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Foreword
Information about a real patient is presented in stages (boldface type) to an expert clinician (Dr Bhatt), who responds to the information, sharing his reasoning with the reader (regular type). A discussion by the authors follows.
Patient presentation: A 54-year-old man was transferred from an outside institution after he presented to the emergency department following the sudden onset of nonradiating, substernal chest pressure, dyspnea, diaphoresis, and nausea while brushing his teeth. Before transfer, the patient received a full dose of aspirin and was started on unfractionated heparin with biomarker and electrocardiographic evidence of a non–ST-segment–elevation myocardial infarction.
His medical history included hypertension, dyslipidemia, long-standing severe atopic dermatitis, and remote large-cell non-Hodgkin lymphoma that had remained in remission for the past 9 years after treatment with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone. Over the preceding year, the patient had suffered recurrent admissions for acutely decompensated heart failure with a newly appreciated depressed left ventricular (LV) ejection fraction of 20% and evidence of global hypokinesis by echocardiography. Regadenoson radionuclide myocardial perfusion imaging had demonstrated a moderate-sized scar in the midanterior wall with no evidence of ischemia. During the same time period, the patient had developed rapidly progressive end-stage renal disease of unknown origin requiring the initiation of hemodialysis. The patient had not yet undergone a renal biopsy. Renal ultrasound had incidentally demonstrated a 4.3-cm infrarenal abdominal aortic aneurysm (AAA) and bilateral common iliac artery aneurysms (right, 2.6 cm; left, 1.7 cm). A computerized tomography (CT) scan had additionally detected a 1.7-cm superior mesenteric artery aneurysm with a dissection.
The patient’s medications included daily aspirin 81 mg, atorvastatin 80 mg, lisinopril 2.5 mg, metoprolol succinate 25 mg, furosemide 20 mg, a multivitamin, and sublingual nitroglycerin as needed. He had no allergies to medicines and no history of smoking, alcohol use, or drug use. His father had undergone coronary artery bypass grafting (CABG) at 60 years of age. The patient denied fevers, weight loss, fatigue, headache, jaw or arm claudication, vision or hearing changes, vertigo, diarrhea, oral or urogenital lesions, and pain of the back, abdomen, or joints.
Dr Bhatt: Several features of the patient’s recent history are concerning. The cause of the patient’s severe LV systolic dysfunction remains undefined. Evidence from large epidemiological studies suggests that in some populations, >60% of unexplained cardiomyopathies may be attributable to coronary heart disease.1 This patient’s family history of early coronary artery disease, personal history of classic coronary artery disease risk factors, and regional findings on his myocardial perfusion study support this possibility. In terms of alternative potential causes for his cardiomyopathy, the patient’s exposure to doxorubicin places him at up to a 5-fold risk of developing impaired myocardial function, depending on the total cumulative dose of anthracyclines that he received, concomitant radiation exposure, and exposure to additional cardiotoxic medications.2 Additionally, the patient’s diffuse aneurysmal disease and rapidly progressive renal disease raise the concern for a possible underlying connective tissue disease, vasculitis, or infectious process. Lastly, renovascular disease is an important and often underrecognized source of recurrent pulmonary edema. This is especially true in the context of a rising serum creatinine level and history of hypertension.
In the setting of this patient’s non–ST-segment–elevation myocardial infarction with high-risk characteristics, including severe LV dysfunction and recurrent episodes of angina despite medical therapy over the past year, coronary arteriography would be the appropriate next step. Indeed, some experts feel that most patients with unexplained significant LV dysfunction should undergo coronary angiography regardless of stress test findings. Given the extent of the patient’s aneurysmal disease and concern for a possible underlying systemic process, a complete CT vascular survey to exclude additional territories of disease would also be reasonable once his non–ST-segment–elevation myocardial infarction is addressed. Finally, to establish the cause of the patient’s end-stage renal disease, a complete serological workup and a core renal biopsy should ultimately be performed.
