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Biomedical subjects

M A Khamashta

Publications and source records attributed to M A Khamashta.

At least 109 records · Page 6Linked to original sources
PubMed2000

Lipoprotein(a) oxidation and autoantibodies: a new path in atherothrombosis.

Lipoprotein(a) (Lp(a)) is considered a vascular pathogen of outstanding importance. High plasma levels of this lipoprotein are associated with premature arterial disease; however, the mechanisms involved have not been clarified. The atherosclerotic process is increasingly regarded as a chronic inflammatory reaction in the arterial wall where oxidation-mediated endothelial injury involving modified forms of low-density lipoprotein (LDL) seems to be a key event. Autoimmune pathways are involved in the progression of atherosclerosis and humoral response to oxidatively modified LDL can be considered among these pathways. A number of factors can be encountered in the pathogenesis of the accelerated arterial disease seen in patients with antiphospholipid (Hughes) syndrome (APS) and systemic lupus erythematosus (SLE). Among these, high levels of Lp(a) have been described in both and increasing evidence indicates that patients with antiphospholipid antibodies (aPL) are under oxidative stress. Recent studies suggest that the so-called 'oxidation theory of atherosclerosis' may also be applied to Lp(a). This fact makes this lipoprotein potentially suitable as a target of the immune system and antibodies reacting against oxidatively-modified Lp(a) by malondialdehyde have been recently described in APS and SLE. It is therefore likely that an immune response to the oxidized moiety of Lp(a) might be influential in the pathogenicity of this lipoprotein and, subsequently, of atherosclerosis.

Antiphospholipid Syndrome↗
PubMed2000

Therapy of systemic lupus erythematosus: new agents and new evidence.

Systemic lupus erythematosus (SLE) is a disease of relatively low prevalence with a wide range of clinical manifestations. Due in part to these two facts, there is little new evidence on the treatment of lupus. In fact, randomised controlled studies and prospective series are few and usually involve a small number of patients. Despite this, some therapies have shown to be beneficial within the last five years, while others emerge as possibilities in the near future. Among the former, antimalarials appear to be the treatment of choice for maintaining mild to moderate disease in remission. Methotrexate may be an alternative to other corticosteroid-sparing drugs, especially in patients with active arthritis and skin disease. Cyclosporin can be of use in proteinuric nephritis, although the incidence of hypertension with this drug is high. Thalidomide is useful for refractory skin lesions, but the efficacy of lower, less toxic doses is still to be studied. Immunoglobulins should probably be limited to selected patients with manifestations such as thrombocytopoenia. Experience is more limited with cladribine, fludarabine, tacrolimus, danazol and pentoxifylline. New therapies for severe SLE include mycophenolate mofetil, a potent immunosuppressive drug with a reasonable safety profile and immunoablative therapy with or without stem cell transplantation, in highly resistant cases or those with a poor prognosis. Other recently developed molecules, including anti-CD40L monoclonal antibodies (mAbs), are still under investigation.

Clinical Trials as Topic↗
PubMed2000

Antiendothelial cell antibodies in inflammatory myopathies: distribution among clinical and serologic groups and association with interstitial lung disease.

OBJECTIVE: To determine the prevalence and associations of antiendothelial cell antibodies (AECA) in a well characterized cohort of patients with idiopathic inflammatory myopathies (IIM). METHODS: Clinical characteristics, AECA, and myositis-specific autoantibodies were assessed by standard methods in 56 subjects with IIM. RESULTS: AECA were found in 20/56 patients with IIM, were seen in all the major clinical and serologic IIM groups, and were found in 10/15 patients with interstitial lung disease (ILD) (chi squared 6.5, p<0.01 with Yates' correction, relative risk 2.7, specificity 86% and sensitivity 50%). Antisynthetase antibodies, also associated with ILD as described (chi squared = 26.5, p<0.001 with Yates' correction, relative risk 8.7, specificity 95%, sensitivity 77%), did not correlate with the presence of AECA. CONCLUSION: AECA appear to be present in all forms of IIM and are markers for ILD that are independent of anti-synthetase autoantibodies. AECA may be a useful serologic marker for ILD in IIM.

