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Biomedical subjects

D A Isenberg

Publications and source records attributed to D A Isenberg.

At least 91 records · Page 5Linked to original sources
PubMed2001

The effect of interleukin-10 and of interleukin-12 on the in vitro production of anti-double-stranded DNA antibodies from patients with systemic lupus erythematosus.

IL-10 and IL-12 are cytokines which are important in regulating immune responses. Plasma levels of IL-10 and autoantibodies against double-stranded DNA (dsDNA) often mirror disease activity in patients with SLE. IL-12 secretion from SLE patients' blood mononuclear cells also correlates with disease activity, but has an inverse relationship. The aim of this study was to measure the effect of IL-10 and of IL-12 on the production of IgG autoantibodies from patients with SLE, both cross-sectionally and longitudinally. Peripheral blood mononuclear cells (PBMC) were cultured with IL-10 (at 20 ng/ml or 2 ng/ml) or IL-12 (at 2 ng/ml or 0.2 ng/ml) or without cytokine and the supernatanants tested for the production of double-stranded DNA antibodies (dsDNA abs), single-stranded DNA antibodies (ssDNA abs) and total IgG antibodies (IgG abs) by ELISA. The BILAG disease activity index was recorded at each patient visit (a global score of six or more is regarded as active disease). In general, treatment with IL-10 caused PBMCs from patients with inactive disease to increase their antissDNA and dsDNA ab production (by upto 354% and 186%, respectively) while patients with active disease decreased their antibody production (by upto 91% and 97%, respectively). Overall there was a correlation between disease activity and change in antissDNA and dsDNA ab production (r = - 0.51; P = 0.03 and r = - 0.48; P = 0.042, respectively). Treatment with IL-12 at 0.2 ng/ml inhibited antissDNA and dsDNA antibody production, having the greatest effect on patients with active disease (decreasing antissDNA and dsDNA antibody production by upto 75% and 73%, respectively). This resulted in a significant correlation between disease activity and change in antissDNA antibody production (r = - 0.76; P = 0.03), but significance was not reached with antidsDNA antibody production (P = 0.06). Together these data suggest that the effect of these cytokines on antibody production by SLE PBMCs involves several factors; one of which is disease activity.

Adolescent↗
PubMed2001

A human anti-dsDNA monoclonal antibody caused hyaline thrombi formation in kidneys of 'leaky' SCID mice.

There are few studies assessing the pathogenicity of human monoclonal anti-DNA antibodies. The use of SCID mice avoids the problem of rejection of the human hybridoma cells thus allowing in vivo assessment of human immunoglobulins. Using electron microscopy we have shown that the human IgG anti-dsDNA monoclonal antibody, RH14, is nephritogenic in SCID mice, causing morphological changes in the kidney due to immunoglobulin deposition. The problem with using SCID mice is that they have an abnormal immune system; normally they are used at about 2 months of age, at which time they have virtually no functional T or B cells. It is known that older SCID mice become increasingly 'leaky', that is they develop some mature lymphocyte clones. Our aim was to assess if implanting anti-DNA antibodies into older 'leaky' SCID mice would result in pathology which was observable by light microscopy. Eight-month-old SCID mice were implanted with human hybridoma cells secreting either RH14 an anti-dsDNA IgG, CL24, an antiphospholipid antibody or an irrelevant human IgG control. As previously, RH14 deposited in the kidney and caused proteinuria but unexpectedly we also observed hyaline thrombi in the kidney glomeruli and peritubular capillaries. These thrombi occurred only in the case of RH14 implanted mice and were found to stain positively for human IgG and fibrin. However, apart from the interesting thrombi, we did not observe any greater pathological damage resulting from the anti-dsDNA antibody deposition than we had seen in the younger mice; indeed, the electron microscopic findings were more limited.

Animals↗
PubMed2001

Rheumatic diseases and malignancy--is there an association?

An association between rheumatic diseases and malignancy has been claimed in a variety of settings. This editorial reviews published data addressing the overall risk of malignancy, and of particular types of cancer, in the context of various autoimmune rheumatic diseases. For patients with Sjögren's syndrome, systemic sclerosis with pulmonary fibrosis, or with dermatomyositis/polymyositis there is a documented association with an increased risk of malignant disease. Patients with rheumatoid arthritis may also have an increased risk of cancer. It is still controversial whether systemic lupus erythematosus is associated with an increased risk of developing malignancy. More epidemiologic studies are needed to try and clarify many of these associations, in particular the potential risks associated with cytotoxic therapy.