Patient presentation (continued): On arrival after transfer, the patient was in no acute distress. His heart rate was 69 bpm with a blood pressure of 128/82 mm Hg that was equal in both arms. Oxygen saturation was 98% on room air. Jugular venous pressure was 10 cm H2O. There were no carotid or subclavian bruits, and there was no cervical lymphadenopathy. Lungs were clear to auscultation. Cardiac examination revealed a regular rate and rhythm with normal S1 and S2, no murmurs, no gallops, no rubs, and a nondisplaced point of maximum impulse. There was no organomegaly. He had easily palpable carotid, radial, femoral, popliteal, dorsalis pedis, and posterior tibial pulses bilaterally with normal, nontender temporal arteries. Neurological examination was normal. There was no joint swelling, warmth, or tenderness. His skin had areas of hypopigmentation with no mucosal lesions.
The patient had a positive troponin T at 0.16 ng/mL (reference range, <0.01 ng/mL) and an elevated N-terminal brain natriuretic peptide of >70 000 pg/mL (reference, 0–900 pg/mL). His admission ECG demonstrated new T-wave inversions in the anteroseptal precordial leads(Figure 1). His chest x-ray showed mild interstitial edema. Echocardiography was unchanged from prior studies over the preceding year, with an LV ejection fraction of 25%, normal LV dimensions, global LV hypokinesis, preserved right ventricular size and function, and no evidence of significant valvular disease. Coronary arteriography identified a giant 15-mm aneurysm in the left main coronary artery, a giant 22-mm aneurysm in the ostium of the right coronary artery (RCA), diffuse ectasia throughout the coronary tree, and high-grade stenoses in the mid left anterior descending artery, proximal left circumflex artery, and distal RCA(Figure 2 and Movies I and II in the online-only Data Supplement). Subsequent CT angiograms of the head, neck, chest, and abdomen demonstrated no evidence of additional aneurysmal disease.
Admission ECG demonstrating sinus rhythm with premature atrial complexes, left ventricular hypertrophy with repolarization abnormalities, and new T-wave inversions in the anteroseptal precordial leads.
Coronary arteriography demonstrating a 15-mm ostial aneurysm of the left coronary artery with a 99% stenosis in the mid left anterior descending artery (A, right anterior oblique caudal view), an 80% stenosis in the left circumflex artery (B, left anterior oblique caudal view), and a 22-mm ostial aneurysm with a 99% midvessel stenosis of the right coronary artery (C, left anterior oblique view). Diffuse ectasia was present throughout the coronary circulation.
Dr Bhatt: Coronary artery aneurysms are rare with an estimated incidence between 0.3% and 5.3% based on several large, retrospective angiographic series.3 The RCA is most commonly affected, and it is very unusual to observe aneurysmal disease in either the left main coronary artery or both the right and left system concurrently. There are no randomized trials to guide the use of surgical, percutaneous, or medical management strategies in addressing coronary artery aneurysms. However, a substudy of the Coronary Artery Surgery Study (CASS) registry identified no overall survival difference among patients who underwent CABG with evidence of atherosclerotic coronary artery disease with concomitant coronary artery aneurysms compared with those with atherosclerotic coronary artery disease alone.4 The patient’s multivessel, severe stenotic disease in the context of his recurrent angina and depressed LV systolic function warrants evaluation for surgical bypass. The coronary aneurysms raise the possibility of nonatherosclerotic causes of the patient’s lesions, and a CT coronary angiogram may help further characterize this pathology.
The patient’s coronary artery aneurysms provide important additional information to help define what now appears to be almost assuredly a systemic condition. The list of diseases known to be associated with coronary artery aneurysms is broad and has been comprehensively reviewed elsewhere.3 This patient’s history and physical examination make several iatrogenic, drug-related, traumatic, congenital, infectious, and connective tissue disorder causes less likely and specifically raise concern for a possible underlying inflammatory disorder. Further serological testing would help narrow possible inflammatory causes of the patient’s disease.
