Abstract
Background: In 2018, diagnostic criteria were introduced for IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis (PA/RPF). This study assessed the existing criteria and formulated an improved version.
Methods and Results: Between August 2022 and January 2023, we retrospectively analyzed 110 Japanese patients diagnosed with IgG4-related disease (IgG4-RD) involving cardiovascular and/or retroperitoneal manifestations, along with 73 non-IgG4-RD patients (“mimickers”) identified by experts. Patients were stratified into derivation (n=88) and validation (n=95) groups. Classification as IgG4-RD or non-IgG4-RD was based on the 2018 diagnostic criteria and various revised versions. Sensitivity and specificity were calculated using experts’ diagnosis as the gold standard for the diagnosis of true IgG4-RD and mimickers. In the derivation group, the 2018 criteria showed 58.5% sensitivity and 100% specificity. The revised version, incorporating “radiologic findings of pericarditis”, “eosinophilic infiltration or lymphoid follicles”, and “probable diagnosis of extra-PA/-RPF lesions”, improved sensitivity to 69.8% while maintaining 100% specificity. In the validation group, the original and revised criteria had sensitivities of 68.4% and 77.2%, respectively, and specificities of 97.4% and 94.7%, respectively.
Conclusions: Proposed 2023 revised IgG4-related cardiovascular/retroperitoneal disease criteria show significantly enhanced sensitivity while preserving high specificity, achieved through the inclusion of new items in radiologic, pathological, and extra-cardiovascular/retroperitoneal organ categories.
IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition characterized by extensive infiltration of lymphocytes and plasma cells, featuring abundant IgG4-positive plasma cells, storiform fibrosis, and typically an elevated serum IgG4 concentration. This condition leads to the enlargement of, formation of nodules in, or thickening of the affected organ(s).1,2 IgG4-RD can manifest in various organs either simultaneously or metachronously. Although several diagnostic criteria have been proposed for IgG4-RD, none of the individual clinical, serological, radiological, or pathological features alone is adequate for a definitive diagnosis. Therefore, the integration of evidence from all 4 elements is crucial.3
The 2020 revised Japanese comprehensive diagnostic (CD) criteria for IgG4-RD4 enhance the diagnosis of IgG4-RD across organs, relying on characteristic swelling or masses in affected organs, elevated serum IgG4 concentrations, and histopathological findings, including copious infiltration of IgG4-positive plasma cells. Elevated serum IgG4 concentrations and tissue sampling from affected organs are pivotal for a definitive CD criteria-based diagnosis; however, challenges exist, particularly in certain organs such as the retroperitoneum, which may have a lower likelihood of elevated serum IgG4 concentrations5 or pose safety concerns for biopsy. In Japan, the Ministry of Health, Labour, and Welfare (MHLW) recommends the use of organ-specific criteria for each affected organ in IgG4-RD,6–13 in conjunction with CD criteria, to account for organ-specific considerations in the definitive diagnosis.14,15
In 2018, a joint working group comprising members from the Japanese Circulation Society and the MHLW study group proposed diagnostic criteria for IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis (IgG4-PA/RPF; Table 1).12,13 These criteria were subsequently approved by the MHLW as organ-specific diagnostic criteria, demonstrating higher sensitivity than the CD criteria in a validation study with 99 patients.13 However, their real-life clinical practice value, especially in terms of specificity, requires further evaluation. With this consideration, the aim of the present study was to assess the validity of and potential issues with the IgG4-PA/RPF criteria from 2018 and propose modifications, culminating in the development of a revised 2023 version.
Table 1.
2018 Diagnostic Criteria for IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis
| A. Diagnostic factors |
| 1. Abnormal radiologic findings |
| a. Low-density hypertrophic thickening or soft tissue masses surrounding the aorta and its major branches *1, *2, *3, *4 |
| b. Soft tissue masses in renal pelvic wall and/or around the ureter *5 |
| c. Soft tissue masses in the pelvis and paravertebral area |
| 2. Elevated serum IgG4 concentration (IgG4 ≥135 mg/dL) |
| 3. Histologic findings of the periaortic/periarterial and/or retroperitoneal regions |
| a. (i), (ii), (iii)/(iv) |
| b. (i), (ii) |
| (i) Marked lymphocyte and plasmacyte infiltration and fibrosis *6, *7, *8 |
| (ii) IgG4-positive plasma cell infiltration: |
| Surgical samples: IgG4-positive plasma cells >30/HPF and ratio of IgG4/IgG positive cells >40% |
| Biopsy samples: IgG4-positive plasma cells >10/HPF and ratio of IgG4/IgG positive cells >40% |
| (iii) Storiform fibrosis |
| (iv) Obliterative phlebitis |
| 4. Other organ involvement |
When IgG4-related disease is definitively diagnosed in the ophthalmus, salivary glands, pancreas, bile duct, kidney or
lung by comprehensive diagnostic criteria or organ-specific diagnostic criteria for the indicated organs |
| B. Diagnosis |
| Definite diagnosis (definite): 1(a/b/c) + 3a or 1(a/b/c) + 2 + 4 |
| Probable diagnosis (probable): 1(a/b/c) + 3b or 1(a/b/c) + 4 or 3a |
| Possible diagnosis (probable): 1(a/b/c) + 2 or 3b |
| C. Appendix |
*1. Stenosis of the vessel lumen is not present in the aorta; however, lumen narrowing may be observed in medium-
sized vessels |
| *2. Occasionally accompanied by lumen dilatation or aneurysm formation |
*3. It is necessary to exclude atherosclerosis, arterial dissection, infectious diseases (bacteria, tuberculosis,
syphilis, etc.), other forms of vasculitis, malignant diseases (such as malignant lymphoma and cancers), and Erdheim-
Chester disease |
| *4. The lesions may, in general, involve medium-to-large-sized vessels |
| *5. Soft tissue masses is common in the renal pelvis and upper ureter |
*6. Infiltration of lymphocytes and plasma cells is observed in the periarterial regions; vasculitis in the medial layer may
be present in the thoracic aorta |
*7. Findings of obliterative phlebitis may be more easily assessed by Elastica van Gieson staining than
hematoxylin-eosin staining |
*8. Necrosis, granuloma, and neutrophil infiltration are not usually observed; when these findings are present,
differential diagnosis should be carefully undertaken |
Note, “/” indicates “or”. HPF, high-power field.
