ARTHRITIS & RHEUMATISMVol. 60, No. 10, October 2009, pp 3139–3145DOI 10.1002/art.24798© 2009, American College of Rheumatology

IgG4-Related Systemic Disease and Lymphoplasmacytic Aortitis

John H. Stone, Arezou Khosroshahi, Alan Hilgenberg,† Amy Spooner,Eric M. Isselbacher, and James R. Stone

We describe herein a patient who developed adissection of the ascending aorta in the setting ofIgG4-related systemic disease, linking IgG4-related sys-temic disease with a newly-recognized subset of nonin-fectious aortitis. At the time of aortic surgery, a trans-mural lymphoplasmacytic infiltrate was detected in thepatient’s aorta, with a principal focus of inflammationwithin the media. Immunohistochemical studies demon-strated that >50% of the plasma cells in the lesionstained for IgG4. By in situ hybridization, the plasmacells showed polytypic staining for kappa and lambdalight chains, consistent with a polyclonal plasma cellinfiltrate. Serologic evaluation revealed that the pa-tient’s IgG4 levels were elevated nearly 10-fold. Fouryears before aortic surgery, the patient had undergone amediastinal lymph node biopsy. Reexamination of thelymph node revealed features consistent with IgG4-related systemic disease, which had not been recognizedat the time of the original biopsy. Glucocorticoid ther-apy for the IgG4-related systemic disease yielded aprompt response. Recognition that IgG4-related sys-temic disease can involve the ascending as well as thedescending abdominal aorta indicates the need for achange in the way idiopathic aortitis is regarded. Thiscase offers new potential considerations for short- andlong-term management of noninfectious aortitis, be-cause of the frequent good response of IgG4-relatedsystemic disease to glucocorticoid treatment withoutadditional therapy. Treatment of the aortitis may pre-vent progression of the IgG4-related systemic disease toinvolvement of other organs. IgG4-related systemic dis-

ease should be considered in all patients with aortitisjudged to be of unknown etiology.

“Noninfectious aortitis” refers to a variety ofclinically distinct conditions that lead to chronic inflam-mation within the aortic wall (1). There are severalmajor categories of inflammatory aortitis. First, aortitisis a complication of a number of primary systemicvasculitides or other rheumatologic conditions (2–7).Diseases such as giant cell arteritis, Takayasu arteritis,rheumatoid arthritis, and related conditions usuallycause lesions within the ascending aorta (8,9). Second,there is a condition known as isolated aortitis, in whichthere are no clinical features of an underlying disordersuch as a primary systemic vasculitis. Isolated aortitis isdetected in a small but significant subset of patients whoundergo surgery on the ascending aorta (9,10).

A third major category of inflammatory aortitis istermed chronic periaortitis (11). Chronic periaortitis, incontrast to the other forms of idiopathic aortitis, in-volves the abdominal aorta (12). This designation en-compasses idiopathic retroperitoneal fibrosis and in-flammatory abdominal aortic aneurysms, sometimesreferred to together as perianeurysmal retroperitonealfibrosis (11,13,14). In general, overlap between chronicperiaortitis and the other forms of idiopathic aortitis hasbeen viewed as unusual. In many instances, “chronicperiaortitis” has not been differentiated clearly from theatherosclerotic aneurysms that have the type of adven-titial inflammation typical of atherosclerosis. Since 2008,a small number of cases of chronic periaortitis have beenreported in association with IgG4-related systemic dis-ease (15–18).

We describe herein a patient who represents, toour knowledge, the first reported case in which IgG4-related systemic disease was recognized to be associatedwith a dissected ascending aorta. Further investigationrevealed that several years before the patient’s aorticsurgery, he had undergone a mediastinal lymph nodebiopsy with results that (in retrospect) were also consis-tent with IgG4-related systemic disease.

John H. Stone, MD, MPH, Arezou Khosroshahi, MD, AmySpooner, MD, Eric M. Isselbacher, MD, James R. Stone, MD, PhD:Massachusetts General Hospital, Boston.

†Dr. Hilgenberg is deceased.Address correspondence and reprint requests to John H.

Stone, MD, MPH, Rheumatology Unit, Massachusetts General Hos-pital, 55 Fruit Street, Yawkey 2, Boston, MA 02114. E-mail:jhstone@partners.org.

Submitted for publication February 13, 2009; accepted inrevised form June 5, 2009.

