Lisa R. Sammaritano

Activation of cultured vascular endothelial cells by antiphospholipid antibodies.

Circulating antiphospholipid antibodies (aPL) are associated with a syndrome of thrombosis, recurrent fetal loss, and thrombocytopenia. We have demonstrated the activation of cultured human umbilical vein endothelial cells (HUVEC) by IgG from patients with anticardiolipin antibodies (aCL). Incubation of HUVEC for 4 h with purified IgG (100 micrograms/ml) from patients with high-titer aCL induced a 2.3-fold increase in monocyte adhesion over that seen in HUVEC incubated with IgGs from normal subjects. The effect of aCL was not attributable to LPS contamination, Fc receptors, or immune complexes. Monocyte adhesion was not induced when the aCL were added in serum-free media but was restored by the addition of purified beta 2GP1, previously described as a necessary cofactor for aCL reactivity. Purified rabbit polyclonal IgG raised against beta 2GP1 also induced monocyte adhesion when incubated with HUVEC. Preadsorption of patient serum with cardiolipin reduced monocyte adhesion by 60%. Immunofluorescent microscopy demonstrated that endothelial cells incubated with patient IgG expressed cell adhesion molecules, including E-selectin, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1. These data support the hypothesis that aPL activate vascular endothelial cells, thereby leading to a pro-thrombotic state.

