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Biomedical subjects

M A Khamashta

Publications and source records attributed to M A Khamashta.

At least 55 records · Page 3Linked to original sources
PubMed2003

Oxidized low-density lipoprotein as a risk factor of thrombosis in antiphospholipid syndrome.

Beta2-Glycoprotein I (beta2-GPI) is a major antigen for anticardiolipin antibodies (aCL, Abs) present in patients with antiphospholipid syndrome (APS). We recently reported that oxidized LDL(oxLDL) is subsequently targeted by beta2-GPI and anti-beta2-GPI auto-Abs and that-carboxyl variants of 7-ketocholesteryl esters, such as 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and 7-ketocholesteryl-12-carboxy (keto) octadodecanoate (oxLig-2), are ligands for beta2-GPI (J Lipid Re 2001; 42: 697; J Lipid Res 2002; 43: 1486). These beta2-GPI ligands provide an electrostatic interaction between oxLDL and beta2-GPI followed by forming stable complexes (such as Schiff base adducts). The omega-carboxyl function in these ligand is responsible for beta2-GPI binding to oxLDL and the oxLDL-beta2-GPI complexes are anti-beta2-GPI auto-Ab-dependently taken up by macrophages (i.e., by phagocytosis). Our recent observations are consistent with the evidence that beta2-GPI co-localizes with lymphocytes and mononuclear cells in human athero-plaques. Thus, autoimmune thrombogenesis (atherogenesis) is linked to interaction of anti-beta2-GPI Abs with the beta2-GPI-oxLDL complexes. We propose an alternative idea, that an immune response against the beta2-GPI-oxLDL complexes may be involved in mechanisms in the development of atherosclerosis, which has been explained by the theory of 'the response to injury'.

Antigen-Antibody Complex↗
PubMed2003

Water intoxication induced by low-dose cyclophosphamide in two patients with systemic lupus erythematosus.

Cyclophosphamide (CY) is an alkylating agent used to treat a variety of autoimmune disorders. Water intoxication is a well-known complication of high-dose intravenous (i.v.) CY, but is rare in patients treated with low dose i.v. CY. We describe two patients with lupus nephritis and water intoxication following low dose i.v. CY. The first patient was treated with oral prednisolone and azathioprine for eight weeks with inadequate response and persistent renal inflammatory activity. Eight hours after the first i.v. CY pulse she had a grand mal seizure. The second patient had WHO class III lupus nephritis, and after a single i.v. CY pulse developed vomiting, diarrhoea and grand mal seizures. They were both fluid-restricted and their serum sodium levels returned to normal. In conclusion, even at low doses i.v. CY may induce hyponatremia related to inappropriate antidiuretic hormone secretion. This potentially life-threatening complication of i.v. CY could be minimized by avoidance of overhydration following pulse i.v. CY.

Antineoplastic Agents, Alkylating↗
PubMed2002

Human Ro60 (SSA2) genomic organization and sequence alterations, examined in cutaneous lupus erythematosus.

BACKGROUND: The Ro 60 kDa protein (Ro60 or SSA2) is the major component of the Ro ribonucleoprotein (Ro RNP) complex, to which an immune response is a specific feature of several autoimmune diseases. The genomic organization and any sequence variation within the DNA encoding Ro60 are unknown. OBJECTIVES: To characterize the Ro60 gene structure and to assess whether any sequence alterations might be associated with serum anti-Ro antibody in subacute cutaneous lupus erythematosus (SCLE), thus potentially providing new insight into disease pathogenesis. METHODS: The cDNA sequence for Ro60 was obtained from the NCBI database and used for a BLAST search for a clone containing the entire genomic sequence. The intron-exon borders were confirmed by designing intronic primer pairs to flank each exon, which were then used to amplify genomic DNA for automated sequencing from 36 caucasian patients with SCLE (anti-Ro positive) and 49 with discoid LE (DLE, anti-Ro negative), in addition to 36 healthy caucasian controls. RESULTS: Heteroduplex analysis of polymerase chain reaction (PCR) products from patients and controls spanning all Ro60 exons (1-8) revealed a common bandshift in the PCR products spanning exon 7. Sequencing of the corresponding PCR products demonstrated an A > G substitution at nucleotide position 1318-7, within the consensus acceptor splice site of exon 7 (GenBank XM001901). The allele frequencies were major allele A (0.71) and minor allele G (0.29) in 72 control chromosomes, with no significant differences found between SCLE patients, DLE patients and controls. CONCLUSIONS: The genomic organization of the DNA encoding the Ro60 protein is described, including a common polymorphism within the consensus acceptor splice site of exon 7. Our delineation of a strategy for the genomic amplification of Ro60 forms a basis for further examination of the pathological functions of the Ro RNP in autoimmune disease.