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The finding of IgG4-related systemic disease inthe ascending aorta has important implications regard-ing current classification schemes for noninfectious aor-titis. The ability of IgG4-related systemic disease toinvolve either the ascending or the abdominal portionsof the aorta suggests that IgG4-related systemic diseaseshould be considered in any patient with aortitis ofunknown cause. Serum IgG4 levels are elevated in themajority of patients with this condition, but not all.Whenever histopathologic samples from the aorta areavailable, immunohistochemical staining for IgG4-bearing plasma cells is essential.

CASE REPORT

The patient, a 65-year-old man with atrial fibril-lation, underwent a computed tomography (CT) scan ofthe heart for pulmonary vein mapping. This was per-formed in anticipation of pulmonary vein isolation andatrial fibrillation ablation. The CT scan showed a focalaortic dissection in the ascending aorta (Figure 1). Thedissection arose �4 cm above the level of the coronaryarteries and terminated at the level of the right commoncarotid artery. No aortic wall thickening was identifiedon preoperative CT scans. Findings in the descendingand abdominal aortic regions were notable only fordiffuse calcific arteriosclerosis.

Five weeks later, the patient underwent repair ofthe ascending aorta and the aortic hemiarch. The aorticvalve was replaced with a Carpentier-Edwards bovine

bioprosthesis, and a single-vessel coronary artery bypassgraft was performed. His postoperative course was un-eventful. However, the aortic pathologic examinationshowed active plasma cell aortitis (see below) (Figure 2).This led to a rheumatology evaluation.

Four years before the diagnosis of his aorticdissection, the patient had been found to have medias-tinal lymphadenopathy, with lymph nodes up to 3 cm indiameter. The patient had undergone biopsy of a sub-carinal lymph node via mediastinoscopy. The evaluationwas terminated when examination of the biopsied noderevealed only reactive follicular hyperplasia with sinushistiocytosis, considered a normal finding.

The patient’s earlier medical history was signifi-cant for diabetes mellitus, hypertension, coronary arterydisease, chronic obstructive pulmonary disease, chronicrhinosinusitis with nasal polyps, hypothyroidism, obstruc-tive sleep apnea, and chronic renal insufficiency. He hadundergone a prostatectomy for cancer 12 years before theaortic surgery. The patient reported a 20-pound weight lossin the year that preceded the aortic surgery, as well as aworsening of distal paresthesias in his feet, which wasattributed to diabetic neuropathy. He denied having head-aches, vision changes, jaw claudication, rash, weakness, orsymptoms of polymyalgia rheumatica.

Physical examination on the sixth postoperativeday revealed an irregularly irregular heart rhythm. Therate ranged from 80 to 123 beats per minute. His bloodpressure was 113/78 mm Hg in the left arm and 107/77

Figure 1. Computed tomography (CT) imaging of aortic dissection in the patient. A, Visualization of true and false lumen (TL and FL) in theascending aorta. B, Three-dimensional CT reconstruction image, showing origin of the dissection flap (arrow).

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mm Hg in the right. The respiratory rate was 12 perminute. He was afebrile. The temporal arteries werenontender and exhibited palpable pulses. The brachial,radial, and dorsalis pedal pulses were intact. There wereno carotid, subclavian, abdominal, or femoral arterybruits. Cardiac auscultation revealed no murmurs, rubs,or gallops. Findings of the musculoskeletal examinationwere remarkable for moderate bony hypertrophy of bothknees, but synovitis was absent. No rash was detected.The neurologic examination was nonfocal, and the onlynotable finding was decreased sensation to light touch inthe distal lower extremities.

The erythrocyte sedimentation rate (ESR) was 62mm/hour (normal �20), and the C-reactive protein(CRP) level was 154 mg/liter (normal �8). Six weeksbefore surgery, these values had been 53 mm/hour and12.8 mg/dl, respectively. Prior to surgery, the patient hadhad mild normochromic, normocytic anemia, with ahematocrit value of 37.4% (normal 41–53) and a meancorpuscular volume of 77 fl (normal 80–100). The serumcreatinine level was 1.5 mg/dl (normal 0.8–1.2). Other

findings of the complete blood cell count, electrolytepanel, and serum chemistry investigations were normal.Serologic testing revealed positive antinuclear antibodyat a titer of 1:160 (speckled pattern) and a rheumatoidfactor level of 50 IU/ml (normal �30). Findings of arapid plasma reagin test and a fluorescent treponemalantibody absorption assay were both negative.

