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M A Khamashta

Publications and source records attributed to M A Khamashta.

At least 19 recordsLinked to original sources
PubMed2007

Anti-beta2GPI-antibody-induced endothelial cell gene expression profiling reveals induction of novel pro-inflammatory genes potentially involved in primary antiphospholipid syndrome.

OBJECTIVE: To determine the effects of primary antiphospholipid syndrome (PAPS)-derived anti-beta(2)GPI antibodies on gene expression in human umbilical vein endothelial cells (HUVEC) by gene profiling using microarrays. METHODS: Anti-beta(2)GPI antibodies purified from sera of patients with PAPS or control IgG isolated from normal subjects were incubated with HUVEC for 4 h before isolation of RNA and processing for hybridisation to Affymetrix Human Genome U133A-2.0 arrays. Data were analysed using a combination of the MAS 5.0 (Affymetrix) and GeneSpring (Agilent) software programmes. For selected genes microarray data were confirmed by real-time PCR analysis or at the protein level by ELISA. RESULTS: A total of 101 genes were found to be upregulated and 14 genes were downregulated twofold or more in response to anti-beta(2)GPI antibodies. A number of novel genes not previously associated with APS were induced, including chemokines CCL20, CXCL3, CX3CL1, CXCL5, CXCL2 and CXCL1, the receptors Tenascin C, OLR1, IL-18 receptor 1, and growth factors CSF2, CSF3 IL-6, IL1beta and FGF18. The majority of downregulated genes were transcription factors/signalling molecules including ID2. Quantitative real-time RT-PCR analysis confirmed the microarray results for selected genes (CSF3, CX3CL1, FGF18, ID2, SOD2, Tenascin C). CONCLUSIONS: This study reveals a complex gene expression response in HUVEC to anti-beta(2)GPI antibodies with multiple chemokines, pro-inflammatory cytokines, pro-thrombotic and pro-adhesive genes regulated by these antibodies in vitro. Some of these newly identified anti-beta(2)GPI antibody-regulated genes could contribute to the vasculopathy associated with this disease.

Adult↗
PubMed2006

Mycophenolate mofetil treatment in resistant myositis.

OBJECTIVES: To assess the efficacy and tolerability of mycophenolate mofetil (MMF) in six patients with myositis refractory to conventional immunosuppressive therapy. METHODS: Six patients were identified from hospital notes. All had previously failed to respond to other immunosuppressive treatments. Efficacy was measured as changes in muscle strength, creatine kinase (CK) levels and prednisolone dose. RESULTS: The mean age of the group was 49.8 +/- 9.1 yrs, 6 (100%) were female and Caucasian. Patients had failed to respond to a median of 3 (range 1-3) immunosuppressive drugs. They received MMF for a mean of 22.3 +/- 18.9 months with a mean MMF dose of 1.6 +/- 0.5 g/day. The mean initial prednisolone dose was 13.7 +/- 7.7 mg and the mean follow up dose was 8.5 +/- 4.9 mg/day (P = 0.03). CK levels were reduced from mean 2395 IU/l +/- 1202.8 to 746.6 +/- 555.8 IU/l (P = 0.03). CONCLUSION: Our data demonstrate that MMF may be effective in myositis, previously unresponsive to conventional immunosuppressive drugs.

Adult↗
PubMed2006

[Systematic lupus erythematosus and antiphospholipid syndrome during pregnancy].

Women with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are subject to several complications during pregnancy, including reactivation of SLE, thrombosis, miscarriage, neonatal lupus, pregnancy-induced hypertension, pulmonary hypertension and drug toxicity. Correct management of these patients requires combined medical-obstetric care, close surveillance of baby's growth and well-being, control of SLE activity and correct thromboprophylaxis. With good care, most pregnancies in women with SLE and APS end successfully.

Anticoagulants↗
PubMed2006

Prevalence of the antiphospholipid syndrome in primary systemic vasculitis.

