We describe herein a patient who developed a dissection of the ascending aorta in the setting of IgG4-related systemic disease, linking IgG4-related systemic disease with a newly-recognized subset of noninfectious aortitis. At the time of aortic surgery, a transmural lymphoplasmacytic infiltrate was detected in the patient's aorta, with a principal focus of inflammation within the media. Immunohistochemical studies demonstrated that >50% of the plasma cells in the lesion stained for IgG4. By in situ hybridization, the plasma cells showed polytypic staining for kappa and lambda light chains, consistent with a polyclonal plasma cell infiltrate. Serologic evaluation revealed that the patient's IgG4 levels were elevated nearly 10-fold. Four years before aortic surgery, the patient had undergone a mediastinal lymph node biopsy. Reexamination of the lymph node revealed features consistent with IgG4-related systemic disease, which had not been recognized at the time of the original biopsy. Glucocorticoid therapy for the IgG4-related systemic disease yielded a prompt response. Recognition that IgG4-related systemic disease can involve the ascending as well as the descending abdominal aorta indicates the need for a change in the way idiopathic aortitis is regarded. This case offers new potential considerations for short- and long-term management of noninfectious aortitis, because of the frequent good response of IgG4-related systemic disease to glucocorticoid treatment without additional therapy. Treatment of the aortitis may prevent progression of the IgG4-related systemic disease to involvement of other organs. IgG4-related systemic disease should be considered in all patients with aortitis judged to be of unknown etiology.
“Noninfectious aortitis” refers to a variety of clinically distinct conditions that lead to chronic inflammation within the aortic wall (1). There are several major categories of inflammatory aortitis. First, aortitis is a complication of a number of primary systemic vasculitides or other rheumatologic conditions (2–7). Diseases such as giant cell arteritis, Takayasu arteritis, rheumatoid arthritis, and related conditions usually cause lesions within the ascending aorta (8, 9). Second, there is a condition known as isolated aortitis, in which there are no clinical features of an underlying disorder such as a primary systemic vasculitis. Isolated aortitis is detected in a small but significant subset of patients who undergo surgery on the ascending aorta (9, 10).
A third major category of inflammatory aortitis is termed chronic periaortitis (11). Chronic periaortitis, in contrast to the other forms of idiopathic aortitis, involves the abdominal aorta (12). This designation encompasses idiopathic retroperitoneal fibrosis and inflammatory abdominal aortic aneurysms, sometimes referred to together as perianeurysmal retroperitoneal fibrosis (11, 13, 14). In general, overlap between chronic periaortitis and the other forms of idiopathic aortitis has been viewed as unusual. In many instances, “chronic periaortitis” has not been differentiated clearly from the atherosclerotic aneurysms that have the type of adventitial inflammation typical of atherosclerosis. Since 2008, a small number of cases of chronic periaortitis have been reported in association with IgG4-related systemic disease (15–18).
We describe herein a patient who represents, to our knowledge, the first reported case in which IgG4-related systemic disease was recognized to be associated with a dissected ascending aorta. Further investigation revealed that several years before the patient's aortic surgery, he had undergone a mediastinal lymph node biopsy with results that (in retrospect) were also consistent with IgG4-related systemic disease.
The finding of IgG4-related systemic disease in the ascending aorta has important implications regarding current classification schemes for noninfectious aortitis. The ability of IgG4-related systemic disease to involve either the ascending or the abdominal portions of the aorta suggests that IgG4-related systemic disease should be considered in any patient with aortitis of unknown cause. Serum IgG4 levels are elevated in the majority of patients with this condition, but not all. Whenever histopathologic samples from the aorta are available, immunohistochemical staining for IgG4-bearing plasma cells is essential.
The patient, a 65-year-old man with atrial fibrillation, underwent a computed tomography (CT) scan of the heart for pulmonary vein mapping. This was performed in anticipation of pulmonary vein isolation and atrial fibrillation ablation. The CT scan showed a focal aortic dissection in the ascending aorta (Figure 1). The dissection arose ∼4 cm above the level of the coronary arteries and terminated at the level of the right common carotid artery. No aortic wall thickening was identified on preoperative CT scans. Findings in the descending and abdominal aortic regions were notable only for diffuse calcific arteriosclerosis.