Patient presentation (continued): Serological studies demonstrated negative hepatitis B and C antibodies, HIV antibody, rapid plasma reagin, antinuclear antibody, anti-neutrophil cytoplasmic antibody, and cryoglobulins with an elevated erythrocyte sedimentation rate (ESR) of 112 mm/h (reference, 0–13 mm/h), C-reactive protein (CRP) of 100 mg/L (reference, 0–3 mg/L), and rheumatoid factor of 44 IU/mL (reference, 0–15 IU/mL). Serum immunofixation demonstrated a polyclonal gammopathy with elevated levels of immunoglobulin G (IgG) at 5849 mg/dL (reference, 700–1600 mg/dL) and IgE at 6000 kU/L (reference mean, 13.2 kU/L). Total white blood cell count was 9500 per 1 μL (reference, 4000–10 900 per 1 μL) with a normal differential (0.7% eosinophils). Urine sediment was bland with nonnephrotic-range proteinuria. CT coronary angiography demonstrated large coronary artery aneurysms involving the left main coronary artery, proximal left anterior descending artery, and proximal RCA with diffuse ectasia throughout the RCA. There were severe mid left anterior descending and ostial left circumflex artery stenoses without significant plaque. Marked circumferential mural thickening with associated enhancement of the wall of the coronaries and the aorta was also appreciated(Figure 3).
Computerized tomography coronary angiography demonstrating significant circumferential wall thickening throughout the proximal left anterior descending artery (LAD; A), proximal left circumflex artery (LCX; C), and proximal to mid right coronary artery (RCA; D) with a wall thickness measuring up to 4 mm, as shown in a short-axis view of the proximal LAD (B).
Dr Bhatt: The patient’s CT coronary angiogram demonstrated severe mural thickening with enhancement of the wall and no significant associated atherosclerotic plaque, which is consistent with an underlying vasculitis. Although the differential diagnosis for a systemic immune-mediated vasculitis is broad, this patient’s demographics, serological testing, and concomitant renal disease help narrow the list. Of the large-vessel vasculitides, Takayasu vasculitis affects men in <10% of known cases and rarely occurs in patients after the fourth decade of life.5 Giant-cell arteritis is not usually associated with renal failure. Moreover, this patient complained of no neurological or musculoskeletal symptoms that might support this diagnosis. The patient reported no childhood history of Kawasaki disease and had no classic findings or symptoms to suggest polyarteritis nodosa, sarcoidosis, or an inflammatory disorder such as Behçet syndrome, relapsing polychondritis, rheumatoid arthritis, ankylosing spondylosis, or systemic lupus erythematosus.
IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder that is more common in men than women and has a median age at presentation of 62.5 years.6 Patients often are noted to have a long-standing history of allergic diseases, including atopic dermatitis as in the case of this patient.7,8 IgG4-RD can affect nearly every organ system in the body and is a well-established cause of cardiovascular and renal disease.7,9 The prompt diagnosis of IgG4-RD is important because it is often associated with multiorgan pathology and can be effectively treated with immunosuppressive therapy. In a multicenter, retrospective analysis of glucocorticoid use in the treatment of IgG4-RD manifested by pancreatitis, initial remission was achieved in 98% of patients treated with steroids.10 To aid in the diagnosis of IgG4-RD, the concentrations of serological IgG subclasses can be tested. However, elevated serological levels of IgG4 are relatively nonspecific, with a positive predictive value for IgG4-RD of only 34%.11 The diagnosis of IgG4-RD therefore rests on histopathological analysis of biopsied tissue. Given the patient’s severe multiorgan disease, initiation of empirical corticosteroid treatment and a renal core biopsy would be appropriate next steps.
