igg4-related systemic disease and lymphoplasmacytic aortitis
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ARTHRITIS & RHEUMATISMVol. 60, No. 10, October 2009, pp 31393145DOI 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 thepatients 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-tients 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 (27).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 (1518).
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 patients 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:firstname.lastname@example.org.
Submitted for publication February 13, 2009; accepted inrevised form June 5, 2009.
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.
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 patients 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).
3140 STONE ET AL
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 4153) and a meancorpuscular volume of 77 fl (normal 80100). The serumcreatinine level was 1.5 mg/dl (normal 0.81.2). 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 patients 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