BACKGROUND: The antiphospholipid (APS or Hughes') syndrome, anticardiolipin antibodies (aCL), and the lupus anticoagulant (LA) are associated with systemic lupus erythematosus, malignancy, infection, and drugs. It has been described in patients with primary systemic vasculitis (PSV). OBJECTIVE: To determine the prevalence of APS in patients with PSV attending a vasculitis clinic and the prevalence of patients with positive aCL and/or the LA who do not fulfil the classification criteria for APS. METHODS: All case notes of patients attending the vasculitis clinic over a 12 month period were reviewed. Outpatients and inpatients were both included and were assessed for features of the APS and presence of aPL. Patients with positive aCL or LA tests were classified according to the significance of these results. RESULTS: Of 144 patients with PSV, 25 had positive aCL or LA on at least one occasion, representing a point prevalence of 17%. Of these, nine had definite APS (classified by the Sapporo criteria) and a further four patients had clinical and serological features of APS, although insufficient to satisfy the Sapporo criteria. Twelve had only positive aPL. CONCLUSION: The antiphospholipid syndrome, aCL, and the LA may occur in association with PSV.

Adolescent↗
PubMed2006

Treatment of menorrhagia associated with oral anticoagulation: efficacy and safety of the levonorgestrel releasing intrauterine device (Mirena coil).

Menorrhagia is common in women receiving oral anticoagulation. In healthy women, reductions of up to 90% of menstrual loss have been described with the levonorgestrel releasing intrauterine device (LNG-IUS). However there is no data about the use of LNG-IUS in women receiving oral anticoagulation and so we assessed the efficacy and safety of LNG-IUS in this setting. Patients with menorrhagia who used LNG-IUS and warfarin were contacted by post and asked to complete a questionnaire assessing the extent and duration of menstrual bleeding, quality of life and treatment satisfaction. The questionnaire was sent to 23 patients and returned by 17. The amount of bleeding was reduced with the LNG-IUS in 10 (58.8%) women; amenorrhea occurred in four (23.5%), no change in blood loss in one (5.9%) and greater blood loss in two (11.8%) patients. The number of sanitary pads used was less in 12 (70.6%) patients; same in one (5.9%) patient, more in two (11.8%) patients and two (11.8%) did not remember. Five patients (29.4%) had shorter duration of bleeding, four (23.5%) had amenorrhoea, four (23.5%) had longer periods and four (23.5%) had same duration by subjective assessment. Eight (47.1%) patients felt very satisfied, four (23.5%) felt satisfied, two (11.8%) felt dissatisfied with the treatment, one felt very dissatisfied (5.9%) and two (11.8%) did not respond to the question. This small study suggests LNG-IUS is effective in reducing the duration and amount of menstrual bleeding in women with menorrhagia associated with oral anticoagulation. We feel the use of LNG-IUS is a major advance in reducing menorrhagia in women on oral anticoagulation as the previous alternative--hysterectomy--is associated with an increased risk of thrombosis and bleeding.

Administration, Oral↗
PubMed2006

Laboratory diagnosis and management challenges in the antiphospholipid syndrome.

The antiphospholipid syndrome (APS) is characterized by recurrent arterial and/or venous thrombosis and pregnancy morbidity manifested by early or late losses. Laboratory diagnosis ofAPS relies on the demonstration of a positive test for antiphospholipid antibodies (aPL). In clinical practice, the gold standard tests are those that detect anticardiolipin antibodies (aCL) and/or the lupus anticoagulant (LA). Although other specificities for aPL have been described their clinical utility and standardization has still to be established. Persistence of aPL positive tests must be demonstrated, and other causes and underlying factors considered. Although it is universally recognized that the routine screening tests (aCL and/or LA) might miss some cases, careful differential diagnosis and repeat testing are mandatory before the diagnosis of 'seronegative APS' can be made. Correct identification of patients with APS is important, because prophylactic anticoagulant therapy can prevent thrombosis from recurring, and treatment of affected women during pregnancy can improve fetal and maternal outcome.

Abortion, Habitual↗
PubMed2005

Reduction of proteinuria with mycophenolate mofetil in predominantly membranous lupus nephropathy.