Methods
Patients and Materials
Between August 1, 2022, and January 31, 2023, we enrolled 110 patients diagnosed with IgG4-RD involving cardiovascular and/or retroperitoneal manifestations, along with 73 non-IgG4-RD patients (“mimickers”). The gold standard for the diagnosis of true IgG4-RD or mimickers was a final diagnosis made by experts, requiring agreement from more than 2 experts. A diagnosis of true IgG4-RD was based on clinical, serological, radiological, and pathological features consistent with IgG4-RD, a positive response to glucocorticoid treatment, and the exclusion of other diseases. In the present study, “mimickers” were defined as patients suspected of having IgG4-RD but with a final expert diagnosis of non-IgG4-RD based on clinical, serological, radiological, and pathological features, clinical course, and relevant diagnostic or classification criteria. All 183 patients were randomly divided into 2 groups, a derivation group (53 true IgG4-RD, 35 mimickers) and a validation group (57 true IgG4-RD, 38 mimickers).
Medical records were retrospectively reviewed, and clinical factors at diagnosis, including age, sex, and serum IgG, IgG4, IgE, CH50, C3, C4, C-reactive protein (CRP), and creatinine concentrations, were determined. Additional factors determined included peripheral blood white blood cell and eosinophil counts, the presence or absence of extra-cardiovascular/retroperitoneal organ involvement, fulfillment of CD and organ-specific criteria, comorbidities (allergic predisposition, diabetes, hypertension, dyslipidemia, atherosclerotic disease), smoking history, and radiological findings of the affected aorta/artery, including wall thickness, lumen diameter, and outer diameter.
Factors before/at diagnosis were also assessed, including rheumatoid factor, anti-nuclear antibodies, and various disease-specific autoantibodies, including anti-Ro/SSA, anti-La/SSB, anti-neutrophil cytoplasmic, anti-double-stranded DNA, anti-ribonucleoprotein, and anti-Smith (Sm) antibodies.
In 75 patients (41%), cardiovascular/retroperitoneal lesions were sampled and tissue samples were evaluated for optical microscopy findings consistent with IgG4-RD, such as lymphoplasmacytic infiltration, storiform fibrosis, and obliterating phlebitis.16 Characteristics of cardiovascular/retroperitoneal lesions, including lymphoid follicles and eosinophilic infiltration,17 were also assessed. In addition, neutrophil-predominant cell infiltration, epithelioid granuloma formation, and necrotizing vasculitis, which are considered not to be observed in IgG4-RD lesion tissues,16 were evaluated. The number of IgG4- and IgG-positive cells per high-power field was counted, with a mean value from 3 high-power fields used for the specimen.
The upper limit of normal for serum IgG4 concentrations was set at 135 mg/dL, a common threshold in various Japanese diagnostic criteria for IgG4-RD.4,6–13
This study was approved by the Institutional Ethics Board of the Medical Ethics Committee of Kanazawa University (Reference no. 2022-042) and the collaborating institutions, and was performed in accordance with the tenets of the 1964 Helsinki Declaration and its later amendments. The requirements for patient approval and informed consent were waived due to the retrospective nature of the study involving patient records, images, and pathologies. Information regarding the nature of the study was provided to patients.
Statistical Analysis
Statistical analyses were conducted using SPSS v.25. Continuous variables are presented as the median with interquartile range (IQR); categorical variables are presented as frequencies and percentages. The Mann-Whitney U test was used to assess the significance of differences between groups for continuous variables, whereas Fisher’s exact probability test was used to evaluate the significance of differences in frequencies. Significance was defined as two-tailed P<0.05.
Results
Patient Profiles of the Derivation Group
The derivation group comprised 53 true IgG4-RD patients and 35 mimickers; patient profiles are provided in Table 2. Both groups were predominantly male (89% and 66% of true IgG4-RD patients and 35 mimickers, respectively), with a median age of 72 years. Approximately half the true IgG4-RD patients had multiple organ involvement, with salivary glands (32%), lacrimal glands (23%), the pancreas (17%), kidney (11%), and lung (13%) being commonly affected. Conditions among the mimickers included non-IgG4-related idiopathic inflammatory aortic aneurysm (n=17), atherosclerotic or infectious aneurysm (n=9), vasculitis (n=6), lymphoma (n=2), and plasmacytoma (n=1).
Table 2.