Five weeks later, the patient underwent repair of the ascending aorta and the aortic hemiarch. The aortic valve was replaced with a Carpentier-Edwards bovine bioprosthesis, and a single-vessel coronary artery bypass graft was performed. His postoperative course was uneventful. However, the aortic pathologic examination showed active plasma cell aortitis (see below) (Figure 2). This led to a rheumatology evaluation.
Four years before the diagnosis of his aortic dissection, the patient had been found to have mediastinal lymphadenopathy, with lymph nodes up to 3 cm in diameter. The patient had undergone biopsy of a subcarinal lymph node via mediastinoscopy. The evaluation was terminated when examination of the biopsied node revealed only reactive follicular hyperplasia with sinus histiocytosis, considered a normal finding.
The patient's earlier medical history was significant for diabetes mellitus, hypertension, coronary artery disease, chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps, hypothyroidism, obstructive sleep apnea, and chronic renal insufficiency. He had undergone a prostatectomy for cancer 12 years before the aortic surgery. The patient reported a 20-pound weight loss in the year that preceded the aortic surgery, as well as a worsening of distal paresthesias in his feet, which was attributed to diabetic neuropathy. He denied having headaches, vision changes, jaw claudication, rash, weakness, or symptoms of polymyalgia rheumatica.
Physical examination on the sixth postoperative day revealed an irregularly irregular heart rhythm. The rate ranged from 80 to 123 beats per minute. His blood pressure was 113/78 mm Hg in the left arm and 107/77 mm Hg in the right. The respiratory rate was 12 per minute. He was afebrile. The temporal arteries were nontender and exhibited palpable pulses. The brachial, radial, and dorsalis pedal pulses were intact. There were no carotid, subclavian, abdominal, or femoral artery bruits. Cardiac auscultation revealed no murmurs, rubs, or gallops. Findings of the musculoskeletal examination were remarkable for moderate bony hypertrophy of both knees, but synovitis was absent. No rash was detected. The neurologic examination was nonfocal, and the only notable finding was decreased sensation to light touch in the distal lower extremities.
The erythrocyte sedimentation rate (ESR) was 62 mm/hour (normal <20), and the C-reactive protein (CRP) level was 154 mg/liter (normal <8). Six weeks before surgery, these values had been 53 mm/hour and 12.8 mg/dl, respectively. Prior to surgery, the patient had had mild normochromic, normocytic anemia, with a hematocrit value of 37.4% (normal 41–53) and a mean corpuscular volume of 77 fl (normal 80–100). The serum creatinine level was 1.5 mg/dl (normal 0.8–1.2). Other findings of the complete blood cell count, electrolyte panel, and serum chemistry investigations were normal. Serologic testing revealed positive antinuclear antibody at a titer of 1:160 (speckled pattern) and a rheumatoid factor level of 50 IU/ml (normal <30). Findings of a rapid plasma reagin test and a fluorescent treponemal antibody absorption assay were both negative.
Review of the patient's chest and abdominal CT scans confirmed that the enlarged lymph nodes first evaluated in 2004 were still present but had remained stable in size. Findings in the other thoracic and abdominal organs were unremarkable, including findings in the descending and abdominal aortic regions, both of which showed only calcific arteriosclerosis.
The results of histopathologic and immunohistochemical studies performed on the resected aorta are shown in Figure 3. The major histopathologic finding was lymphoplasmacytic infiltration of the aortic wall (Figure 3A). The infiltrate was not granulomatous, and giant cells were not present. The abundant plasma cells stained for CD138 (Figure 3B). The plasma cell infiltrate was transmural and focused predominantly within the media, with lesser involvement of the adventitia and intima. The majority of the plasma cell infiltrate was not associated with the dissection (and therefore not consistent with a reparative response to the dissection). Lymphoid follicles and moderate to focally severe fibrosis were present in the adventitia (Figure 2). The adventitial arteries did not exhibit obliterative endarteritis.
The lymphoplasmacytic infiltrate within the aorta was reminiscent of the type of inflammation observed in IgG4-related systemic disease, i.e., autoimmune pancreatitis (AIP) or sialadenitis associated with IgG4 deposition. For this reason, immunohistochemical studies for IgG4 were performed. More than 50% of the plasma cells present stained for IgG4 (Figure 3D). By in situ hybridization, the plasma cells exhibited polytypic staining for kappa and lambda light chains, consistent with a polyclonal plasma cell infiltrate. Congo red staining for amyloid was negative.