INTRODUCTION: Lupus membranous nephropathy (LMN) presents a difficult clinical problem as no particular treatment has been proven to be effective. Studies have shown good results with mycophenolate mofetil (MMF) in proliferative lupus nephropathy (LN) (WHO class III and IV disease). OBJECTIVES: To study whether MMF treatment was effective in membranous predominant LN in patients resistant to or intolerant of other immunosuppressive agents. PATIENTS AND METHODS: We retrospectively studied 10 patients with systemic lupus erythematosus who had biopsy-proven predominant LMN (six Vc patients and four Va or Vb patients). Previous treatments included cyclophosphamide, azathioprine, ciclosporin and corticosteroids. The following parameters were recorded at baseline and follow-up: blood pressure, ECLAM, proteinuria, serum albumin and creatinine, routine haematology and immunology. RESULTS: The study included eight women and two men, mean age 38.4 +/- 7.1 yr (range 30-49 yr). The racial distribution was as follows: five Caucasian, and five Black patients. The mean treatment time with MMF was 18.8 +/- 15.4 months (range 3-52 months). Twenty-four-hour urinary protein excretion was reduced from median 2.26 g (range 0-7.92 g) to median 0.66 g (range 0.08-3.85 g) at follow-up (P = 0.0039). Serum albumin increased significantly after treatment from median 29.5 g/l (range 14.0-42.0 g/l) to 33.5 g/l (range 23.0-40.0 g/l) at follow-up (P = 0.04). There were no significant changes in serum creatinine (P = 0.55). CONCLUSION: MMF is a potentially useful immunosuppressive agent in reducing the proteinuria associated with membranous predominant LN.

Adult↗
PubMed2005

Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the "Euro-Lupus Project".

The "Euro-Lupus Cohort" is composed by 1000 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.

Age of Onset↗
PubMed2005

The placental bed in pregnancies complicated by primary antiphospholipid syndrome.

UNLABELLED: Pregnancy in women with primary antiphospholipid syndrome (APS) is frequently associated with placental insufficiency leading to intrauterine growth restriction (IUGR)+/-fetal death, pre-eclampsia, placental abruption, premature delivery or thrombosis. The aim of this study was to investigate the placental bed in APS pregnancies for evidence of impaired trophoblast invasion, endothelial cell activation (ECA) and macrophage infiltration. METHODS: Biopsies from the presumed site of the placental bed were obtained from 12 women with treated primary APS and 16 controls. Immunohistochemical methods were employed to investigate expression of cytokeratin (trophoblasts), alpha-actin (smooth muscle), CD68 (macrophages) and VCAM-1 (as marker of ECA). Fibrinoid and elastin distribution and expression were determined by periodic acid/Schiff and orcein stain, respectively. RESULTS: Three APS pregnancies developed IUGR, one with concurrent pre-eclampsia. Eight of 12 APS biopsies were confirmed to be from the placental bed; one patient failed to meet APS criteria and was excluded from analysis; six included spiral arteries in the biopsy; 11 of 16 controls' biopsies were from the placental bed. APS biopsies had a higher concentration of inflammatory cells (p=0.0001), particularly macrophages (p=0.014). Three APS biopsies showed necrosis with hyperplastic vessels; one demonstrated arterial thromboses, but none had profound vasculopathy/atherosis or ECA. CONCLUSION: Inflammatory mechanisms in the placental bed may contribute to APS pregnancy complications.

Antiphospholipid Syndrome↗
PubMed2005

Stroke and antiphospholipid syndrome: the treatment debate.

Antiphospholipid syndrome (APS) is one of the most frequent acquired thrombophilias. Thromboses can be at both the venous and arterial level, are usually recurrent and frequently affect cerebral circulation. Although it is difficult to predict which patients with antiphospholipid antibodies (aPL) will develop thrombosis, once a thrombotic event has taken place, secondary prevention is mandatory. Recommendations for treatment of APS have long been based on studies with a retrospective design. Recently, three prospective studies (two controlled and one uncontrolled small series) have addressed the role of antiaggregant and anticoagulant therapy in patients with stroke and aPL. However, results from prospective and retrospective studies are not in full agreement. In addition to the obvious differences in design, other factors such as the important variability in the study groups account for the discrepancy. While future investigation must better define homogeneous subsets of patients with APS, current secondary prophylaxis of thrombosis in these patients must be tailored according to individual estimated risk of recurrences, risk of haemorrhage and severity of potential recurrent events. Due to the often devastating consequences of stroke, we believe there is a place for prolonged, high-intensity anticoagulation in patients with APS and cerebral arterial thrombosis.

Anticoagulants↗
PubMed2005

Antiphospholipid antibody tests: spreading the net.