Baseline Clinical Characteristics of the 53 Patients With IgG4-RD and 35 Mimickers in the Derivation Group
| |
IgG4-RD
(n=53) |
Mimickers
(n=35) |
P value |
| Age (years) |
72 [65–78] |
72 [64–76] |
0.710 |
| Male sex |
89 |
66 |
0.014** |
| Allergy |
36 |
26 |
0.476 |
| Serum IgG (mg/dL) |
1,927 [1,526–2,537] |
1,399 [1,035–1,637] |
<0.001** |
| Serum IgG4 (mg/dL) |
361 [181–1,090] |
49 [27–89] |
<0.001** |
| Serum IgG4/IgG ratio (%) |
20.4 [13.4–40.5] |
4.3 [2.5–7.0] |
<0.001** |
| Serum IgE (IU/mL) |
641 [250–1,278] |
28 [13–165] |
<0.001** |
| Serum CH50 (U/mL) |
57 [44–60] |
61 [57–75] |
0.017** |
| Serum C3 (mg/dL) |
97 [76–114] |
125 [98–156] |
0.028** |
| Serum C4 (mg/dL) |
22 [15–32] |
31 [19–46] |
0.034** |
| Serum CRP (mg/dL) |
0.20 [0.10–0.50] |
1.32 [0.37–3.91] |
<0.001** |
| Serum creatinine* (mg/dL) |
0.93 [0.73–1.21] |
0.83 [0.69–1.11] |
0.274 |
| Eosinophil count (/μL) |
185 [70–326] |
78 [0–239] |
0.005** |
| Disease-specific autoantibodies |
11 |
3 |
0.236 |
| Items of diagnostic criteria |
| 1. Radiologic findings |
81 |
69 |
0.207 |
| 2. Elevated serum IgG4 concentrations |
83 |
4 |
<0.001** |
| 3. Pathological findings |
| 3a. LP and IgG4+PC with SF or OP |
17 |
0 |
0.011** |
| 3b. LP and IgG4+PC without SF or OP |
9 |
0 |
0.152 |
| 4. Definitive extra-C/-R organ lesions |
48 |
0 |
<0.001** |
| Biopsy of C/R lesion |
38 |
46 |
0.510 |
Unless indicated otherwise, data are given as the median [interquartile range] or as a percentage. *Note, to convert creatinine from mg/dL to μmol/L, multiply by 88.4. **Note, P<0.05. CH50, 50% hemolytic complement; CRP, C-reactive protein; C/R, cardiovascular/retroperitoneal; IgG4-RD, IgG4-related disease; LP and IgG4+PC, lymphoplasmacytic infiltration with copious IgG4-positive plasma cells; OP, obliterative phlebitis; SF, storiform fibrosis.
True IgG4-RD patients exhibited significant male predominance, higher serum IgG, IgG4, and IgE concentrations, higher eosinophil counts, and lower serum CH50, C3, C4, and CRP concentrations compared with mimickers. Regarding fulfilling the original IgG4-PA/RPF diagnostic criteria, patients with true IgG4-RD exhibited a higher frequency of elevated serum IgG4 concentrations, lymphoplasmacytic infiltration featuring abundant IgG4-positive plasma cells with obliterative phlebitis and/or storiform fibrosis, and a definitive diagnosis of extra-cardiovascular/retroperitoneal lesions compared with mimickers. The proportion of biopsied cases in the true IgG4-RD and mimicker groups was 38% and 46%, respectively.
Performance of the 2018 Diagnostic Criteria for IgG4-PA/RPF
Among the 53 patients with true IgG4-RD, 28 were classified as “definite”, 3 as “probable”, 16 as “possible” and 6 as “unlikely” based on the 2018 IgG4-PA/RPF diagnostic criteria. In contrast, among the 35 mimickers, none met the criteria for “definite” or “probable”, 1 was classified as “possible”, and 34 were classified as “unlikely”. When classifying definite and probable cases as “IgG4-RD” and possible and unlikely cases as “non-IgG4-RD”, the 2018 original diagnostic criteria demonstrated a sensitivity of 58.5% (31/53) and a specificity of 100% (35/35).
Characteristics of False-Negative Patients
False-negative patients had similar laboratory and serological findings to true-positive patients. However, false-negative patients had significantly lower rates of meeting radiologic criteria (64% vs. 94%; P=0.011), lymphoplasmacytic infiltration accompanied by abundant IgG4-positive plasma cells with obliterative phlebitis and/or storiform fibrosis (0% vs. 29%; P=0.007), and a definitive diagnosis of extra-cardiovascular/retroperitoneal lesions (10% vs. 75%; P<0.001) based on the original diagnostic criteria for IgG4-PA/RPF. In addition, the false-negative patients had a lower prevalence of lesions in the pancreas (0% vs. 32%; P=0.006), salivary gland (10% vs. 54%; P=0.002), and renal parenchyma (0% vs. 21%; P=0.034). The rate of biopsies was similar among false-negative and true-positive patients (41% vs. 35%, respectively; P=0.777; Table 3).
Table 3.
Comparison of False-Negative and True-Positive Cases With True IgG4-RD in the Derivation Group
| |
False negatives
(n=22) |
True positives
(n=31) |
P value |
| Age (years) |
74 [68–80] |
71 [63–75] |
0.129 |
| Male sex |
82 |
94 |
0.219 |
| Allergy |
21 |
45 |
0.130 |
| Serum IgG (mg/dL) |
1,744 [1,376–2,193] |
2,054 [1,623–2,956] |
0.132 |
| Serum IgG4 (mg/dL) |
313 [181–433] |
499 [177–1,213] |
0.170 |
| Serum IgG4/IgG ratio (%) |
16 [13–25] |
29 [14–45] |
0.183 |
| Serum IgE (IU/mL) |
297 [154–1,877] |
835 [419–1,196] |
0.190 |
| Serum CH50 (U/mL) |
60 [49–68] |
53 [43–60] |
0.102 |
| Serum C3 (mg/dL) |
108 [85–122] |
91 [70–109] |
0.079 |
| Serum C4 (mg/dL) |
26 [13–36] |
19 [15–27] |
0.118 |
| Serum CRP (mg/dL) |
0.20 [0.07–0.78] |
0.18 [0.10–0.50] |
0.591 |
| Serum creatinine* (mg/dL) |
0.89 [0.67–1.21] |
0.93 [0.77–1.31] |
0.692 |
| Eosinophil count (/μL) |
185 [75–239] |
185 [70–615] |
0.312 |
| Disease-specific autoantibodies |
14 |
10 |
0.683 |
| Aortic/arterial wall thickness (mm) |
7.9 [2.8–10.0] |
5.8 [4.0–7.2] |
0.396 |
| Lumen diameter (mm) |
25.0 [13.5–46.3] |
15.9 [14.1–40.8] |
0.367 |
| Aortic/arterial outer diameter (mm) |
46.0 [27.4–56.5] |
26.9 [20.7–35.3] |
0.029** |
| Items of diagnostic criteria |
| 1. Radiologic findings |
64 |
94 |
0.011** |
| 2. Elevated serum IgG4 concentrations |
83 |
82 |
1.000 |
| 3. Pathological findings |
| 3a. LP and IgG4+PC with SF or OP |
0 |
29 |
0.007** |
| 3b. LP and IgG4+PC without SF or OP |
18 |
3 |
0.147 |
| 4. Definitive extra-C/-R organ lesions |
10 |
75 |
<0.001** |
| Pancreatic lesion |
0 |
32 |
0.006** |
| Salivary gland lesion |
10 |
54 |
0.002** |
| Lacrimal gland lesion |
10 |
36 |
0.051 |
| Renal lesion |
0 |
21 |
0.034** |
| Lung lesion |
5 |
21 |
0.214 |
| Biopsy of C/R lesion |
41 |
35 |
0.777 |
Unless indicated otherwise, data are given as the median [interquartile range] or as a percentage. *Note, to convert creatinine from mg/dL to μmol/L, multiply by 88.4. **Note, P<0.05. Abbreviations as in Table 2.