The finding of numerous IgG4-positive plasma cells within the aortic wall led to additional serologic investigations. The serum IgG level was increased substantially (1,863 mg/dl [normal 614–1,295]). The serum IgG4 level was dramatically elevated at 1,340 mg/dl (normal 8–140); thus, a large component of the overall IgG elevation was accounted for by the >10-fold elevation in the IgG4 level. Serum and urine protein electrophoresis demonstrated normal patterns, aside from the peak in the gamma region.
Finally, the serologic and histologic findings led to reexamination of the lymph node that had been removed 4 years earlier. This lymph node, previously regarded as showing reactive changes, stained heavily for plasma cells, >50% of which stained for IgG4 (Figure 4). IgG4-related systemic disease with aortitis was diagnosed.
Five weeks after the aortic surgical procedure, the patient began treatment with prednisone (40 mg/day). The prednisone dosage was tapered to 30 mg/day after 1 month. Four months after the initiation of prednisone therapy, the ESR was 16 mm/hour and the serum CRP level was 3.8 mg/dl. The serum IgG4 level was 347 mg/dl. At a followup assessment 7 months after surgery, the patient's IgG4-related systemic disease remained well controlled with tapering doses of glucocorticoids (prednisone 20 mg/day). The serum IgG4 level remained somewhat elevated (418 mg/dl), but levels of acute-phase reactants remained low (ESR 18 mm/hour, serum CRP 6.7 mg/dl). CT angiography of the aorta showed no change in the patient's mediastinal adenopathy and normal postoperative changes in the ascending aorta, without the appearance of new aortic abnormalities in other parts of the vessel.
The disorder now termed IgG4-related systemic disease remains largely unknown to most clinicians. The full clinical spectrum of this condition and its underlying pathophysiology are poorly understood. However, there is rapidly emerging evidence that IgG4-related systemic disease is a protean condition capable of involving multiple organs in an insidious manner, sometimes simultaneously but often metachronously (19). Rheumatologists might encounter IgG4-related systemic disease in a variety of settings, ranging from consultation to rule out Sjögren's syndrome in patients with submandibular gland involvement to questions about management of noninfectious aortitis (20).
We describe here what we believe to be the first reported case of IgG4-related systemic disease associated with a dissection in the ascending aorta. IgG4-related systemic disease predominantly affects older men—the same demographic group that more commonly undergoes aortic surgery—and features of IgG4-related systemic disease seen upon aortic surgery could be mistaken for features of a number of primary rheumatic disorders, particularly giant cell arteritis and isolated aortitis. The growing recognition of IgG4-related systemic disease as a clinical entity underscores the importance of considering this diagnosis in patients with any type of idiopathic aortitis, not only those whose presentations are consistent with the “chronic periaortitis” previously reported to affect the abdominal aorta (11).
Noninfectious aortitis occurs in the setting of a number of large-vessel vasculitides, including giant cell arteritis, Takayasu arteritis, Behçet's syndrome, and Cogan's syndrome (2, 21–26). Certain connective tissue diseases, e.g., rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, and relapsing polychondritis, also occasionally lead to aortitis (3–6, 27). Sarcoidosis can cause aortitis and may be difficult to distinguish from Takayasu arteritis (7, 28). When these conditions lead to chronic aortic inflammation, the most common site of involvement is the ascending aorta (8).
Isolated aortitis is another form of chronic aortic inflammation (1). This disorder is often detected incidentally at the time of aortic surgery, because patients are usually aware of few if any systemic symptoms. Studies of large series of patients indicate that at least 4% of aortic root replacements lead to the discovery of isolated aortitis (9, 10). As with idiopathic aortitis associated with the rheumatic conditions mentioned above, isolated aortitis is believed to involve the ascending aorta most frequently.
