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Biomedical subjects

M D Lockshin

Publications and source records attributed to M D Lockshin.

At least 37 records · Page 2Linked to original sources
PubMed1996

Pathogenesis of the antiphospholipid antibody syndrome.

Endothelial and/or platelet activation likely initiates thrombus formation. Whether antiphospholipid antibody (aPL) is an activator, a toxic response, or a protective response is not clear, nor is it certain whether aPL is germ-line encoded or antigen-driven. The pregnancy model is particularly informative. Alternative hypotheses about thrombogenicity which relegate aPL to the role of bystander have not yet been excluded.

Abortion, Spontaneous↗
PubMed1995

Systemic lupus erythematosus: emerging concepts. Part 2: Dermatologic and joint disease, the antiphospholipid antibody syndrome, pregnancy and hormonal therapy, morbidity and mortality, and pathogenesis.

PURPOSE: To review 1) advances in the pathogenesis, diagnosis, and management of dermatologic and joint disease and the antiphospholipid antibody syndrome in patients with systemic lupus erythematosus; 2) controversies related to pregnancy and hormonal therapy and to morbidity and mortality in these patients; and 3) current views on the pathogenesis of systemic lupus erythematosus. DATA SOURCES AND STUDY SELECTION: Review of the English-language medical literature with emphasis on articles published within the last 5 years. More than 400 articles were reviewed. DATA SYNTHESIS: Despite considerable overlap, cutaneous lesions specific to lupus erythematosus may be divided into subsets with distinct clinical, histologic, and immunofluorescent features. A recent short-term, prospective, uncontrolled trial found hydroxychloroquine and retinoids to be of similar efficacy in the treatment of cutaneous lupus erythematosus. Optimal treatment for patients with lupus and the anticardiolipin antibody syndrome remains to be defined; uncontrolled, retrospective, and treatment-withdrawal studies suggest that warfarin may be more protective than aspirin. Whether pregnancy induces lupus flares has not yet been established; existing data suggest both that it does and that it does not. Oral contraceptive use and postmenopausal estrogen replacement therapy appear not to cause clinical deterioration in patients with lupus. Recent studies have documented a substantial improvement in the survival of patients with systemic lupus erythematosus; they found 5-year survival rates of 90% or more and 10-year survival rates of more than 80%. Most data suggest that systemic lupus erythematosus results from the activation of self-reactive T cells and B cells by genetic or environmental factors. CONCLUSIONS: The optimal treatment for dermatologic disease and the antiphospholipid antibody syndrome in patients with systemic lupus erythematosus remains unknown. Although mortality has decreased substantially, the morbidity related to the disease itself and to complications of therapy is still considerable. More studies are needed to further elucidate the effects of pregnancy on this condition and the pathogenetic mechanisms responsible for the development of this disease.

Antiphospholipid Syndrome↗
PubMed1995

Systemic lupus erythematosus: emerging concepts. Part 1: Renal, neuropsychiatric, cardiovascular, pulmonary, and hematologic disease.

PURPOSE: To review advances and controversies in the diagnosis and management of systemic lupus erythematosus with visceral involvement (renal, neuropsychiatric, cardiopulmonary, and hematologic disease). DATA SOURCES AND STUDY SELECTION: Review of the English-language medical literature with emphasis on articles published in the last 5 years. More than 400 articles were reviewed. DATA SYNTHESIS: Recent debates pertaining to lupus nephritis have focused on the value of kidney biopsy data and the role of cytotoxic drug therapies. Many studies have shown that estimates of prognosis are enhanced by consideration of clinical, demographic, and histologic features. For patients with severe lupus nephritis, an extended course of pulse cyclophosphamide therapy is more effective than a 6-month course of pulse methylprednisolone therapy in preserving renal function. Adding a quarterly maintenance regimen to monthly pulse cyclophosphamide therapy reduces the rate of exacerbations. Plasmapheresis appears not to enhance the effectiveness of prednisone and daily oral cyclophosphamide. Small case series have shown pulses of cyclophosphamide to be beneficial in patients with lupus and neuropsychiatric disease refractory to glucocorticoid therapy, acute pulmonary disease (pneumonitis or hemorrhage), and thrombocytopenia. Patients with systemic lupus erythematosus have an increased prevalence of valvular and atherosclerotic heart disease, apparently because of factors related to the disease itself and to drug therapy. CONCLUSIONS: Cytotoxic agents are superior to glucocorticoid therapy for the treatment of proliferative lupus nephritis, but the optimal duration and intensity of cytotoxic therapy remain undefined. Definitive studies of the treatment of autoimmune thrombocytopenia and acute pulmonary disease and of the diagnosis and treatment of neuropsychiatric disease are not available.

Cardiovascular Diseases↗
PubMed1994

Antiphospholipid antibody: future developments.