Patient presentation (continued): The patient was initiated on prednisone 60 mg daily. A temporal artery biopsy demonstrated no evidence of giant-cell arteritis or alternative abnormality. Serological analysis of IgG subclasses demonstrated a significant elevation in IgG4 of 1980 mg/dL (reference, 2.4–121 mg/dL), as well as modest elevations in IgG1 at 1530 mg/dL (reference, 341–894 mg/dL), IgG2 at 1490 mg/dL (reference, 171–632 mg/dL), and IgG3 at 139 mg/dL (reference, 18.4–106 mg/dL). Histopathological analysis of a core renal biopsy demonstrated a moderate mixed inflammatory infiltrate in the interstitium made up of mononuclear cells, eosinophils, and plasma cells. The most active areas of inflammation included >20 IgG4-positive plasma cells per high-power field(Figure 4A and 4B). By electron microscopy, the glomeruli showed numerous subepithelial and focal subendothelial electron-dense deposits(Figure 4C). There were also many large, electron-dense deposits in the tubular basement membranes and focally scattered deposits in the interstitium. Immunofluorescence analysis demonstrated IgG4 dominance in these glomerular peripheral capillary wall and tubular basement membrane deposits(Figure 4D). The findings of membranous nephropathy and chronic active interstitial nephritis with clusters of IgG4-positive plasma cells and IgG4 dominance in the glomerular peripheral wall and tubular basement membrane deposits are characteristic of kidney involvement by IgG4-RD.
A, Hematoxylin and eosin section showing a lymphoplasmacytic infiltrate featuring plasma cells, lymphocytes, eosinophils, and rare neutrophils (arrows show 2 representative plasma cells) in the renal parenchyma with (B) immunohistochemical staining for immunoglobulin G4 (IgG4) demonstrating >20 IgG4-positive cells per high-power field (arrows show dark cytoplasmic staining; nuclei are in blue). C, Electron microscopy showing numerous subepithelial electron-dense deposits in the glomerular basement membrane (asterisks). D, Immunofluorescence studies demonstrating IgG4 dominance in the glomerular peripheral capillary wall and tubular basement membrane deposits. IgG indicates immunoglobulin G.
Dr Bhatt: The histological findings from a core renal biopsy confirm the diagnosis of IgG4-RD. At this time, it would be important to consider B-cell depletion with rituximab, given the severity of the patient’s disease and the involvement of vital organs. Several recent reports demonstrate that treatment with rituximab can lead to rapid improvements in both IgG4 serum levels and clinical disease control.12,13 Furthermore, rituximab has recently been shown to be safe and effective in a prospective, single-arm, open-label pilot study of 30 patients with IgG4-RD.14 A key question in the management of this patient involves the optimal timing for possible CABG. Under ideal circumstances, CABG would be deferred for a short period of time to allow the patient’s active vasculitis to respond to immunosuppressive therapy and for his corticosteroids to be downtitrated to improve postsurgical wound healing. Significant clinical improvement has been reported within 2 to 4 weeks of rituximab initiation.12–14 There is no standard by which to assess for disease activity of IgG4-RD affecting the vasculature. 18F-fluorodeoxyglucose positron emission tomography/CT (FDG PET/CT) has successfully been used to identify coronary artery involvement of IgG4-RD and to follow up disease activity in IgG4-RD and Takayasu vasculitis.15–20 FDG PET/CT could therefore be considered to gauge the extent of the patient’s active inflammation before and after therapy. Additionally, serological IgG4, ESR, and CRP levels have been shown to respond to treatment with corticosteroids and rituximab and seem to correlate with clinical improvement.12,13
Patient presentation (continued): Baseline FDG PET/CT obtained before the initiation of corticosteroids demonstrated mild inflammation in the ascending aorta with no evidence of inflammation in the other large vessels(Figure 5). Incomplete suppression of glucose utilization by the myocardium precluded evaluation of the coronary arteries. Regadenoson N-13 ammonia rest/stress PET/CT obtained to assess for viability demonstrated large areas of severe myocardial ischemia in all 3 major coronary artery territories, with a summed stress score of 42 and a summed difference score of 36. After 28 days of corticosteroid therapy and 4 days after the patients received 1 g rituximab, his ESR and CRP were significantly improved at 15 mm/h (reference, 0–12 mm/h) and 3.3 mg/L (reference, 0–3 mg/L), respectively. Before planned repeat FDG PET/CT to reassess aortic and coronary artery disease activity, the patient developed new resting chest pain that required the initiation of high-dose intravenous nitroglycerin. The patient was immediately taken for surgery, at which time the visualized segments of the aorta and the left internal mammary artery appeared white with a fibrinous discoloration. The left internal mammary artery dissected easily and had diminished flow and thus could not be used for bypass. The patient received saphenous vein grafts to the left anterior descending artery, left circumflex artery, and RCA with excellent flows.