Review of the patient’s chest and abdominal CTscans confirmed that the enlarged lymph nodes firstevaluated in 2004 were still present but had remainedstable in size. Findings in the other thoracic and abdom-inal organs were unremarkable, including findings in thedescending and abdominal aortic regions, both of whichshowed only calcific arteriosclerosis.

Figure 3. Characterization of the plasma cell infiltrates within themedia of the aorta, by immunohistochemistry and in situ hybridization.A, Hematoxylin and eosin staining. B and C, Immunohistochemicalstaining for the plasma cell marker CD138 (B) and the T cell markerCD3 (C). D, Immunohistochemical staining for IgG4. Substantiallymore than half of the plasma cells exhibited IgG4 staining. E and F, Insitu hybridization staining for kappa light chain (E) and lambda lightchain (F). (Original magnification � 400.)

Figure 2. Hematoxylin and eosin–stained section of the patient’sresected aorta, showing lymphoplasmacytic aortitis. Lymphoid aggre-gates in the adventitia (arrowheads) and plasma cell infiltrates in themedia (arrows) were observed. Dashed line indicates the intima–media boundary (original magnification � 25).

AORTITIS IN IgG4-RELATED SYSTEMIC DISEASE 3141

The results of histopathologic and immunohisto-chemical studies performed on the resected aorta areshown in Figure 3. The major histopathologic findingwas lymphoplasmacytic infiltration of the aortic wall(Figure 3A). The infiltrate was not granulomatous, andgiant cells were not present. The abundant plasma cellsstained for CD138 (Figure 3B). The plasma cell infiltratewas transmural and focused predominantly within themedia, with lesser involvement of the adventitia andintima. The majority of the plasma cell infiltrate was notassociated with the dissection (and therefore not consis-tent with a reparative response to the dissection). Lym-phoid follicles and moderate to focally severe fibrosiswere present in the adventitia (Figure 2). The adventitialarteries did not exhibit obliterative endarteritis.

The lymphoplasmacytic infiltrate within the aortawas reminiscent of the type of inflammation observed inIgG4-related systemic disease, i.e., autoimmune pancre-atitis (AIP) or sialadenitis associated with IgG4 deposi-tion. For this reason, immunohistochemical studies forIgG4 were performed. More than 50% of the plasmacells present stained for IgG4 (Figure 3D). By in situhybridization, the plasma cells exhibited polytypic stain-ing for kappa and lambda light chains, consistent with apolyclonal plasma cell infiltrate. Congo red staining foramyloid was negative.

The finding of numerous IgG4-positive plasmacells within the aortic wall led to additional serologicinvestigations. The serum IgG level was increased sub-stantially (1,863 mg/dl [normal 614–1,295]). The serumIgG4 level was dramatically elevated at 1,340 mg/dl(normal 8–140); thus, a large component of the overallIgG elevation was accounted for by the �10-fold eleva-tion in the IgG4 level. Serum and urine protein electro-phoresis demonstrated normal patterns, aside from thepeak in the gamma region.

Finally, the serologic and histologic findings led

to reexamination of the lymph node that had beenremoved 4 years earlier. This lymph node, previouslyregarded as showing reactive changes, stained heavily forplasma cells, �50% of which stained for IgG4 (Figure4). IgG4-related systemic disease with aortitis was diag-nosed.

Five weeks after the aortic surgical procedure,the patient began treatment with prednisone (40 mg/day). The prednisone dosage was tapered to 30 mg/dayafter 1 month. Four months after the initiation ofprednisone therapy, the ESR was 16 mm/hour and theserum CRP level was 3.8 mg/dl. The serum IgG4 levelwas 347 mg/dl. At a followup assessment 7 months aftersurgery, the patient’s IgG4-related systemic disease re-mained well controlled with tapering doses of glucocor-ticoids (prednisone 20 mg/day). The serum IgG4 levelremained somewhat elevated (418 mg/dl), but levels ofacute-phase reactants remained low (ESR 18 mm/hour,serum CRP 6.7 mg/dl). CT angiography of the aortashowed no change in the patient’s mediastinal adeno-pathy and normal postoperative changes in the ascend-ing aorta, without the appearance of new aortic abnor-malities in other parts of the vessel.

