Multimodality Imaging Features of Immunoglobulin G4–related Vessel Involvement

Abstract

Immunoglobulin 4 (IgG4)–related disease is a chronic immune-mediated fibroinflammatory disorder. Involvement of the vascular system, including large- and medium-sized vessels, is increasingly recognized. The varied appearances of vascular involvement reflect the sequela of chronic inflammation and fibrosis and can include aortitis and periaortitis with resultant complications such as aneurysm formation and dissection. A diagnosis of IgG4–related large vessel involvement should be considered when there is known or suspected IgG4-related disease elsewhere. Other organs that are typically affected in IgG4-related disease include the lacrimal and salivary glands, thyroid, pancreas, biliary tree, lungs, kidneys, and meninges. Diagnosis typically requires careful correlation with clinical, imaging, serum, and pathologic findings. Patients may be managed with corticosteroid therapy or the anti-CD20 monoclonal antibody, rituximab, if needed. The varied clinical presentations and imaging features of large vessel involvement are discussed herein.

Keywords: Vascular, Inflammation, Aorta, IgG4-related Vessel Involvement

© RSNA, 2024

Summary

Immunoglobulin G4–related disease is a chronic fibroinflammatory immune-mediated disorder with multisystem involvement; large and medium vessel involvement is increasingly recognized and can result in complications such as aneurysm formation and dissection.

Introduction

Immunoglobulin 4 (IgG4)–related disease (IgG4-RD) was initially described in a cohort of patients with autoimmune pancreatitis who were found to have elevated serum IgG4 levels. It has now been described in virtually every organ and is recognized as a multisystem disease with strikingly similar histopathologic appearances in each of these organs (1–5). While elevated IgG4 levels can be observed in both the affected organ and the serum of patients, it is not strictly necessary for the diagnosis, although semiquantitative analysis of IgG4 levels is used (3,6,7). Instead, it is the specific histopathologic appearance identified following tissue biopsy that is essential for diagnosis, with the main histopathologic features being storiform fibrosis, eosinophilic infiltrate, and obliterative phlebitis (1).

Although the precise pathogenesis of IgG4-RD remains unclear, aberrant innate and adaptive immune responses are considered the main mechanisms for its development (8). Potential triggers include infectious agents and host autoimmunity. A suspected infectious agent that may have a role in the development of IgG4-RD is Helicobacter pylori (9,10). Given the predilection of IgG4-RD to exocrine organs such as the salivary glands and pancreas, an exaggerated T helper 2 cell immune response to autoantigens commonly found at these sites, including carbonic anhydrases and pancreatic secretory trypsin inhibitor, may act as initial stimuli for an exaggerated autoimmune response (1). Regardless of the initial inciting event, a cascade of cytokines results in eosinophilia, elevated serum IgG4 and IgE levels, and ultimately the development of fibrosis and end-organ dysfunction (Fig 1) (1).

Figure 1:

Overview of the pathophysiology of immunoglobulin G4 (IgG4)–related disease. A combination of environmental factors and a genetic predisposition likely contribute to an exaggerated immune response, resulting in a cascade of events and culminating in tissue fibrosis. Ultimately, lymphadenopathy and end-organ involvement result. TGF-β = transforming growth factor β. (Reprinted, with permission, from Mangun Kaur Randhawa.)

As previously discussed, IgG4-RD can affect virtually every organ in the body. Following the cascade of immune events described above, there is resultant tumefactive enlargement of the affected organs and end-organ damage; epithelial damage may occur due to immune complex deposition and inflammation (1). Due to the wide-ranging organ involvement and varied clinical manifestations, IgG4-RD requires careful correlation of serum, clinical, radiologic, and pathologic findings for diagnosis. The American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) criteria (Table 1) were established to develop and validate a diagnostic classification system for international use (11). These stepwise criteria combine radiologic findings and inclusion and exclusion criteria to develop a cumulative scoring system for IgG4-RD. A score above 20, which combines clinical, serum, pathologic, and radiologic findings, meets criteria for IgG4-RD.