18F-fluorodeoxyglucose (FDG) positron emission tomography–computerized tomography demonstrating only mild inflammation in the ascending aorta (purple). Diffuse myocardial FDG uptake suggesting incomplete suppression of glucose utilization by the myocardium precluded evaluation of the coronary arteries.
Biopsy samples were obtained from the pericardium, aortic adventitia, left internal mammary artery, and saphenous vein. There was evidence of a scant perivascular lymphoplasmacytic infiltrate in the pericardium and patchy lymphoplasmacytic infiltrate in the aortic adventitia(Figure 6A). Immunohistochemistry of the aortic adventitia demonstrated up to 23 IgG4-positive cells per high-power field and a ratio of IgG4 to IgG >50%(Figure 6B and 6C). Immunofluorescence studies of several small arteries in the aortic adventitia demonstrated positivity for IgG1 and IgG4. Further analysis of these small arteries by electron microscopy demonstrated subendothelial electron-dense deposits throughout the vasculature(Figure 6D). These likely corresponded to the areas of IgG4 deposition by immunofluorescence and were thought likely to represent immune complex deposition. These findings were consistent with the renal biopsy findings and a diagnosis of cardiovascular involvement of the patient’s systemic IgG4-RD.
A, Hematoxylin and eosin section showing a lymphoplasmacytic infiltrate in the aortic adventitia with immunohistochemical staining for IgG (B) and IgG4 (C) demonstrating >20 IgG4-positive cells per high-power field and a ratio of IgG4 to IgG >50%. D, Electron microscopy of a small artery in the aortic adventitia showing electron-dense deposits in the subendothelial space. BM indicates basement membrane; EC, endothelial cell; EL, elastic lamina; IgG, immunoglobulin G; and L, lumen. *Subendothelial deposits.
The patient recovered from his surgery without complication and was able to be discharged home. He was weaned off of corticosteroids during the following 8 weeks and has been maintained on 1-g rituximab infusions every 6 months for the past 18 months without recurrence of ischemic chest pain. His IgG4 subclass concentration normalized to 73.4 mg/dL (reference, 3.9–86.4 mg/dL) 18 months after discharge. His ESR remained stable at 22 mm/h (reference, 0–12 mm/h), and his CRP remained stable at 12.7 mg/L (reference, 0–8 mg/L for non–high-sensitivity CRP) at 18 months after discharge. His LV ejection fraction normalized with normal LV dimensions and no evidence of regional wall motion abnormalities by repeat echocardiography 4 months after discharge. Surveillance abdominal ultrasound demonstrated stable appearance of his aortic and bilateral iliac artery aneurysms 12 months after discharge. His superior mesenteric artery aneurysm is being followed up with serial CT scans, and he has remained without ischemic abdominal pain. He remains on hemodialysis.
Dr Bhatt: The biopsy sample from the aortic adventitia was consistent with the core renal biopsy and a diagnosis of cardiovascular involvement of the patient’s IgG4-RD. The patient improved symptomatically with normalization of his serological IgG4 and inflammatory markers after corticosteroid treatment and B-cell depletion. His LV ejection fraction normalized after successful CABG. His renal disease did not respond to immunosuppressive treatment, which may be reflective of the degree of renal fibrosis before the initiation of therapy.7 It would be interesting to image the patient’s coronary and peripheral vasculature after prolonged immunosuppressive therapy. Various modalities of serial imaging have been used to detect therapeutic response of coronary pseudotumors and iliac artery vascular wall thickening to immunosuppression.17,19 Depending on the extent of fibrosis before therapy, the patient’s aneurysmal disease may respond to continued immunosuppressive therapy. Surveillance imaging will be imperative.
This patient showed clinical and serological response to his initial immunosuppressive regimen. A major challenge in the treatment of IgG4-RD is the high rate of relapse. Therefore, the primary goals of care for this patient moving forward will be the management of his immunosuppressive regimen to maintain remission and vigilant surveillance of his known diffuse vascular disease.