DISCUSSION

The disorder now termed IgG4-related systemicdisease remains largely unknown to most clinicians. Thefull clinical spectrum of this condition and its underlyingpathophysiology are poorly understood. However, thereis rapidly emerging evidence that IgG4-related systemicdisease is a protean condition capable of involvingmultiple organs in an insidious manner, sometimessimultaneously but often metachronously (19). Rheuma-tologists might encounter IgG4-related systemic diseasein a variety of settings, ranging from consultation to ruleout Sjogren’s syndrome in patients with submandibular

Figure 4. Mediastinal lymph node with IgG4 plasma cell infiltrate. A, Hematoxylin and eosin staining. B, Immunohistochemical staining for theplasma cell marker CD138. C, Immunohistochemical staining for IgG4. Substantially more than half of the plasma cells exhibited IgG4 staining.(Original magnification � 200.)

3142 STONE ET AL

gland involvement to questions about management ofnoninfectious aortitis (20).

We describe here what we believe to be the firstreported case of IgG4-related systemic disease associatedwith a dissection in the ascending aorta. IgG4-relatedsystemic disease predominantly affects older men—thesame demographic group that more commonly under-goes aortic surgery—and features of IgG4-related sys-temic disease seen upon aortic surgery could be mis-taken for features of a number of primary rheumaticdisorders, particularly giant cell arteritis and isolatedaortitis. The growing recognition of IgG4-related sys-temic disease as a clinical entity underscores the impor-tance of considering this diagnosis in patients with anytype of idiopathic aortitis, not only those whose presen-tations are consistent with the “chronic periaortitis”previously reported to affect the abdominal aorta (11).

Noninfectious aortitis occurs in the setting of anumber of large-vessel vasculitides, including giant cellarteritis, Takayasu arteritis, Behcet’s syndrome, andCogan’s syndrome (2,21–26). Certain connective tissuediseases, e.g., rheumatoid arthritis, ankylosing spondyli-tis, systemic lupus erythematosus, and relapsing poly-chondritis, also occasionally lead to aortitis (3–6,27).Sarcoidosis can cause aortitis and may be difficult todistinguish from Takayasu arteritis (7,28). When theseconditions lead to chronic aortic inflammation, the mostcommon site of involvement is the ascending aorta (8).

Isolated aortitis is another form of chronic aorticinflammation (1). This disorder is often detected inci-dentally at the time of aortic surgery, because patientsare usually aware of few if any systemic symptoms.Studies of large series of patients indicate that at least4% of aortic root replacements lead to the discovery ofisolated aortitis (9,10). As with idiopathic aortitis asso-ciated with the rheumatic conditions mentioned above,isolated aortitis is believed to involve the ascendingaorta most frequently.

In recent years, some cases of chronic periaortitishave been recognized as part of a spectrum of diseaseknown as IgG4-related systemic disease (19,29). Theconcept of IgG4-related systemic disease has emergedslowly since the mid-1990s, when the idea of “auto-immune pancreatitis” was first formulated (30,31). AIPdiffers from acute pancreatitis in a number of importantways. AIP normally presents with painless jaundicerather than with severe mid-epigastric abdominal painthat radiates to the back. Serum concentrations ofpancreatic enzymes are typically normal in AIP. Imagingof AIP by CT usually demonstrates diffuse enlargementof the pancreas with homogeneous attenuation and aperipheral rim of a hypoattenuation “halo” (31). Thus,

AIP is more likely to mimic adenocarcinoma of thepancreas than to be confused with acute pancreatitis (30).

AIP is considered to be a cardinal manifestationof IgG4-related systemic disease, but evidence of AIP isnot always present, as was the case in our patient.IgG4-related systemic disease can involve the biliarytract, liver, salivary gland, lung, kidney, lymph node,retroperitoneum, and other organs in the absence ofpancreatic disease (19,32). Of note, cases of AIP asso-ciated with aortitis of the abdominal aorta have beenreported (17,18). In addition, because of the tendency ofthe disease to evolve in a metachronous manner, evi-dence of pancreatic disease sometimes emerges onlyafter dysfunction in other organ systems has been rec-ognized (20).

Regardless of the specific type of organ involve-ment in IgG4-related systemic disease, histopathologicfindings are similar throughout all affected tissues. Thecharacteristic findings include dense lymphoplasmacyticinflammation, sclerosis, and (when an exocrine gland isinvolved) periductal inflammation and acinar atrophy.Other pathologic hallmarks are inflammatory pseudo-tumors of the involved organ and obliterative phlebitis(33). Periductal granulomas and multinucleated giantcells are observed occasionally. Serum levels of IgG4 areelevated in �75% of patients with IgG4-related systemicdisease (34,35). The number of associated extrapancre-atic lesions is significantly greater in patients with highserum IgG4 levels (36). However, the sine qua non ofthe disorder is the presence of a lymphoplasmacyticinfiltrate within the involved tissue, with the majority ofthe plasma cells staining for IgG4.

