Libman-Sacks endocarditis and associated cerebrovascular disease: The role of medical therapy

Background Libman-Sacks endocarditis in patients with systemic lupus erythematosus (SLE) is commonly complicated with embolic cerebrovascular disease (CVD) or valve dysfunction for which high-risk valve surgery is frequently performed. However, the role of medical therapy alone for Libman-Sacks endocarditis and associated acute CVD remains undefined. Objective To determine in this cross-sectional and longitudinal study if conventional anti-inflammatory and anti-thrombotic therapy may be an effective therapy in SLE patients with Libman-Sacks endocarditis and associated acute CVD. Methods and materials 17 SLE patients with Libman-Sacks endocarditis detected by two-and-three-dimensional transesophageal echocardiography (TEE) and complicated with acute CVD [stroke/TIA, focal brain injury on MRI, or cognitive dysfunction] were treated with conventional anti-inflammatory and anti-thrombotic therapy for a median of 6 months and then underwent repeat TEE, transcranial Doppler, brain MRI, and neurocognitive testing for re-assessment of Libman-Sacks endocarditis and CVD. Results Valve vegetations decreased in number, diameter, and area (all p ≤0.01); associated valve regurgitation significantly improved (p = 0.04), and valve thickening did not progress (p = 0.56). In 13 (76%) patients, valve vegetations or valve regurgitation resolved or improved in number and size or by ≥1 degree, respectively, as compared to 4 (24%) patients in whom vegetations or valve regurgitation persisted unchanged or increased in size or by ≥1 degree (p = 0.03). Also, cerebromicroembolism, lobar and global gray and white matter cerebral perfusion, ischemic brain lesion load, and neurocognitive dysfunction resolved or significantly improved (all p ≤0.04). Conclusion These preliminary data suggest that combined conventional anti-inflammatory and antithrombotic therapy may be an effective treatment for Libman-Sacks endocarditis and its associated CVD and may obviate the need for high-risk valve surgery.


Introduction
Libman-Sacks endocarditis is common in systemic lupus erythematosus (SLE) and is frequently complicated with 1) embolic cerebrovascular disease (CVD) manifested as cerebromicroembolism, stroke or transient ischemic attacks (TIA), ischemic brain injury on MRI, or cognitive dysfunction and disability [1][2][3]; 2) acute or chronic progressive valve dysfunction [4]; 3) frequent need for high risk valve surgery [5,6]; and 4) increased morbidity and mortality [4][5][6]. Guidelines and experts' consensus are available on medical therapy for most SLErelated clinical syndromes [7][8][9], but they do not exist for Libman-Sacks endocarditis and its associated CVD due to lack of studies on medical therapy alone and lack of comparative studies on medical versus surgical therapy. However, patients with Libman-Sacks endocarditis complicated with CVD or valve dysfunction frequently undergo valve replacement or repair with 3-5 times higher morbidity and mortality than in general populations without SLE [4][5][6]. Based on the immune-mediated inflammatory and thrombotic pathogenesis of Libman-Sacks endocarditis and its associated thromboembolic CVD [1][2][3][10][11][12], combined anti-inflammatory and anti-thrombotic therapy may be a reasonable and effective initial therapy for this condition. To assess this hypothesis, we conducted this cross-sectional and longitudinal study in a well-characterized cohort of SLE patients with Libman-Sacks endocarditis and acute CVD treated with conventional anti-inflammatory and anti-thrombotic therapy and who then underwent repeat cardiac and cerebrovascular clinical and imaging re-evaluations.