Potential Problems in the IgG4-PA/RPF 2018 Diagnostic Criteria and Development of Revised 2023 Diagnostic Criteria for IgG4-Related Cardiovascular/Retroperitoneal Disease
Analysis of patients in the derivation group revealed potential issues with the IgG4-PA/RPF 2018 diagnostic criteria. Consequently, we revised specific elements of the original criteria and assessed the sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio for each revised version within the derivation cohort. Through these evaluations, we identified the version that demonstrated optimal performance, aligning closely with our target criteria (positive and negative likelihood ratios >10.0 and <0.10, respectively). This selected version now serves as the candidate for the revised 2023 diagnostic criteria for IgG4-related cardiovascular/retroperitoneal disease.
Cardiovascular/Retroperitoneal Lesions Not Included in the Radiologic Findings In addition to lesions in the renal pelvis, around the ureter, and within the pelvic retroperitoneum, periarterial lesions in various arteries, including the coronary, mesenteric, and splenic arteries, can fulfill the radiologic findings of the 2018 diagnostic criteria for IgG4-PA/RPF. However, in the present study, pericardial lesions such as thickening and effusion could not be considered as positive radiologic findings due to their absence in the criteria. Indeed, 3 patients with pericardial lesions were classified as non-IgG4-RD due to the lack of mention of pericardial lesions in the radiologic findings criteria. When we included pericardial thickening and/or effusion as an item of radiologic cardiovascular/retroperitoneal findings (Revision A), the sensitivity increased from 58.5% to 62.3%s, while the specificity remained unchanged at 100%.
Lower Probability of Elevated Serum IgG4 Concentration in Patients With Lesions Limited to the Cardiovascular/Retroperitoneal Region It is known that elevated serum IgG4 concentrations are less frequently observed in patients with lesions limited to the cardiovascular/retroperitoneal regions.5 Conversely, an elevated serum IgG4/IgG ratio >8% has been reported to have a sensitivity of 95.5% with a specificity of 87.5% for diagnosing IgG4-RD.18 When we changed the serological item “Elevated serum IgG4 concentration (IgG4 ≥135 mg/dL)” to “Elevated serum IgG4 concentration (IgG4 ≥135 mg/dL) or elevated serum IgG4/IgG ratio (IgG4/IgG >8%)” (Revision B), both the sensitivity and specificity remained unchanged.
Characteristic Pathological Findings Other Than Storiform Fibrosis and Obliterating Phlebitis In a previous study, we observed that needle biopsy specimens had a lower frequency of storiform fibrosis and/or obliterating phlebitis positivity than autopsy or surgical specimens.13 Other frequent and characteristic pathological findings, such as eosinophilic infiltration and lymphoid follicles, were also reported in cardiovascular/retroperitoneal lesions.13,17,19 When we incorporated eosinophilic infiltration and lymphoid follicles into the histologic items (Revision C), the sensitivity increased from 58.5% to 66.0%, while the specificity remained unchanged at 100%.
Extra-Cardiovascular/Retroperitoneal Organ Involvement When defining “IgG4-RD” as including both definite and probable cases, as opposed to only definite cases, previous studies have demonstrated improved sensitivity, while specificity remains unchanged.8,13 We therefore added “probable diagnoses of extra-cardiovascular/retroperitoneal organ involvement based on the CD criteria and/or organ-specific criteria for each organ” to the other organ involvement item (Revision D), which resulted in unchanged sensitivity and specificity.
We developed 5 additional patterns (Revisions E–I) and assessed their performance in the derivation cohort. Revision E combined Revisions A–C; Revision F combined Revisions A, B, and D; Revision G combined Revisions A, C, and D; Revision H combined Revisions B–D; and Revision I included all Revisions A–D. The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of the 2018 IgG4-PA/RPF criteria and Revisions A–I are presented in Table 4. Of these, Revisions E, G, and I showed the highest performance (positive likelihood ratio +∞ and negative likelihood ratio 0.30), leading us to select them as candidates for the revised 2023 diagnostic criteria for IgG4-related cardiovascular/retroperitoneal disease.
Table 4.
