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Biomedical subjects

D A Isenberg

Publications and source records attributed to D A Isenberg.

At least 127 records · Page 7Linked to original sources
PubMed2000

Underestimating the value of women: assessing the indirect costs of women with systemic lupus erythematosus. Tri-Nation Study Group.

OBJECTIVE: Indirect costs result from diminished productivity and are incorporated in cost-benefit analysis to guide health resource allocation. Valuing the productivity impairment of those not involved in labor market activities is controversial but important for diseases affecting predominantly women if allocation decisions are to be economically efficient and equitable. We compared indirect costs incurred by women with systemic lupus erythematosus (SLE), a prototypical women's disease, calculated under varying assumptions for the value of diminished labor market and non-labor market activity. METHODS: Six hundred forty-eight female patients with SLE reported on employment status and time lost by themselves and their caregivers from labor market and non-labor market activities over a 6 month period. RESULTS: Average annual indirect costs ranged from $1,424 to $22,604 (1997 Canadian dollars) dependent on the value assigned to labor market and non-labor market activity. CONCLUSION: Indirect cost estimates that fail to consider longterm labor market absenteeism and diminished non-labor market productivity and do not use gender neutral wages to value labor market activity may lead to decisions that jeopardize resources for women's diseases.

Absenteeism↗
PubMed1999

Immunization with a peptide of Sm B/B' results in limited epitope spreading but not autoimmune disease.

An experimental model of systemic lupus erythematosus has recently been described in normal animals. We sought to confirm and extend this model, which involved immunization of normal rabbits and mice with a peptide of Sm B/B', PPPGMRPP. This peptide is an early target of the immune response in anti-Sm-positive patients with lupus. The peptide was used in a multiple Ag peptide format, with multiple copies of PPPGMRPP bound to an inert lysine backbone. New Zealand White rabbits and A/J and C57BL/10ScSn mouse strains were immunized with PPPGMRPP-MAP. Pepscan assays were used to determine the epitope spreading of the anti-PPPGMRPP-MAP response to other octamers of SmB/B' following immunization. We obtained high titer anti-PPPGMRPP-MAP IgG responses in the New Zealand White rabbits and A/J mice. The rabbits immunized with PPPGMRPP-MAP showed varying degrees of epitope spreading, while the A/J mice showed no spreading. We observed no autoantibodies to dsDNA or other anti-nuclear autoantibodies in our animals by ELISA or immunofluorescence, although anti-nuclear autoantibodies were found by Western blotting in some of the rabbits. No evidence of clinical disease was seen in our normal animals. These data underline the difficulties often associated with the reproduction of animal models in different laboratories.

Animals↗
PubMed1999

Structure-function analysis and the molecular origins of anti-DNA antibodies in systemic lupus erythematosus.

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE or 'lupus') develop a wide variety of clinical and serological manifestations including the presence of antibodies to double-stranded DNA (dsDNA), which are often diagnostic and potentially pathogenic. In this review, we have examined the links between the structure and function of anti-dsDNA antibodies, emphasising their clinical associations. We have also reviewed studies involving animal models, the analysis of human antibody sequences and studies of, and using, computer modelling and crystal structure.

Journal Article↗
PubMed1999

Signal transducer and activator of transcription-1 and heat shock factor-1 interact and activate the transcription of the Hsp-70 and Hsp-90beta gene promoters.

We have previously demonstrated that interleukin-6 (IL-6) increases the levels of the heat shock protein 90 (Hsp-90) and activates the Hsp-90beta promoter via the IL-6-activated transcription factors NF-IL6 and signal transducer and activator of transcription-3 (STAT-3). Here, we show that interferon-gamma (IFN-gamma) treatment increases the levels of Hsp-70 and Hsp-90 and also enhances the activity of the Hsp-70 and Hsp-90beta promoters with these effects being dependent on activation of the STAT-1 transcription factor by IFN-gamma. These effects were not seen in a STAT-1-deficient cell line, indicating that IFN-gamma modulates Hsp induction via a STAT-1-dependent pathway. The effect of IFN-gamma/STAT-1 was mediated via a short region of the Hsp-70/Hsp-90 promoters, which also mediates the effects of NF-IL6 and STAT-3 and can bind STAT-1. This region also contains a binding site for the stress-activated transcription factor HSF-1. We show that STAT-1 and HSF-1 interact with one another via a protein-protein interaction and produce a strong activation of transcription, which is in contrast to our previous finding that STAT-3 and HSF-1 antagonize one another. To our knowledge this is the first report of HSF-1 interacting directly via a protein-protein interaction with another transcription factor. Such protein-protein interactions and the binding of a number of different stress and cytokine-activated transcription factors to a short region of the Hsp-90 and Hsp-70 gene promoters are likely to play a very important role in Hsp gene activation by non-stressful stimuli and the integration of these responses with the stress response of these genes.