Study population
This study was part of a principal study design and protocol approved by the National Institutes of Health and Institutional Review Board (IRB) of the University of New Mexico School of Medicine that determined an association of Libman-Sacks endocarditis and embolic cerebrovascular disease (CVD) in SLE [1].
The primary study included 76 patients with SLE and 26 apparently healthy volunteers ageand-sex frequency (3 patients to 1 control ratio) matched to patients to validate blinded interpretation of tests and provide a normal reference. From December 2006 to December 2012, patients were recruited by the study coordinator from 266 patients regularly followed at the outpatient rheumatology clinics or inpatient services of the University of New Mexico Health Sciences Center. Controls were recruited from available listings of volunteers in the Office of Research of the Health Sciences Center, employees of the University of New Mexico, or patients' relatives or acquaintances. All participants provided IRB-approved informed written consent obtained by the study research coordinator. This study was conducted according to the principles of the Declaration of Helsinki.
All 102 participants underwent a standardized protocol of clinical and laboratory evaluations, transesophageal echocardiography (TEE), transcranial Doppler, brain MRI and neurocognitive testing within 1 week of enrollment.
To assess the effect of medical therapy on Libman-Sacks endocarditis and its associated embolic CVD, 17 patients with both conditions underwent repeat clinical, laboratory, cardiac and cerebrovascular evaluations after a median of 6 months (interquartile range, 2.1-9.6) of clinically indicated and patients' provider guided anti-inflammatory and anti-thrombotic therapy. These 17 patients [age 36 ± 12 years (range, 18-57), 14 (82%) women, 53% Hispanic, with body mass index of 27.12 ± 7.5 Kg/m 2 , age at onset of SLE 29.31 ± 12.08, and SLE duration of 7.53 ± 6.10 years] constitute this study population and their selection is summarized in Fig 1. All initial and follow-up studies were coded, de-identified, randomly intermixed, and interpreted by experienced observers blinded to subjects' clinical and imaging data, baseline findings, and each other's readings.
Limited data on the response to medical therapy of overall vegetations' number and area, cerebromicroembolism, and brain perfusion and lesion load was reported in the manuscript of the primary study determining an association of Libman-Sacks endocarditis with embolic CVD [1]. However, this manuscript aimed to assess the response to anti-inflammatory and anti-thrombotic therapy of Libman-Sacks endocarditis and its associated CVD expands significantly on 1) new individual data on the type of CVD and type and duration of anti-inflammatory and anti-thrombotic therapy, and 2) extensive new data on the response to medical therapy of a) parameters of inflammation and thrombogenesis, b) mitral and aortic valve vegetations' number, area, and diameter; c) valve regurgitation and valve thickness; d) overall and mitral and aortic valve vegetations' number, area, and diameter assessed by 3-dimensional (3D) TEE; e) cerebral perfusion and lesion load of the left and right side of each cerebral lobe and right and left cerebral hemispheres, respectively; and f) neurocognitive function on specific components of the clinical domains of memory and motor function.

Clinical and laboratory evaluations
During initial and follow-up studies, patients were characterized with regard to general demographics, SLE activity and damage, standard autoantibodies, and parameters of inflammation, platelet activation, and fibrinolysis. SLE disease activity was determined with the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) [13]. The Neuro-SLEDAI-2K is composed of the neurologic components of SLEDAI-2K (seizure, psychosis, organic brain syndrome, visual disturbance, cranial neuropathy, lupus headache, and stroke), each of which is given a score ranging from 0 to 8 and then summed. SLE damage was determined with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) [13]. The Neuro-SDI measures the neurologic components of SDI (retinal or optic atrophy, cognitive disorder or psychosis, seizures, stroke, cranial neuropathy, and transverse myelitis).