Performance of the 2018 Diagnostic Criteria for IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis and Each of the Revisions in the Derivation Group
| |
Sensitivity
(%) |
Specificity
(%) |
PLR |
NLR |
| 2018 original criteria |
58.5 |
100 |
+ ∞ |
0.42 |
| Revision A |
62.3 |
100 |
+ ∞ |
0.38 |
| Revision B |
58.5 |
100 |
+ ∞ |
0.42 |
| Revision C |
66.0 |
100 |
+ ∞ |
0.34 |
| Revision D |
58.5 |
100 |
+ ∞ |
0.42 |
| Revision E (Revisions A–C combined) |
69.8 |
100 |
+ ∞ |
0.30 |
| Revision F (Revisions A, B, and D combined) |
62.3 |
100 |
+ ∞ |
0.38 |
| Revision G (Revisions A, C, and D combined) |
69.8 |
100 |
+ ∞ |
0.30 |
| Revision H (Revisions B–D combined) |
66.0 |
100 |
+ ∞ |
0.34 |
| Revision I (Revisions A–D combined) |
69.8 |
100 |
+ ∞ |
0.30 |
Revision A: addition of “pericardial thickening and/or effusion” to the items of radiologic cardiovascular/retroperitoneal findings. Revision B: change in the serological item “Elevated serum IgG4 concentration (IgG4 ≥135 mg/dL)” to “Elevated serum IgG4 concentration (IgG4 ≥135 mg/dL) or elevated serum IgG4/IgG ratio (IgG4/IgG >8%)”. Revision C: addition of “eosinophilic infiltration” and “lymphoid follicles” to the histologic items. Revision D: addition of “probable diagnoses of extra-cardiovascular/retroperitoneal organ involvement based on the comprehensive diagnostic criteria and/or organ-specific criteria for each organ” to the other organ involvement item. NLR, negative likelihood ratio; PLR, positive likelihood ratio.
Performance of the Revised 2023 Diagnostic Criteria for IgG4-Related Cardiovascular/Retroperitoneal Disease in the Validation Group
In the validation group, which comprised 57 patients with true IgG4-RD and 38 mimickers, the performance of the candidates for the revised 2023 diagnostic criteria for IgG4-related cardiovascular/retroperitoneal disease was assessed.
The characteristics of the 57 patients with true IgG4-RD and the 38 mimickers are presented in Table 5. Patients in both the true IgG4-RD and mimickers groups had a relatively advanced age (median 69 and 71 years, respectively) with a male predominance (91% and 63%, respectively). Most patients with true IgG4-RD exhibited multiple organ involvement, with 22% having single organ involvement. Affected organs in the true IgG4-RD group included the salivary glands in 18 (32%) patients, the lacrimal glands in 12 (21%) patients, the pancreas in 9 (16%) patients, the kidney in 17 (30%) patients, and the lung in 5 (9%) patients. The final diagnoses in the mimickers group were non-IgG4-related idiopathic inflammatory aortic aneurysm (n=17), atherosclerotic or infectious aneurysm (n=6), vasculitis (n=8), lymphoma (n=2), non-IgG4-related idiopathic retroperitoneal fibrosis (n=1), aortic dissection (n=1), inflammatory myofibroblastic tumor (n=1), renal pelvic cancer (n=1), and cancer of unknown origin (n=1).
Table 5.
Baseline Clinical Characteristics of 53 Patients With IgG4-RD and 35 Mimickers in the Validation Group
| |
IgG4-RD
(n=57) |
Mimickers
(n=38) |
P value |
| Age (years) |
69 [62–76] |
71 [59–74] |
0.770 |
| Male sex |
91 |
63 |
0.001** |
| Allergy |
40 |
18 |
0.033** |
| Serum IgG (mg/dL) |
2,058 [1,554–2,563] |
1,211 [984–1,914] |
<0.001** |
| Serum IgG4 (mg/dL) |
322 [152–766] |
49 [31–93] |
<0.001** |
| Serum IgG4/IgG ratio (%) |
18.6 [9.6–34.9] |
4.4 [3.0–8.7] |
<0.001** |
| Serum IgE (IU/mL) |
312 [94–703] |
146 [39–491] |
0.229 |
| Serum CH50 (U/mL) |
58 [44–64] |
64 [60–71] |
0.020** |
| Serum C3 (mg/dL) |
99 [83–112] |
135 [123–169] |
<0.001** |
| Serum C4 (mg/dL) |
24 [13–32] |
33 [29–36] |
0.003** |
| Serum CRP (mg/dL) |
0.30 [0.10–0.70] |
0.90 [0.17–4.07] |
0.004** |
| Serum creatinine* (mg/dL) |
0.99 [0.83–1.26] |
0.87 [0.70–1.12] |
0.039** |
| Eosinophil count (/μL) |
188 [106–302] |
88 [29–175] |
0.004** |
| Disease-specific autoantibodies |
5 |
11 |
0.432 |
| Items of diagnostic criteria |
| 1. Radiologic findings |
86 |
74 |
0.182 |
| 2. Elevated serum IgG4 levels |
88 |
16 |
<0.001** |
| 3. Pathological findings |
| 3a. LP and IgG4+PC with SF or OP |
19 |
0 |
0.003** |
| 3b. LP and IgG4+PC without SF or OP |
14 |
0 |
0.020** |
| 4. Definitive extra-C/-R organ lesion(s) |
55 |
4 |
<0.001** |
| Biopsy of C/R lesion |
35 |
50 |
0.202 |
Unless indicated otherwise, data are given as the median [interquartile range] or as a percentage. *Note, to convert creatinine from mg/dL to μmol/L, multiply by 88.4. **Note, P<0.05. Abbreviations as in Table 2.
In this validation, we further evaluated the performance of the criteria by defining definite, probable, and possible cases as “IgG4-RD” and only categorizing unlikely cases as “non-IgG4-RD”. Among the candidates, Revision G showed the highest performance, leading its selection as the revised 2023 criteria (Table 6).
Table 6.
