher in the group with pericardial thickening than in the group without it (P = 0.011; Fig. 7A ). We further investigated the differences between the groups with vs without pericardial thickening in the Kaplan-Meier event-free survival curve for CAEs after the diagnosis of IgG4-RD . Although the frequency of CAEs was not significantly different between the groups (P = 0.141), the pericardial-thickening group had significantly worse event-free survival than the group without pericardial thickening (log-rank test, P = 0.017; Fig. 7, B and C).
Table 4Clinical features of patients with vs without pericardial thickening (PT) in IgG4-related disease
Characteristic
PT (−) (n = 14)
PT (+) (n = 5)
P
Age, y
69.7 ± 7.8
63.6 ± 5.6
0.130
Sex, male
11 (78.6)
4 (80.0)
> 0.999
Medical history
Hypertension
13 (92.9)
3 (60.0)
0.155
Diabetes
6 (42.9)
3 (60.0)
0.629
Dyslipidemia
9 (64.3)
4 (80.0)
> 0.999
Smoking history
7 (50.0)
4 (80.0)
0.338
CKD
4 (28.6)
4 (80.0)
0.110
Laboratory examination, mg/dL
IgG4 [11－121]
705.0 (193.0–1057.0)
383.0 (264.5–1790.0)
0.500
IgG4 ≥ 135
12 (85.7)
5 (100.0)
> 0.999
Diagnosis
Definite/probable/possible
5 (35.7) / 2 (14.2) / 7 (50.0)
2 (40.0) / 0 (0) / 3 (60.0)
Values are n (%), mean ± standard deviation, or median (interquartile range). Values in brackets are reference ranges in our centre.
Figure 7Correlation between pericardial thickening and coronary artery events (CAEs) complicated by IgG4-related disease (IgG4-RD). (A) The concomitant frequencies of coronary periarteritis (CP) in patients with vs without pericardial thickening (PT) are presented as numbers and were compared using Fisher’s exact test. (B) The frequencies of incident CAEs in patients with vs without PT are presented as numbers and were compared using Fisher’s exact test. (C) The Kaplan-Meier analysis was performed to assess the differences in the event-free survival for CAEs after the diagnosis of IgG4-RD with vs without PT, and the log-rank test was used to compare the distributions of the event-free survival for CAEs. ∗P < 0.05. n.s., not significant.
was complicated by severe IHD, causing tumour-forming CP and multiple systemic aneurysms. Corticosteroid therapy was initiated, following which the inflammatory lesions shrank. However, the large, well-developed, common hepatic, and splenic aneurysms did not change. The patient died of splenic aneurysm rupture in the sixth month of treatment with a worsening clinical course. An autopsy revealed infiltration of IgG4-positive plasmacytes into the coronary wall and a thinned splenic aneurysm wall.
showed concomitant coronary artery dilation, pericardial inflammatory nodules, and a coronary-pulmonary fistula aneurysm, in addition to several IgG4-RD lesions. Each feature was located close to the thickened pericardium. These lesions might have resulted from inflammation of the pericardial space, which extended to the coronary-pulmonary artery vessels, leading to the formation of aneurysms. The patient underwent surgical intervention to treat coronary-pulmonary fistula aneurysm.
had a history of autoimmune pancreatitis. Moreover, prominent luminal enlargement (aneurysm) and diffuse periarterial inflammatory thickening of the coronary artery were observed. This patient underwent PCI of the LAD and was treated with prednisolone; however, aneurysmal formation in the peripheral RCA was exacerbated, and the patient eventually underwent aneurysmectomy and CABG.
Case 4 (Figs. 1C and 3D) had a history of autoimmune pancreatitis and IHD in the LAD and proximal RCA, without massive aneurysms or multiple ectasias and stenoses. The patient underwent PCI for the LAD and was treated with prednisolone after revascularization. Prednisolone was administered in the other case with pericardial thickening (Figs. 1H and 3E), and the pericardial thickening and CP improved, At this point, the patient had no CAEs.
Discussion
In this study, we demonstrated that the clinical course of CAEs worsens in patients with IgG4-RD complicated by CP and pericardial thickening. In particular, the relationship between pericardial thickening and CAEs seems to have a high level of clinical significance. Therefore, the aggressive prediction of CAEs in patients with IgG4-RD is important when pericardial thickening is detected during image evaluation. Based on our findings, we propose that patients with IgG4-RD complicated by CP or pericardial thickening should undergo a more extensive cardiac workup, including stress scintigraphy, cardiac contrast-enhanced CT, and coronary angiography.
IgG4-RD is a disease in which IgG4-positive plasma cells infiltrate several organs and form masses, diffuse thickening, swelling, and fibrotic lesions; however, pericardial thickening is not a common complication. Sugimoto et al. and Ibe et al. reported cases of constrictive pericarditis with the upregulation of serum IgG4 levels.
Furthermore, Kabara et al. reported a case of a patient who had elevated serum IgG4 levels and presented with massive pericardial effusion with infiltration of IgG4-positive plasma cells, which was confirmed by fine-needle aspiration cytology.
Other cases have shown fluorodeoxyglucose accumulation in the pericardium on positron emission tomography, suggesting that the pericardium is a site where IgG4-related inflammation is likely to occur.