Transesophageal echocardiography
All 17 participants underwent initial and follow-up two-dimensional (2D) TEE imaging and 10 of them also underwent initial and follow-up three dimensional (3D) TEE imaging with IE-33 Philips systems with digitally acquired images for off-line interpretation and measurements. The detailed methodology of 2D and 3D TEE images acquisition and interpretation has been delineated in previous publications [1][2][3]. Libman-Sacks vegetations by either technique were defined as abnormal localized, protruding, and sessile echodensities >3 mm in diameter with well-defined borders either as part of or adjacent to valve leaflets, annulus, subvalvular apparatus, or endocardial surfaces [1][2][3]. By 2D and 3D TEE, the maximum diameter and area of vegetations were measured by planimetry. High inter-observer agreement for detection of mitral or aortic valve vegetations by 2D TEE (91%, kappa = 0.80) and 3D TEE (96%, kappa = 0.92) was demonstrated [1,3]. Valve regurgitation was assessed by standard 2D TEE color-Doppler criteria according to guidelines and classified as trivial, mild, moderate, moderate to severe, or severe regurgitation [1,14]. Similarly, valve thickening was quantitatively assessed using 2D TEE guided M-mode imaging and measured at the base, mid, and distal portions of the anterior mitral leaflet, proximal and distal portions of the posterior mitral leaflet, and body and tip portions of the aortic valve cusps and then averaged [1][2][3]15].

Transcranial doppler
During initial and follow-up studies, both middle cerebral arteries were interrogated for 90 minutes for detection of microembolism defined as audible, high intensity (>13db), and <100ms unidirectional signals within both Doppler blood flow velocity and vessel lumen [16].

Brain MRI-MRA
Initial and follow-up standard T1-weighted, fluid attenuated inversion recovery (FLAIR), and diffusion-weighted images were obtained. Dynamic susceptibility contrast MRI was also performed to assess brain perfusion [1,17]. Focal brain injury was defined as recent or old cerebral infarcts or �5 small focal periventricular or deep white abnormalities. Hemispheric and whole brain lesion load in cm 3 was determined using semi-automated methods [18]. Quantitative assessment of brain perfusion and qualitative and quantitative assessment of brain injury were performed by 3 independent experts, respectively.

Neurocognitive evaluation
Participants underwent initial and follow-up neurocognitive testing for attention, memory, motor function, processing speed, executive function, and global neurocognitive function [19].

Statistical analysis
Patients' baseline descriptive statistics were mean ± SD, or median and interquartile ranges in asymmetrically distributed variables, or frequencies (%). Neurocognitive z-scores were computed using healthy controls as reference. From initial to follow-up studies, the effect of therapy on parameters of inflammation and thrombogenesis, Libman-Sacks endocarditis (valve vegetations, regurgitation, and thickness), cerebrovascular disease (cerebral microembolism, perfusion, and lesion load), and cognitive dysfunction were all assessed by Wilcoxon's signed

Effect of medical therapy on parameters of inflammation and thrombogenesis
From initial to follow-up studies, the total, neuro, and non-neuro SLEDAI-2K scores, erythrocyte sedimentation rate, and levels of P-selectin (a cell adhesion molecule indicative of platelet activation and aggregation and endothelial cells activation or injury) decreased (all p�0.04) while platelet count and levels of plasminogen activator inhibitor (this last change is indicative of increased fibrinolysis) and complement C4 increased (all p�0.05) ( Table 2).

Effect of medical therapy on Libman-Sacks endocarditis
From initial to follow-up TEE studies, valve vegetations decreased in number, diameter, and area (all p�0.01); the severity of associated valve regurgitation also improved (p = 0.04), and valve thickening decreased, but not significantly (p = 0.56) ( Tables 3 and 4, Figs 2-6). In 13 (76%) patients, valve vegetations or valve regurgitation resolved or improved in number and size or by �1 degree, respectively, as compared to 4 (24%) patients in whom valve vegetations or regurgitation persisted unchanged or increased in size or by �1 degree (p = 0.03).

Effect of medical therapy on acute cerebrovascular disease
From initial to follow-up studies, cerebromicroembolism, lobar and global gray and white matter cerebral perfusion, ischemic brain lesion load, and neurocognitive dysfunction resolved or improved (all p �0.04) ( Table 5