Antibodies, Antinuclear↗
PubMed2002

Mycophenolate mofetil for systemic lupus erythematosus refractory to other immunosuppressive agents.

BACKGROUND: Mycophenolate mofetil (MMF) is an immunosuppressive drug widely used in solid organ transplantation, and it may play an increasing role in autoimmune disease. MMF has been introduced as a novel immunosuppressive agent in systemic lupus erythematosus (SLE), often in patients intolerant of or resistant to conventional immunosuppressive regimens. METHODS: We studied 21 patients with SLE, most of whom had previously received courses of cyclophosphamide therapy and had also received courses of azathioprine or methotrexate. Indications for treatment included uncontrolled disease activity and worsening renal involvement. RESULTS: MMF treatment resulted in reduced disease activity, as assessed by the SLEDAI (SLE disease activity index) (P=0.0001) and decreased proteinuria (P=0.027) while allowing a significant reduction in oral corticosteroid dose (P=0.0001). Levels of complement factors C3 and C4 and anti-double-stranded DNA antibodies were not significantly affected. CONCLUSION: MMF appears to be a safe and effective alternative immunosuppressant for extra-renal and renal disease in SLE not responding to conventional immunosuppressive treatment.

Adult↗
PubMed2002

Antiphospholipid antibodies do not a syndrome make.

The association of antiphospholipid antibodies (aPLs) with a poor obstetric history and/or thrombotic event is typical of the antiphospholipid syndrome (APS). We report four cases of poor pregnancy outcome where a diagnostic label of APS resulted in delayed recognition of other causes of pregnancy loss. Pregnancy outcomes in these women were not improved with antithrombotic therapy alone. Successful outcomes were achieved only when other causes of recurrent miscarriage were considered and treated.

Abortion, Habitual↗
PubMed2002

Hypertension as the presenting feature of the antiphospholipid syndrome.

The antiphospholipid or Hughes syndrome is the association between antiphospholipid antibodies (aPL), venous and arterial thromboses and pregnancy morbidity. Antiphospholipid syndrome (APS) commonly coexists with autoimmune diseases usually systemic lupus erythematosus (SLE), when it is known as secondary APS. When present in isolation it is known as primary APS (PAPS). Although the kidney may be affected in APS, its involvement is perhaps not as well described as that of other organs. Thrombotic microangiopathy (TMA) affecting the kidney has been reported as a manifestation in both primary and secondary APS. This report describes hypertension related to underlying renal TMA as a presenting symptom of APS.

Adult↗
PubMed2002

Heparin and osteoporosis during pregnancy: 2002 update.

Although significant bone mass loss is rare during pregnancy, some situations may increase the risk of symptomatic osteoporosis. Heparin may be necessary for a number of pregnant women with systemic lupus erythematosus and antiphospholipid syndrome. The osteopenic effect of heparin is low even during pregnancy, and recent data point to a more favourable profile of low-molecular-weight heparins as compared with unfractionated heparin. Lactation results in a significant increase of calcium demands and may be a higher risk period for women at risk for osteoporosis.

Antiphospholipid Syndrome↗
PubMed2002

Lessons from the "Euro-Lupus Cohort".

The "Euro-Lupus Cohort" is composed by 1,000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium - the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors.

Adolescent↗
PubMed2001

Systemic lupus erythematosus.