In September 1991, an NIH workshop on molecular and biological aspects of antiphospholipid antibodies (aPL) identified questions for future studies: are the antibodies defined by the ELISA and by the lupus anticoagulant tests the same? Is aPL directly responsible for disease? What is the antigen? What drives the production of aPL? What is the role of beta 2-glycoprotein I? What accounts for patient heterogeneity? Can a satisfactory animal model be developed? The NIH workshop did not address important clinical questions, including those of pathogenesis and treatment. In 1994 many of these questions have at least partial answers. beta 2-glycoprotein I appears to be an obligatory component of the antigen, abnormal coagulation is the probable central pathogenic event and animal models now exist. There are still critical unknowns that define a future research agenda: the genetics of the aPL syndrome, the relationship of aPL to SLE and mechanisms of pathogenesis (including why clotting is episodic and what is the cellular or anatomical location of the initial injury). Despite a decade of clinical studies, risk prediction for defined patient groups is only now beginning to be studied. There are still almost no randomized, prospective, controlled treatment trials on any aspect of the syndrome nor are there definitive answers regarding which among antiplatelet, anticoagulant or antithrombin therapies is superior, what is the role of immunosuppressive therapy and what experimental therapies might be introduced. The molecular biology of the antigen-antibody interaction will soon be fully understood, then the cellular and the organism biology. Definitive treatment interventions may await this understanding but adequate therapies are available at this time to conduct important and effective prospective clinical trials.

Animals↗
PubMed1994

Characteristics of human immunodeficiency virus and chlorpromazine induced antiphospholipid antibodies: effect of beta 2 glycoprotein I on binding to phospholipid.

OBJECTIVE: To investigate the nature of the target epitope for human immunodeficiency virus (HIV) and chlorpromazine (CPZ) induced antiphospholipid antibodies (aPL) by evaluating the effect of the aPL cofactor (beta 2 glycoprotein I) on phospholipid binding and to compare this with known binding patterns of infection induced and autoimmune aPL. METHODS: aPL positive sera from 17 patients with HIV and 16 patients with schizophrenia treated with CPZ were tested and compared with aPL positive sera from 20 patients with syphilis and 35 with autoimmune disease. Both the sera and either IgG fractions prepared by affinity chromatography or IgM fractions prepared by euglobulin precipitation and gel filtration were tested for binding to cardiolipin (CL) in ELISA in the presence and absence of purified human beta 2 glycoprotein I (beta 2-GPI). Competition studies evaluated biotinylated CPZ IgM aPL binding and the effect on this of added aPL, placental anticoagulant protein I--a phospholipid binding protein that inhibits autoimmune aPL--and CL vesicles. RESULTS: HIV IgG aPL binding to CL was inhibited by beta 2-GPI (51-53%), like syphilis IgG aPL and in contrast to autoimmune IgG aPL. CPZ IgM aPL, like autoimmune IgM aPL, bound more efficiently in the presence of beta 2-GPI, with binding increases of 31-149%. Binding of biotinylated CPZ IgM aPL to CL was competitively inhibited by autoimmune IgG aPL (47%) and CPZ aPL (92%) but not by HIV IgG aPL or normal IgG. Placental anticoagulant protein I and CL vesicles completely prevented binding of CPZ IgM aPL to CL (100 and 96% inhibition, respectively). CONCLUSIONS: Findings indicate that CPZ aPL resembles the autoimmune aPL, whereas aPL found in HIV infection do not appear to be of autoimmune type.

Antibodies, Antiphospholipid↗
PubMed1994

Antiphospholipid antibody syndrome.

The antiphospholipid syndrome is now well recognized and is separable from SLE, but better quantitation of both the clinical elements and the serologic definitions is still needed. It is likely for autoimmune but not for infection-induced aPL that the antigen is not phospholipid itself but a complex formed by phospholipid and beta 2 glycoprotein I. There are few treatment trials yet published. Those that are available suggest that antiplatelet therapy or anticoagulant therapy are more valuable than is immunosuppression.

Animals↗
PubMed1993

Identification of mothers at risk for congenital heart block and other neonatal lupus syndromes in their children. Comparison of enzyme-linked immunosorbent assay and immunoblot for measurement of anti-SS-A/Ro and anti-SS-B/La antibodies.