PLOS ONE
Medical therapy of Libman-Sacks endocarditis

Discussion
Although expert consensus and clinical guidelines are available for medical therapy of SLErelated cutaneous vasculitis, discoid lupus, interstitial lung disease, alveolitis, arthritis,     nephritis, pulmonary hypertension, pericarditis, antiphospholipid syndrome, and neuropsychiatric SLE [7][8][9]20], no expert consensus nor guidelines exist for the specific treatment of Libman-Sacks endocarditis and its associated CVD. However, clinicians and surgeons generally advise surgical treatment of Libman-Sacks endocarditis complicated with significant valvular dysfunction or large vegetations and embolization without considering the potential role of anti-inflammatory and anti-thrombotic therapy in resolving or improving this valvulopathy. Therefore, the role of medical therapy for Libman-Sacks endocarditis is a critical issue that has not been adequately addressed. This observational cross-sectional and longitudinal study of Libman-Sacks endocarditis complicated with acute CVD and treated with conventional anti-inflammatory and antithrombotic therapy revealed 3 major findings: 1) clinical parameters of SLE activity and laboratory parameters of inflammation, platelet activity and aggregation, and fibrinolysis improved; 2) Libman-Sacks vegetations and valve regurgitation resolved or significantly improved and valve thickening did not progress; and 3) associated cerebromicroembolism, brain perfusion, brain lesion load, and neurocognitive dysfunction also resolved or improved. To our knowledge, this is the first study to demonstrate a beneficial effect of anti-inflammatory and anti-thrombotic therapy for Libman-Sacks endocarditis and its associated CVD and suggests that medical therapy might obviate the need for high risk valve surgery in SLE patients. The rationale and benefit of anti-inflammatory and anti-thrombotic therapy for Libman-Sacks endocarditis is supported not only by its well-defined autoimmune inflammatory and thrombotic pathogenesis on light and immunofluorescent microscopy, but also by the transition on immune-histopathology from active to mixed or healed Libman-Sacks vegetations with consequent decreased risk of embolism [1][2][3][10][11][12]. Active vegetations are those with central myxoid degeneration, fibrinoid necrosis, fibrous connective tissue, and hemorrhages surrounded by fibrinous exudate, proliferating capillaries and fibroblasts, polymorphonuclear cell inflammation and peripherally by proteinaceous material, fibrin deposition, and platelet thrombi. In these vegetations, deposition of immunoglobulins IgG, IgM, and IgA, anticardiolipin antibodies, and C1q, C3, and C4 complement within the walls of vessels in the inner zone of neovascularization are also present. Mixed vegetations are those with intermixed areas of activity and healing with decreased platelet thrombi with variable degrees of hyalinization and endothelialization and decreased degree of immunoglobulins and complement deposition. Healed vegetations are those with fibroblastic proliferation, central fibrosis, neovascularization, minimal to no inflammation, and absent or organized or hyalinized thrombus with partial or full endothelialization, and absent immune-complex deposition.
The beneficial effect of anticoagulation or antiplatelet therapy frequently combined with hydroxychloroquine therapy in SLE patients with antiphospholipid (aPL) syndrome frequently (39% to 77% of cases) manifested with arterial thrombosis (predominantly stroke or TIA) further support our study findings. Randomized controlled trials and retrospective studies in aPL syndrome including 38% to 59% of cases with SLE have demonstrated a significant reduction  in the rate of recurrent arterial thrombotic events in patients treated with high or moderate intensity warfarin therapy or with single or dual antiplatelet therapy [21][22][23][24][25][26]. Although valvular heart disease in these studies was not studied or reported, high prevalence rates of Libman-Sacks endocarditis have been reported using TEE in SLE patients with aPL antibodies [12,27].
Hydroxychloroquine is now a standard therapy in SLE patients due to its anti-inflammatory, anti-thrombotic, and immunomodulatory effects [28][29][30]. In a prospective study of 232 SLE patients treated with hydroxychloroquine, chloroquine, or both for a median of 52 months, a significant protective effect against thrombosis was demonstrated (HR 0.28, 95% CI 0.08-0.90) [31]. Finally, few isolated case reports have shown that immunosuppressive therapy combined with anti-thrombotic and hydroxychloroquine therapy resolve or improve Libman-Sacks endocarditis and its associated CVD [32][33][34].
The surgical treatment of Libman-Sacks endocarditis is predicated on the assumption that this valvular heart disease may be permanent, progressive, or remain as a high-risk substrate for thromboembolism and valve dysfunction. However, the active underlying systemic and endocardial inflammatory and thrombogenic processes present in Libman-Sacks endocarditis are known to predispose patients to post-operative complications such as: 1) embolism of valve vegetations [35]; 2) prosthesis dehiscence [36]; 3) prosthetic valve stenosis and/or regurgitation due to thrombosis, premature degeneration, or pannus formation [37]; 4) infective endocarditis [38]; 5) autoimmune-mediated bioprosthetic valvulitis, perforation, or accelerated degeneration requiring even higher risk re-do valve surgery [36,37,39]; and 6) life-long bleeding and teratogenic complications of needed warfarin therapy [40]. As evidence of the high risk of valve surgery in SLE patients, Bouma W, et al [5] reported a review of 41 young SLE patients (68% <50 years old) with Libman-Sacks endocarditis who underwent mitral valve replacement with a mechanical or bioprosthetic valve in 30 (73%) or valve repair in 11 (27%) patients. In 9 (22%) patients, no post-operative data was available. Of the 32 subjects with post-operative data, 4 (13%) died and 8 (25%) others had post-operative stroke or peripheral/visceral embolism, myocardial infarction, valve thrombosis, or development of recurrent valve regurgitation, valve stenosis, or arteriovenous fistula. Also, Foroughi M, et al [6], reported a review of another 84 young SLE patients (80% <50 years old) who underwent valve replacement in 72 (86%) and valve repair in 12 (14%) for Libman-Sacks endocarditis complicated with significant valve dysfunction. No post-operative follow-up data was available in 36 (43%) patients, also suggesting a poor outcome. During a post-operative follow-up period of 2 months to 10 years in the remaining 48 patients, 12 (25%) died and 13 (27%) others had postoperative ischemic and hemorrhagic stroke, transient ischemic attack, myocardial infarction, ventricular arrhythmias, heart failure, sepsis, renal failure, or re-do valve replacement. These 2 important reviews demonstrate 3-5 times higher surgical morbidity (25% -30%) and mortality (13% -25%) in SLE patients as compared to those without SLE. These morbidity and mortality rates may be underestimated due to lack of follow-up data in 22% -43% of patients. Therefore, since Libman-Sacks endocarditis is potentially reversible, an initial aggressive trial of combined anti-inflammatory and anti-thrombotic therapy should be considered before committing these patients to high risk and irreversible valve surgery.

