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Biomedical subjects

Michael D Lockshin

Publications and source records attributed to Michael D Lockshin.

At least 19 recordsLinked to original sources
PubMed2006

Preclinical carotid atherosclerosis in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis is associated with increased morbidity and mortality because of cardiovascular disease, independent of traditional risk factors. OBJECTIVE: To determine the prevalence of preclinical atherosclerosis in patients with rheumatoid arthritis and to identify clinical and biological markers for atherosclerotic disease in this patient population. DESIGN: Matched, cross-sectional study. SETTING: Hospital for Special Surgery in New York City. PATIENTS: 98 consecutive outpatients with rheumatoid arthritis who were followed by rheumatologists and 98 controls matched on age, sex, and ethnicity. MEASUREMENTS: Cardiovascular risk factor ascertainment and carotid ultrasonography in all participants; disease severity, disease treatment, and inflammatory markers in patients with rheumatoid arthritis. RESULTS: Despite a more favorable risk factor profile, patients with rheumatoid arthritis had a 3-fold increase in carotid atherosclerotic plaque (44% vs. 15%; P < 0.001). The relationship between rheumatoid arthritis and carotid atherosclerotic plaque remained after accounting for age, serum cholesterol levels, smoking history, and hypertensive status; adjusted predicted prevalence was 7.4% (95% CI, 3.4% to 15.2%) for the control group and 38.5% (CI, 25.4% to 53.5%) for patients with rheumatoid arthritis. Age (P < 0.001) and current cigarette use (P < 0.014) were also significantly associated with carotid atherosclerotic plaque. Among patients with rheumatoid arthritis, atherosclerosis was related to age, hypertension status, and use of tumor necrosis factor-alpha inhibitors (a possible marker of disease severity). LIMITATIONS: The study had a cross-sectional design, and inflammatory markers were determined only once. CONCLUSIONS: Patients with rheumatoid arthritis have a high prevalence of preclinical atherosclerosis independent of traditional risk factors, suggesting that chronic inflammation and, possibly, disease severity are atherogenic in this population.

Adult↗
PubMed2006

Relationship between serum NR2a antibodies and cognitive dysfunction in systemic lupus erythematosus.

OBJECTIVE: To assess the association between serum NR2a antibodies and cognitive dysfunction in systemic lupus erythematosus (SLE). METHODS: The study population consisted of English-speaking adults who met American College of Rheumatology (ACR) criteria for SLE and had at least 1 serum sample stored in the Hospital for Special Surgery Autoimmune Registry and Repository. Demographic and clinical information was obtained, and patients completed the neuropsychological test battery recommended by the ACR, the Center for Epidemiologic Studies Depression Scale, and the Spielberger State-Trait Anxiety Inventory. Cognitive impairment was defined as scores >1.5 SD below the mean of age-matched published normative data on at least 2 neuropsychological tests. Sera were tested for NR2a antibodies by enzyme-linked immunosorbent assay. Performance on neuropsychological tests was compared between NR2a-positive and NR2a-negative patients. RESULTS: Of the 93 patients, 24 (25.8%) were positive for NR2a antibodies. Of the 48 patients who were cognitively impaired based on test results, 31% were positive for NR2a antibodies, compared with 20% of those who were not cognitively impaired (P = 0.24). Among antibody-positive patients, the mean +/- SD number of neuropsychological tests with abnormal results was 2.3 +/- 2.2, compared with 2.0 +/- 1.8 in the antibody-negative group (P = 0.59). Similar nonsignificant differences were found when impairment was defined using a more stringent definition (i.e., test scores >2.0 SD below the mean) and using a neuropsychologist's clinical ratings. No association was detected between NR2a antibody positivity and depressive symptoms (P = 0.73) or anxiety (P = 0.42). CONCLUSION: No significant association was found between NR2a antibody positivity and cognitive dysfunction, depressive symptoms, or anxiety. These results indicate that the presence of these antibodies alone does not have a direct effect on cognitive functioning or any other neuropsychiatric manifestation of SLE.

Adult↗
PubMed2006

Relationship of antiphospholipid antibodies to cardiovascular manifestations of systemic lupus erythematosus.