Binding Sites↗
PubMed1999

A longitudinal study of anticardiolipin antibody levels and cognitive functioning in systemic lupus erythematosus.

OBJECTIVE: To determine the relationship between persistently raised anticardiolipin antibody (aCL) levels and neuropsychological performance in patients with systemic lupus erythematosus (SLE). METHODS: Forty-five patients with SLE underwent a detailed neuropsychological assessment on 2 occasions 12-18 months apart. Serum samples stored since the time of previous assessments as well as samples obtained 6 months to 2 years before the first neuropsychological assessment were tested for IgG aCL levels. Patients were divided into 4 groups according to the number of times their aCL levels were elevated (never, once, twice, 3 times). A wide-ranging battery of new neuropsychological tests was utilized, and the results were compared with double-stranded DNA (dsDNA) antibody levels, C3 levels, and results of magnetic resonance imaging (MRI). RESULTS: Analysis of variance revealed that the group with persistently elevated aCL levels performed less well than the other groups. At the first neuropsychological assessment, poorer performance by this group was noted for letter cancellation (P = 0.02), trail making task B (P = 0.04), and digit span (P = 0.03). At the second assessment, letter cancellation (P = 0.01), trail making task A (P = 0.03), trail making task B (P = 0.01), word fluency (P = 0.01), and reaction time (P = 0.05) were impaired. In contrast, no significant differences in neuropsychological test results were identified with respect to DNA antibody or C3 levels. MRI abnormalities were associated with both persistent elevation of aCL levels and low C3 levels. CONCLUSION: Levels of IgG aCL that were persistently elevated over a 2-3-year period (as opposed to never or occasionally elevated) were associated with significantly poorer performance in cognitive function by patients with SLE. Tasks requiring speed of attention and concentration appear to be particularly affected.

Adult↗
PubMed1999

Malignant lymphoma in primary Sjögren's syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjögren's Syndrome.

OBJECTIVE: Several reports have noted an increased incidence of malignant lymphoma in patients with Sjögren's syndrome (SS). Each case series has consisted of a limited number of patients with malignant non-Hodgkin's lymphoma (MNHL). In this report, we describe the disease characteristics, the clinical course, and the evolution in 33 patients followed up in 9 European medical centers. METHODS: The pool of MNHL patients from participating centers in a European Concerted Action on SS were analyzed. We report on the disease characteristics, its evolution, prognosis, current treatment practices, and survival. RESULTS: The MNHLs in this study were primarily situated in the marginal zone (48.5%), with the manifestations mostly extranodal (78.8%) and most often identified in the salivary glands (54.6%). Lymphadenopathy (65.6%), skin vasculitis (33.3%), peripheral nerve involvement (24.2%), low-grade fever (25.0%), anemia (48.1%), and lymphopenia (78.6%) were observed significantly more frequently than in the general SS population. Patients with high-to-intermediate grade lymphoma had significantly worse survival (P = 0.041). The presence of B symptoms (fever, night sweats, and weight loss) and a large tumor diameter (>7 cm) were additional independent risk factors for death. CONCLUSION: The novel observations of this study were those related to the type of MNHL, the survival prognosis, and the very high frequency of skin vasculitis, peripheral nerve involvement, anemia, and lymphopenia. Some of the previously reported results on extranodal manifestations were confirmed.

Follow-Up Studies↗
PubMed1999

The association of anti-Ro52 autoantibodies with myositis and scleroderma autoantibodies.

The presence of autoantibodies to the Ro52 protein in sera from patients with idiopathic inflammatory myopathies has recently been reported. These antibodies were found predominately in sera with the myositis-specific autoantibody anti-histidyl-tRNA synthetase (anti-Jo-1). In this report, we analysed sera from 216 patients to determine whether anti-Ro52 antibodies are associated with myositis autoantibodies other than anti-Jo-1. These included sera containing antibodies that recognize threonyl- or alanyl-tRNA synthetases, Mi-2, PM-Scl, signal recognition particle (SRP), as well as the systemic sclerosis-related antibodies anti-topoisomerase I (Scl-70) and anti-centromere. A high proportion of sera that contain anti-aminoacyl-tRNA synthetase antibodies, anti-SRP, or anti-PM-Scl antibodies were found to contain antibodies to the Ro52 protein. In contrast, in sera containing anti-Mi-2, anti-Scl-70 or anti-centromere antibodies, anti-Ro52 antibodies were absent or occurred infrequently. In addition, only one serum from 41 rheumatoid arthritis patients was positive for anti-Ro52 autoantibodies. These data indicate that anti-Ro52 antibodies are produced in particular subsets of myositis patients, and are not limited to sera with anti-Jo-1 antibodies.

