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Biomedical subjects

M A Khamashta

Publications and source records attributed to M A Khamashta.

At least 73 records · Page 4Linked to original sources
PubMed2001

HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients.

OBJECTIVES: We investigated the association between HLA class II haplotypes and antiphospholipid syndrome (APS). METHODS: HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with APS. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with APS [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary APS patients with anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and APS development in different and heterogeneous fashion.

Adolescent↗
PubMed2001

Chromium-51 ethylenediamine tetraacetic acid glomerular filtration rate: a better predictor than glomerular filtration rate calculated by the Cockcroft-Gault formula for renal involvement in systemic lupus erythematosus patients.

OBJECTIVE: To investigate whether the ethylenediamine tetraacetic acid (EDTA) glomerular filtration rate (GFR) is a better indicator of the degree of renal involvement than serum creatinine concentration or creatinine clearance calculated by the Cockroft-Gault formula. METHODS: We studied prospectively all systemic lupus erythematosus (SLE) patients with normal or borderline serum creatinine concentration (<110 micromol/l) and urinary sediment abnormalities and/or proteinuria in the last 2 yr. EDTA-GFR, serum creatinine concentration, calculated creatinine clearance (Cockroft-Gault formula) and 24-h urine protein were determined at the same time. Renal biopsies were performed in patients with low values of EDTA-GFR or significant proteinuria. RESULTS: Twenty-three patients were identified, of whom 22 were females. The average age of the patients was 31.6+/-8.2 yr. Biopsies were assigned to WHO classes as follows: class II, 1 patient; class III, 6 patients; class IV, 10 patients; class V, 6 patients. The average serum creatinine concentration, EDTA-GFR and calculated creatinine clearance were 79.8+/-mol/l, 74.5 ml/min and 97 ml/min respectively. EDTA-GFR showed abnormal values (<80 ml/min) in 15 of the 23 patients (65.2%) while calculated creatinine clearance was abnormal (<80 ml/min) in three of the 23 patients (13%) (P<0.001). Using the Pearson correlation test, we did not find any correlation between EDTA-GFR or creatinine clearance values and the sum of activity and chronicity indices. CONCLUSION: GFR performed by EDTA-GFR correctly predicted renal involvement in SLE patients, whereas GFR calculated by the Cockcroft-Gault formula may have underestimated renal function. Significant numbers of patients with WHO class III, IV or V lupus nephritis may be missed if biochemical creatinine clearance or serum creatinine concentration alone is used to assess renal disease.

Adolescent↗
PubMed2001

Characteristics of patients with antiphospholipid syndrome with major bleeding after oral anticoagulant treatment.

OBJECTIVE: To study the demographic and clinical characteristics of patients with antiphospholipid syndrome (APS) with serious haemorrhagic complications of anticoagulant treatment in an attempt to establish risk factors for bleeding. METHODS: Patients with APS who were attending our lupus unit and who presented with severe bleeding while receiving oral anticoagulation were studied retrospectively. Severe bleeding was defined by the need for admission to hospital. Demographic data, clinical features, concomitant diseases and drugs, warfarin doses, duration of anticoagulation, and International Normalised Ratios (INR) at the time of bleeding were collected. RESULTS: Fifteen patients were included in the study (12 with systemic lupus erythematosus (SLE) plus APS and 3 with primary APS). The median age was 41.7 (range 27-66) and the median duration of the disease was 12.9 years (range 3-22). Duration of anticoagulation was between 10 days and 17 years. The INR at the time of bleeding was under 3 in 4 patients, between 3 and 4 in 5 patients and above 4 in 6 patients. There were 4 episodes of subdural haematoma, 4 episodes of renal haematoma (two after renal biopsy), 2 episodes of ovarian haemorrhage, 2 episodes of rectal haemorrhage, 1 episode of menorrhagia, 1 episode of haemarthrosis, and 1 episode of spinal haematoma. Concomitant drugs were aspirin in 9 patients, antibiotics in 2 patients, and azathioprine in 3 patients. In 6 patients hypertension was present as a concomitant disease. There were no deaths due to bleeding. Anticoagulant treatment was restarted in all patients and 3 of them had a new episode of bleeding. CONCLUSION: No relation was established between age, duration of oral anticoagulant treatment, and bleeding. Concomitant drugs, mainly aspirin, and high blood pressure were present at the time of bleeding in a large number of patients.

Adult↗
PubMed2001

Placentation, antiphospholipid syndrome and pregnancy outcome.

The antiphospholipid antibodies (aPLs) are a diverse group of autoantibodies associated with a pattern of disease known as antiphospholipid syndrome (APS). Pregnancy complications secondary to placental insufficiency are key features of this disease. The mechanisms underlying the placental pathology remain unclear. In this article the process of placentation in healthy and pathological pregnancies is reviewed. The evidence for defective placentation in APS pregnancies and involvement of aPLs in this process is summarized. Finally hypotheses based on the interpretation of these studies are discussed.