OBJECTIVE: To examine the hypothesis that testing for new antiphospholipid antibody specificities may help to identify the antiphospholipid syndrome (APS) in patients with systemic lupus erythematosus (SLE) with thrombosis who are repeatedly negative for anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA). METHODS: Three groups of patients with SLE were studied: (a) SLE/APS (n = 56): 51 female, mean (SD) age 46 (11) years, fulfilling 1999 Sapporo criteria for the APS; (b) SLE/thrombosis (n = 56): 53 female, age 42.6 (12) years, all with a history of thrombosis and persistently negative for aCL and/or LA; (c) SLE only (n = 56): 53 female, age 40 (11) years, without a history of thrombotic events. aCL and LA were retested in all samples. All patients were tested for anti-beta(2)-glycoprotein I (anti-beta(2)GPI) and antiprothrombin antibodies (aPT) by coating prothrombin on irradiated plates or using phosphatidylserine-prothrombin complex as the antigen (aPS-PT). RESULTS: Anti-beta(2)GPI were only present in patients from the SLE/APS group, all of whom were also positive for aCL. aPT and aPS-PT were also more commonly found in SLE/APS than in SLE/thrombosis or SLE only groups (54% v 5%, p<0.0001 or v 16%, p<0.0001 for aPT and 63% v 2%, p<0.0001 or v 11%, p<0.0001 for aPS-PT, respectively). No differences were found between SLE/thrombosis and SLE only groups (p = 1.5 for beta(2)GPI, p = 0.1 for aPT, and p = 0.1 for aPS-PT). CONCLUSION: Testing for aPT in patients with SLE with thrombosis, but persistently negative for aCL and LA, may be helpful in some selected cases. Anti-beta(2)GPI are not present in patients who are negative for aCL.

Adult↗
PubMed2005

Antiferritin antibodies discovered by phage display expression cloning are associated with radiographic damage in rheumatoid arthritis.

OBJECTIVE: Several autoantibodies have been described in individuals with rheumatoid arthritis (RA), leading to interest in the use of such antibodies as diagnostic or prognostic markers in RA as well as in their relevance to disease pathology. The objective of this study was to use a phage display expression cloning system to identify novel autoantibody targets in RA. METHODS: We used immunoscreening of a phage-displayed complementary DNA (cDNA) library to isolate a cDNA clone encoding the ferritin heavy chain polypeptide. Antiferritin antibody levels in patients with early and established RA, healthy controls, and disease controls were measured by enzyme-linked immunosorbent assay. Antibody-positive and antibody-negative individuals were compared with respect to disease severity as measured by the modified Larsen score, demographic variables, rheumatoid factor status, and carriage of HLA-DRB1 shared epitope alleles. RESULTS: Antiferritin antibodies were present in 60 (16%) of 366 patients with established RA, 23 (19%) of 118 patients with early RA, 2 (2.7%) of 73 healthy blood donors, 2 (2.1%) of 94 individuals with osteoarthritis, and 2 (2.1%) of 97 patients with systemic lupus erythematosus (P < 0.01, RA patients versus healthy and disease controls). Antiferritin antibodies were more common in men than in women (28.4% versus 12.2%; P < 0.001), and antiferritin levels were associated with the severity of joint damage (P = 0.01). CONCLUSION: Antiferritin antibodies are observed in a subset of patients with RA, are present early in the disease course, and are associated with the severity of radiographic damage. Further studies are required to explore their potential as diagnostic and prognostic markers in RA.

Adult↗
PubMed2005

Prevalence of an abnormal ankle-brachial index in patients with primary antiphospholipid syndrome: preliminary data.

OBJECTIVES: To evaluate the prevalence of abnormal ankle-brachial indexes (ABIs), their relationship with other cardiovascular risk factors and/or the presence of antiphospholipid antibodies (aPL), and the clinical use of the ABI in patients with primary antiphospholipid syndrome (primary APS). METHODS: An 8 MHz Doppler probe was used in the arms and legs to assess the ABI in 43 patients with primary APS (mean (SD) age 40.2 (7.9) years) and 49 healthy subjects (aged 41.0 (11.7)) matched for age and sex. Data on traditional cardiovascular risk factors, such as hypertension, hypercholesterolaemia, presence of diabetes mellitus, nephrotic syndrome or renal failure, smoking, and other variables, were collected at that time for all subjects. A ratio of the highest blood pressure from the posterior tibial or pedal arteries of each leg to the highest blood pressure from the brachial arteries <1.00 was considered abnormal. RESULTS: Abnormal ABIs were found in 8/43 (19%) patients with primary APS and 2/49 (4%) controls (p = 0.026). No correlation between abnormal ABI and traditional cardiovascular risk factors nor with the presence of aPL was found. CONCLUSION: Abnormal ABIs are more common in primary APS than in healthy controls, possibly indicating a subclinical atherosclerotic process in these patients.

Adult↗