https://orcid.org/0000-0001-5370-4907
IgG4-related disease can involve the heart valves and lead to premature prosthetic valve failures.
DearEditor, We present a case of a 78-year-old male with severe valvular heart disease requiring multiple valve replacements and repairs. The aetiology of his valvular dysfunction was determined to be immunoglobulin G4-related disease (IgG4-RD).
Six years prior to presentation, the patient had developed dyspnea on exertion (DOE). Cardiac workup demonstrated severe aortic stenosis and moderate mitral regurgitation. He underwent an open aortic and mitral valve replacement with bioprosthetic valves.
Two years later, the patient experienced recurrent DOE and orthopnea. His cardiologist noted a worsening systolic murmur. Transesophageal echocardiogram revealed prolapse of the posterior leaflet of the bioprosthetic mitral valve resulting in a paravalvular leak and severe prosthetic stenosis. A few months later, he underwent a percutaneous mitral valve repair followed by a valve-in-valve transcatheter mitral valve replacement. Post-procedure transthoracic echocardiogram showed mild residual mitral regurgitation.
During that admission at an outside hospital, CT angiography of the chest showed bilateral mediastinal and hilar lymphadenopathy, bibasilar lung opacities and pulmonary nodules. Four weeks later, a positron emission tomography CT of the chest showed resolution of the previously noted lymphadenopathy and no metabolically active pulmonary disease. It is unclear from the outside hospital records whether the patient received any intervention, particularly glucocorticoids, between the times of those two CT scans.
Over the next two years, the patient developed a chronic cough. He had repeated evaluations and was treated with short courses of antibiotics, inhaled and oral glucocorticoids, and bronchodilators with minimal relief. When he returned to his cardiologist for the first time in two years, a transthoracic echocardiogram revealed moderate to severe mitral stenosis, moderate to severe aortic regurgitation, and mild to moderate aortic stenosis. An outpatient evaluation for transcatheter aortic valve replacement was begun.
Two months later, the patient presented to the emergency department for evaluation of a productive cough, pleuritic chest pain and DOE. During this hospitalization, he also reported fatigue and mild night sweats over the preceding few months. Physical examination was notable for symmetric non-tender submandibular gland enlargement, which the patient thought had been present for months to years. A CT of the neck, chest, abdomen and pelvis demonstrated symmetric submandibular gland enlargement, bibasilar lung airspace opacities, pulmonary nodules, and extensive mediastinal and hilar lymphadenopathy (Supplementary Fig. S1, available at Rheumatology online). Workup for infectious, inflammatory and neoplastic conditions revealed elevated total serum IgG (3,245 mg/dl, reference range 723–1,685 mg/dl) and IgG4 levels (981.7 mg/dl, reference range 4–86 mg/dl).
The patient subsequently had a CT-guided lung biopsy, the pathology of which showed chronic pneumonitis and interstitial fibrosis with dense IgG4-positive plasmacytic infiltration. He was started on prednisone followed by rituximab and had rapid resolution of his chest pain and cough as well as radiologic improvement in lung opacities and lymphadenopathy (Supplementary Fig. S1, available at Rheumatology online). Pathology samples from his initial aortic and mitral valve replacement surgery six years earlier were then obtained and re-examined. Both valves exhibited dense lymphoplasmacytic infiltration with >50 IgG4+ cells per high-powered field and an IgG4+/IgG+ cell ratio >50% (Fig. 1). His clinical and histologic findings met the 2019 ACR/EULAR classification criteria for IgG4-RD [1].
Mitral valve
(A) Low power (25×; scale bar=4 mm) micrograph showing valvular tissue with chronic inflammation and dystrophic calcification. (B) High power (100×; scale bar=1.6 mm) showing chronic inflammation characterized by mature lymphocytes and many plasma cells. (C) CD138 immunohistochemistry (200×; scale bar=0.8 mm) highlighting plasma cells. (D) IgG4 stain (200×; scale bar=0.8 mm) showing an increased proportion of plasma cells with IgG4 subset restriction (>50%).
The patient was deemed a poor candidate for transcatheter or surgical valve replacement because of his overall condition. A few months later, he expired during a hospitalization for a heart failure exacerbation.
IgG4-related disease is a systemic fibroinflammatory condition that can affect most organ systems. The disease was first described less than two decades ago, and its pathophysiology and clinical manifestations are now active areas of investigation. Cardiovascular hallmarks of the disease include aortitis, ranging from asymptomatic aneurysm to aortic rupture, and periaortitis, which may lead to obstructive uropathy, lower extremity oedema, or testicular pain [2]. However, cardiac involvement of IgG4-RD has rarely been reported [3].
We describe a case of severe calcific aortic and mitral valve disease with rapid failure of both bioprosthetic replacements requiring repeated intervention over the span of six years before the diagnosis of IgG4-RD was established. IgG4-rich plasma cell infiltration has been described in one case of mitral stenosis without other systemic signs of IgG4-RD, and aortic valve involvement has been observed in a few patients with other systemic manifestations of the disease [4–8].
This case is the first to our knowledge, however, to demonstrate that valvulitis can be the first clinical manifestation of IgG4-RD and can precede other symptoms by years. It is also the first to demonstrate that if left untreated, IgG4-related valvulitis can potentially result in early and recurrent prosthetic valve failure. This finding may have been caused by recurrence of valvulitis after valve replacement, consistent with the hypothesis that the inflammation is driven by circulating cells or antigens that are not removed during valve replacement. Whether this patient’s valvulopathy would have improved with earlier immunosuppression remains unknown. This case highlights the need for further research delineating the role of IgG4-RD in valvular heart disease.
Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.
Disclosure statement: A.B. discloses consulting roles with Janssen and Saofi-Aventis. The other authors have declared no conflicts of interest.
Supplementary data
Supplementary data are available at Rheumatology online.
Comments