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Cerebral Embolism Complicating Libman-Sacks Endocarditis — Full Recovery Using Recombinant Tissue Plasminogen Activator

Ischemic stroke occurs in 10-20% of patients with systemic lupus erythematosus (SLE), and emboli from a cardiac source may occur in 70-90% of these patients. We describe a patient with SLE who had a thromboembolic stroke due to Libman-Sacks endocarditis and made a good recovery after early administration of recombinant tissue plasminogen activator (rTPA).

A 28-year-old woman was admitted with sudden complete aphasia and right side weakness that occurred in our lupus clinic waiting room. She had developed SLE 10 years previously, with renal, neuropsychiatric, and skin involvement and was treated with prednisolone, intravenous cyclophosphamide, azathioprine, and hydroxychloroquine. On admission, her SLE was in remission with hydroxychloroquine 200 mg and prednisolone 7.5 mg daily. She had no "traditional" cardiovascular risk factors and was not taking an oral contraceptive.

Clinical examination revealed blood pressure 130/60, pulse 80/min and regular. No cardiac murmur was detected. She had a right upper motor neurone facial weakness, a dense right hemiparesis, right side visual neglect, and right hemi inattention. There was increased tone and exaggerated tendon reflexes on the right and the right plantar was extensor. She was unable to walk. Fundoscopy was normal. Laboratory investigations revealed white blood cells 8200/mm³, hemoglobin 13.6 g/dl, platelets 171,000/mm³, erythrocyte sedimentation rate 2 mm/h, C-reactive protein < 5 mg/l, glucose 4.9 mmol/l, total cholesterol 5.6 mmol/l, triglycerides 2.08 mmol/l, creatinine 86 µmmol/l, creatinine clearance 86 ml/min, total protein excretion 1.69 g/24 h, glomerular filtration rate 111.9 ml/min, antinuclear antibodies weakly positive, anti-DNA negative, extractable nuclear antigens were SSA/Ro positive; RNP, Sm, SSB/La negative; complement C3 1.12 g/l (normal 0.75-1.65) and C4 0.45 g/l (normal 0.11-0.43); lupus anticoagulant negative, IgG, IgM and IgA anticardiolipin antibodies negative. Blood cultures yielded 8 bottles sterile. Chest radiograph was normal.

Transesophageal echocardiogram revealed a mass attached to the tip of the posterior mitral leaflet consistent with a Libman-Sacks vegetation (Figure 1). Carotid artery Doppler showed normal flow with no stenosis. An urgent brain magnetic resonance image (MRI) excluded an intracerebral hemorrhage, and showed a large infarct in the left external capsule. A second MRI 4 days later showed that the left external capsule infarcts were smaller, but there were other small infarcts in the posterior part of the claustrum, posterior parietal region, and much of the temporal lobe on this side.

A diagnosis of left middle cerebral artery territory infarction secondary to thromboembolism from the cardiac vegetations was made.

She made a rapid recovery following administration of rTPA intravenously at 0.9 mg/kg within 3 h of onset of the symptoms we had witnessed. Her speech rapidly returned to normal within 24 h. At discharge, she was walking well with only minor weakness of right hip flexion. Warfarin with a maintenance international normalized ratio of 2.0-3.0 was started. At followup 18 months later she has remained well with no residual neurological deficit. She remains negative for antiphospholipid antibodies (aPL).

In 1924, Libman and Sacks reported a unique nonbacterial valvular and mural verrucous endocarditis¹. The incidence of valvular lesions in patients with SLE is about 40%^2,3, although with transesophageal echocardiography this can be higher (61%)³. Valvular masses and thickening can occur together, can both be associated with valve dysfunction, most commonly regurgitation, and are believed to be characteristic of SLE. The mitral valve is mainly affected, followed by the aortic valve^2,4-7. Although the majority of valvular lesions are clinically silent, complications include stroke, peripheral embolism, heart failure, and infective endocarditis, and may be the sole manifestation of Libman-Sacks endocarditis. Valve replacement is occasionally required.

