Article ID: CJ-17-1131
Sterile valve leaflet vegetation, papillary muscles and mural endocardium constitute Libman-Sacks endocarditis (LSE).1 This condition, associated with antiphospholipid antibodies (aPL), excepting other criteria for antiphospholipid syndrome (APS) or systemic lupus erythematosus (SLE), is called aPL-associated cardiac valve disease.1 Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) are diagnostic benchmarks for LSE.2 Management of LSE is not standardized. Treatment in symptomatic valvular disease consists of anti-thrombotic agents according to APS therapeutic guidelines, namely vitamin K antagonists (VKA).1 Occasionally, despite efficient anticoagulation, these drugs are ineffective, highlighting the need for new treatment for LSE. Approximately 4–6% of patients require valve surgery, considered a high-risk procedure in APS with high thrombotic/bleeding risk. Surgery is carried out only in the case of severe valvular lesions, cardiac dysfunction or hemodynamic instability.1 Anti-malarial hydroxychloroquine (HCQ) is crucial to SLE therapy due to its immunomodulatory properties and potential anti-thrombotic effects.3 In aPL-associated cardiac valve disease, HCQ may represent novel therapy. We report the case of a 21-year-old man with medical history of unprovoked deep vein thrombosis (DVT), referred for recurrent DVT.
On admission, the patient’s condition was satisfactory and hemodynamics were stable. Electrocardiography indicated sinus rhythm (85 beats/min) and incomplete right bundle branch block with no other conduction/repolarization disorders. There were no clinical signs of peripheral embolism or cardiac decompensation. DVT and acute pulmonary embolism were diagnosed on Doppler ultrasound (US) and high-resolution pulmonary computed tomography, respectively. Initial TTE, performed by a highly trained cardiologist, indicated normal left ventricular function with no evidence of myocardial kinetic disorders. A tricuspid valve with thickened leaflets was apparent, as were the moderate-sized, non-calcified, mobile sessile vegetations on the septal leaflet, the largest of which measured 15 mm×7 mm (Figure A, Movie S1). The 3 leaflets of the tricuspid valve were affected by vegetation: 1 was pedunculated, the others partially mobile. Only TTE was performed because it was sufficient for the diagnosis, given that the echogenicity was excellent according to the expert cardiologist. Grade 3/4 tricuspid leakage (TL) was observed (Figure B). Pulmonary arterial hypertension was absent and systolic pulmonary artery pressure was 35 mmHg. Immunological evaluation was positive for lupus anticoagulant (Rosner index >15%) and for non-specific antinuclear antibodies (1/1,280). Testing for antibodies against IgG anti-cardiolipin (aCL) was positive (48 UGPL), reconfirmed at 3 months. Testing for IgM aCL, IgM and IgG β2-glycoprotein1 antibodies, however, was negative. Blood cultures to detect microorganisms including Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella (HACEK) were sterile; reactive C-protein was normal; and viral serology was negative. These findings, combined with a multidisciplinary consensus, resulted in a diagnosis of LSE and approval of management. This patient was ultimately diagnosed with LSE in association with APS based on recurrent venous thromboembolism and high titer-positive IgG aCL antibodies. In the absence of SLE criteria, primary APS as specified by Sydney criteria1 was suspected. Surgical procedures for the present LES patient could not be selected because of their poor performance.4 Initial treatment with low-molecular-weight heparin was rapidly replaced by international normalized ratio 2–3 warfarin therapy and HCQ (400 mg/day). At 6-month follow-up, there was significant improvement. On TTE, LSE vegetation size had substantially decreased (Figure C, Movie S2). Color US showed improvement in TL grade (2/4; Figure D). At 3-year follow-up, treatment consisted of combination therapy, improving quality of life. On TTE, LSE vegetations had disappeared. In terms of IG, excepting antithrombotic therapy, there is no specific therapy for LSE. The present patient was consulted regarding the benefits/risks of continuing combined AVK-HCQ after the disappearance of LSE. This decision was also dependent on IG in anti-thrombotic therapy management regarding recurrent venous thrombosis.5 Classically patients on HCQ are at a lower risk of thrombosis (OR, 0.21; 95% CI: 0.06–0.81).3 In a prospective non-randomized study of APS patients without SLE, the protective role of HCQ in recurrence of thrombotic events was confirmed.3 To our knowledge this is the first case of LSE involving tricuspid