Discussion
IgG4-RD is a nongranulomatous, immune-mediated disorder characterized pathologically by the presence of tumefactive lesions and evidence of storiform fibrosis with a lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells on histological analysis.7 The key features of IgG4-RD were first identified in patients with autoimmune pancreatitis.21 IgG4-RD was recognized as a systemic disease in 2003 when these histological features were identified in an extrapancreatic specimen.22 IgG4-RD has subsequently been found to affect nearly every organ system in the body, including the cardiovascular system.7
Cardiovascular involvement of IgG4-RD was first reported in 2008 in several patients who presented with inflammatory AAA disease.23–26 Over the following years, IgG4-RD was further associated with aneurysmal disease of the ascending aorta, pulmonary arteries, subclavian arteries, iliac arteries, femoral arteries, popliteal arteries, mesenteric arteries, and splenic arteries.17,25–31 A retrospective analysis of a large case series of patients who underwent surgery for noninfectious thoracic aortitis at a single American academic institution demonstrated histological evidence of IgG4-RD in 9% of these cases.32 Interestingly, one of the first case reports of IgG4-related aortitis additionally described a large, tumefactive lesion surrounding the RCA.25 There have since been a growing number of reports of IgG4-RD associated with periarterial pseudotumors, aneurysms, and stenoses in the coronary tree.20,33–35 A small number of recent reports also have described the sudden cardiac death of patients with autopsy findings showing coronary aneurysmal disease and histopathology consistent with IgG4-RD.36,37 Finally, cardiovascular manifestations of IgG4-RD have been reported to include rare cases of constrictive pericarditis.7
The pathophysiology underlying IgG4-RD remains an area of active investigation. IgG4 antibodies exhibit minimal binding to C1q and the Fc-gamma receptors, making them relatively poor activators of the classic complement cascade and effector function.38 In light of these anti-inflammatory features, IgG4 monoclonal antibodies are in clinical use for the treatment of multiple sclerosis, Crohn disease, and paroxysmal nocturnal hemoglobinuria.38 However, the IgG4 antibody has been postulated to play a pathological role in some circumstances. IgG4 antibody binding to desmoglein-1 leads to the direct disruption of epithelial structure and subsequent skin blistering in pemphigus foliaceus.38 Similarly, IgG4 antibodies that recognize and neutralize ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif) are thought to play a central role in the development of thrombotic thrombocytopenic purpura.38 Other IgG subclasses such as IgG1 may exhibit distinct tissue and antigen-binding specificity yet can also play an analogous pathological role as IgG4 in autoimmune diseases such as pemphigus foliaceus.39 This raises the possibility that other members of the IgG subclass may contribute to pathogenicity. Interestingly, we cannot exclude the possibility that our patient’s elevated levels of IgG1 also may be contributory. It therefore remains unclear whether IgG4 antibodies mediate, protect against, or simply serve as a biomarker for the fibroinflammatory changes observed in IgG4-RD.
Analysis of IgG4-related sclerosing pancreatitis and cholangitis samples has demonstrated the overproduction of T helper 2 (Th2) and T regulatory cytokines, including interleukin (IL)-4, IL-5, IL-10, IL-13, and tumor growth factor-β.40 Similar observations have been made in salivary gland tissue in patients with IgG4-RD.41,42 This has led to speculation that an as-yet unidentified inciting event may lead to T-cell polarization toward a modified Th2/regulatory T-cell response in IgG4-RD.43 Whether this inciting event involves certain genetic predisposing factors, molecular mimicry, or autoimmunity remains unknown.7 Fascinatingly, the modified Th2 response has also been demonstrated to predominate in patients with AAA disease.44 Extensive characterization of human tissue from AAA samples has demonstrated the preferential expression of Th2-mediated IL-4, IL-5, and IL-10.45,46 The Th2 response has additionally been shown to specifically induce AAA formation and to increase matrix metalloproteinase-9 and -12 in murine models.47,48 Finally, IgE is known to lead to CD4+ T-cell, mast cell, and macrophage activation and to contribute to AAA pathogenesis.49 Taken together, it is likely that a triggering event may lead to a modified Th2/regulatory T-cell cytokine response and B-cell class switching to IgE and IgG4, which, in turn, may stimulate mast cell, macrophage, eosinophil, fibroblast, and myofibroblast activation. This model correlates well with the fibroinflammatory changes that are characteristic of IgG4-RD and much of the pathology that is now known to underlie AAA disease in general. A key unanswered question in the field is the role of the IgG4 antibody in this Th2 response. Whether the IgG4 antibody may offer a useful biomarker, therapeutic target, or therapeutic tool in the treatment of IgG4-RD, and perhaps aneurysmal disease in general, remains an active area of investigation.