Performance of the 2018 Diagnostic Criteria for IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis and Each of the Revisions in the Validation Group
| |
Sensitivity
(%) |
Specificity
(%) |
PLR |
NLR |
| Definite and probable diagnosis as “IgG4-RD” |
| 2018 original criteria |
68.4 |
97.4 |
26.31 |
0.32 |
| Revision E (Revisions A–C combined) |
71.9 |
97.4 |
27.65 |
0.29 |
| Revision G (Revisions A, C, and D combined) |
77.2 |
94.7 |
14.57 |
0.24 |
| Revision I (Revisions A–D combined) |
77.2 |
94.7 |
14.57 |
0.24 |
| Definite, probable, and possible diagnosis as “IgG4-RD” |
| 2018 original criteria |
100 |
92.1 |
12.66 |
0 |
| Revision E (Revisions A–C combined) |
100 |
89.5 |
9.52 |
0 |
| Revision G (Revisions A, C, and D combined) |
100 |
92.1 |
12.66 |
0 |
| Revision I (Revisions A–D combined) |
100 |
89.5 |
9.52 |
0 |
Revision A: addition of “pericardial thickening and/or effusion” to the items of radiologic cardiovascular/retroperitoneal findings. Revision B: change in the serological item “Elevated serum IgG4 concentration (IgG4 ≥135 mg/dL)” to “Elevated serum IgG4 concentration (IgG4 ≥135 mg/dL) or elevated serum IgG4/IgG ratio (IgG4/IgG >8%)”. Revision C: addition of “eosinophilic infiltration” and “lymphoid follicles” to the histologic items. Revision D: addition of “probable diagnoses of extra-cardiovascular/retroperitoneal organ involvement based on the comprehensive diagnostic criteria and/or organ-specific criteria for each organ” to the other organ involvement item. IgG4-RD, IgG4-related disease; NLR, negative likelihood ratio; PLR, positive likelihood ratio.
Proposal of Revised 2023 Diagnostic Criteria for IgG4-Related Cardiovascular/Retroperitoneal Disease
The revised 2023 version of the diagnostic criteria for IgG4-related cardiovascular/retroperitoneal disease is presented in Table 7. With the addition of “eosinophilic infiltration” and “lymphoid follicles” to the histologic items, we included diagnostic factors 1+3a′ in the “definite” diagnosis category and diagnostic factors 3a′ in the “probable” diagnosis category in the revised version.
Table 7.
Revised 2023 Diagnostic Criteria for IgG4-Related Cardiovascular/Retroperitoneal Disease
| A. Diagnostic factors |
| 1. Abnormal radiologic findings |
a. Low-density hypertrophic thickening or soft tissue masses surrounding the aorta and its major branches *1,
*2, *3, *4 |
| b. Soft tissue masses in renal pelvic wall and/or around the ureter *5 |
| c. Soft tissue masses in the pelvis and paravertebral area |
| d. Pericardial thickening or pericardial effusion *6 |
| 2. Elevated serum IgG4 concentration (IgG4 ≥135 mg/dL) |
| 3. Histologic findings of the periaortic/periarterial and/or retroperitoneal regions |
| a. (i), (ii), (iii)/(iv) |
| a′. (i), (ii), (v)/(vi) |
| b. (i), (ii) |
| (i) Marked lymphocyte and plasmacyte infiltration and fibrosis *7, *8, *9 |
| (ii) IgG4-positive plasma cell infiltration: |
| Surgical samples: IgG4-positive plasma cells >30/HPF and ratio of IgG4/IgG positive cells >40% |
| Biopsy samples: IgG4-positive plasma cells >10/HPF and ratio of IgG4/IgG positive cells >40% |
| (iii) Storiform fibrosis |
| (iv) Obliterative phlebitis |
| (v) Eosinophilic infiltration: eosinophils >5/HPF |
| (vi) Lymphoid follicles |
| 4. Other organ involvement |
When a definitive or probable diagnosis of IgG4-related disease is made in the ophthalmic region, salivary
glands, pancreas, bile duct, kidney or lung by comprehensive diagnostic criteria or organ-specific diagnostic
criteria for the indicated organs |
| B. Diagnosis |
| Definite diagnosis (definite): 1(a/b/c/d) + 3a or 1(a/b/c/d) + 3a′ or 1(a/b/c/d) + 2 + 4 |
| Probable diagnosis (probable): 1(a/b/c/d) + 3b or 1(a/b/c/d) + 4 or 3a or 3a′ |
| Possible diagnosis (probable): 1(a/b/c/d) + 2 or 3b |
| C. Appendix |
*1. Stenosis of the vessel lumen is not present in the aorta; however, lumen narrowing may be observed in
medium-sized vessels |
| *2. Occasionally accompanied by lumen dilatation or aneurysm formation |
*3. It is necessary to exclude atherosclerosis, arterial dissection, infectious diseases (bacteria, tuberculosis,
syphilis, etc.), other forms of vasculitis, malignant diseases, such as malignant lymphoma and cancers, and
Erdheim-Chester disease |
| *4. The lesions may, in general, involve medium-to-large-sized vessels |
| *5. It is common in the renal pelvis and upper ureter |
*6. It is necessary to exclude infectious diseases (bacteria, tuberculosis, virus, etc.), autoimmune or
autoinflammatory diseases, and malignancy such as malignant lymphoma and cancers |
*7. Infiltration of lymphocytes and plasma cells is observed in the periarterial regions; vasculitis in the medial layer
may be present in the thoracic aorta |
*8. Findings of obliterative phlebitis may be more easily assessed by Elastica van Gieson staining than
hematoxylin-eosin staining |
*9. Necrosis, granuloma, and neutrophil infiltration are not usually observed; when these findings are present,
differential diagnosis should be carefully undertaken |
Note, “/” indicates “or”. HPF, high-power field.
Using the revised criteria, 34 of 57 true IgG4-RD cases were classified as “definite”, 10 were classified as “probable”, 13 were classified as “possible”, and none was classified as “unlikely”, resulting in an improved sensitivity of 77.2%. The performance among the mimickers remained almost unchanged from the previous version (1 was classified as “definite”, 1 was classified as “probable”, 1 was classified as “possible”, and 35 were classified as “unlikely”), maintaining a high specificity of 94.7%.
The revised criteria classified 2 mimickers as “IgG4-RD” in the validation cohort, but none in the derivation cohort. Table 8 shows the clinicopathological findings in the 2 mimickers (1 definite, 1 probable). Their final diagnoses were chronic aortic dissection of the descending thoracic aorta and follicular lymphoma.