Table 1:

The ACR/EULAR Criteria for the Diagnosis of IgG4-related Disease

Vascular Involvement in IgG4-RD

Concomitant vascular involvement, including periaortitis and periarteritis, is identified in 10%–30% of cases of IgG4-RD; however, the true prevalence may be underestimated due to the underrecognition of IgG4-RD as a clinical entity (12). IgG4 large and medium vessel involvement may also represent an isolated clinical entity, without organ involvement elsewhere (13,14). We reviewed our locally maintained database of patients with known or suspected IgG4-RD between January 2009 and November 2019 from the Center for IgG4-Related Disease at Massachusetts General Hospital in the Division of Rheumatology, Allergy, and Immunology; 85 patients with suspected IgG4-related large and medium vessel involvement were identified from a total of 387 (22%). Institutional review board approval for this retrospective review was granted prior to the study commencement. The diagnosis of IgG4-RD was established using the ACR/EULAR classification criteria for IgG4-RD (11). Identifying IgG4-related large and medium vessel involvement has important clinical implications. First, as IgG4-RD may metachronously involve organs, identification of IgG4-related large and medium vessel involvement may portend future involvement by other organs (15,16). Conversely, the presence of IgG4-RD in nonvascular organs should prompt scrutiny of the vasculature at surveillance imaging to assess for the development of large and medium vessel involvement (Figs 2, 3). Finally, IgG4-related large and medium vessel involvement may respond to less invasive medical management, although more research is needed in this area (12).

Figure 2:

Organ involvement and vascular involvement in immunoglobulin G4 (IgG4)–related disease. In addition to lymphadenopathy, IgG4-related disease can have a broad spectrum of manifestations reflecting the organs involved. Vascular involvement can be classified as either primary or secondary. (Reprinted, with permission, from Mangun Kaur Randhawa.)

Figure 3:

Images in a 74-year-old male patient presenting with painless jaundice. (A) Axial contrast-enhanced CT image through the upper abdomen demonstrates pancreatic ductal dilatation (arrow). (B) Axial image through the pelvis demonstrates ill-defined soft tissue surrounding the inferior mesenteric artery (arrow). (C) Axial contrast-enhanced T1-weighted MR image of the pancreas demonstrates irregular pancreatic ductal dilatation with an abrupt transition in the pancreatic head (arrow), which is concerning for an underlying pancreatic neoplasm. (D) Coronal postcontrast T1-weighted MR image shows an endoscopic biliary stent (arrow) had been placed at an outside institution. The patient underwent pancreaticoduodenectomy (Whipple procedure). Pathology demonstrated a lymphoplasmacytic inflammatory infiltrate with a storiform pattern of fibrosis compatible with immunoglobulin G4–related disease. (E, F) Postoperative PET/CT images, to assess for additional sites of disease, show a persistent and fluorodeoxyglucose-avid soft tissue mass around the inferior mesenteric artery (arrows).

Classification of IgG4-related Large and Medium Vessel Involvement

In our experience, large and medium vessel involvement in IgG4-RD can be classified as primary or secondary (17). Primary involvement is characterized by vessel wall thickening, vessel wall enhancement, or increased fluorodeoxyglucose (FDG) avidity on fluorine 18 FDG PET images. Secondary IgG4-related vascular involvement is characterized by perivascular soft tissue with minimal vessel wall findings (Fig 4). Primary vascular involvement appears to have an inflammatory response that is centered on the vessel wall itself, while secondary involvement is characterized by a perivascular soft tissue with enhancement or FDG avidity. Crucially, arterial involvement in primary IgG4-related vasculitis can lead to aneurysm formation, complicated by dissection or perforation (Figs 5, 6) (17). In contrast to other forms of large- and medium-sized vessel vasculitis (eg, giant cell arteritis), primary IgG4-related vasculitis tends to have an inflammatory infiltrate centered on the adventitia, and to a lesser extent on the media (17). In contrast, secondary IgG4-related large and medium vessel involvement appears to be primarily due to the compressive effect of the periaortic mass, with vessel stenosis and mass effect on adjacent structures (eg, the ureters) seen as a more predominant feature.