Several studies have reported a 10 to 20% incidence of ischemic stroke in patients with SLE, with valvular vegetations, valvulitis, or left-heart thrombus identified as the cardioembolic source in 70 to 90% of those patients^3,8. However, each patient should be assessed carefully to consider other etiologies. Patients with SLE can have cerebritis and vasculitis, and 30% of patients with lupus have aPL that are associated with thrombosis. Furthermore, thromboembolism may result from accelerated atheroma.

Several investigators have correlated aPL with a higher prevalence of heart valve disease^2,4,9,10. However, Roldan, et al, using transesophageal echocardiography, found no difference between aPL positive and aPL negative patients with SLE¹¹. Vianna, et al compared antiphospholipid syndrome (APS) secondary to SLE with primary APS, and reported a higher incidence of valvular heart disease in the APS/SLE group of patients⁷. The significance of aPL in the pathogenesis of the valvular lesions in patients with SLE is not clear.

Our patient received rTPA within 3 h and recovered fully. Thrombolytic therapy with rTPA is approved for acute ischemic stroke from thromboembolic arterial occlusion. The recommendations are for patients over age 18 years, clinical diagnosis of stroke with a meaningful neurologic deficit, clearly defined time of onset of < 180 min before treatment, and a baseline computerized tomography scan showing no evidence of intracranial hemorrhage. rTPA is administered intravenously in a dose of 0.9 mg/kg (maximum 90 mg) with 10% of the total dose given as an initial bolus and the remainder infused over 60 min. rTPA has improved longterm quality of life by reducing disability and should be considered where logistically feasible^12,13.

BEATRIZ JOVEN, MD; SUSANA MELLOR-PITA, MD; DAVID D'CRUZ, MD, FRCP; MOHAMMED SHARIEF, PhD, FRCP; MUNTHER KHAMASHTA, PhD, FRCP; GRAHAM R.V. HUGHES, MD, FRCP, Lupus Research Unit, The Rayne Institute, St. Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.

1. Libman E, Sacks B. A hitherto undescribed form of valvular and mural endocarditis. Arch Intern Med 1924;33:701-37.

2. Khamashta M, Cervera R, Asherson RA, et al. Association of antibodies against phospholipids with heart valve disease in systemic lupus erythematosus. Lancet 1990;335:1541-4.

3. Roldan CA, Shively BK, Crawford MH. An echocardiographic study of valvular heart disease associated with systemic lupus erythematosus. N Engl J Med 1996;335:1424-30.

4. Nihoyannopoulos P, Gómez PM, Jayshree J, Loizou S, Walport MJ, Oakley CM. Cardiac abnormalities in systemic lupus erythematosus: association with raised anticardiolipin antibodies. Circulation 1990;82:369-75.

5. Mandell BF. Cardiovascular involvement in systemic lupus erythematosus. Semin Arthritis Rheum 1987;17:126-41.

6. Pope JM, Canny CLB, Bell DA. Cerebral ischemic events associated with endocarditis, retinal vascular disease, and lupus anticoagulant. Am J Med 1991;90:299-309.

7. Vianna JL, Khamashta MA, Ordi-Ros J, et al. Comparison of the primary and secondary antiphospholipid syndrome: a European multicenter study of 114 patients. Am J Med 1994;96:3-9.

8. Futrell N, Millikan C. Frequency, etiology, and prevention of stroke in patients with systemic lupus erythematosus. Stroke 1989; 20:583-98.

9. Ford PM, Ford SE, Lillicrap DP. Association of lupus anticoagulant with severe valvular heart disease in systemic lupus erythematosus. J Rheumatol 1988;15:597-600.

10. Cervera R, Font J, Pare C, et al. Cardiac disease in systemic lupus erythematosus: prospective study of 70 patients. Ann Rheum Dis 1992;51:156-9.

11. Roldan CA, Shively BK, Lau CC, Gurule FT, Smith EA, Crawford MH. Systemic lupus erythematosus valve disease by transesophageal echocardiography and the role of antiphospholipid antibodies. J Am Coll Cardiol 1992;20:1127-34.