Adult↗
PubMed2000

Fibrinogen in systemic lupus erythematosus: more than an acute phase reactant?

OBJECTIVE: To investigate whether plasma fibrinogen (FNG) measured longitudinally in a cohort of patients with systemic lupus erythematosus (SLE) increased over observational time faster than in a control group, and whether its increase might depend upon age, disease duration, disease activity, and medications. METHODS: Hospital based retrospective study with repeated measurements of plasma FNG and C-reactive protein (CRP) for patients and controls and erythrocyte sedimentation rate (ESR) and lupus activity index (LAI) for patients only. Study groups included patients with SLE: n = 96 (95% female), and healthy controls: n = 39 (95% female). Of the patients, 42% had SLE only, 23% had SLE with antiphospholipid antibodies (aPL), and 34% had SLE with aPL related thrombosis. RESULTS: Median baseline FNG was higher in patients (357 mg/dl; 95% CI 339-375) than in controls (271 mg/dl; 95% CI 251-291) by 86 mg/dl (95% CI 56-115, p < 0.001); in older subjects than younger (in patients and in controls); in patients with thrombosis than in other patient groups (by an average of 35 mg/dl; 95% CI 9-61 mg/dl): and in patients with longer disease duration (p = 0.05). Mean FNG increased faster in patients (19 mg/dl/year; 95% CI 12-26 mg/dl) than in controls (2.6 mg/dl/year; 95% CI 2.0-3.2 mg/dl). The increase was faster than the age effect and independent of patient group and disease activity. CONCLUSION: Plasma FNG in patients with SLE increases throughout followup regardless of disease activity, mimicking the age related increment observed in population based studies. The rapidity of the increment may reflect the prematurity of vascular disease typical of SLE.

Acute-Phase Proteins↗
PubMed1999

A chimeric antibody with the human gamma1 constant region as a putative standard for assays to detect IgG beta2-glycoprotein I-dependent anticardiolipin and anti-beta2-glycoprotein I antibodies.

OBJECTIVE: Thromboembolic manifestations or thrombocytopenia in association with anticardiolipin antibodies (aCL) or lupus anticoagulant are known as the antiphospholipid syndrome (APS). Efforts have been made to elucidate precise clinical features and adequate therapeutic options for treating patients with APS. However, the lack of a proper international standard for measurement of aCL makes it difficult to compare data derived from different laboratories. We attempted to design a chimeric antibody with human gamma constant regions and variable regions of WBCAL-1, a monoclonal antibody established from an APS-prone mouse which has a specificity similar to that of aCL in sera from humans with APS. METHODS: Variable-region genes of WBCAL-1, which were cloned using reverse transcription-polymerase chain reaction, were inserted into plasmids containing human gamma1 and kappa constant-region genes. The construct was transfected to a mouse myeloma cell line. Stable transfectants that secreted a chimeric antibody, HCAL, into the culture supernatant were obtained. The reactivity of HCAL to cardiolipin and to beta2-glycoprotein I (beta2GPI) was studied using a solid-phase enzyme immunoassay. The binding of HCAL was compared with the binding of standards for IgG aCL and anti-beta2GPI antibody assays done in 18 independent laboratories. RESULTS: In the presence of beta2GPI, HCAL bound to the wells of cardiolipin-coated microtiter plates in a dose-dependent manner and reacted with beta2GPI on oxygenated polystyrene plates. The aCL activity of HCAL can be converted into GPL units (IgG phospholipid units), which is widely used to quantify IgG aCL activity, using the following formula: 1 GPL unit = 32.9 x (concentration of HCAL [in microg/ml])(0.503). The reactivity of HCAL to cardiolipin or beta2GPI was similar to the reactivity of standards for IgG aCL or anti-beta2GPI antibody assays done in collaborative laboratories. CONCLUSION: Because the reactivity of HCAL is similar to that of aCL in sera from humans with APS, HCAL will be useful as a standard for human IgG aCL and anti-beta2GPI antibody assays.

Amino Acid Sequence↗
PubMed1999

Autoantibodies against malondialdehyde-modified lipoprotein(a) in antiphospholipid syndrome.