Amino Acyl-tRNA Synthetases↗
PubMed1999

Interleukin-10 activates heat-shock protein 90beta gene expression.

Elevated levels of the cytokine interleukin-10 (IL-10) have been reported in patients with active systemic lupus erythematosus (SLE). Any role for IL-10 in the pathogenesis of SLE is likely to involve the activation of expression of specific genes within its target cells. We have previously reported elevated levels of the 90 000 MW heat-shock protein (hsp 90) and autoantibodies to hsp 90 in patients with SLE. Recent studies have shown that the cytokine IL-6 activates hsp 90 gene expression via specific transcription factors that include STAT-3 (signal transducer and activator of transcription 3). In view of the known role of STAT proteins in IL-10 signalling pathways, we have investigated the effect of IL-10 on hsp 90 gene expression. Here we report that IL-10 enhances the expression of hsp 90 in both a human hepatoma cell line (HepG2) stably expressing the human IL-10 receptor and peripheral blood mononuclear cells (PBMC). In reporter gene assays IL-10 is able to activate both the hsp 90alpha and hsp 90beta promoters directly. Furthermore, a short region of the hsp 90beta promoter which is activated in response to IL-10, contains a STAT-3 binding site. This element but not a mutant derivative unable to bind STAT-3, is able to confer a response to IL-10 on a heterologous promoter. These results may be understood in terms of the shared signalling mechanisms of IL-10 and IL-6 and provide evidence of a role for IL-10 in the overexpression of hsp 90 in SLE, with possible pathological consequences.

Acute-Phase Proteins↗
PubMed1999

A review of gastrointestinal manifestations of systemic lupus erythematosus.

In this review, we analyse critically the effects of systemic lupus erythematosus (SLE) on the gastrointestinal (GI) tract from mouth to anus, attempting to distinguish the features that are most likely to be due to therapy. GI manifestations of SLE include mouth ulcers, dysphagia, anorexia, nausea, vomiting, haemorrhage and abdominal pain. GI vasculitis is usually accompanied by evidence of active disease in other organs. Early recognition of the significance of these symptoms offers the best opportunity to improve the symptoms and to aid long-term survival.

Gastrointestinal Diseases↗
PubMed1999

The association of socio-economic status, race, psychosocial factors and outcome in patients with systemic lupus erythematosus.

OBJECTIVE: To determine the relationship between socio-economic status, race, psychosocial factors and outcome in patients with systemic lupus erythematosus (SLE). METHODS: One hundred and ninety-five patients with SLE were studied at two centres in the UK (London and Birmingham). Information about sociodemographics, income, employment status, social support and satisfaction with care was obtained. Outcomes were assessed by end-organ damage, disease activity and employment status. RESULTS: Non-Caucasian race, longer disease duration, higher disease activity and lower level of education were associated with more organ damage in SLE. More satisfaction with access to care and interpersonal aspects of care, but less satisfaction with time spent with doctors, were also associated with more damage. Very long disease duration was associated with higher disease activity. Patients with higher disease activity, lower level of education and from the Birmingham centre were more likely not to be working due to their lupus. CONCLUSION: Race and socio-economic status, as well as clinical and psychosocial factors, determine outcome in SLE.

Adult↗
PubMed1999

Oxidative stress in systemic lupus erythematosus and allied conditions with vascular involvement.

OBJECTIVE: To evaluate the occurrence and clinical significance of lipid peroxidation (oxidative stress) in rheumatic diseases characterized by vascular involvement. PATIENTS AND METHODS: Plasma 8-epi-PGF2alpha (oxidative stress marker) was measured by gas chromatography-mass spectrometry in 36 patients with systemic lupus erythematosus (SLE), 13 with systemic sclerosis (SSc), 13 with systemic vasculitis [Wegener's granulomatosis (WG), n = 4; Churg Strauss syndrome (CSS), n = 3; Behcet syndrome, n = 6], 12 with rheumatoid arthritis (RA) and in 23 healthy controls (n = 23). RESULTS: 8-epi-PGF2alpha levels were higher in patients with SLE (P = 0.007), SSc (P < 0.001) and vasculitis (P = 0.001) than in controls. In SLE, a positive Coombs' test and arterial hypertension independently predicted 8-epi-PGF2alpha concentrations (P = 0.004 and P = 0.001, respectively). SLE patients not taking prednisolone showed higher 8-epi-PGF2alpha concentrations than SLE patients on prednisolone (P = 0.02). In the latter group, a dose response relationship was noted between 8-epi-PGF2alpha and steroid dosage (r = 0.6, P = 0.0003). In WG and CSS, 8-epi-PGF2alpha concentrations correlated with disease activity (r = 0.8, P = 0.01) and were higher than in patients with Behcet disease (P = 0.003). CONCLUSIONS: Oxidative stress may be pathogenetically relevant in some autoimmune rheumatic diseases with vascular involvement. Amelioration of some clinical manifestations of these diseases may be envisaged by targeting lipid peroxidation with dietary or pharmacological antioxidants.