Figure 4:

Images in a 61-year-old female patient who presented to her local hospital with increasing lower back pain. CT of the abdomen was performed. (A) Axial image demonstrates a preaortic soft tissue mass (arrow). (B) Coronal reformat demonstrates right hydroureteronephrosis (arrow). The patient had bilateral nephroureteral stents placed and later returned for CT-guided biopsy of the retroperitoneal mass. (C) The biopsy sample demonstrates a lymphoplasmacytic inflammatory infiltrate in a background of fibrosis. (Hematoxylin-eosin stain; original magnification, 400×.) (D) Immunostains for immunoglobulin G (IgG) and immunoglobulin G4 (IgG4) demonstrate a substantial increase in IgG4-positive plasma cells as a proportion of all IgG-positive plasma cells (arrows). (IgG4; original magnification, 400×.)

Figure 5:

Images in a 62-year-old male patient who presented to his primary care physician for an annual physical examination. Urinalysis demonstrated hematuria, and subsequent evaluation with CT revealed a type II thoracoabdominal aortic aneurysm measuring up to 5.2 cm in the descending thoracic aorta. (A, sagittal contrast-enhanced CT image of thoracic aorta, arrow). The patient underwent resection and graft repair of the descending thoracoabdominal aortic aneurysm. Microscopic examination of the specimen demonstrated unexpectedly prominent inflammatory changes, with an active aortitis, lymphoplasmacytic inflammation, and background fibrosis with foci of a storiform pattern. The findings were consistent with immunoglobulin G4 (IgG4)–related disease manifesting with isolated large and medium vessel involvement and thoracoabdominal aortic aneurysm. Two years later, the patient’s acute phase reactants remained high, and repeat imaging showed ill-defined periaortic soft tissue surrounding the graft (B, axial contrast-enhanced CT image of abdominal aorta, arrow), which demonstrated increased fluorodeoxyglucose (FDG) avidity (C, sagittal reformat from fluorine 18 FDG PET study, arrow). Appearances were consistent with recrudescent IgG4 large vessel involvement.

Figure 6:

Images in a 60-year-old male patient presenting to the emergency department with a 1-week history of bilateral lower quadrant pain of subacute onset. Contrast-enhanced CT scan performed at an outside hospital identified an infrarenal aortic aneurysm with an outpouching of contrast material suspicious for ulceration versus a mycotic aneurysm (not shown). The patient was transferred to the care of a vascular surgery team, and dedicated CT angiography was performed. White cell count and serum lactate levels were elevated. Despite negative blood cultures, the patient was started on empirical antimicrobial therapy. CT angiography demonstrates partially thrombosed pseudoaneurysms in the infrarenal abdominal aorta (arrows, axial CT images A and B) with a focal dissection (arrow in A). (C) Three-dimensional volume-rendered CT image demonstrates adjacent saccular outpouchings (arrow). The patient was taken to surgery for axillobifemoral bypass, resection of aortic aneurysm, and excisional debridement of retroperitoneal and periaortic tissues. Final pathology was suspicious for immunoglobulin G4–related aortitis.

Multiple other classification systems for IgG4-related large and medium vessel involvement have been proposed. A classification system by Ozawa and colleagues (18) has defined IgG4-related large and medium vessel involvement based on the anatomic location of vascular involvement. Type 1 is localized to the abdominal aorta, below the renal arteries. Type 2 extends further into the medium-sized iliac arteries. Type 3 involves the ascending aorta only. Type 4 affects the medium-sized vessels only, and type 5 is used to describe all other sites of involvement (Table 2). A further classification system has been proposed by Qi et al (19) that describes periaortic soft tissue thickening and aortic caliber: type A, periaortic soft tissue with an aorta of normal caliber; type B, periaortic soft tissue with mild luminal stenosis; type C, periaortic soft tissue with moderate luminal stenosis; type D, aneurysmal dilatation with periaortic soft tissue (<50% of the expected normal diameter with wall thickening); type E, aneurysm with periaortic soft tissue (>50% of the expected normal diameter with wall thickening) (Table 3).