OBJECTIVE: To demonstrate the existence of antibodies that react against malondialdehyde (MDA)-modified lipoprotein(a) (MDA-Lp[a]), a molecule that exhibits behavioral similarities to MDA-modified low-density lipoprotein (MDA-LDL), and to assess the possible relationship of these antibodies (anti-MDA-Lp[a]) to anti-MDA-LDL antibodies (anti-MDA-LDL) in the antiphospholipid syndrome (APS). METHODS: We studied 104 patients with APS (61 with primary APS and 43 with APS secondary to systemic lupus erythematosus) and 106 healthy controls. Anti-MDA-Lp(a) were measured by enzyme-linked immunosorbent assay (ELISA) using MDA-Lp(a) as antigen. Plasma levels of Lp(a) were determined. Anti-MDA-LDL, anticardiolipin antibodies (aCL), and anti-beta2-glycoprotein I antibodies (anti-beta2GPI) were also measured by ELISA. Inhibition assays were performed to determine the presence of cross-reactivity between anti-MDA-Lp(a) and anti-MDA-LDL. RESULTS: Anti-MDA-Lp(a) were detected in 38 of 104 patients (37%) but in only 6 of 106 controls (6%) (chi2 = 28, P<0.0001). Levels of anti-MDA-Lp(a) were also higher in patients than in controls (P<0.0001). Titers of these antibodies did not correlate with plasma levels of Lp(a). The presence of anti-MDA-Lp(a) was significantly associated with that of anti-MDA-LDL (chi2 = 22.09, P<0.0001). There was a strong correlation between the titers of anti-MDA-Lp(a) and anti-MDA-LDL (r = 0.59, P<0.0001), and inhibition assays showed significant cross-reactivity between the 2 populations of antibodies. Anticardiolipin antibodies and anti-beta2GPI were present in sera from 67 patients (64%) and 48 patients (46%), respectively. No correlation was found between the titer of anti-MDA-Lp(a) and titers of either aCL or anti-beta2GPI. CONCLUSION: We report for the first time the existence of autoantibodies against MDA-Lp(a). The presence of antibodies reacting not only against MDA-LDL but also against MDA-Lp(a) supports the hypothesis of a role for oxidative phenomena in the pathogenesis of APS and atherosclerosis.

Adolescent↗
PubMed1999

Normal expression of tissue factor, thrombomodulin, and annexin V in placentas from women with antiphospholipid syndrome.

OBJECTIVE: Placentas from pregnancies complicated by antiphospholipid syndrome often show thromboses and infarction, which may result from aberrations in placental coagulant pathways. We tested the hypothesis that alterations in tissue factor, thrombomodulin, and annexin V expressions contribute to poor pregnancy outcome associated with antiphospholipid syndrome. STUDY DESIGN: Frozen sections from random biopsy samples of the basal plates of placentas from patients with primary antiphospholipid syndrome (n = 9), patients with secondary antiphospholipid syndrome (n = 3), and gestational age-matched control subjects (n = 10) were immunostained for tissue factor, thrombomodulin, and annexin V. Intensity of immunostaining was assessed by means of quantitative image analysis. Annexin V protein expression was evaluated with Western blotting techniques. RESULTS: Tissue factor was expressed in the perivascular cells of the villous vasculature. Thrombomodulin and annexin V immunostaining was localized to the syncytiotrophoblast. There were no differences in the intensity of immunostaining for tissue factor, thrombomodulin, and annexin V between placentas from women with antiphospholipid syndrome and those from control subjects. Western blot analysis of annexin V expression showed no differences between study patients and control subjects. CONCLUSION: Alterations in placental coagulant pathways involving tissue factor, thrombomodulin, and annexin V do not contribute to poor pregnancy outcome associated with antiphospholipid syndrome.

Adult↗
PubMed1999

Anti-endothelial cell antibodies in systemic vasculitis and systemic lupus erythematosus (SLE): effects of heat inactivation on binding and specificity.