Autoimmune Diseases↗
PubMed2001

Total costs and predictors of costs in patients with systemic lupus erythematosus.

OBJECTIVE: To determine the annual direct, indirect and total costs and predictors of costs in patients with systemic lupus erythematosus (SLE). METHODS: One hundred and five patients with SLE completed questionnaires on health-care utilization and employment history. Predictors of costs were determined by multiple regression analyses using direct, indirect and total costs as outcome variables. Demographics, health status, disease activity, end-organ damage, social support and satisfaction with care were used as predictor variables. RESULTS: The mean annual total cost per patient was pounds sterling 7913. Direct costs were a third and indirect costs two-thirds of the total cost. Higher education level, greater disease activity and lower physical functioning were associated with higher direct, indirect and total costs. Higher direct costs were also associated with greater damage and younger age. CONCLUSION: SLE has a considerable impact on the health-care system and society. Improvement in disease activity and physical health and prevention of end-organ damage may reduce costs in SLE.

Adolescent↗
PubMed2001

Proposed preliminary core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies.

In order to develop a preliminary core set of disease outcome measures for use in clinical trials of idiopathic inflammatory myopathies (IIM), we evaluated those measures used in previous trials, assessed the validation of published instruments and discussed these at an international consensus conference. The initial proposals were further refined by a multidisciplinary group of adult and paediatric specialists experienced in IIM using the Delphi method. The proposed preliminary core set of disease activity measures consists of five domains: physician and patient/parent global assessments of disease activity; muscle strength; physical function; serum activity of muscle enzymes; and an assessment tool to capture extra-skeletal muscle disease activity. The group recommended further development of a core set of disease damage measures for assessment of persistent changes in anatomy, pathology and function of at least 6 months' duration. The group recommended that patient-reported outcomes should include generic health-related quality of life assessments using the Medical Outcomes Study 36-item Short Form (SF-36) health survey in adult IIM patients and a validated quality of life instrument for paediatric patients. We propose the core set of outcome measures as a minimum group of assessments to include in all IIM therapeutic studies. The use of this core set should assist in standardizing outcome measurement and in optimizing therapeutic trials in myositis.

Adult↗
PubMed2001

An analysis of clinical disease activity and nephritis-associated serum autoantibody profiles in patients with systemic lupus erythematosus: a cross-sectional study.

OBJECTIVE: To establish the correlation between lupus nephritis-associated autoantibody levels and the presence/activity of lupus nephritis and global disease activity using cross-sectional data in patients with systemic lupus erythematosus (SLE). METHODS: Disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) index. Antibody levels against single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), histones, nucleosomes and heparan sulphate (HS) were analysed by ELISA in SLE patients with (n=11) and without (n=22) nephritis and in normal controls (n=21). Antibody subclasses were also analysed. RESULTS: Higher levels of anti-dsDNA and anti-HS antibodies were found in patients with lupus nephritis, the level of anti-HS antibodies correlating with the BILAG renal score. Predominant subclasses were IgG1 and IgG3 for dsDNA antibodies, IgG2 for anti-nucleosome antibodies, and IgG2 and IgG3 for anti-HS antibodies. CONCLUSION: Correlation was demonstrated between antibodies to dsDNA, ssDNA, histones, nucleosomes and HS. There is a strong correlation between the level of anti-HS antibodies and disease activity in patients with lupus nephritis as measured by BILAG.

Adult↗
PubMed2001

Comparison of renal disease severity and outcome in patients with primary antiphospholipid syndrome, antiphospholipid syndrome secondary to systemic lupus erythematosus (SLE) and SLE alone.