Antiphospholipid Syndrome↗
PubMed2001

Antiaggregant and anticoagulant therapy in systemic lupus erythematosus and Hughes' syndrome.

Antiaggregant and anticoagulant drugs are essential in the management of the manifestations due to antiphospholipid syndrome (APS) in patients with primary Hughes' syndrome or systemic lupus erythematosus. Coumadin derivatives (warfarin and acenocumarol), heparin and aspirin are used for secondary thromboprophylaxis and treatment of recurrent miscarriage. The available evidence for each indication is reviewed in this paper. There is still debate regarding the optimal intensity of oral anticoagulation, the best drug combination for pregnancy failure in APS and the management of asymptomatic patients with antiphospholipid antibodies.

Anticoagulants↗
PubMed2001

Update on therapy--thalidomide in the treatment of lupus.

Thalidomide has been shown to be an effective treatment for cutaneous forms of lupus erythematous refractory to other therapies. Thalidomide has very serious side effects, including teratogenicity and neuropathy, which limit its clinical use in lupus to such severe refractory cases. Efficacy has been confirmed in several studies, although recurrence after discontinuation of treatment is frequent. More recent experience suggests that lower doses than originally used may be effective, which may result in a reduction in side effects. Much effort has been expended in studying the mechanisms of action of thalidomide, although as yet it is unclear which of the mechanisms identified to date contribute to its efficacy in treating cutaneous forms of lupus erythematosus. Identification of patients suitable for thalidomide therapy requires a rigorous selection process. Potential side effects should be clearly explained, particularly teratogenicity as many patients are young women. Written consent and a negative pregnancy test must be obtained prior to commencement of therapy. Reliable contraceptive measures should be strictly observed by patients taking thalidomide. Close clinical and neurophysiological supervision using nerve conduction studies should be undertaken.

Humans↗
PubMed2001

Polymorphic light eruption and the HLA DRB1*0301 extended haplotype are independent risk factors for cutaneous lupus erythematosus.

Recent evidence suggests that polymorphic light eruption (PLE) is an inherited photosensitivity disorder which may predispose to cutaneous lupus erythematosus (LE). In this study we examine the relative risk (RR) attributable to the presence of PLE, together with the effect of the major histocompatibility complex (MHC) in the development of cutaneous LE. Eighty-five Caucasian patients with annular subacute cutaneous LE (SCLE) and discoid LE (DLE) were recruited, together with 102 first degree relatives and 200 healthy local Caucasian controls. Symptoms suggestive of PLE were elicited in patients and relatives, and human leukocyte antigen (HLA) typing determined by PCR-SSP. Standard association analysis and family transmission disequilibrium testing (TDT) were then used to compare the HLA frequencies between groups. We found a significant (P < 0.05) association of the HL4 A*01, B*08, DRB1*0301 extended haplotype with both SCLE and DLE and also significant association of DLE with the HLA A*03, B*07, DRB1*15 haplotype, with a possible protective effect in SCLE for HLA B*44 and DRB1*04 (P=0.002 and 0.001 respectively). Association was observed between PLE and cutaneous LE (P < 0.001), but not between PLE and any HLA allele. From these figures we estimate, for the general population, that the RR of developing SCLE given the presence of (a) PLE, (b) DRB1*0301 and (c) both PLE and DRB1*0301 is 3.37, 5.45 and 12.03, respectively. For DLE, equivalent RRs are 3.11, 2.15 and 6.94. In conclusion, these data imply the involvement of both PLE and HLA DRB1*0301 in the development of SCLE and DLE. They form a basis for examining the genetic architecture of photosensitivity, some aspects of which may be common to both cutaneous LE and PLE.

Alleles↗
PubMed2001

Atherosclerosis and autoimmunity.

Novel risk factors for the progression of atherosclerosis such as C-reactive protein (CRP) and adhesion molecules have stimulated much recent interest in the role of inflammation in atherosclerotic disease. There is also evidence emerging that autoimmunity may have a role in the pathogenesis of atherosclerosis. In this article we explore the evidence for the role of autoimmunity in human atherosclerosis, both in the general population and in the context of the antiphospholipid syndrome. In particular we will focus on several autoantigens, review the evidence for their role in the process of atherosclerosis and the nature of the immune responses.

Arteriosclerosis↗
PubMed2001

Lupus pregnancy: is heparin a risk factor for osteoporosis?

Regulation of calcium homeostasis during pregnancy is complex. Clinically significant bone mass loss is infrequent; however a subset of women may develop symptomatic osteoporosis related to pregnancy. Lactation is a period of special risk for bone loss. Whatever the effect of heparin on bone loss, vertebral fractures are rare in women treated with heparin during pregnancy. Low molecular weight heparins may have a less deleterious effect on bone than unfractionated heparin. Women with autoimmune diseases, particularly those with lupus and/or the antiphospholipid syndrome may receive heparin throughout pregnancy. Corticosteroids must be reduced as much as possible in these women, and calcium plus vitamin D are recommended. Finally, indications for heparin use must be clearly justified and advice regarding breastfeeding must be offered.