12. Hacke W, Brott T, Caplan L, et al. Thrombolysis in acute ischemic stroke: controlled trials and clinical experience. Neurology 1999;53 Suppl 4:S3-S14.

13. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 2001;119:300S-320S.

14. Adams HP, Brott TG, Furlan AJ, et al. Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke. Circulation 1996;94:1167-74.

Antiinflammatory Effect of Simvastatin in Patients with Rheumatoid Arthritis

Statins, which inhibit 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase, are widely used to treat hyperlipidemia. Recent studies have suggested that statins not only lower plasma lipid levels but also reduce coronary events^1,2, improve outcomes after cardiac transplantation³, and prevent osteoporosis or Alzheimer disease^4,5. In particular, the immunosuppressive effect of statins has been highlighted. In vitro studies have revealed possible mechanisms of immunosuppression by statins, including suppression of natural killer cells^6,7, regulation of DNA synthesis in cycling cells⁸, and an inhibition of monocyte chemotaxis⁹. These lines of evidence suggest a new clinical application of statins as an immunomodulator in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis (RA). To address this issue, we serially evaluated immunological, inflammatory, and clinical variables in patients with RA taking simvastatin for coexisting hypercholesterolemia.

From March to July 2001, 8 patients with RA who also had hypercholesterolemia (> 232 mg/dl) requiring lipid-lowering treatment were enrolled in this study after giving written informed consent. They were 6 women and 2 men with a median age of 57 years (range 49-73). The median duration after the diagnosis of RA was 12 years (range 5-28). All patients except one were stage III or IV by Steinbrocker classification and class III or IV by RA classification. All patients took simvastatin 10 mg per day for 12 weeks. Other treatments, such as disease modifying antirheumatic drugs, glucocorticoids, and nonsteroidal antiinflammatory drugs for RA, had not been changed from 3 months before beginning simvastatin administration through the study period. Clinical and immunological variables were evaluated before simvastatin therapy and at the end of the administration of simvastatin (Table 1).

Table 1. Summary of changes in clinical and laboratory variables before versus at the end of simvastatin therapy. Indicated values are the median (range).

Simvastatin significantly reduced the number of tender joints (p = 0.02) (Figure 1f) and patient self-assessment of disease activity on visual analog scale (VAS; p = 0.03) (Figure 1b). However, the numbers of swollen joints (Figure 1e), patient self-assessment of pain on VAS (Figure 1a), physician global assessment of disease activity on VAS (Figure 1d), and Health Assessment Questionnaire (HAQ; Figure 1c) did not change significantly. Of interest was that erythrocyte sedimentation rate (ESR) and rheumatoid factor (RF) were significantly reduced (ESR, p = 0.01; RF, p = 0.02), and that C-reactive protein (CRP) showed a tendency to decrease (p = 0.12) after simvastatin, especially during the first 4 weeks (Figure 2). Simvastatin was discontinued in 2 patients after 4 weeks and in one after 8 weeks because of their refusal. The reduction in the levels of ESR and CRP was attenuated after the discontinuation of simvastatin in these patients (Figure 2a, b, c). In addition, according to the American College of Rheumatology ACR20 response criteria¹⁰, 7 of 8 patients (88%) at 4 weeks, 5 of 6 patients (83%) at 8 weeks, and 4 of 5 patients (80%) at 12 weeks were defined as responders. On the other hand, addition of simvastatin did not significantly alter the immunological responses including the number of T cells, B cells and natural killer (NK) cells, the ratio between Th1 and Th2, and major histocompatibility complex class II (MHC-II) expression on T cells, B cells, and monocytes among patients.

Figure 1. Changes in clinical variables of RA from beginning ("before") to the end of simvastatin therapy. Y-axes show clinical variables of RA, including (a) patient assessment of pain on VAS, (b) patient assessment of disease activity on VAS, (c) HAQ score, (d) physician assessment of disease activity on VAS, (e) swollen joint count, (f) tender joint count. "Before" represents the data before simvastatin administration and "end" data at 12 weeks or at the end of the study for the dropouts. Patient assessment of pain on VAS (a), HAQ score (c), and physician's assessment of disease activity on VAS (d) did not change between beginning and end of simvastatin therapy. However, patient assessment of disease activity on VAS (b) and tender joint count (f) improved significantly, in spite of no changes in swollen joint count (e).