valve damage (a rare condition with a prevalence of approximately 8%2), to be treated successfully with combined VKA-HCQ. In LSE patients, thromboembolic risk was correlated with IgG aCL antibodies: the risk of thromboembolic complications rose to 25% for IgG aCL antibodies >40 UGPL.2 Anticoagulation is apparently ineffective in reducing valvular lesions, which persist over time. In a prospective study, 56 APS patients receiving anti-thrombotic therapy underwent annual TEE monitoring, of whom 54% had initial valvular involvement. At 5-year follow-up, cardiac involvement was unchanged in 30 patients (64%), while 17 (36%) had new lesions, 15 (88%) had high titer IgG aCL and 2 (12%) had low titer IgG aCL.2 Steroids are reportedly ineffective against valvular lesions and may even have deleterious effects.1 Finally, combined HCQ-VKA may be instrumental in distinct regression of LSE vegetation and of tricuspid insufficiency. Given, however, that VKA was used in combination, the absence of thrombotic events may not necessarily have been due to HCQ. In 1 case of tricuspid valve involvement treated with VKA and corticosteroids,6 at 6-month follow-up there was no improvement in the extent of LSE. HCQ is a well-established therapy and is currently recommended for SLE due to its anti-modulatory effects, and reduced release of pro-inflammatory cytokines interleukin (IL)1, IL6, and tumor necrosis factor-α.3 HCQ also has anti-thrombotic properties that inhibit platelet aggregation and arachidonic acid release.3 It also significantly reduces thrombus size and duration,3 and recent APS consensus guidelines endorse its use as an adjuvant to anticoagulation in the case of recurrent thrombosis despite anticoagulation.5 The major side-effect is reversible retinal deposit damage. To conclude, in the light of recent advances in APS and LSE pathogenesis, in line with the present observations, HCQ in addition to anti-thrombotic therapy in LSE may represent a new efficient combination therapy. A French double-blind, prospective, randomized, multicenter study (PAPIRUS) is ongoing in thrombotic primary APS to confirm the present observations. Recently, the European Medicines Agency granted Angers University Hospital (France) “orphan designation” (EU/3/16/1820) for HCQ in APS treatment. This combination could represent new hope for APS patients.
Trans-thoracic echocardiography (TTE) in a patient with Libman-Sacks endocarditis (LSE) with tricuspid valve involvement. (A) 2D-TTE showed thickened tricuspid valve leaflets and a sessile, non-calcified and mobile vegetation 15 mm×7 mm before treatment (arrow). (B) Color Doppler mode showed grade 3/4 tricuspid insufficiency (arrow) before treatment. (C,D) Six-month follow-up under hydroxychloroquine (HCQ) and warfarin. (C) 2D-TTE showed regression of thickened tricuspid valve leaflets \and significant reduction in LSE vegetation (13 mm×5 mm; arrow). (D) Color Doppler mode showed significant regression of tricuspid insufficiency down to grade 2/4 (arrow).
The authors thank the present patient for written consent to publish this article. The authors also wish to thank Dr. Asgar Bhanji, consultant rheumatologist from Homerton University Hospital in London, and Mrs. Hazel Chaouch for assistance with the article and English language correction.
The authors declare no conflicts of interest.
None.
L.O. contributed to literature search, data collection, data analysis, data interpretation, and writing of the report. V.J., T.L.T., G.M. contributed to literature search, data analysis, data interpretation, and revising of the intellectual content. A.C., F.R., T.-H.M. contributed to patient care, data collection, data analysis, data interpretation, and revising of the intellectual content. C.B. contributed to patient care and devised the treatment strategy including the original aspect of using hydroxychloroquine in LSE, and contributed to literature search, data collection, data analysis, data interpretation, and revising of the intellectual content. All authors read and approved the final version of the manuscript.
Supplementary File 1
Movie S1. Trans-thoracic echocardiography (TTE) in a patient with Libman-Sacks endocarditis with tricuspid valve involvement. 2D-TTE showed thickened tricuspid valve leaflets and a sessile, non-calcified and mobile vegetation, 15 mm×7 mm before treatment.
Supplementary File 2
Movie S2. Six-month follow-up under hydroxychloroquine (HCQ) and warfarin. 2-D trans-thoracic echocardiography showed regression of the thickened tricuspid valve leaflets and significant reduction in Libman-Sacks endocarditis vegetations (13 mm×5 mm).
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-17-1131