Anticoagulants↗
PubMed2001

Plasma tumor necrosis factor alpha levels and the -238*A promoter polymorphism in patients with antiphospholipid syndrome.

OBJECTIVES: To explore the possible involvement of the proinflammatory and prothrombotic cytokine TNFalpha in APS by determining the plasma levels in patients and to test for association of TNFA promoter polymorphisms and HLA class II genotypes with both plasma TNFalpha and disease. PATIENTS AND METHOD: We studied 83 Caucasoid patients with APS and two groups of healthy controls. TNFalpha levels were determined in plasma from 35 patients' and 21 controls using a highly sensitive sandwich ELISA. The full patient group was genotyped together with 95 ethnically matched healthy controls. -308 and -238 TNFA promoter polymorphisms were assessed by ARMS-PCR. HLA-DQB1, DQA1 and DRB1 genotypes were determined by PCR using sequence specific primers. RESULTS: TNFalpha levels were significantly higher in patients with APS than healthy controls (median 2.95 pg/ml [range 0.51-10.75] vs. 0.95 pg/ml [0.51-1.6], respectively; p = 0.0001). Frequencies of TNFA-308*2 genotype did not differ between patients and controls. In contrast, TNFA-238*A positive genotype was more frequent in APS patients with arterial thrombosis and pregnancy loss than in controls (OR 3.7 [95% CI 1.37-10.1], p = 0.007 and OR 3.95 [95% CI 1.3-11.7], p = 0.01; respectively). DQB1*0303-DRB1*0701 haplotype was associated with TNFA-238*A in the control group (OR 96.0 [95% CI 9.6-959], p <0.0001) as well as in APS patient's group (OR 54.2 [95% CI 9.6-306.5], p <0.0001). CONCLUSIONS: Raised plasma TNFalpha levels were found in patients with APS. As a prothrombotic and proinflammatory cytokine, TNFalpha may be involved in the development of clinical features of APS. The lack of correlation between the TNFA-238 polymorphism and plasma levels associated with disease suggests that the TNF genetic marker may only indirectly relate to protein levels by virtue of allelic association with a functional marker which may reside in the HLA class II region.

Adolescent↗
PubMed2001

Absence of conduction defects in the electrocardiograms [correction of echocardiograms] of mothers with children with congenital complete heart block.

OBJECTIVE: To investigate the association between complete congenital heart block (CCHB) in the fetus and adult disease. METHODS: We prospectively studied 111 consecutive patients with systemic lupus erythematosus (SLE) or a positive extractable nuclear antigen (Ro, La, or RNP) attending a connective tissue disease (CTD) clinic and 19 patients who had had children with CCHB. Electrocardiographs were recorded on all patients and subsequently analyzed blindly. RESULTS: There was a significantly shorter PR interval in the mothers of children with CCHB compared to patients attending the CTD clinic (p < 0.02). There was no significant difference in PR interval between Ro positive and Ro negative patients in the CTD clinic. There were no significant differences in QRS or QTc duration between mothers with CCHB children and Ro positive or Ro negative patients attending the CTD clinic. The shorter PR interval in the mothers with CCHB children may be explained by their significantly younger age compared to patients in the CTD clinic (p < 0.02, 95% CI) and the lower incidence of CTD. CONCLUSION: We were unable to confirm the association between anti-Ro antibodies and cardiac conduction defects in adults. This supports theories that CCHB is due to vulnerability peculiar to the fetal heart during a particular stage of development between 16 and 30 weeks of gestation.

Adolescent↗
PubMed2001

Effects of oestradiol and the oestrogen antagonist Ici 182,780 on the delayed type hypersensitivity (DTH) index and on serum levels of IgM and IgG in ovariectomised Balb/C and MRL/Mp-Lpr/Lpr mice, a model of systemic lupus erythematosus (SLE).

The effects of oestradiol and the oestrogen receptor antagonist ICI 182,780 were investigated on the DTH index, serum IgG and IgM levels and spleen weight in female BALB/c and MRLL/MP-lpr/lpr mice. At six weeks, the mice were ovariectomised, and one week later, over a four-week period, given biweekly s.c. doses of (i) 5 microl of olive oil, or (ii) 5 microl of oil containing 3.2 microg of 17beta-oestradiol (E2), or (iii) 5 microl of oil containing (3.2 microl of E2 + ICI 182,780, at a dose of 30 mg/kg), or (iv) the same dose of ICI 182,780 alone, E2 significantly raised the DTH index in BALB/c mice; this effect was prevented if ICI 182,780 was included in the injection. The DTH index in MRL mice was unaffected by any of the treatments. All steroid treatments raised serum IgG levels in BALB/c mice, but those in sera of MRL were unaffected and were significantly higher than those measured in BALB/c mice. ICI 182,780 depressed IgM in BALB/c mice, while all steroid treatments increased IgM in MRL mice. ICI 182,780 depressed spleen weights in both strains. Oestrogen may influence B cell function through ICI 182,780-sensitive receptors, and ICI 182,780 may have agonist actions on the immune system. (200 words).

Animals↗