Preclinical Carotid Atherosclerosis in Patients with Rheumatoid Arthritis

Context Patients with rheumatoid arthritis are prone to premature death from coronary heart disease despite few risk factors. Researchers have wondered if chronic inflammation is a trigger. Content The authors measured inflammatory markers and risk factors for coronary heart disease in 98 matched case-patients and controls (mean age, 48 years). Carotid ultrasonography revealed that 44% of case-patients and 15% of controls had atherosclerotic plaque. Independent predictors of plaque were age, smoking, and rheumatoid arthritis. In patients with rheumatoid arthritis, inflammatory mediators did not predict plaque. Limitations This cross-sectional study cannot prove that rheumatoid arthritis accelerates atherosclerosis. Interpretation Carotid atherosclerotic plaque is much more common in patients with rheumatoid arthritis than in controls. The mechanism remains unknown. The Editors Compared with the general population, patients with rheumatoid arthritis die prematurely (1, 2), primarily because of cardiovascular disease (1-3). Women with this disease have high rates of nonfatal myocardial infarction (4-6), even in the absence of traditional risk factors for atherosclerosis (4, 5, 7). Although markers of disease severity have been linked to an increase in overall mortality rates (1), researchers have not been able to clearly identify specific aspects of rheumatoid arthritis or its treatment that might heighten the risk for cardiovascular disease. Use of corticosteroids or disease-modifying antirheumatic drugs does not appear to increase the risk for cardiovascular events (2). In fact, a large longitudinal study recently reported that death rates from myocardial infarction among North American patients with rheumatoid arthritis had declined to the level seen in the general population (thereby yielding a greater magnitude of decline) in the setting of increased methotrexate use (8). In another U.S. study, methotrexate use was associated with lower all-cause mortality rates in rheumatoid arthritis, mostly because cardiovascular mortality rates were decreased (9). Early diagnosis of atherosclerosis in this population might trigger more aggressive prophylaxis, but we have not determined the prevalence of preclinical atherosclerosis or identified markers for the disease. In this study, we examined the prevalence of atherosclerosis in patients with rheumatoid arthritis by using ultrasonogram-defined carotid artery plaque as a direct measure and proxy for generalized atherosclerosis and as a surrogate for coronary atherosclerosis; we also examined those features of rheumatoid arthritis that predict plaque presence. Previous studies reported that plaque prevalence in rheumatoid arthritis is statistically similar to that of control populations (10, 11). However, in systemic lupus erythematosus, another autoimmune disease characterized by chronic inflammation, cross-sectional studies that were conducted by us and by others showed a marked increase in plaque compared with that seen in carefully matched controls (12, 13). The increased plaque rate in systemic lupus erythematosus is associated with chronic inflammation (not with treatment or with traditional atherosclerosis risk factors), suggesting that similar factors may be at work in rheumatoid arthritis. Preclinical disease may also be identified by using ultrasonography to determine carotid intimamedia thickness, an indirect measure of atherosclerosis. Intimamedia thickness was increased in 2 studies of East Asian patients with rheumatoid arthritis (14, 15) but not in a U.S. study (11). Intimamedia thickness varied more with disease duration (14, 15), but an association with serum C-reactive protein levels and erythrocyte sedimentation rate (2 markers of inflammation) has not been established because of conflicting reports (11, 15). Intimamedia thickness does not always correlate with atherosclerosis, particularly in relatively young individuals with chronic inflammatory disease (12, 13), and it may measure other aspects of vascular disease. Discrete atherosclerotic plaque is a potent independent predictor of incident cardiovascular disease, whereas intimamedia thickness in areas free of discrete plaque has limited value as a marker after traditional risk factors for cardiovascular disease are considered (16-18). Because of conflicting data regarding premature preclinical atherosclerosis in rheumatoid arthritis, we chose to use the direct measure of plaque to examine the prevalence of carotid atherosclerosis in consecutive unselected, nonhospitalized patients with rheumatoid arthritis and matched controls. For our other primary outcome, we sought to determine those clinical and biological measures that best predict the presence of plaque. Methods Study Sample We consecutively recruited patients who met the American College of Rheumatologys classification criteria for a diagnosis (possessing at least 4 of 7 criteria) of rheumatoid arthritis (19) and who were enrolled in the Rheumatoid Arthritis Registry at the Hospital for Special Surgery in New York. Patients were recruited at regular visits with their rheumatologists during a 15-month period (participation rate, 94%). Exclusion criteria were age younger than 18 years, serum creatinine level of 270 mol/L or greater (3.0 mg/dL) or creatinine clearance of 0.50 mL/s or less (30 mL/min), or current or recent (within the past 3 months) pregnancy. We quantified extent of disease by recording extra-articular manifestations (for example, the Sjgren syndrome, leg ulcers, and evidence of vasculitis, such as nail fold infarcts, splinter hemorrhages, and motor neuropathy), active joint count (number of tender or swollen joints), number of joints irreversibly damaged (fixed deformity or surgical replacement) (20), and the patients score on the Multidimensional Health Assessment Questionnaire (21). We recorded treatment by patient interview and chart review. Because treatment is often intermittent or at varying dosages, we tabulated medication use as never, former, or current. An 83-year-old woman had a previous stroke that was documented by magnetic resonance imaging, and a 45-year-old man had had coronary artery bypass surgery; we calculated our results both including and excluding these 2 patients. Patients were matched to controls on the basis of age (within 5 years), sex, and ethnicity. Controls were normotensive and hypertensive individuals who participated in longitudinal studies funded by the National Institutes of Health (22, 23) at the Hypertension Center of The New York Hospital and who underwent similar imaging protocols. We assessed patients for traditional cardiovascular disease risk factors: family history of myocardial infarction in first-degree male relatives younger than 55 years of age or first-degree female relatives younger than 65 years of age, smoking, hypertension (defined as blood pressure of 140/90 mm Hg or higher or the prescribed use of antihypertensive medications), diabetes mellitus (self-reported diagnosis), and fasting serum cholesterol levels. Hypertensive controls were studied after antihypertensive medications had been withheld for 3 or more weeks, whereas antihypertensive medications were not systematically withheld in hypertensive patients with rheumatoid arthritis. Brachial blood pressure was obtained at the end of the ultrasonographic studies after patients had remained in the supine position for 45 to 60 minutes in a quiet, darkened room. Of 100 patients with rheumatoid arthritis, a 74-year-old man was unable to be matched to a suitable control and a woman was excluded because she met diagnostic criteria for systemic lupus erythematosus. The institutional review board approved the study protocol, and all participants gave written informed consent. Carotid Ultrasonography All study participants underwent carotid ultrasonography, which was performed by experienced research sonographers who used an identical protocol. A single cardiologist, who was blinded to the identity of the study participants, interpreted the results. In brief, as previously described (22, 23), participants were studied in the supine position with slight hyperextension of the neck. Both extracranial carotid arterial systems were extensively scanned in multiple planes to optimize identification of atherosclerosis, which was defined as discrete plaque protruding into the lumen at least 50% beyond the diameter of the surrounding wall. Doppler interrogation was performed to evaluate the presence of significant (50% diameter reduction) obstruction. Intimamedia thickness was measured from end-diastolic (minimum dimension) M-mode images of the far wall of the distal common carotid artery. Intimamedia thickness was not measured in a location containing plaque. Mean values of right and left intimamedia thicknesses are presented. Reproducibility of intimamedia thickness and detection of plaque has been well documented (24-26). Carotid ultrasonographic studies were performed in the control group before 1999, whereas studies in the patients with rheumatoid arthritis were performed between 2000 and 2002. Laboratory Assessment Laboratory assessment of the patients with rheumatoid arthritis included routine chemistries and serum rheumatoid factor level. A high-sensitivity assay to determine serum levels of C-reactive protein was analyzed with a Cobas Integra system (Roche Diagnostics, Basel, Switzerland). Serum lipoprotein(a) levels were measured with an immunoturbidometric reagent (Diasorin, Stillwater, Minnesota) on a Roche Diagnostics Cobas Fara II system. Serum interleukin-6 levels were measured by automated enzyme immunoassay (Biosource International, Camarilo, California) on a Roche Diagnostics Cobas Core II analyzer. Serum levels of soluble intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 were measured by enzyme-linked immunosorbent assay (Caltag, Burlingame, California, and R&D Systems, Minneapolis, Minnesota,