Heating sera is used to inactivate complement but may affect the binding characteristics of autoantibodies. We studied the effect of heating sera from patients with systemic vasculitides and SLE on antibody binding to cultured human umbilical vein endothelial cells. Sera from 32 patients with systemic vasculitides, eight with SLE and 10 healthy controls were studied for anti-endothelial cell antibodies (AECA) using an ELISA before and after heating sera to 56 degrees C for 30 min. The median (range) AECA binding index in the patient group increased from 20% (0-153%) to 71.5% (10-259%) (P < 0.0001). The AECA binding index in the control group also increased from 14% (0-52%) to 90% (42-154%) (P < 0.0001). The increased binding was unaffected by the addition of fresh complement or removal of immune complexes and the increased binding after heating persisted even after cooling to 4 degrees C. Specificity experiments showed that after heating, the binding specificity of sera was lost. Removal of immunoglobulin with Protein A abolished the increased binding seen after heating. Heating sera increases AECA binding in both patient and control sera. The mechanism is probably non-specific damage to the immunoglobulin molecule, and heating sera should thus be avoided.

Antibody Specificity↗
PubMed1999

Atheroma: links with antiphospholipid antibodies, Hughes syndrome and lupus.

Antiphospholipid antibodies (aPL) are found in a variety of autoimmune diseases, and are thought to predispose to arterial and venous thrombosis. These antibodies, when investigated in different assays in vitro, activate endothelial cells and promote uptake of modified LDL to macrophages. These observations suggest that aPL can contribute to atheroma development by targeting some of the sequential steps that constitute early atherogenesis. If substantiated by large-scale clinical trials, the pro-atherogenic properties of aPL may merit screening and intervention programs in selected populations.

Antibodies, Antiphospholipid↗
PubMed1999

Correlation between beta2-glycoprotein I valine/leucine247 polymorphism and anti-beta2-glycoprotein I antibodies in patients with primary antiphospholipid syndrome.

OBJECTIVES: Beta2-Glycoprotein I (beta2GPI) exon 7 polymorphism leads to a valine leucine amino acid exchange at position 247 in domain 5 of beta2GPI, between the phospholipid binding site and the cryptic site of the epitopes for anti-beta2GPI antibodies. Therefore, position 247 polymorphism may affect the conformational change of beta2GPI and the exposure of the epitopes for anticardiolipin antibodies (aCL) (= anti-beta2GPI antibodies). In this study we analysed the genetic polymorphism of beta2GPI in a British cohort of well-defined antiphospholipid syndrome (APS) patients. METHODS: This study comprised 88 Caucasoid patients with APS [57 with primary APS and 31 with APS secondary to systemic lupus erythematosus (SLE)]. Polymorphism assignment was determined by polymerase chain reaction followed by allele-specific restriction enzyme digestion (PCR-RFLP). The presence of anti-beta2GPI antibodies was detected by ELISA utilizing irradiated ELISA plates. RESULTS AND CONCLUSIONS: Anti-beta2GPI antibodies were present in 28 of 57 primary APS patients (49%) and in 19 of 31 secondary APS patients (61%). The allele containing valine247 was significantly more frequent in primary APS patients with anti-beta2GPI antibodies than in controls (OR = 2.51, 95%, CI 1.03-6.13, P = 0.0396) or in primary APS patients without anti-beta2GPI antibodies (OR = 2.92, 95% CI 1.16-7.39, P = 0.0204). This tendency was not found in the secondary APS group. In conclusion, the beta2GPI polymorphism, valine/leucine247, is correlated with anti-beta2GPI antibody production in patients with primary APS, and valine247 may be important in the formation of beta2GPI antigenicity.

Adolescent↗
PubMed1999

Splenectomy for refractory thrombocytopenia in the antiphospholipid syndrome.