Figure 2. Changes in inflammatory variables of RA between beginning and at the end of simvastatin therapy. Y-axes show inflammatory variables of RA, including (a) ESR, (b) CRP, (c) RF. Solid lines show values during simvastatin therapy and broken lines show values after discontinuation of simvastatin. ESR, CRP, and RF levels showed tendency to decrease at the end of simvastatin therapy. After the discontinuation of simvastatin in 3 patients, the levels of ESR and CRP rose again.

The mechanism of immunosuppressive effect of statins is not fully understood; however, 2 distinct molecular mechanisms have been proposed recently. One is a repression of the induction of MHC-II expression induced by interferon-g on human endothelial cells and macrophages^11,12. Another is a selective inhibition of the molecular association between leukocyte function antigen-1 (LFA-1) and intercellular adhesion molecule-1 by competitive binding to the L-site of LFA-1¹³. We analyzed the expression levels of MHC-II on T cells, B cells, and monocytes in peripheral blood from 8 patients to clarify the molecular mechanism of our results. However, we could not find significant changes of the MHC-II expression levels on these cells by simvastatin. The analysis of numbers of T cells, B cells, and NK cells showed no consistent changes at the end of the treatment.

This is the first clinical study evaluating the effect of statins on RA. The number of patients in our study was relatively small because we enrolled only those requiring lipid-lowering treatment among RA patients. In addition, most enrolled patients had a long history of RA and had severe joint deformities; therefore, it might not be appropriate to enroll these patients in the study evaluating effects of statins on active manifestations in RA. In spite of these conditions, our data suggest that simvastatin could suppress inflammatory variables as well as clinical symptoms in RA. Based on these findings, we will extend this study to evaluate the benefit of simvastatin in larger numbers of patients with active RA.

HIROKO KANDA, MD, PhD; KEN HAMASAKI, MD; KANAE KUBO, MD, PhD; SHOKO TATEISHI, MD; AKI YONEZUMI, MD; YOSHINOBU KANDA, MD, PhD; KAZUHIKO YAMAMOTO, MD, PhD; TOSHIHIDE MIMURA, MD, PhD, Department of Allergy and Rheumatology, Department of Cell Therapy and Transplantation Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

1. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.

2. Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001;344:1959-65.

3. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333:621-7.

4. Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H. HMG-CoA reductase inhibitors and the risk of fractures. JAMA 2000;283:3205-10.

5. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000;57:1439-43.

6. Cutts JL, Scallen TJ, Watson J, Bankhurst AD. Role of mevalonic acid in the regulation of natural killer cell cytotoxicity. J Cell Physiol 1989;139:550-7.

7. Cutts JL, Bankhurst AD. Reversal of lovastatin-mediated inhibition of natural killer cell cytotoxicity by interleukin 2. J Cell Physiol 1990;145:244-52.

8. Doyle JW, Kandutsch AA. Requirement for mevalonate in cycling cells: quantitative and temporal aspects. J Cell Physiol 1998; 137:133-40.

9. Kruezer J, Bader J, Jahn L, Hautmann M, Kubler W, Von Hodenberg E. Chemotaxis of the monocyte cell line U937: dependence on cholesterol and early mevalonate pathway products. Atherosclerosis 1991;90:203-9.

10. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727-35.

11. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as newly recognized type of immunomodulator. Nature Med 2000;6:1399-402.

12. Sadeghi MM, Tiglio A, Sadigh K, et al. Inhibition of interferon-g-mediated microvascular endothelial cell major histocompatibility complex class II gene activation by HMG-CoA reductase inhibitors. Transplantation 2001;71:1262-8.

13. Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al. Statin selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nature Med 2001;7:687-92.

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