OBJECTIVE: Although antiphospholipid antibodies (aPL) are associated with arterial and venous thrombosis in systemic lupus erythematosus (SLE), the extent to which they influence other cardiovascular manifestations is either controversial or uncertain. We undertook this study to examine the relationships of aPL with valvular, myocardial, and arterial disease in SLE. METHODS: Two hundred patients in an SLE registry, recruited at the time of outpatient visits, underwent comprehensive interviews, physical examinations, laboratory assessments, echocardiography to assess left ventricular (LV) and valvular status, carotid ultrasonography to detect atherosclerosis (discrete plaque), and radial applanation tonometry to measure arterial stiffness. RESULTS: Antiphospholipid antibodies were present(defined as IgG or IgM anticardiolipin > or =40 IU/ml or the presence of lupus anticoagulant) in 42 patients (21%). Mitral valve nodules and moderate-to-severe mitral regurgitation were more common in aPL-positive patients (both 14.3% versus 4.4%; P = 0.02). Thirty-one percent of patients with high titers of IgG aPL (>80 IU/ml) had mitral valve nodules, compared with 20% of patients with mildly to moderately elevated levels of IgG aPL (16-80 IU/ml) and 4% of patients without IgG aPL (overall P < 0.001). Levels of soluble tumor necrosis factor receptors were higher in the presence of both aPL and mitral valve nodules. LV dimensions, systolic function, and carotid artery stiffness as well as prevalences of Raynaud's phenomenon, pulmonary hypertension, and atherosclerosis were similar in aPL-positive and aPL-negative patients. CONCLUSION: Antiphospholipid antibodies in SLE are associated with mitral valve nodules and significant mitral regurgitation, possibly due to valvular endothelial cell activation. However, in this population, they are not associated with evidence of myocardial hypertrophy, systolic dysfunction, coronary or carotid atherosclerosis, or other vascular abnormalities.

Adult↗
PubMed2006

Sex differences in autoimmune disease.

Many, but not all, autoimmune diseases primarily affect women. In humans, severity of illness does not differ between men and women. Men and women respond similarly to infection and vaccination, which suggests that the intrinsic differences in immune response between the sexes do not account for differences in disease frequency. In autoimmune-like illnesses caused by recognized environmental agents, sex discrepancy is usually explained by differences in exposure. Endogenous hormones are not a likely explanation for sex discrepancy; hormones could have an effect if the effect is a threshold rather than quantitative. X and Y chromosomal differences have not been studied in depth. Other possibilities to explain sex discrepancy include chronobiologic difference and various other biologies, such and pregnancy and menstruation, in which men differ from women.

Animals↗
PubMed2006

New treatments for antiphospholipid syndrome.

Challenges in new drug development for APS include the controversy about the strength of association between aPL and thrombotic events, and unknown mechanism of aPL-induced thrombosis. In the long-term management of patients who have APS, controlled studies with warfarin alternatives (such as antiplatelet agents), the new anticoagulant agents (such as direct and indirect thrombin inhibitors), and newer therapeutic agents are vital. It is highly possible that the current "antithrombotic" approach to patients who are aPL-positive will be replaced by a "more specifically targeted, anti-inflammatory or immunomodulatory" approach in the future.

Antiphospholipid Syndrome↗
PubMed2006

Cardiac manifestations in the antiphospholipid syndrome.

Experimental evidence reveals that aPL are not only markers of APS, but also may play a causative role in the development of vascular thrombosis and pregnancy morbidity. The pathogenic mechanisms of aPL seem to be heterogeneous, including endothelial cell activation, the direct inhibition of the activated protein C pathway, abnormalities in platelet function, and in complement activation. aPLs induce proadhesive, proinflammatory, and procoagulant molecules that provide a persuasive explanation for induction of thrombosis in APS. Cardiac manifestations in APS include valve abnormalities (valve thickening and vegetations), occlusive arterial disease (atherosclerosis and myocardial infarction), intracardiac emboli, ventricular dysfunction, and pulmonary hypertension. aPL may be associated with accelerated atherosclerosis in APS patients. Valve disease is the most important and most common cardiac manifestation of APS. The precise mechanism by which valves become deformed is not yet fully known.

Antibodies, Antiphospholipid↗
PubMed2006

Antiphospholipid syndrome.

PURPOSE OF REVIEW: To review the recently published studies that can guide physicians in the management of persistently antiphospholipid antibody (aPL)-positive patients. RECENT FINDINGS: Two recent prospective randomized controlled trials of two intensities of warfarin concluded that both moderate and high-intensity anticoagulation are similarly protective in antiphospholipid syndrome patients after the first thrombosis. Despite lack of controlled studies, there is experimental evidence that hydroxychloroquine and statins may play a role in the management of aPL-positive patients. In the mouse model of antiphospholipid syndrome that involves the injection of high-titer antiphospholipid syndrome human serum, complement activation is essential in aPL-mediated fetal loss and heparin prevents aPL-induced complement activation. SUMMARY: Primary thrombosis prevention in persistently aPL-positive individuals lacks an evidence-based approach; elimination of reversible thrombosis risk factors and prophylaxis during high-risk periods is crucial. Secondary thrombosis prevention in persistently aPL-positive individuals lacks a risk-stratified approach; although the current recommendation is life-long warfarin, the necessity, duration, and the intensity of warfarin are still debated. Catastrophic antiphospholipid syndrome patients usually receive a combination of anticoagulation, corticosteroids, intravenous immunoglobulin, and plasma exchange; there is a clear need to test new agents. A common strategy to prevent fetal loss in aPL-positive patients with history of pregnancy morbidities is low-dose aspirin and heparin; if patients fail this regimen, the next step is the addition of intravenous immunoglobulin although this is not supported by controlled studies. Currently, there is no evidence that anticoagulation is effective for nonthrombotic manifestations of antiphospholipid antibodies.