The pathophysiology of IgG4-associated systemicdisease remains poorly understood. IgG4 is the leastabundant of all serum IgG isotypes, comprising only�6% of the total IgG in healthy individuals (37). SerumIgG4 levels have been reported to be elevated in condi-tions that bear little obvious resemblance to auto-immune pancreatitis and related disorders, such ashuman filariasis, pemphigus vulgaris, and pemphigusfoliaceus (38–40). IgG4 is effectively a monovalentantibody, which generally binds antigens poorly and doesnot fix complement (37). It has been proposed to be acomponent of processes leading to the down-regulationof immune responses. Thus, one way to view the IgG4-staining plasma cells in tissue is that they are part of acounterregulatory response to an inciting event thatremains unknown.

In conclusion, we provide herein the first reportof a patient with IgG4-related systemic disease associ-ated with dissection of the ascending aorta. Recognitionof the fact that IgG4-related systemic disease can involve

AORTITIS IN IgG4-RELATED SYSTEMIC DISEASE 3143

both the ascending and the abdominal aorta signals theneed for a change in the way idiopathic aortitis isregarded. For example, it is now apparent that a poten-tially sizable subset of patients with inflammatory ab-dominal aortic aneurysms actually have an aortic his-topathologic abnormality that is highly consistent withIgG4-related systemic disease (15). It is possible that thesame is true for aortitis involving the ascending aorta,particularly the subset of noninfectious aortitis currentlyconsidered to be “isolated” aortitis.

The findings in our patient have important impli-cations regarding the investigation of aortitis. The caseoffers new potential considerations for treatment andlong-term management of noninfectious aortitis, be-cause IgG4-related systemic disease often responds wellto a prolonged course of glucocorticoid treatment, withno additional therapy required. Treatment of the aortitismay prevent progression of the IgG4-related systemicdisease to involvement of other organs. Finally, this caseunderscores the need for rheumatologists, cardiologists,cardiothoracic surgeons, and pathologists to workclosely together on the challenges posed by noninfec-tious aortitis, to identify the histopathologic and immu-nohistochemical features of each aortic specimen asprecisely as possible, and to interpret these findings inthe context of the whole patient.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising itcritically for important intellectual content, and all authors approvedthe final version to be published. Dr. J. H. Stone had full access to allof the data in the study and takes responsibility for the integrity of thedata 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, Hilgen-berg, Spooner, Isselbacher, J. R. Stone.

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DOI 10.1002/art.24861

Clinical Images: Transient regional osteoporosis

The patient, a 33-year-old woman, developed left ankle pain at week 20 of gestation during her first pregnancy. The pregnancy wascomplicated by diabetes mellitus, fetal cardiac abnormality, and HELLP syndrome (hemolysis, elevated liver enzymes, and lowplatelets), necessitating emergency delivery at 34 weeks. By week 30 of gestation, she was unable to bear weight. Between week 20of gestation and delivery, physical examination, laboratory testing, plain radiography, and magnetic resonance imaging (MRI) wereperformed to investigate the cause of the ankle pain. Inflammatory arthropathy and joint infection were ruled out by physicalexamination and laboratory testing. Plain radiography revealed generalized osteopenia of the bones of the left foot. MRI showedextensive bone marrow edema within the left talus, with similar patchy changes present in adjacent bones. Computed tomography(CT), performed shortly after delivery (left), showed no fractures but did reveal marked osteoporosis of the talus (an almostcomplete absence of trabecular bone) and severe patchy osteoporosis (multiple small lucencies) in the calcaneus and midtarsalbones. Supportive and symptomatic treatment was begun. The patient’s symptoms gradually improved, but mild pain while bearingweight persisted for 8 months after the onset of symptoms. At that time, a second CT scan (right) revealed near-complete resolutionof the osteoporosis of the foot. The findings and clinical course were consistent with transient regional osteoporosis, a disorder ofunknown etiology that usually resolves spontaneously over several months.

Andrew Grey, MD, FRACPNicola Dalbeth, MD, FRACPAnthony Doyle, MBChB, FRANZCRUniversity of AucklandAuckland, New Zealand

AORTITIS IN IgG4-RELATED SYSTEMIC DISEASE 3145