Table 8.
Mimickers Classified as Having IgG4-RD According to the 2023 Revised Diagnostic Criteria for IgG4-Related Cardiovascular/Retroperitoneal Disease
Case
no. |
Radiologic
findings of
C/R lesion |
Serum IgG
(mg/dL) |
Serum IgG4
(mg/dL) |
Biopsied
organ |
Dense LP
infiltration |
SF |
OP |
IgG4+PC
(/HPF) |
Extra-C/-R
organ
involvement |
Final
diagnosis |
| 1 |
None |
NA |
NA |
Descending
thoracic aorta |
+ |
− |
+ |
31–50 |
None |
Chronic
aortic
dissection |
| 2 |
Soft tissue
masses in
renal pelvic
wall |
2,201 |
248 |
Paravertebral
band-like soft
tissue in the
thorax, skin |
+ |
− |
− |
10–30 |
Paravertebral
soft tissue, focal
pancreatic
swelling, skin |
Follicular
lymphoma |
IgG4+PC, IgG4-positive plasma cells; LP, lymphoplasmacytic; NA, not available. Other abbreviations as in Tables 2,4.
To assess the performance of the revised criteria in patients with retroperitoneal lesions without vascular involvement, we calculated the diagnostic sensitivity and specificity in this subgroup, including 23 patients diagnosed with true IgG4-RD and 9 mimickers from both the derivation and validation groups. The results revealed a sensitivity of 69.6% and a specificity of 88.9%. For the same assessment in patients with coronary artery lesions, the revised criteria showed a sensitivity of 71.4% and a specificity of 100% in 7 patients diagnosed with true IgG4-RD and 1 mimicker.
Discussion
This study established that the 2018 diagnostic criteria for IgG4-PA/RPF had good diagnostic specificity in real-life clinical practice. Nonetheless, a considerable proportion of patients with IgG4-related cardiovascular/retroperitoneal lesions diagnosed by experts did not meet the criteria. This was often due to a lack of typical radiologic findings and definitive extra-cardiovascular/retroperitoneal lesions, along with challenges in obtaining sufficient pathological evidence from limited specimens of cardiovascular/retroperitoneal lesions. In light of these findings, our study proposes revised diagnostic criteria tailored specifically to cardiovascular/retroperitoneal lesions in IgG4-RD. These novel criteria may contribute to important advances in the approach to these conditions.
This study was conducted to validate the performance of the diagnostic criteria in commonly encountered challenging circumstances of differential diagnosis. In contrast with our previous study, which proposed the original diagnostic criteria for IgG4-PA/RPF,13 the present study included a large number of mimickers diagnosed by experts, allowing for an evaluation of specificity. The revised 2023 diagnostic criteria for IgG4-related cardiovascular/retroperitoneal disease demonstrated excellent diagnostic specificity overall. However, a very small proportion of mimickers were classified as “IgG4-RD”. One such case involved a patient with chronic aortic dissection exhibiting neither typical radiologic findings nor other organ lesions. The histological findings, which included lymphoplasmacytic infiltration with IgG4-positive plasma cells and obliterative phlebitis, were consistent with IgG4-RD. Hourai et al reported that approximately 5% of tissues from patients with cardiovascular disease undergoing surgery showed evidence of IgG4-positive plasma cells.20 Moreover, studies investigating clinicopathological features in idiopathic retroperitoneal fibrosis reported that obliterative phlebitis was also observed in the non-IgG4-related group.21,22 Therefore, the attending expert diagnosed this patient as a mimicker. Another case involved a patient with follicular lymphoma, presenting with focal pancreatic enlargement, paravertebral band-like soft tissue in the thorax, and elevated serum IgG4 concentrations, all closely resembling IgG4-RD. However, a tissue biopsy revealed lymphoma. Because we may encounter a small number of mimickers that are extremely challenging to differentiate from IgG4-related cardiovascular/retroperitoneal disease, ongoing verification of the specificity of the revised criteria through the accumulation of more cases is necessary.
The low sensitivity observed for the original diagnostic criteria for IgG4-PA/RPF was a significant concern requiring substantial improvement. A comparison between true-positive and false-negative patients revealed that the challenge lay in classifying individuals lacking typical radiologic and pathological findings, as well as definitive extra-cardiovascular/retroperitoneal lesions, as having IgG4-RD. In response, the revised version includes a previously unmentioned radiologic finding of pericardial lesions, introduces new characteristic pathological findings, and allows for the approval of extra-cardiovascular/retroperitoneal lesions based on their probable diagnosis. These changes resulted in improved sensitivity in both the derivation and validation groups. Interestingly, a sensitivity of 100% and a considerably high specificity were achieved when defining definite, probable, and possible cases as “IgG4-RD”, suggesting that the revised criteria can accurately exclude the diagnosis of IgG4-RD in patients classified as “unlikely” and confidently diagnose IgG4-RD in those classified as “definite” and “probable”. Similar to organ lesions other than cardiovascular/retroperitoneal lesions, the interpretation of those classified as “possible” requires further thorough verification.
The addition of findings related to newly recognized cardiovascular lesions is appropriate for improving sensitivity, even though each individual radiologic finding may have insufficient specificity. Many studies have reported patients presenting with pericardial thickening and/or pericardial effusion often experiencing life-threatening heart failure symptoms.23,24 Some of these patients had pericardium-limited involvement, receiving a clinical diagnosis based on the presence of IgG4-positive plasma cells in the pericardium and/or pericardial effusion, whereas others were diagnosed based on pericardial thickening and/or effusion in conjunction with the definitive diagnosis of extra-cardiovascular/retroperitoneal lesions. Importantly, these pericardial lesions were reported to be responsive to glucocorticoid treatment.23 Given the clinical significance of diagnosing these pericardial lesions, we incorporated radiologic findings related to such lesions in the revised criteria, resulting in improved sensitivity as diagnostic criteria. However, because the exclusion of other potential causes of pericarditis is of utmost importance, we added information on pathophysiological conditions that should be differentiated as an appendix to the criteria. Further verification of the accuracy of these criteria is necessary.