Arterial Stiffness in Chronic Inflammatory Diseases

Chronic inflammatory diseases are associated with premature atherosclerosis; however, it is unknown whether arterial stiffness is increased in this setting, possibly as a manifestation of vascular disease preceding and/or independent of atherosclerosis. Carotid ultrasonography and radial applanation tonometry were performed in 101 patients with systemic lupus erythematosus, 80 patients with rheumatoid arthritis, and 105 healthy control subjects. The 3 groups were comparable in age, gender, and carotid artery absolute and relative wall thickness. Atherosclerotic plaque was more common in lupus (46%) and rheumatoid arthritis (38%) patients than in controls (23%) (P<0.003). Although control subjects had higher central and peripheral blood pressures, arterial stiffness was increased in patient groups compared with controls (lupus, rheumatoid arthritis, controls, respectively: &bgr;: 3.36 versus 3.22 versus 2.60, P<0.001; Young’s modulus: 441 versus 452 versus 366 mm Hg/cm, P=0.004; Peterson’s elastic modulus: 278 versus 273 versus 216 mm Hg, P<0.001) after adjustment for differences in mean brachial pressure. In multivariate analysis involving the entire population, arterial stiffness was independently related to age, serum glucose, and the presence of chronic inflammatory disease. In multivariate analysis restricted to the patients, arterial stiffness was independently related to age at diagnosis, disease duration, serum cholesterol, and C-reactive protein (and IL-6, when substituted for C-reactive protein). When analyses were repeated in the 186 study subjects without carotid plaque, arterial stiffness remained significantly elevated in patient groups after adjustment for differences in age and mean brachial pressure. In conclusion, arterial stiffness is increased in chronic inflammatory disorders independent of the presence of atherosclerosis and is related to disease duration, cholesterol, and the inflammatory mediator C-reactive protein and the cytokine that stimulates its production, IL-6.

Validation of the Sapporo criteria for antiphospholipid syndrome.

OBJECTIVE To test the Sapporo criteria for the classification of the antiphospholipid syndrome (APS). METHODS We classified 243 consecutive patients who had clinical diagnoses of primary APS (n = 49), secondary APS (n = 26), systemic lupus erythematosus (SLE) without clinical APS (n = 131), and lupus-like disease without clinical APS (n = 37). RESULTS Sensitivity, specificity, positive predictive value, and negative predictive value were 0.71, 0.98, 0.95, and 0.88, respectively. False-negative findings were the result of patients being classified on the basis of minor criteria that were not included in the Sapporo criteria, such as livedo reticularis, thrombocytopenia, low-titer IgG or IgM anticardiolipin antibody, IgA anticardiolipin antibody, and anti-beta2-glycoprotein I antibody. Some patients with false-negative results were true seronegative cases. CONCLUSION The Sapporo criteria for APS compare favorably with the American College of Rheumatology criteria for SLE and are usable for clinical studies.

Antiphospholipid antibody syndrome: Immunologic and clinical aspects☆

Antiphospholipid antibody is associated with a clinical syndrome of vascular thrombosis, thrombocytopenia, recurrent fetal loss, and livedo reticularis, whether or not a clinical diagnosis of systemic lupus erythematosus (SLE) coexists. A positive antiphospholipid antibody test is defined by enzyme-linked immunosorbent assay (ELISA) (antiphospholipid antibody itself) or by coagulation assay (lupus anticoagulant). These are similar but not identical antibodies. The test for syphilis is less closely related to the preceding two and is less regularly associated with clinical complications. The mechanism of action of either antiphospholipid antibody or lupus anticoagulant is as yet unknown. SLE-induced but not infection-induced antiphospholipid antibody has immunoglobulin G2 (IgG2) and IgG4 predominance. It recognizes all negatively charged phospholipids, but various physical characteristics of the phospholipids alter the recognition patterns. Treatment for the antiphospholipid antibody syndrome has not been clearly defined. Anticoagulation with aspirin, heparin, or warfarin is currently favored. A role for corticosteroid remains to be demonstrated.

