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Biomedical subjects

M Khamashta

Publications and source records attributed to M Khamashta.

At least 19 recordsLinked to original sources
PubMed2007

Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: an international inception cohort study.

OBJECTIVE: To describe the prevalence, characteristics, attribution, and clinical significance of neuropsychiatric (NP) events in an international inception cohort of systemic lupus erythematosus (SLE) patients. METHODS: The study was conducted by the Systemic Lupus International Collaborating Clinics (SLICC). Patients were enrolled within 15 months of fulfilling the American College of Rheumatology (ACR) SLE classification criteria. All NP events within a predefined enrollment window were identified using the ACR case definitions of 19 NP syndromes. Decision rules were derived to determine the proportion of NP disease attributable to SLE. Clinical significance was determined using the Short Form 36 (SF-36) Health Survey and the SLICC/ACR Damage Index (SDI). RESULTS: A total of 572 patients (88% female) were recruited, with a mean +/- SD age of 35 +/- 14 years. The mean +/- SD disease duration was 5.2 +/- 4.2 months. Within the enrollment window, 158 of 572 patients (28%) had at least 1 NP event. In total, there were 242 NP events that encompassed 15 of 19 NP syndromes. The proportion of NP events attributed to SLE varied from 19% to 38% using alternate attribution models and occurred in 6.1-11.7% of patients. Those with NP events, regardless of attribution, had lower scores on the SF-36 and higher SDI scores compared with patients with no NP events. CONCLUSION: Twenty-eight percent of SLE patients experienced at least 1 NP event around the time of diagnosis of SLE, of which only a minority were attributed to SLE. Regardless of attribution, the occurrence of NP events was associated with reduced quality of life and increased organ damage.

Adult↗
PubMed2006

Vascular endothelial growth factor expression in monocytes from patients with primary antiphospholipid syndrome.

BACKGROUND: One of the described mechanisms leading to thrombosis in antiphospholipid syndrome (APS) is overexpression of tissue factor (TF) in the monocytes and endothelial cells of patients with antiphospholipid antibodies (aPL). Vascular endothelial growth factor (VEGF) may stimulate monocyte TF expression through its receptor, the tyrosine kinase Flt-1. OBJECTIVES: This study aimed to analyze the following in monocytes of 55 primary APS patients: VEGF and Flt-1 expression levels, their potential regulation by aPL, and the association of VEGF and Flt-1 expression with the increased TF expression found in APS patients. RESULTS: Purified monocytes from APS patients showed higher levels of VEGF and Flt-1 than healthy donors, which further correlated with immunoglobulin G (IgG) anticardiolipin titers and TF expression rank. Moreover, monocyte VEGF and Flt-1 levels were significantly higher in patients with than in patients without previous thrombosis. In vitro, IgG from APS patients increased monocyte VEGF and Flt-1 expression in a dose-dependent manner. VEGF and Flt-1 expression was significantly inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580; this suggests the involvement of this kinase in the aPL-induced VEGF and Flt-1 upregulation. CONCLUSIONS: Our data show, for the first time in vivo, that monocytes from primary APS patients have an increased expression of VEGF and Flt-1. Furthermore, in vitro results indicated that this cytokine is produced by monocytes when treated with aPL, and that the p38 MAPK signaling pathway plays an important role. Thus, VEGF might act as a regulatory factor in aPL-mediated monocyte activation and TF expression, thereby contributing to the proinflammatory-prothrombotic phenotype of APS patients.

Adolescent↗
PubMed2006

Endocrinologic manifestations of the antiphospholipid syndrome.

Our objective was to study the endocrinologic manifestations of the antiphospholipid syndrome (APS). We reviewed the medical literature from 1968 until 2005 using MEDLINE and the key words: APS, anticardiolipin antibodies, lupus anticoagulant, antiphospholipid antibodies, adrenal, thyroid, parathyroid, pituitary, diabetes, ovaries and testes. Adrenal insufficiency is the most common endocrinologic manifestation and can be the presenting symptom of APS. In patients with autoimmune thyroid disease circulating aPL have been detected. However, no clinical manifestations of APS have been described. A few cases of hypopituitarism have been reported, including a case of Sheehan's syndrome. aPL has been detected in the sera of diabetic patients, probably associated with some macroangiopathic complications. Finally only very few cases of ovarian and testicular involvement have been reported. The adrenals are the most commonly involved glands in the APS. Clinicians should keep a high index of suspicion for adrenal insufficiency in patients with APS.

Adrenal Insufficiency↗
PubMed2006

European attempts to set guidelines for improving diagnostics of autoimmune rheumatic disorders.