OBJECTIVE: To ascertain the clinical presentation, histopathology and outcome of renal involvement in patients with primary antiphospholipid syndrome (PAPS), antiphospholipid syndrome secondary to systemic lupus erythematosus (SAPS) and systemic lupus erythematosus alone. METHOD: A retrospective analysis was undertaken of 20 patients with PAPS, 25 patients with SAPS and 275 patients with systemic lupus erythematosus to ascertain the frequency and pattern of renal involvement. RESULTS: Renal involvement was found most frequently in patients with SAPS, in whom it occurred in 68% of patients. Renal disease was equally common in patients with PAPS and systemic lupus erythematosus alone where it was seen in 30% of patients. Patients with systemic lupus erythematosus most frequently presented with nephrotic syndrome due to glomerulonephritis, whereas those with PAPS and SAPS were more likely to present with hypertension and reduced glomerular filtration rate. No patients with PAPS developed end-stage renal failure compared with 5.9% of patients with SAPS and 16.9% of patients with systemic lupus erythematosus alone; 23.5% of patients with SAPS died compared with 15.7% of patients with systemic lupus erythematosus alone and no patients with PAPS. CONCLUSION: Renal involvement is a major feature of both PAPS and SAPS, where renal thrombosis frequently leads to reduced glomerular filtration rate and hypertension. One-third of patients with systemic lupus erythematosus alone develop glomerulonephritis leading to renal disease which most commonly presents with nephrotic syndrome. Patients with PAPS were less likely to develop end-stage renal failure or die during the follow-up period.

Adolescent↗
PubMed2001

Assessment of inflammatory myositis.

The assessment of disease activity and damage in patients with idiopathic inflammatory myositis remains inadequate. In this review we describe current approaches to the assessment of disease activity and damage. These include serologic, biochemical, radiographic, and histologic approaches. None of these methods are individually effective in differentiating disease activity from damage. Invariably combinations of these methods are needed to comprehensively assess the extent of both muscular and extramuscular disease. Recent developments (in serology, imaging, and genetics) are mentioned. These may prove to be useful in assessing the full extent of idiopathic inflammatory myositis; however, they are not widely available at present and are confined to research studies

Blood↗
PubMed2001

Use of anti-citrullinated peptide and anti-RA33 antibodies in distinguishing erosive arthritis in patients with systemic lupus erythematosus and rheumatoid arthritis.

OBJECTIVES: Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) can both present with an erosive arthritis with the small joints of the hands affected. Therefore a serological marker would be useful to distinguish between these two diseases at onset. In this study anti-RA33 antibodies, which are found in patients with SLE and RA, and anti-citrullinated peptide antibodies (anti-CCP), which have recently been described as highly specific for RA, were assessed. METHODS: Two hundred and thirty one patients receiving long term follow up for SLE were evaluated for arthritis and classified as erosive and non-erosive disease. Sixty six patients were tested for anti-RA33 and anti-CCP antibodies. All the patients were tested for rheumatoid factor (RF) and HLA-DR4 status. RESULTS: Ten patients had erosive disease, six of whom were RF positive (60%), and six anti-RA33 positive (60%), whereas only two were anti-CCP positive (20%). Two hundred and twenty one patients had non-erosive disease, 40 of whom were RF positive (18%), 14 were anti-RA33 positive (6%), whereas only one patient was found to be anti-CCP positive (0.5%). CONCLUSION: The presence of anti-CCP antibodies may be useful in distinguishing RA from erosive SLE. Anti-RA33 antibodies and RF are unhelpful.

Antibodies, Antinuclear↗
PubMed2001

Counter-proliferative effects of nucleosomal antigens in cultures from lupus patients.

Blood mononuclear cells from 20 lupus patients were cultured in the presence of nucleosomal antigens to determine whether they induce lymphocyte proliferation. The predominant effect seen, however, was one of inhibition of the background proliferation. Such inhibition was rare with cells from female or male controls. Nucleohistone (NH), crude histone and enriched preparations of histones H2A/H4, H2B and H3 showed this effect in approximately one-third of patients, but H1 and single-stranded (ss) DNA had no such activity. Double-stranded (ds) DNA may show this inhibitory action, but further tests are required. ssDNA was the only antigen that showed evidence (two patients) of disease-related stimulation of proliferation. Histones and NH induced proliferation in many subjects but the strongest responders were controls. Patients responded poorly to tuberculin PPD but gave an exceptionally strong proliferative response to pokeweed mitogen. It is suggested that the inhibition of background proliferation in patients is a consequence of the interaction of nucleosomal antigens with sensitised T cells. If T cell sensitisation to histones is an important factor in the development of lupus, the disease may be preventable in those at risk by inducing tolerance to the appropriate peptides.

Adult↗
PubMed2001

Spontaneous rupture of the spleen: an unusual complication of systemic lupus erythematosus.

Although splenic abnormalities are widely recognised in patients with lupus, spontaneous rupture of the spleen is rare. We describe a patient whose spleen ruptured spontaneously 19 years after the onset of her disease, and compare this case with four others that have been described in the previous literature. Possible contributing factors to this rupture are discussed.