Adult↗
PubMed1999

Animal models of the antiphospholipid syndrome.

The antiphospholipid antibody syndrome (APS) is characterized by thrombocytopenia, recurrent thromboembolic phenomena and recurrent fetal loss, in association with anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA). Owing to the ethical and practical restrictions of experimentation on humans, we have to look to animal experimentation to broaden our knowledge of the pathogenesis and management of APS. Work has been carried out predominantly on strains of naive mice in which APS has been induced, passively and actively, using autoantibodies, autoantigens and other antigens. Studies of autoimmune-prone mice and naive rabbits are present in the literature, to a lesser degree. We review the various animal models of the pathogenesis of APS, whether spontaneous or induced, which have been developed over the years. Although several of the models have provided insights into the relationship between antiphospholipid antibodies and fetal loss, very few give guidance to explain the link with thrombosis. Novel or experimental therapeutic regimens have to be tested on appropriate animal models before any kind of human clinical trials may proceed. The regimens devised thus far are also reviewed.

Animals↗
PubMed1999

Ro/SSA and La/SSB specific IgA autoantibodies in serum of patients with Sjögren's syndrome and systemic lupus erythematosus.

OBJECTIVE: To investigate the occurrence of IgA autoantibodies to Ro 52 kDa, Ro 60 kDa and La antigen in serum of patients with primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE). METHODS: Recombinant Ro 52 kDa, Ro 60 kDa and La antigens were used to analyse autoantibodies in serum from 25 patients with pSS, 30 patients with SLE and 20 controls using a semiquantitative immunoblotting approach. RESULTS: Among the patients with pSS, 21 (84%) had detectable IgA autoantibodies to Ro 52 kDa, 13 (52%) to Ro 60 kDa and 20 (80%) to La antigen. The corresponding results for the patients with SLE were 22 (73%), 14 (47%) and 20 (67%), respectively. No IgA autoantibodies against the three antigens were detected in 20 normal controls. A comparison of several clinical features with the titres of IgA antibodies to Ro 52 kDa, Ro 60 kDa and La, revealed a significant relation between IgA anti-Ro 52 and IgA anti-La to sicca (p< 0.05). Semiquantitative data suggest that IgG is the dominating antibody to the three antigens followed by IgM > IgA in both SLE and pSS patients. Specificity studies of IgA autoantibodies with different subfragments of Ro 52 kDa and Ro 60 kDa antigens showed that IgA antibodies did not differ from IgG and IgM in their recognition pattern. CONCLUSION: These results suggest that besides IgM and IgG, IgA autoantibodies are also detected at high frequency in patients with pSS and SLE. Further studies are necessary to evaluate the contribution of these IgA autoantibodies to inflammation as well as their diagnostic value.

Adult↗
PubMed1999

Immunisation of patients with systemic lupus erythematosus: the current state of play.

Concerns regarding the safety and efficacy of immunisation in patients with SLE have persisted for over 50 y and indeed infection remains a leading cause of morbidity and mortality in these patients. There have been many anecdotal reports in the literature linking vaccination with either induction or exacerbation of SLE disease. However prospective studies have shown that immunisation with inactivated/killed vaccines is probably safe in patients with SLE. Individuals on immunosuppressive agents and/or high dose steroid (more than 20 mg/d) should not receive live vaccines, as stated in guidelines proposed by the British Society of Rheumatology. The safety of hepatitis B vaccination in patients with SLE is as yet undetermined and a prospective study is required. However until such evidence becomes available the advice of the BSR should be followed and patients with SLE who are at risk of exposure should be vaccinated. It remains uncertain whether the immune response to immunisation is significantly impaired by active disease and/or immunosuppressive treatment and to what extent. Most patients do however seem to mount a satisfactory immune response though this may not be quantitatively and qualitatively the same as healthy controls.

Communicable Disease Control↗
PubMed1999

Autoimmune rheumatic diseases and the heart.

Involvement of the heart is a common finding in autoimmune rheumatic diseases. Although clinically silent changes are common, potentially life-threatening manifestations are well known but early recognition is important if appropriate therapy is to be instituted.

Antiphospholipid Syndrome↗