The rational way to set a diagnosis and estimate a prognosis in rheumatology is to start by setting a tentative diagnosis and then follow a fixed scheme for laboratory testing, eg, by using an agreed algorithm. The use of order algorithms can be extended to post-test algorithms that will assist clinicians in approaching the right diagnosis and prognosis. New methods used in autoimmune serology do not deliver results that can be directly compared to those of older methods, and thus the new methods need to be thoroughly tested with sera from differential diagnostically relevant disease controls to set a clinically meaningful cut-off for positivity. Borderline positive results need to be treated with special care to avoid misuse. Early diagnosis is of great importance, and serological results can be very useful if used the right way. European efforts to secure rational diagnostic work-up in autoimmune rheumatic disease have led to a better dialogue between clinicians and laboratory scientists in several countries.

Algorithms↗
PubMed2005

Ethnic and geographical variation in antiphospholipid (Hughes) syndrome.

Investigation of the clinical epidemiology of the antiphospholipid syndrome (APS) is in its early stages. During the past 20 years, studies of antiphospholipid antibodies (aPL) and APS have been made in many countries and ethno-geographical groups. aPL appear to occur in all populations studied, with some variations noted in their frequency and in the clinical complications. Environmental and genetic factors contribute to ethnic variation and susceptibility to APS and thus inter-ethnic differences in disease patterns may be due to environmental or genetic factors, or both.

Antibodies, Antiphospholipid↗
PubMed2005

BILAG 2004. Development and initial validation of an updated version of the British Isles Lupus Assessment Group's disease activity index for patients with systemic lupus erythematosus.

OBJECTIVE: To devise a more discriminating version of the British Isles Lupus Assessment Group (BILAG) disease activity index and to show that it is reliable. METHODS: A nominal consensus approach was undertaken by members of BILAG to update and improve the BILAG lupus disease activity index. The index has been revised following intense consultations over a 1-yr period. It has been assessed in two real-patient exercises. These involved patients with diverse clinical features of SLE, including gastrointestinal, hepatic and ophthalmic problems, which the earlier versions of the index did not fully take into account. Reliability in terms of the ability to differentiate patients was assessed by calculating intraclass correlation coefficients. The level of agreement between physicians was determined by calculating the ratio of estimates of the standard error (SE) attributable to the physicians to the SE attributable to the patients. RESULTS: Good reliability and high levels of physician agreement were observed in one or both exercises in the constitutional, mucocutaneous, neurological, cardiorespiratory, renal, ophthalmic and haematological systems. In contrast, the musculoskeletal system did not score as well, although providing more clear-cut glossary definitions should greatly improve the situation. CONCLUSIONS: Some significant changes in the BILAG disease activity index to assess patients with SLE are proposed. The process of demonstrating validity and reliability has started with these two exercises assessing real patients. Further validation studies are under way. BILAG 2004 is likely to be valuable in clinical trials assessing new therapies for the treatment of SLE, as it provides a more comprehensive system-based disease activity measure than has been available previously.

Adult↗
PubMed2003

Prophylaxis of the antiphospholipid syndrome: a consensus report.

Hypothetical circumstances that may require prophylaxis for a potential antiphospholipid syndrome (primary prophylaxis), or in some instances when there already had been some manifestations ofthe syndrome (secondary prophylaxis), were presented to a panel of experts for their consideration on potential prophylactic intervention. These were subsequently presented to the participants in the First International Consensus on Treatment of the Antiphospholipid Syndrome. In most instances there was consensus in adding low dose aspirin, an exception being aspirin allergy when other antiaggregants could be used in nonpregnant subjects. General measures to prevent thrombosis and other vasoprotective actions should also be provided. Higher risk of fetal loss or thrombosis called for anticoagulation with coumadin in nonpregnant subjects or subcutaneous low molecular weight heparin in pregnant ones. When indicated, prophylaxis of the antiphospholipid syndrome should be provided in systemic lupus erythematosus patients who are being treated for their disease. In no instance should corticosteroids or immunosuppresants be given as prophylactic of an antiphospholipid syndrome.

Anticoagulants↗
PubMed2003

Stroke and the antiphospholipid syndrome: consensus meeting Taormina 2002.