This review covers major advances in clinical issues related to systemic lupus erythematosus (SLE) published between 1995 and 2000. The classification criteria for both SLE and antiphospholipid syndrome (APS) have been updated, and up to 19 different subsets of neuropsychiatric lupus have been defined. New epidemiological data show that the incidence of new cases and the survival of patients with SLE are both increasing. Several randomised controlled trials have defined the role of cyclophosphamide, methotrexate, antimalarials, and hormonal treatment in the management of SLE. New data are available for drugs such as ciclosporin and thalidomide. Finally, several new treatments for severe refractory cases, such as mycophenolate mofetil and stem-cell transplantation, are being increasingly used. New data also refer to management of thrombosis in APS and high-risk pregnancies in women with SLE or APS.

Antiphospholipid Syndrome↗
PubMed2001

Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype.

OBJECTIVE: To investigate the ability of statins, the inhibitors of the hydroxymethylglutaryl-coenzyme A reductase enzyme, to affect endothelial cell activation induced by anti-beta2-glycoprotein I (anti-beta2GPI) antibodies in vitro. METHODS: Human umbilical vein endothelial cell (HUVEC) activation was evaluated as U937 monocyte adhesion, E-selectin, and intercellular adhesion molecule I (ICAM-1) expression by cell enzyme-linked immunosorbent assay and as interleukin-6 (IL-6) messenger RNA (mRNA) expression by RNA protection assay. E-selectin-specific nuclear factor kappaB (NF-kappaB) DNA-binding activity was evaluated by the gel-shift assay. HUVECs were activated by polyclonal affinity-purified IgG, human monoclonal IgM anti-beta2GPI antibodies, human recombinant IL-1beta, tumor necrosis factor alpha, or lipopolysaccharide (LPS). RESULTS: Fluvastatin reduced, in a concentration-dependent manner (1-10 microM), the adhesion of U937 to HUVECs and the expression of E-selectin and ICAM-1 induced by anti-beta2GPI antibodies as well as by cytokines or LPS. Another lipophilic statin, simvastatin, displayed similar effects but to a lesser extent than fluvastatin. The inhibition of E-selectin expression exerted by fluvastatin was related to the impairment of NF-kappaB binding to DNA. Moreover, the drug attenuated the expression of IL-6 mRNA in HUVEC exposed to anti-beta2GPI antibodies or cytokines. Incubation of HUVECs with mevalonate (100 microM), concomitantly with fluvastatin, greatly prevented the inhibitory effect of statin. CONCLUSION: Endothelial activation mediated by anti-beta2GPI antibody can be inhibited by statins. Because of the suggested role of endothelial cell activation in the pathogenesis of antiphospholipid syndrome (APS), our data provide, for the first time, a rationale for using statins as an additional therapeutic tool in APS.

Antibodies, Antiphospholipid↗
PubMed2001

Management of pregnancy in antiphospholipid syndrome.

Pregnant women with APS are at high risk of maternal and fetal pregnancy complications. Multidisciplinary teams expert in this condition should coordinate management. Even with current management strategies, the risk of maternal thrombosis, fetal loss, or other adverse obstetric outcomes remains. Close monitoring of the various aspects of this condition may reduce maternal morbidity and improve fetal outcome. The pathogenesis of the adverse pregnancy outcome in APS has not yet been fully elucidated, although active research in this field continues. Until this is ascertained, we must accept that many aspects of management are purely empiric, and it is our duty to counsel patients thoroughly so that they understand the risks and benefits of the treatment options they are offered.

Adrenal Cortex Hormones↗
PubMed2001

Treatment of systemic lupus erythematosus.

The treatment of systemic lupus erythematosus (SLE) is mainly based on a number of "traditional" drugs such as corticosteroids, antimalarials, azathioprine and cyclophosphamide. However, this scenario is rapidly changing due to the introduction of new compounds. Some of these new agents have been successfully used in other diseases, while others are being specifically designed to interfere with the immune abnormalities seen in SLE. As our knowledge on the mechanisms of immune response increases, new drugs that can interfere with T and B cell interaction and activation, production of anti-dsDNA autoantibodies, immune-complexes deposition and cytokine activation have been developed and some of these are now under investigation in SLE. Although initial data regarding their safety and efficacy are encouraging, caution must be taken before these drugs are considered as the treatment of choice for specific SLE manifestations. Specifically, controlled clinical trials with sufficient number of patients are necessary. If the promising results already available are confirmed, the use of these drugs might represent the keystone in the future management of SLE and other autoimmune diseases.