The addition of new characteristic pathological findings, specifically eosinophilic infiltration and lymphoid follicles, to the revised criteria aims to enable the identification of characteristic features from limited tissue specimens. In our previous study, we noted that eosinophilic infiltration and lymphoid follicles were present in 40% and 49%, respectively, of patients with IgG4-PA/RPF who underwent tissue biopsy.13 Furthermore, these findings are recognized as characteristic not only of IgG4-PA/RPF, but also of other IgG4-RD lesions, including those affecting the salivary glands. Because the specificity of these findings has not been sufficiently investigated, it is essential to continue validation with a wider variety of mimickers. Despite this, it should be noted that the specificity did not decrease with the addition of these new pathological findings in this study. Continuous validation with diverse cases will contribute to a more comprehensive understanding of the specificity of these characteristic pathological features.
By incorporating the probable diagnosis of extra-cardiovascular/retroperitoneal lesions into the criteria, sensitivity improved, capturing more true cases and reducing the likelihood of false negatives. Importantly, this improvement was achieved without a significant decrease in specificity, maintaining a high level of accuracy in excluding non-cases in the present study. Similarly, previous studies investigating IgG4-related kidney disease and IgG4-PA/RPF demonstrated that diagnostic sensitivities improved from 87% to 91% and from 74% to 80%, respectively,8,13 by incorporating the probable extra-cardiovascular/retroperitoneal lesion diagnosis into the criteria. In the former study, specificity remained unchanged at 90%.8 Based on the probable diagnosis, the revised criteria acknowledge the presence of extra-cardiovascular/retroperitoneal lesions. Consequently, sensitivity improved, and the decrease in specificity was relatively minor and considered acceptable.
The present study suggests that the diagnostic accuracy of the revised criteria is different when considering narrowly defined retroperitoneal lesions excluding vascular involvement compared with cases involving vascular lesions. Specifically, in patients with lesions of the renal pelvis, ureter, and pelvic retroperitoneum without vascular involvement, the sensitivity and specificity of the revised criteria were 69.6% and 88.9%, respectively. This resulted in decreased overall accuracy. Further verification studies analyzing an ever-growing number of patients are required in the future due to the small number of cases in the present study. In cases involving lesions of the renal pelvis, ureter, and pelvic retroperitoneum, issues such as renal dysfunction due to urinary tract obstruction become major clinical concerns. In addition, therapeutic considerations, such as prompt glucocorticoid treatment and urological interventions, may differ from those for vascular lesions. Given these variations, it may be necessary to establish separate diagnostic criteria specifically tailored for narrowly defined retroperitoneal lesions.
Recently, there has been increased attention on coronary artery lesions in IgG4-RD. Matsumoto et al25 reported many cases with coronary periarteritis and/or aneurysm. Literature reviews by Akiyama et al26 and Kawahara et al27 reported that patients with IgG4-related coronary artery involvement often exhibited stenotic lesions (54–67% of patients), aneurysmal lesions (42–43%), and diffuse wall thickening (92–96%). Glucocorticoid treatment, either alone or in combination with percutaneous coronary intervention or cardiac surgery, has proven effective in managing most cases of IgG4-related coronary artery involvement. However, 46% of cases with coronary artery aneurysm showed worsening of the outer diameter of the coronary aneurysms,27 underscoring the importance of establishing an appropriate diagnosis and treatment strategy. In the present study, the revised diagnostic criteria for IgG4-related cardiovascular/retroperitoneal disease demonstrated an acceptable sensitivity and specificity for the diagnosis of patients with coronary artery lesions.
This study has several limitations. First, a significant proportion of mimickers were diagnosed as non-IgG4-related idiopathic inflammatory aortic aneurysm/retroperitoneal fibrosis by experts based on serological and histopathological findings. Although some features, including elevated serum IgG4 concentrations and the frequency of extra-cardiovascular/retroperitoneal organ lesions and relapses, have been reported to differ between IgG4-RD and non-IgG4-RD,21,22,28 definitive pathophysiological differences remain unclear. A larger-scale longitudinal study is needed to clarify the significance of differentiating between the 2, especially in terms of prognostic differences. Second, the limited number of patients in the present study may restrict the generalizability of the results, although the study cohort is one of the largest multicenter cohorts of IgG4-related cardiovascular/retroperitoneal patients accumulated to date. Third, the study was conducted only in Japan, albeit with patients enrolled from extensive areas across the country. Clarification of the effects lifestyle and geography, as well as diagnostic accuracy in different populations, would benefit through multinational studies. To further improve the diagnosis of IgG4-RD, examination of the diagnostic accuracy of the proposed new criteria through a larger-scale multicenter prospective study is necessary.
In conclusion, the proposed 2023 revised criteria for IgG4-related cardiovascular/retroperitoneal disease demonstrate significantly improved sensitivity and maintain high specificity through the addition of new radiologic, pathological, and extra-cardiovascular/retroperitoneal organ items. Although confirmation of these results will require a larger-scale multicenter study, the present observations offer valuable insights to inform the establishment of optimal diagnostic strategies for the spectrum of IgG4-related cardiovascular/retroperitoneal disease in real-life clinical practice.
Acknowledgments
The authors thank David Price at english-services-for-scientists.com (from United Kingdom) for his critical reading of the manuscript.
Sources of Funding
This work was supported by Health and Labour Sciences Research Grants for the Study of Intractable Diseases from the Ministry of Health, Labor and Welfare, Japan.
Disclosures
N.I. is a member of Circulation Journal’s Editorial Team. The remaining authors declare that there are no conflicts of interest.
IRB Information
This study was approved by the Institutional Ethics Board of the Medical Ethics Committee of Kanazawa University (Reference no. 2022-042).
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