However, the significance and clinical presentation of pericardial thickening associated with IgG4-RD are unknown.
Herein, all 5 patients with the complication of pericardial thickening had concomitant CP, 4 (80%) of whom had CAEs, and one (20%) of whom had no CAEs (Fig. 7, A and B). The frequency of incident CAEs was not significantly different between the groups with vs without pericardial thickening; however, the group with pericardial thickening had a significantly worse clinical course of CAEs than did the group without pericardial thickening (Fig. 7, B and C). Case reports have shown that IgG4-RD with pericardial involvement had a fatal outcome with a rapid worsening of the clinical course.
Thus, in cases of IgG4-RD with pericardial thickening, the treatment strategy is often decided with caution, and the clinical course is likely to worsen.
Additionally, we found that the frequency of incident CAEs was significantly higher in the CP group than in the non-CP group (Fig. 5A). Angiographically distinguishing the etiology of IHD (atherosclerosis or IgG4-induced inflammation) may be difficult. Studies have reported both a diffuse-wall-thickening type and a stenotic type, including occlusive thrombi, in CP.
Sakamoto et al. reported that serum IgG4 concentrations were higher in patients with angiographically proven IHD than in those without IHD. This finding suggests that IgG4-related immune-inflammation also contributes to the development and progression of coronary artery atherosclerosis.
Indeed, the patients in this study were more likely to be older men with multiple coronary risk factors (Table 1). Several patients were at high risk of atherosclerotic IHD, and 2 patients (20.0%) in the non-CP group were CAE-related complications after the diagnosis of IgG4-RD (Fig. 5A). However, the 2 aforementioned patients in the non-CP group did not have the complication of pericardial thickening, and they had lesions that could be treated with conventional PCI, posing no confusion regarding the treatment strategy. The clinical course remained favourable without worsening, and no deaths related to CAEs were observed in the non-CP group (Fig. 5B). Hence, the presence or absence of CP and pericardial thickening may help predict the clinical course of CAEs in patients with IgG4-RD.
We also found that the concomitant frequency of IgG4-related CP was substantially higher in the group with pericardial thickening than in the group without it (Fig. 7A). However, this phenomenon was not observed in patients with IgG4-RD, regardless of the presence of AP (Fig. 6A). This trend suggests that pericardial thickening reflects the intense inflammation of the coronary artery. Although we could not find any difference in the frequency of incident retroperitoneal fibrosis between the AP and non-AP groups (Table 3), studies reported that the close location of the aorta and retroperitoneum corresponds to the coincident occurrence of AP and retroperitoneal fibrosis.
and our findings suggest that the strong inflammation of CP propagates from the adventitia to the intima, media, and pericardium. Based on these findings, diffuse pericardial thickening can be considered a subset of CP. However, the data from this study are not sufficient to elucidate any causality between CP and pericardial thickening. Further studies are required to better understand the unique manifestations of IgG4-RD.
This study had several limitations. First, it was a single-centre retrospective study with a small sample size, conducted in Japan. Therefore, we could not investigate the causality between CP and pericardial thickening in relation to CAEs. Second, we could not include all patients who visited our hospital; therefore, we limited our analysis to those patients who visited the cardiology department. Indeed, the clinical phenotype of the patient population in this study did not belong to groups 1-4 as described by Wallace et al.
The reason the results of the group distribution were inconsistent with previous reports is that cases in the current study were restricted to those involving a cardiologist. Third, cardiac contrast-enhanced CT scans were performed in cases of chest pain and electrocardiographic and echocardiographic abnormalities, and/or when deemed necessary by the attending physician. Therefore, cardiac contrast-enhanced CT scans were not performed for any of the19 patients included in this study, and mild CP may not have been fully evaluated. However, we believe that further clarification of the clinical signs of IgG4-RD is required for a more accurate diagnosis of IgG4-RD.
Conclusion
Identification of CP and pericardial thickening, but not AP, in IgG4-RD could predict the occurrence and clinical course of CAEs complicated by IgG4-RD. To the best of our knowledge, this study is the first to focus on the characteristics of CAEs in patients with IgG4-RD, based on their association with the surrounding pericardium. For patients diagnosed with IgG4-RD, proactive evaluation of CP and pericardial thickening and early prediction of CAEs may help clarify treatment strategies.
Data availability
The data that support the findings of this study are available from the corresponding author on reasonable request.
Funding Sources
The authors have no funding sources to declare.
Disclosures
E.A. is a member of a department endowed by NIPRO-Corp., Terumo-Corp., Senko Medical-Instrument-Mfg., Century-Medical, Inc., ONO-pharmaceutical-Co., Ltd. Medtronic-JAPAN Co., Ltd, Nippon-Shinyaku Co., Ltd, Mochida Pharmaceutical Co., Boehringer Ingelheim Pharmaceuticals Inc., Abiomed-Inc, AQuA-Inc, Fukuda-Denshi Co., Ltd, and Sun-Medical-Technology-Research Corp; and received research funds from Bristol-Myers Squibb Co. The other authors have no conflicts of interest to disclose.
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High serum IgG4 concentrations in patients with sclerosing pancreatitis.
Clinical and pathological characteristics of IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis diagnosed based on experts' diagnosis.
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