Adjuvants, Immunologic↗
PubMed2001

Familial clustering of polymorphic light eruption in relatives of patients with lupus erythematosus: evidence of a shared pathogenesis.

BACKGROUND: Abnormal photosensitivity is a common feature of many forms of lupus erythematosus (LE). OBJECTIVES: To examine the role of polymorphic light eruption (PLE) as a possible predisposing factor for cutaneous forms of LE. METHODS: Eighty-five patients with well-characterized subacute cutaneous LE (SCLE) and discoid LE (DLE) were recruited from outpatient clinics, and the prevalence of PLE determined by detailed interview and clinical examination. RESULTS: Symptoms consistent with PLE were reported in 61% and 55% of SCLE and DLE patients, respectively; this was significantly higher than the overall population prevalence of 13.6% (P < 0.001), giving a relative risk (RR) for PLE in SCLE patients of 3.37 (95% confidence interval, CI 2.46--4.28) and DLE patients of 3.11 (95% CI 2.31--3.91). PLE developed before the onset of LE in 61% of cases (median interval 12 years, range 1--40), concomitantly in 24%, and subsequently in a further 15% (median interval 3.5 years, range 1--25). To delineate the relationship between PLE and LE further, the prevalence of PLE was determined in 103 otherwise unaffected first-degree relatives of SCLE and DLE probands; we had previously demonstrated clustering of PLE in families, reflecting a strong genetic component. We found a significantly higher PLE prevalence in relatives of the LE probands than in the general population (P < 0.001), giving an RR for PLE of 2.29 (95% CI 1.55--3.03) and 2.61 (95% CI 1.32--3.89) for female and male relatives, respectively. CONCLUSIONS: The high prevalence of PLE in LE patients, together with clustering of PLE among first-degree relatives of SCLE and DLE probands, suggests that there may be a shared pathogenetic basis for PLE and cutaneous LE. We propose that predisposition to PLE may contribute to the LE phenotype in otherwise susceptible individuals.

Confidence Intervals↗
PubMed2001

A candidate gene analysis of three related photosensitivity disorders: cutaneous lupus erythematosus, polymorphic light eruption and actinic prurigo.

BACKGROUND: Polymorphic light eruption (PLE) is a common inherited photosensitivity disorder, which may predispose to several related but distinct conditions, including subacute cutaneous lupus erythematosus (SCLE), discoid lupus erythematosus (DLE) and actinic prurigo (AP). OBJECTIVES: To examine specific candidate genes for shared susceptibility alleles between these related phenotypes. METHODS: Eighty-five caucasian patients with annular SCLE or DLE were recruited, in addition to 102 first-degree relatives. The prevalence of PLE in both the patient and relative groups was determined by detailed interview and clinical examination. Eighty-five patients with pure PLE and 59 patients with AP were also recruited. Candidate genes were analysed by typing of single nucleotide polymorphisms of IL10 (-1082 G/A and -819 C/T), FCGR2A (131 R/H), SELE (128 S/R), ICAM1 (241 G/R and 469 E/K), IL1A (+ 4845 G/T), IL1B (-511 C/T and + 3954 C/T), IL1RN (+ 2018 T/C) and TNF (-308 G/A) using polymerase chain reaction (PCR) with sequence-specific primers and 5'-nuclease PCR. RESULTS: A significant association was found between SCLE and the rare TNF -308 A allele when compared with patients with DLE (P = 0.043), PLE (P = 0.001), AP (P < 0.001) and healthy controls (P < 0.001). However, there was strong linkage disequilibrium between TNF -308 A and the HLA A*01, B*08, DRB1*0301 haplotype. A negative association was also found between SCLE and the IL1B + 3954 T allele (P = 0.039), but the significance was lost on correction for multiple testing. CONCLUSIONS: We have demonstrated the association of SCLE with the rare TNF -308 A allele, which may be pathogenic or, alternatively, a marker allele for the extended HLA A*01, B*08, DRB1*0301 haplotype that is associated with a number of autoimmune conditions. Although many of the other loci that we chose failed to demonstrate an association, a candidate gene approach remains the most logical one, and the most likely to yield positive results in the future.

Alleles↗