OBJECTIVE: To identify the fine specificity patterns of maternal anti-SS-A/Ro and anti-SS-B/La antibodies that are associated with the birth of a child with transient or permanent manifestations of neonatal lupus syndromes, and to suggest a predictor algorithm for use in counseling. METHODS: Sera were obtained from 4 groups of mothers: 57 whose children had congenital heart block, 12 whose children had transient dermatologic or hepatic manifestations of neonatal lupus but no detectable cardiac involvement, 152 with systemic lupus erythematosus and related autoimmune diseases, who gave birth to healthy infants, and 30 with autoimmune diseases whose pregnancy resulted in miscarriage, fetal death, or early postpartum death unrelated to neonatal lupus. Antibodies to SS-A/Ro and SS-B/La were assessed by enzyme-linked immunosorbent assay (ELISA) and by sodium dodecyl sulfate (SDS)-immunoblot. RESULTS: Anti-SS-A/Ro antibodies were identified by ELISA in 100%, 91%, 47%, and 43% of the mothers of infants with heart block, with transient neonatal lupus, healthy infants, and fetal death, respectively. High titers of anti-SS-A/Ro antibodies were present more often in mothers of children with cardiac disease or transient neonatal lupus than in either of the other 2 groups. Maternal antibodies to SS-B/La were detected by ELISA in 76% of the heart block group, 73% of the cutaneous neonatal lupus group, 15% of the group with healthy children, and 7% of the fetal death group. On SDS-immunoblot, sera from 91% of the heart block group mothers who had antibodies to SS-A/Ro but not to SS-B/La recognized at least 1 SS-A/Ro antigen, with significantly greater reactivity against the 52-kd component. In contrast, only 62% of the anti-SS-A/Ro positive, anti-SS-B/La negative responders in the healthy group recognized the 52-kd and/or the 60-kd component. Although there was no profile of anti-SS-A/Ro response unique to the mothers of children with heart block or cutaneous manifestations of neonatal lupus, only 1% of the healthy infants were born to mothers with antibodies directed to both the 52-kd SS-A/Ro and 48-kd SS-B/La antigens and not to the 60-kd SS-A/Ro antigen. CONCLUSION: Women with antibodies to both SS-A/Ro and SS-B/La have an increased risk of giving birth to children with neonatal lupus, especially if the anti-SS-A/Ro response identifies the 52-kd component on SDS-immunoblot. Women whose sera contain only anti-SS-A/Ro antibodies in low titer and only recognize determinants that are altered by conditions of SDS-immunoblot have a low risk for giving birth to a child with neonatal lupus. Specific antibody profiles do not distinguish among the manifestations of the neonatal lupus syndromes.

Animals↗
PubMed1993

Effect of counselor training on skills development and psychosocial status of volunteers with systemic lupus erythematosus.

Volunteers with systemic lupus erythematosus were recruited for a telephone service to provide psychosocial support to peers. The volunteers attended an 8-week counselor training program. The aim was to evaluate the impact of the training on counselors' skill development and to record possible changes in the counselors' psychosocial status. A second group of trainees (n = 15) was used as a delayed control for the first group (n = 14). The data were analyzed using multivariate repeated measures analysis of variance. Tests chosen to monitor psychosocial status included: Arthritis Impact Measurement Scales Anxiety and Depression subscales, Arthritis Helplessness Index, Wallston General Self-Efficacy Scale, University of California at Los Angeles Loneliness Scale, Rosenberg Self-Esteem, and Campbell Personal Competence scales. Tests selected to measure skills and knowledge.

Clinical Competence↗
PubMed1993

Neurologic complications of antiphospholipid antibodies.

Antibodies directed against phospholipids are highly associated with venous and arterial thrombotic episodes, which are often recurrent. There seems to be a skewed frequency of cerebral and ocular events when the arterial circulation is affected. Other neurologic syndromes, including dementia, migraine, chorea, transverse myelopathy, Guillain Barré syndrome, transient global amnesia, seizures, motor neuron disease, myasthenia gravis, and depression, have also been described in association with aPL. Although some of them (for example, dementia, chorea, seizures, and transient global amnesia) could well be the result of aPL-related cerebrovascular disease, the relationship of aPL to the underlying pathophysiology of these syndromes is less clear. Clues that should lead one to consider evaluating for these antibodies include recurrent thrombosis (especially in young people), recurrent fetal loss, and thrombocytopenia. Associated laboratory abnormalities may include a biologically false-positive VDRL test, abnormal ANA or anti-DNA titers, and a high ESR. If the APTT is positive on routine screening and does not correct with mixing studies, a LA should be highly suspected. More sensitive and specific tests are usually necessary to detect aPL, however. Many in vitro and, more recently, in vivo systems strongly suggest that aPL may be directly implicated in the pathogenesis of thrombosis, as opposed to being markers of a procoagulant state. The management of patients with aPL-associated thrombosis can be difficult. Prospective studies are needed to determine the optimal treatment strategies for this group of patients.

Antibodies, Antiphospholipid↗
PubMed1993

Which patients with antiphospholipid antibody should be treated and how?

The tests for antiphospholipid antibody are relatively crude but usable. Asymptomatic persons with incidentally discovered antiphospholipid antibody do not need treatment. Those with symptoms are best treated with anticoagulation, but data specifically supporting aspirin, heparin, or warfarin or combinations thereof remain to be generated. High-dose corticosteroid therapy has at best equivocal efficacy and much toxicity and should be used only for lupus activity and not for phenomena of the antiphospholipid antibody syndrome. The roles of low-dose corticosteroid therapy, immunosuppressive agents, and other treatments are unknown.

Adrenal Cortex Hormones↗