In recent years, some cases of chronic periaortitis have been recognized as part of a spectrum of disease known as IgG4-related systemic disease (19, 29). The concept of IgG4-related systemic disease has emerged slowly since the mid-1990s, when the idea of “autoimmune pancreatitis” was first formulated (30, 31). AIP differs from acute pancreatitis in a number of important ways. AIP normally presents with painless jaundice rather than with severe mid-epigastric abdominal pain that radiates to the back. Serum concentrations of pancreatic enzymes are typically normal in AIP. Imaging of AIP by CT usually demonstrates diffuse enlargement of the pancreas with homogeneous attenuation and a peripheral rim of a hypoattenuation “halo” (31). Thus, AIP is more likely to mimic adenocarcinoma of the pancreas than to be confused with acute pancreatitis (30).
AIP is considered to be a cardinal manifestation of IgG4-related systemic disease, but evidence of AIP is not always present, as was the case in our patient. IgG4-related systemic disease can involve the biliary tract, liver, salivary gland, lung, kidney, lymph node, retroperitoneum, and other organs in the absence of pancreatic disease (19, 32). Of note, cases of AIP associated with aortitis of the abdominal aorta have been reported (17, 18). In addition, because of the tendency of the disease to evolve in a metachronous manner, evidence of pancreatic disease sometimes emerges only after dysfunction in other organ systems has been recognized (20).
Regardless of the specific type of organ involvement in IgG4-related systemic disease, histopathologic findings are similar throughout all affected tissues. The characteristic findings include dense lymphoplasmacytic inflammation, sclerosis, and (when an exocrine gland is involved) periductal inflammation and acinar atrophy. Other pathologic hallmarks are inflammatory pseudotumors of the involved organ and obliterative phlebitis (33). Periductal granulomas and multinucleated giant cells are observed occasionally. Serum levels of IgG4 are elevated in ∼75% of patients with IgG4-related systemic disease (34, 35). The number of associated extrapancreatic lesions is significantly greater in patients with high serum IgG4 levels (36). However, the sine qua non of the disorder is the presence of a lymphoplasmacytic infiltrate within the involved tissue, with the majority of the plasma cells staining for IgG4.
The pathophysiology of IgG4-associated systemic disease remains poorly understood. IgG4 is the least abundant of all serum IgG isotypes, comprising only ∼6% of the total IgG in healthy individuals (37). Serum IgG4 levels have been reported to be elevated in conditions that bear little obvious resemblance to autoimmune pancreatitis and related disorders, such as human filariasis, pemphigus vulgaris, and pemphigus foliaceus (38–40). IgG4 is effectively a monovalent antibody, which generally binds antigens poorly and does not fix complement (37). It has been proposed to be a component of processes leading to the down-regulation of immune responses. Thus, one way to view the IgG4-staining plasma cells in tissue is that they are part of a counterregulatory response to an inciting event that remains unknown.
In conclusion, we provide herein the first report of a patient with IgG4-related systemic disease associated with dissection of the ascending aorta. Recognition of the fact that IgG4-related systemic disease can involve both the ascending and the abdominal aorta signals the need for a change in the way idiopathic aortitis is regarded. For example, it is now apparent that a potentially sizable subset of patients with inflammatory abdominal aortic aneurysms actually have an aortic histopathologic abnormality that is highly consistent with IgG4-related systemic disease (15). It is possible that the same is true for aortitis involving the ascending aorta, particularly the subset of noninfectious aortitis currently considered to be “isolated” aortitis.
The findings in our patient have important implications regarding the investigation of aortitis. The case offers new potential considerations for treatment and long-term management of noninfectious aortitis, because IgG4-related systemic disease often responds well to a prolonged course of glucocorticoid treatment, with no additional therapy required. Treatment of the aortitis may prevent progression of the IgG4-related systemic disease to involvement of other organs. Finally, this case underscores the need for rheumatologists, cardiologists, cardiothoracic surgeons, and pathologists to work closely together on the challenges posed by noninfectious aortitis, to identify the histopathologic and immunohistochemical features of each aortic specimen as precisely as possible, and to interpret these findings in the context of the whole patient.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. J. H. Stone had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. J. H. Stone, Khosroshahi, Hilgenberg, Spooner, Isselbacher, J. R. Stone.
Acquisition of data. J. H. Stone, Khosroshahi, Hilgenberg, Spooner, Isselbacher, J. R. Stone.
Analysis and interpretation of data. J. H. Stone, Khosroshahi, Hilgenberg, Spooner, Isselbacher, J. R. Stone.