Adult↗
PubMed2006

Update on antiphospholipid syndrome.

Revised criteria for the antiphospholipid syndrome were published in 2006. Major changes from the 1999 criteria are an increase in the time between two laboratory studies required for diagnosis from 6 to 12 weeks, the acceptance of antibody to beta2 glycoprotein I as a criterion, the exclusion of older age persons, and the acknowledgment of several associated findings such as livedo, heart valve disease, and antibody to prothrombin. New concepts of pathogenesis now invoke complement activation and participation of the innate immune system upstream to thrombosis. Warfarin remains the treatment of choice for patients who have suffered thrombosis, but antiplatelet agents and heparin are options. Target INR is 2.0-3.0. Treatment is potentially life-long, though options for withdrawal of treatment are under investigation.

Animals↗
PubMed2005

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: beta: 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.

Adult↗
PubMed2004

What is antiphospholipid syndrome?

The description of antiphospholipid syndrome (APS) is vascular thrombosis and/or pregnancy morbidity occurring in persons with antiphospholipid antibodies (aPL). However, because of an unclear etiopathogenesis and the heterogeneous nature of aPL and of aPL-related clinical manifestations, a single, unambiguous definition of APS does not exist. In this paper, we describe a structured approach to APS, discuss the controversies, and offer descriptions of APS that include: an autoimmune systemic disease with a spectrum of (mostly thrombotic) clinical manifestations, an overdiagnosed disease when aPL is present but has no proven direct causative role in the clinical manifestations, and a disease of controversies that requires clarification of etiology and mechanisms and risk-stratified controlled clinical studies.

Antiphospholipid Syndrome↗
PubMed2004

How much warfarin is enough in APS related thrombosis?

Warfarin is the best available, most effective treatment for the secondary prevention of recurrent thrombosis in antiphospholipid syndrome (APS) patients. However, warfarin is cumbersome for both patients and physicians because of risk for bleeding and the need for frequent monitoring. Much detail regarding optimal management of APS patients still lacks an evidence-based approach. Asymptomatic patients should not receive warfarin. An optimal treatment for patients with livedo, cardiac valve disease, leg ulcers or microangiopathic nephropathy is unknown; it is likely that warfarin is ineffective for these manifestations of the APS. In low risk patients who have not previously failed warfarin, moderate intensity anticoagulation (target international normalized ratio [INR] 2.5) is as effective as, and safer than, high intensity anticoagulation (INR 3.5), at least for patients with venous thrombosis. Current recommendations, based on the opinion rather than on documentation, state that warfarin should be prescribed for the APS patient's life; studies that challenge this conclusion for carefully defined low risk patients whose thromboses occurred with trigger events will be welcome, as will be studies examining alternatives to warfarin, including antiplatelet drugs.

Antibodies, Antiphospholipid↗
PubMed2003

Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus.

BACKGROUND: Although systemic lupus erythematosus is associated with premature myocardial infarction, the prevalence of underlying atherosclerosis and its relation to traditional risk factors for cardiovascular disease and lupus-related factors have not been examined in a case-control study. METHODS: In 197 patients with lupus and 197 matched controls, we performed carotid ultrasonography, echocardiography, and an assessment for risk factors for cardiovascular disease. The patients were also evaluated with respect to their clinical and serologic features, inflammatory mediators, and disease treatment. RESULTS: The risk factors for cardiovascular disease were similar among patients and controls. Atherosclerosis (carotid plaque) was more prevalent among patients than the controls (37.1 percent vs. 15.2 percent, P<0.001). In multivariate analysis, only older age, the presence of systemic lupus erythematosus (odds ratio, 4.8; 95 percent confidence interval, 2.6 to 8.7), and a higher serum cholesterol level were independently related to the presence of plaque. As compared with patients without plaque, patients with plaque were older, had a longer duration of disease and more disease-related damage, and were less likely to have multiple autoantibodies or to have been treated with prednisone, cyclophosphamide, or hydroxychloroquine. In multivariate analyses including patients with lupus, independent predictors of plaque were a longer duration of disease, a higher damage-index score, a lower incidence of the use of cyclophosphamide, and the absence of anti-Smith antibodies. CONCLUSIONS: Atherosclerosis occurs prematurely in patients with systemic lupus erythematosus and is independent of traditional risk factors for cardiovascular disease. The clinical profile of patients with lupus and atherosclerosis suggests a role for disease-related factors in atherogenesis and underscores the need for trials of more focused and effective antiinflammatory therapy.

Adrenal Cortex Hormones↗