Study limitations
Although a small population was studied, to the best of our knowledge, this is the first integrated clinical, laboratory, and multimodality imaging, cross-sectional and longitudinal study to demonstrate a beneficial effect of medical therapy for Libman-Sacks endocarditis and its associated CVD. Although medical therapy was not controlled nor standardized, the antiinflammatory and antithrombotic therapy used in the study conforms with standard clinical practice and recommendations for the treatment of SLE and CVD by the American College of Rheumatology and European League Against Rheumatism [7][8][9]20]. Also, a placebo-controlled group may not be ethically feasible. Since only 4 (22%) patients had moderate to severe valve regurgitation, the effect of medical therapy on advanced valve dysfunction may be underrepresented. However, the prevalence rates of significant valve dysfunction described in this study are similar to those reported in previous series and are generally lower than those of embolic CVD in Libman-Sacks endocarditis [1][2][3]15].

Conclusions
The findings of this study suggest that Libman-Sacks endocarditis and associated acute CVD often resolve or significantly improve with conventional anti-inflammatory and antithrombotic therapy. These results argue for a multidisciplinary approach and an initial trial of medical therapy for Libman-Sacks endocarditis with close clinical follow-up and reimaging before considering high-risk valve surgery. However, a larger randomized cross-sectional and longitudinal study of antiplatelet versus anticoagulant therapy combined with standard antiinflammatory therapy is needed to confirm these findings.