OBJECTIVE: Thrombocytopenia, usually mild, is one of the clinical criteria of the antiphospholipid syndrome (APS). Rarely, this disorder requires treatment and, due to the shared characteristics with idiopathic thrombocytopenic purpura (ITP), similar rules are followed. We report our experience in patients who required splenectomy after being refractory to steroids and immunosuppressive therapy. METHODS: Fifty-five APS patients with a platelet count of < 100 x 10(9)/l at least twice were analysed retrospectively. Therapeutic response or remission was considered when the platelet count was > 100 x 10(9)/l after 1 month and with no relapse on stopping or tapering the steroid dose. No response or refractory disease was defined as an absence of increase in platelet count, a total count that never exceeded 50 x 10(9)/l during treatment or when the dose requirements were such that the patient developed serious side-effects. RESULTS: Fifty patients were classified as having secondary APS associated with systemic lupus erythematosus (SLE) and five were identified as primary APS (PAPS). Splenectomy was performed in 11 cases (20%), two PAPS and nine SLE-APS, with an average time of 28 +/- 9 months after the development of thrombocytopenia. Eight patients were initially characterized as ITP (six SLE-APS, two PAPS) with an average time of 4.4 +/- 1.1 yr until the APS diagnosis. All but two were responsive to splenectomy. CONCLUSION: Splenectomy was required in 11 (20%) of the patients with APS-associated thrombocytopenia. There was a high rate of good and long-term response.

Adult↗
PubMed1999

Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients. European Working Party on Systemic Lupus Erythematosus.

In the present study we assessed the frequency and characteristics of the main causes of morbidity and mortality in SLE during a 5-year period and analyzed the prognostic significance for morbidity and mortality of the main immunologic parameters used in clinical practice. We started in 1990 a multicenter study of 1,000 patients from 7 European countries. All had medical histories documented and underwent medical interview and routine general physical examination when entered in the study, and all were followed prospectively by the same physicians during the ensuing 5 years (1990-1995). Four hundred thirteen patients (41.3%) presented 1 or more episodes of arthritis, 264 (26.4%) had malar rash, 222 (22.2%) active nephropathy, 139 (13.9%) fever, 136 (13.6%) neurologic involvement, 132 (13.2%) Raynaud phenomenon, 129 (12.9%) serositis (pleuritis and/or pericarditis), 95 (9.5%) thrombocytopenia, and 72 (7.2%) thrombosis. Two hundred seventy patients (27%) presented infections, 113 (11.3%) hypertension, 75 (7.5%) osteoporosis, and 59 (5.9%) cytopenia due to immunosuppressive agents. Sixteen patients (1.6%) developed malignancies, with the most frequent primary localizations the uterus and the breast. Several immunologic parameters (anti-dsDNA or antiphospholipid antibodies) were found to have a predictive value for the development of SLE manifestations during the period of the study. Forty-five patients (4.5%) died; the most frequent causes of death were divided similarly among active SLE (28.9%), infections (28.9%), and thromboses (26.7%). A survival probability of 95% at 5 years was found. A lower survival probability (92%) was detected in those patients who presented at the beginning of the study with nephropathy.

Adolescent↗
PubMed1999

Risk of thrombosis in patients with antiphospholipid antibodies and factor V Leiden mutation.

OBJECTIVE: Antiphospholipid antibodies (aPL) are thrombophilic risk markers in patients with systemic lupus erythematosus (SLE) or primary antiphospholipid syndrome (APS). The risk factors for recurrent venous or arterial thrombosis and indications for longterm anticoagulation therapy are debated. We hypothesized that carrying a second thrombophilic defect, factor V Leiden mutation, would increase the risk for thrombosis in patients with aPL. METHODS: Seventy-five patients with primary APS and 83 with SLE and aPL with or without thrombosis followed at 2 university hospitals were studied. Factor V mutation rate was analyzed in patients and in 200 healthy blood donors by polymerase chain reaction analysis. RESULTS: The prevalence of factor V Leiden mutation in patients with SLE and aPL or primary APS was similar to controls. Patients with deep vein thrombosis or arterial thrombosis did not have a significantly increased rate of factor V mutation compared to controls or to patients with aPL without thrombosis. CONCLUSION: Factor V Leiden mutation is not significantly associated with vein thrombosis in patients with aPL. However, due to the sample size we cannot rule out synergy between both factor V Leiden and aPL. A trend toward increased risk for thrombosis was detected in patients with the mutation and this should be analyzed in a larger study.

Adult↗