Table 2:

Classification for Large and Medium Vessel Involvement in IgG4-related Disease

Table 3:

Classification for Large and Medium Vessel Involvement in IgG4-related Disease

Distribution of Vascular Involvement

When we reviewed our own database, 54% (38 of 70) of patients had type A imaging findings (ie, periaortic soft tissue with a normal caliber). Type C was the next most common pattern, present in 16% (11 of 70) of patients where periaortic soft tissue was associated with moderate luminal narrowing. Type B, periaortic soft tissue with mild stenosis, was seen in 11% (eight of 70) of patients. Type D and E, where there was aneurysmal dilatation either less than or greater than 50% of the expected luminal diameter, were present in 9% (six of 70) and 3% (two of 70) of cases, respectively. Five (7%) patients could not be classified as their imaging was following operative intervention (n = 4) or they had attenuation correction only for PET imaging (n = 1). In cases with thoracic manifestations of IgG4-RD, the imaging findings included the following: perivascular thickening of the ascending aortic and aortic arch (n = 5), thickening of the descending thoracic aorta (n = 1), thickening of the aortic arch with occlusion of the left common carotid artery (n = 1), aneurysms of the thoracic aorta involving the aortic root (n = 5), thoracic aorta dissection (n = 2), and aneurysmal dilatation of the descending thoracic aorta (n = 1). A previous study examined contrast-enhanced CT scans only in IgG4-related vascular disease and included 65 patients (20). While they also identified aortoiliac involvement as the most common distribution, they identified isolated aortic involvement as the second most common distribution. In our cohort, we identified thoracic involvement as the second most frequent distribution and identified a greater number of individual cases with thoracic involvement as compared with this study (n = 17 [24%] vs eight [12%]) (18). Possible reasons for the increased frequency of thoracic involvement in our cohort may include a greater number of thoracic imaging studies included, particularly PET imaging, and that some patients included in our database had pathology-confirmed involvement of the thoracic aorta at surgery. Involvement of the thoracic aorta and great vessels is an important consideration for patients presenting with acute onset chest pain, as it may portend dissection or thoracic aneurysm formation (21).

Management of IgG4-related Large and Medium Vessel Disease

Given the predilection of IgG4-RD to involve the aorta, early consideration should be given to performing vascular imaging to minimize associated potential complications, such as those described above. Given the potential for either primary vessel wall involvement or secondary periaortic soft tissue involvement, PET imaging with a contemporaneous or recent CT angiography is the ideal imaging modality for detection of vessel wall inflammation and/or a periaortic inflammatory mass (17). Whole-body PET/CT also provides the opportunity to assess for metachronous involvement of additional organs.

The mainstay of therapy for patients with IgG4-RD is corticosteroid therapy, at least as initial therapy, as its long-term use can be problematic (22). In their study, Ozawa and colleagues described pre-existing luminal dilatation as the main risk factor for the development of worsening aneurysmal dilatation following corticosteroid therapy (18). The anti-CD20 monoclonal antibody, rituximab, has been studied as both an alternative to corticosteroids for remission induction and maintenance therapy (23,24).

Conclusion

IgG4-related large and medium vessel involvement affects between 10% and 30% of patients with known or suspected IgG4-RD. Although it can be observed with concomitant visceral involvement in typical locations for IgG4-RD (eg, pancreas, kidneys, thyroid, salivary glands), it can also occur in isolation. Primary involvement can result in aneurysm formation and dissection. PET with CT angiography is the imaging modality of choice for the assessment of both primary and secondary vessel involvement. Glucocorticoids and rituximab therapy are the mainstay of treatment.