Ischaemic stroke is the only neurological manifestation accepted as a clinical diagnostic criterion for the antiphospholipid syndrome (APS). This association is reasonably well established in patients first diagnosed with APS but is less clear in randomly selected stroke patients who test positive on one occasion for antiphospholipid antibodies and who have no other evidence of systemic autoimmune disease. We propose a grading system that posits stroke to be definitely, likely or possibly associated with antiphospholipid antibodies (aPL). Further, there are limited prospective data to determine appropriate treatment. There is controversy as to whether the presence of aPL even increases risk of a recurrent stroke or other thromboembolic event, although data point to persistent medium-high titre aCL and/or LA as risk factors for recurrence. In the absence of data to guide clinicians on the best treatment, we cannot make strong recommnendations as to optimal therapy, nor can we propose clear consensus treatment guidelines.

Administration, Oral↗
PubMed2003

Treatment of pregnant patients with antiphospholipid syndrome.

Antiphospholipid Syndrome (APS) has been widely recognized as a risk factor for the recurrence of both thrombosis and pregnancy losses; however the optimal treatment of patients is debatable. The aim of this paper was to establish a consensus among experts on the treatment of APS in pregnancy. A questionnaire that described possible different clinical situations was sent to the International Advisory Board of the 10th International Congress on Antiphospholipid Antibodies. Sixteen experts from different medical branches and different geographic areas sent their replies. The consensus was that treatment for APS pregnant patients should be low molecular weight heparin (LMWH) and low dose aspirin (LDA). The dosage, and frequency of LMWH depends on different situations, including the body weight and past history. Patients with previous thromboses usually receive two injections per day. Warfarin can also be used from 14 to 34 weeks, for patients with previous stroke or severe arterial thromboses. The use of intravenous immunoglobulin (IVIG) seems to be restricted to patients with pregnancy losses despite conventional treatment. The experts usually advised barrier methods of contraception, intrauterine device (if the patient is not taking corticosteroids) or progestins. Oral contraception with oestrogens was usually avoided.

Adult↗
PubMed2001

Estrogen and progesterone receptors in murine models of systemic lupus erythematosus.

Estrogens are believed to play a role in the etiology of both human and murine systemic lupus erythematosus (lupus; SLE), presumably through the agency of their cellular receptor proteins. There is now considerable interest in the molecular mechanism of action of estrogens in immune tissues, particularly with regard to autoimmune disorders, which are generally more prevalent in women. In this laboratory, an attempt is being made to characterize estrogen receptors in murine models of SLE and to try and relate this to estrogen receptor function in vivo. The initial aim was to compare binding properties of estrogen receptors in brain, reproductive and immune tissues of BALB/c and MRL/MP-lpr/lpr mice. The latter strain spontaneously develops an autoimmune disease resembling human systemic lupus erythematosus (lupus; SLE). It is hypothesized that estradiol, through its receptors, mediates the progression of murine SLE, and that in autoimmune disease, the estrogen receptor is functionally and/or structurally changed. Initial studies suggest that there are differences in estrogen receptors between BALB/c mice, which do not get autoimmune disease, and two strains that do, MRL/MP-lpr/lpr and NZB/W mice. In MRL mice, these differences may be reflected in impaired priming of the progesterone receptor.

Animals↗
PubMed2001

Contraceptive practices in women with systemic lupus erythematosus and/or antiphospholipid syndrome: what advice should we be giving?

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune oestrogen-mediated disease. Antiphospholipid syndrome (APS) is an autoimmune acquired thrombophilia. These two conditions may co-exist and are most frequently diagnosed in young women. Hormonal contraception may promote lupus activity and thromboses. Medical practitioners may not know what advice to give these women regarding contraception. OBJECTIVES: To determine the past and present contraceptive practices of women with SLE and/or APS, and to establish the incidence of complications related to use of various contraceptives. Also, the contraceptive information given to women following diagnosis was evaluated. STUDY DESIGN: Observational questionnaire-based study of 86 women with SLE and/or APS attending the Lupus/Thrombophilia Clinics at St. Thomas' Hospital. RESULTS: One of the 19 (5%) women with SLE using the combined oral contraceptive pill (COCP) at the time of diagnosis reported a severe lupus 'flare'. Seven of the 32 (22%) women with APS using the COCP suffered from thromboses during use. There were no problems specific to women with SLE and/or APS using any other form of contraception. Thirty-nine (45%) women received no contraceptive information following their diagnosis, 37 (46%) were told to avoid the COCP due to the increase in lupus 'flare' and/or thromboses. CONCLUSION: There is no clinically significant association between COCP use and lupus 'flare'. The high incidence of thromboses in women with APS using the COCP containing either second or third generation progestogens suggests that these women should be advised against using this form of contraception. Women with SLE and/or APS should be given more information about contraceptive issues.

Adolescent↗
PubMed2000

Strain differences in binding properties of estrogen receptors in immature and adult BALB/c and MRL/MP-lpr/lpr mice, a model of systemic lupus erythematosus.