Adult↗
PubMed2000

Molecular cloning and expression of the Fabs of human autoantibodies in Escherichia coli. Determination of the heavy or light chain contribution to the anti-DNA/-cardiolipin activity of the Fab.

The Fabs of three human autoantibodies (B3/33H11, anti-DNA; UK4, anti-phospholipid) and six related hybrids have been cloned, expressed in Escherichia coli, and purified to homogeneity. SDS-polyacrylamide gel electrophoresis and Western blot analysis of the recombinant Fab demonstrated the purified Fab to be of correct size and in assembled form. Protein expression levels of up to 5-9 mg per liter of culture were achievable. A sensitive and reliable comparative anti-DNA enzyme-linked immunosorbent assay, involving a defined biotinylated 35-mer oligonucleotide in its single- or double-stranded form, is also described. Crithidia assay and anti-DNA or anti-cardiolipin antibody enzyme-linked immunosorbent assay analyses demonstrated convincing binding of the recombinant Fab proteins to DNA/cardiolipin, confirming the expression of functional molecule. The comparative DNA/cardiolipin binding analyses of the nine Fabs revealed that the anti-DNA (light, B3/33H11) or anti-cardiolipin (heavy, UK4) activity lies predominantly on one of the two chains. However, a compatible partner chain is necessary for optimum antigen binding activity of the antibody.

Animals↗
PubMed2000

Anti-SSA/Ro52 autoantibodies blocking the cardiac 5-HT4 serotoninergic receptor could explain neonatal lupus congenital heart block.

The 52-kDa SSA/Ro (Ro52) ribonucleoprotein is an antigenic target strongly associated with the autoimmune response in mothers whose children develop neonatal lupus and congenital heart block. When sera from patients with systemic lupus erythematosus were used as autoimmune controls in an enzyme immunoassay to screen for antibodies against the human serotoninergic 5-HT4-receptor, a high correlation was found between the presence of anti-Ro52 protein antibodies in such sera and antibodies reacting with a synthetic peptide, corresponding to the second extracellular loop of the human 5-HT4 receptor (amino acid residues 165-185). Homology scanning between the 5-HT4 peptide and the sequence of the Ro52 protein indicated two potential common epitopes located between residues 365 and 396 of the Ro52 protein. Cross-reactivity was found between the peptide derived from the 5-HT4 receptor, and a peptide corresponding to residues 365-382 of the Ro52 protein. Autoantibodies, affinity-purified on the 5-HT4 receptor peptide, specifically recognized both the Ro52 protein and the 5-HT4 receptor protein in immunoblots. The affinity-purified antibodies antagonized the serotonin-induced L-type Ca channel activation on human atrial cells. This effect could explain the electrophysiological abnormalities in neonatal lupus.

Adult↗
PubMed2000

The use of alternative medical therapies in patients with systemic lupus erythematosus. Trination Study Group.

OBJECTIVE: As part of an ongoing study of health resource utilization and diminished productivity in patients with systemic lupus erythematosus (SLE), the use of alternative medical therapies was assessed. METHODS: A cohort of 707 patients with SLE from 3 countries completed questionnaires on demographics, social support, health status (using the Short Form 36 health survey), satisfaction with health care, health resource utilization (conventional resources and alternative therapies), and time losses in labor market and non-labor market activities. Annual direct and indirect costs (1997 Canadian dollars) were calculated and compared for users and nonusers of alternative medical therapies. RESULTS: Among the 707 patients, 352 (49.8%) were found to use alternative therapies and at similar rates across Canada, the United States, and the United Kingdom. Users were younger and better educated than nonusers, exhibited poorer levels of self-rated health status and satisfaction with medical care, and had minimal to no objective evidence of worse disease (according to the revised Systemic Lupus Activity Measure instrument). The mean of log direct medical costs for conventional resources was higher for users of select alternative therapies compared with nonusers. In a logistic regression, neither the number of alternative therapies used nor the individual therapy increased the probability of incurring indirect costs. CONCLUSION: The use of alternative medical therapies is common in patients with SLE. Users of many alternative medical therapies accrue greater conventional medical costs compared with nonusers. The use of alternative medical therapy may be a marker for care-seeking behavior associated with higher consumption of conventional medical resources in the absence of demonstrable additional morbidity and should be considered in future cost analyses of patients with SLE.

Adult↗