The optimal strategy to treat the cardiovascular manifestations of IgG4-RD remains unknown. As previously mentioned, a retrospective survey of >500 patients treated for IgG4-related autoimmune pancreatitis found that induction of remission was successful in 98% of patients with steroid therapy.10 The size of the pancreatic pseudotumors responded in 80% of the cases.10 On the basis of a very small number of initial case reports, similar results may be possible in treating lesions in the cardiovascular system.19 The optimal surgical or percutaneous approach to addressing vascular disease caused by IgG4-RD has not yet been studied. Until further information is available, it may be reasonable to approach these patients in a manner similar to that used in those with other vasculitides or inflammatory disease.
A major challenge in the treatment of IgG4-RD is the high rate of recurrence after successful remission. Relapse rates among patients treated with corticosteroids for IgG4-related autoimmune pancreatitis have been reported to be as high as 32% within 6 months and 92% within 3 years.10 Encouragingly, corticosteroid retreatment was effective in 97% of these cases. The specific relapse rates for extrapancreatic IgG4-RD are unknown.50 Corticosteroids, azathioprine, mycophenolate mofetil, 6-mercaptopurine, cyclophosphamide, methotrexate, rituximab, and bortezomib have all been used as maintenance therapy with the goal of preventing IgG4-RD relapse.7,50 There has been special interest recently in the use of rituximab to maintain disease remission. It has been hypothesized that IgG4+ B cells may be crucial for antigen presentation to Th2 effector cells and that these B cells may additionally provide proliferative factors to support the T-cell response.43 A recent case series and a small, prospective, single-arm pilot study have demonstrated that B-cell depletion with rituximab appeared effective in preventing IgG4-RD relapse.12,14 Importantly, these initial experiences seemed to demonstrate no significant difference in efficacy or safety outcomes based on the organ system affected by IgG4-RD and thus may be applicable to the management of IgG4-related cardiovascular disease.
Conclusions
IgG4-RD should be considered in patients with periarterial tumefactive, aneurysmal, or stenotic vascular disease. Suspicion should be especially heightened in middle-aged and older men with atopy and unexplained multiorgan dysfunction. The diagnosis is dependent on histological analysis of biopsied tissue. Prompt treatment with immunosuppressive agents is critical to prevent end-stage fibrotic damage. The pathophysiology of IgG4-RD is under active investigation, with several areas of probable overlap with AAA and other aneurysmal disease. As clinical experience grows, the optimal medical and surgical approaches to address the cardiovascular manifestations of IgG4-RD will continue to be clarified.
Acknowledgment
This work was presented in part at the American Heart Association Scientific Sessions 2015 as the Laennec Young Clinician Award winner.
Disclosures
Dr Bhatt reports serving on advisory boards for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; on the board of directors for Boston VA Research Institute and Society of Cardiovascular Patient Care; as chair of the American Heart Association Quality Oversight Committee; and on the Data monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute. Dr Bhatt has received honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor, associate editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (CME steering committees). Dr Bhatt has received research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, and The Medicines Company; and royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease). He has been a site coinvestigator for Biotronik, Boston Scientific, and St. Jude Medical; has been a trustee for the American College of Cardiology; and has performed unfunded research for FlowCo, PLx Pharma, Takeda. The other authors report no conflicts.
Footnotes
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.020758/-/DC1.
- © 2016 American Heart Association, Inc.
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