The aim was to compare binding properties of estrogen receptors in brain, reproductive and immune tissues of immature and adult female BALB/c mice, and in the same tissues of MRL/MP-lpr/lpr mice. The latter strain spontaneously develops an autoimmune disease resembling human systemic lupus erythematosus (lupus; SLE). It is hypothesized that estradiol, through its receptors, mediates the progression of murine SLE. High-speed cytosols were prepared from hypothalamus, spleen, thymus and uterus of both strains, and incubated with the synthetic estrogen (3)H-moxestrol (NEN). Scatchard plots were derived from binding isotherms obtained after in vitro incubation. In addition, cervical lymph nodes from MRL mice could be used, but were too small in BALB/c mice. There was a significant increase in the affinity of the binding reaction i.e. a decrease in the apparent molar dissociation constant (Kd), in immune tissues and uterus with maturation in MRL but not BALB/c mice, whose tissues had, overall, a lower affinity for (3)H-moxestrol. Receptor concentrations were significantly higher in spleen and cervical lymph nodes of adult compared with immature MRL mice, but the opposite pattern was observed in BALB/c mouse spleen on maturation. These properties of estrogen receptors in MRL mice may underlie estrogen-mediated exacerbation of murine SLE.

Age Factors↗
PubMed1999

Evidence for sexual dimorphism of estrogen receptors in hypothalamus and thymus of neonatal and immature Wistar rats.

It is hypothesized that the rat thymus is sexually differentiated. To begin testing this, we used the 5-day-old rat, whose hypothalamus is sexually differentiated during this period. Cytosolic estrogen receptors (ER) were measured in cytosols prepared from the brain, thymus and uterus of Wistar rats at 5, 18 and 30 days post-partum. ER concentrations were significantly higher in hypothalamus in cytosols of female 5-day-old rats, and this difference had disappeared by day 18. The pattern in thymus was identical to that observed in hypothalamus, suggesting the presence in the thymus of the aromatase system that converts androgen to estrogen, and that estrogen-mediated sexual differentiation of thymus might be proceeding at 5 days. Unlike the case for hypothalamus, no experimental model exists at present for testing functional sexual differentiation in thymus. Therefore we tested the effects of aromatase inhibitors on estrogen receptor activity in thymus well after the five-day period, and before atrophy of the thymus has commenced. Male and female rats were implanted at 15 days of age with SILASTIC implants containing 5 mg of estradiol or with 25 mg of the aromatase inhibitor 4-hydroxyandrostenedione (4-OHA) and cytosolic ER prepared at 30 days and activity measured. Administration of estradiol resulted in failure to detect available receptor, suggesting that the binding components measured were ER. After 4-OHA administration, ER concentrations were significantly increased in cytosols from male but not female hypothalamus and thymus. There is therefore a basis for exploring further the hypothesis that rat thymus is sexually differentiated.

Age Factors↗
PubMed1999

Lymphocyte activation markers and von Willebrand factor antigen in Wegener's granulomatosis: potential markers for disease activity.

OBJECTIVE: To examine 3 soluble circulating T cell antigens: interleukin 2 receptors (sIL-2r), CD4 (sCD4), and CD8 (sCD8) with von Willebrand factor antigen levels (vWF:Ag) and antiendothelial cell antibodies (AECA) as indices of endothelial involvement in patients with Wegener's granulomatosis (WG). METHODS: We studied 23 patients with WG, of whom 11 had active disease with renal involvement, and 20 healthy controls. sIL-2r, sCD4, sCD8, vWF:Ag, and AECA were measured by ELISA. RESULTS: Median sIL-2r levels in patients were higher than controls (789.5 vs. 551 U/ml, p<0.01). sCD4 levels were higher in patients: 17.0 vs. 15.2 U/ml (p<0.005) and correlated with sIL-2r levels. sIL-2r and sCD4 levels correlated with disease activity scores, antineutrophil cytoplasmic antibodies (ANCA), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and neutrophil counts. sCD8 levels were also higher: 260.5 vs. 127 U/ml (p<0.001) and correlated with CRP levels but not with disease activity. vWF:Ag levels were elevated in patients (median 296% vs. controls 109%; p<0.001) and correlated with disease activity, ESR, CRP, ANCA titers, and serum creatinine levels. AECA levels did not differ from controls (5% vs. 7%). CONCLUSION: Circulating levels of sIL-2r, sCD4, sCD8, and vWF:Ag are elevated in active WG, indicating T cell and endothelial activation. sIL-2r, sCD4, and vWF:Ag are potentially useful disease activity markers.

Adult↗