Placental pathology in systemic lupus erythematosus: A prospective study ☆ ☆☆ ★ ★★

OBJECTIVES Systemic lupus erythematosus and antiphospholipid antibody, often identified in patients with systemic lupus erythematosus, are associated with poor pregnancy outcome. This study distinguishes between the effect of each of these factors on gestational outcome and placental pathologic conditions in pregnant patients with systemic lupus erythematosus. STUDY DESIGN Thirty-seven pregnancies and 40 placentas from 33 women with systemic lupus erythematosus were studied prospectively. RESULTS Systemic lupus erythematosus alone, but not systemic lupus erythematosus activity, was associated with increased spontaneous abortions, preterm gestations, and fetal growth restriction. Placental correlates were ischemic-hypoxic change, decidual vasculopathy, decidual and fetal thrombi, chronic villitis, and decreased placental weight. Extensive infarction and fetal death were important antiphospholipid antibody-related findings. CONCLUSIONS Decidual vasculopathy/coagulopathy appears to mediate the antiphospholipid antibody-related and much of the systemic lupus erythematosus-related deleterious effect on the placenta and gestational outcome. The presence of antiphospholipid antibody largely, but not invariably, predicts fetal death. Antiphospholipid antibody-independent chronic villitis may represent a second mechanism of systemic lupus erythematosus-related change.

Ovulation induction and in vitro fertilization in systemic lupus erythematosus and antiphospholipid syndrome

OBJECTIVE During ovulation induction (OI), ovarian stimulation is accomplished by hormonal manipulation, which includes administration of gonadotropins, gonadotropin-releasing hormone agonists, follicle-stimulating hormone, and luteinizing hormone. In in vitro fertilization (IVF), progesterone is often added. Because of the possibility of hormone-associated flare or thrombosis, patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (primary APS) undergoing OI/IVF are potentially at increased risk. The present study was conducted in order to assess this risk. METHODS Nineteen women who underwent 68 cycles of OI/IVF were studied by interview and retrospective chart review. RESULTS Four OI/IVF cycles (25%) in SLE patients resulted in increased lupus activity and 2 (13%) in ovarian hyperstimulation syndrome. One patient with primary APS who was given heparin during multiple cycles developed osteopenia. No thrombosis occurred. Pregnancy complications included toxemia, lupus flare, gastrointestinal hemorrhage due to Mallory-Weiss tear, polygestation, and diabetes. Postpartum complications included nephritis flare, costochondritis, and suicidal depression. Lupus flares occurred at expected rates. Five of 16 cycles (31%) in 7 SLE patients, 5 of 48 cycles (10%) in 10 primary APS patients, and 0 of 5 cycles in 2 women with antiphospholipid antibody (without SLE or primary APS) resulted in liveborn children, including multiple gestations (3 twin sets with 4 surviving infants and 2 triplet sets with 3 surviving infants). Seven of 14 living children (50%) were premature, 3 had neonatal lupus, and 1 had pulmonic stenosis. Five surviving infants (38%) had complications unrelated to prematurity. CONCLUSION Although OI/IVF can be successful in SLE and primary APS patients, rates of fetal and maternal complications are high.

Prevalence and relation to risk factors of carotid atherosclerosis and left ventricular hypertrophy in systemic lupus erythematosus and antiphospholipid antibody syndrome

The prevalence of preclinical cardiovascular disease was determined in women with systemic lupus erythematosus (SLE) and control subjects matched for traditional risk factors. Compared with control subjects, patients with SLE had a higher prevalence of carotid atherosclerosis (41% vs 9%, p < 0.005) and left ventricular hypertrophy (32% vs 5%, p < 0.005), supporting the possibility that chronic inflammation predisposes to premature cardiovascular disease in SLE.

Predictors of pregnancy outcomes in patients with lupus: A cohort study

Background Since systemic lupus erythematosus (SLE) affects women of reproductive age, pregnancy is a major concern.

International consensus for a definition of disease flare in lupus

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: “A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment.” The LFA proposes this definition for lupus flare on the basis of its high face validity.