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D A Isenberg

Publications and source records attributed to D A Isenberg.

At least 37 records · Page 2Linked to original sources
PubMed2005

New therapies for systemic lupus erythematosus.

In the past 40 years, prognosis for patients with systemic lupus erythematosus (SLE) has improved, with 10-year survival now approximately 90%. This is due probably to a combination of earlier disease diagnosis and diagnosis of milder disease, due in part to availability of multiple serological tests for SLE, use of steroids and other immunosuppressive agents, and availability of renal dialysis and transplantation. Despite this, however, the potential for significant morbidity and mortality remains in the group of patients with partially responsive or treatment resistant disease. More recently, advancements in the understanding of molecular mechanisms involved in the pathogenesis of SLE have translated to the development of novel therapies, offering possible alternatives to this patient cohort. Discussion of these pharmacological options and ongoing research forms the basis of this review.

Antirheumatic Agents↗
PubMed2005

Natural killer cell activity in families of patients with systemic lupus erythematosus: demonstration of a killing defect in patients.

Natural killer (NK) cell cytotoxic activity and cell frequency, expressed as a percentage of total lymphocytes, have been determined in peripheral blood mononuclear cells from first-degree relatives of patients with systemic lupus erythematosus (SLE), the patients themselves, a group of rheumatoid arthritis (RA) patients and controls. Low levels of killing activity relative to controls were found in some members of all groups with the extent of depression falling into two ranges. Moderate reductions were seen in female (3/31, 10%) and male (4/14, 29%) relatives of SLE patients, female (12/60, 20%) and male (3/4, 75%) SLE patients and female RA patients (6/17, 35%). A more profound depression of killing activity was confined to other female SLE patients (15/60, 25%). There were strong correlations in all groups between killing activity and percentage of NK cells, but analysis of the ratio of these parameters and studies with purified preparations of NK cells suggest that the reduced activity in SLE frequently involves a defect in the killing capacity of the individual cells in addition to the reduced levels of NK cells. Azathioprine (AZA), which was used in treatment of 12 SLE patients, was invariably associated with low values of killing activity. It appears to substantially reduce the percentage of NK and B cells in an action unconnected with the NK cell abnormalities associated with SLE. The finding of low killing activity in relatives and a correlation between their activity and that of their patients support the view that NK cell deficiency is a genetic determinant of SLE. NK cells in SLE may produce insufficient levels of cytokines required for the regulation of IgG production.

Adolescent↗
PubMed2005

How to monitor SLE in routine clinical practice.

A century ago syphilis was regarded as the great masquerader. Its modern equivalent is lupus. It may present to a wide range of specialists and its outcome, while much improved, remains uncertain in a significant number of patients.

Biomarkers↗
PubMed2005

Raised levels of interleukin 6 in systemic lupus erythematosus correlate with anaemia.

OBJECTIVES: Raised levels of the cytokines interleukin (IL) 6 and IL10 have been reported in patients with systemic lupus erythematosus (SLE). OBJECTIVE: To determine if levels of IL6 and IL10 correlate with organ/system-specific disease activity in SLE, using the British Isles Lupus Assessment Group (BILAG) Disease Activity Index. METHODS: Levels of IL6 and IL10 in serum samples from 171 patients with SLE and 50 normal controls were determined by enzyme linked immunosorbent assay (ELISA). Levels of cytokines in individual patients with SLE were compared with the presence or absence of active disease in eight organ/systems using the BILAG index. RESULTS: Levels of IL6 were significantly higher (p = 0.005) in patients with active compared with inactive haematological disease, as scored by the BILAG index. Further analysis showed that this association was dependent on an inverse correlation (p = 0.002, r = -0.26) between IL6 levels and haemoglobin levels in patients with SLE. In contrast, IL10 levels did not correlate with individual organ/system disease activity. CONCLUSIONS: Raised levels of IL6 in SLE may influence the development of anaemia in this disease. These findings are in agreement with an increasing number of studies, which support physiological links between IL6 and anaemia. Importantly, with the exception of the haematological system, our studies do not provide evidence of any individual organ/system which would respond to therapeutic manipulation of either IL6 or IL10 levels.

Adolescent↗
PubMed2005

Development of additional autoimmune diseases in a population of patients with primary Sjögren's syndrome.

BACKGROUND: To investigate whether patients with primary Sjögren's syndrome (pSS) have an increased tendency to develop other autoimmune diseases. METHODS: A retrospective case note review was carried out on 114 patients in whom a diagnosis of pSS had been made in a department of rheumatology from 1979 onwards. The year of diagnosis of pSS was recorded, plus the diagnosis and year of diagnosis of any other identified autoimmune disease. RESULTS: Of the 114 patients with pSS, seven (6%) were male and 107 (94%) female. Mean age at diagnosis of pSS was 53 years (range 21 to 83). Patients were followed up for an average of 10.5 years (range 0 to 23). Thirty eight patients (33.3%) were diagnosed as having another autoimmune disease, while nine (7.9%) had two or more. Thirteen additional autoimmune diseases were identified. Twenty five diagnoses (51.0%) were made before the diagnosis of pSS, three (6.1%) within the same year, and 21 (42.9%) after the diagnosis. Hypothyroidism was the most common autoimmune disease (n = 16). CONCLUSIONS: Although pSS is a relatively benign condition, affected individuals have an increased tendency to develop additional autoimmune diseases. Patients with pSS should be monitored on a regular basis for such diseases.

Adult↗
PubMed2005

Novel therapies in lupus nephritis.

Renal disease continues to cause major morbidity and some mortality for around 30-40% of patients with systemic lupus erythematosus (SLE). Although the combinations of prednisolone and azathioprine or prednisolone and cyclophosphamide have been beneficial to many patients with SLE, they are not always effective and have significant side effects. It is very encouraging that new immunosuppressive drugs such as mycophenolate mofetil and more targeted therapies e.g., anti-CD20 are coming rapidly to larger scale clinical trials. The treatment of lupus nephritis is set to change quite rapidly in the next decade. In this review we highlight the likely major therapeutic advances.

Hematopoietic Stem Cell Transplantation↗
PubMed2005

Antiphospholipid antibodies are induced by in vitro fertilization and correlate with paraoxonase activity and total antioxidant capacity of plasma in infertile women.

The objectives of this study were to determine whether antiphosholipid antibodies are associated with in vitro fertilization (IVF), and assess the potential biological effects of these antibodies. Sera from seventy infertile women (18 before IVF, 13 submitted to one IVF cycle and 39 after three cycles) and 28 healthy controls were collected. Anticardiolipin (anti-CL) and antiphosphatidylserine (anti-PS) antibodies, paraoxonase (PON) and Total Anti-oxidant Capacity of plasma (TAC) were measured. Anti-CL and anti-PS titres were significantly increased in treated patients compared with patients before treatment or controls (P < 0.001). There were no differences regarding anti-CL and anti-PS titres between controls and untreated patients nor when different types of infertility were considered. PON activity and TAC were significantly reduced in treated patients when compared to untreated and controls (P < 0.001; P < 0.002). PON correlated inversely with anti-CL and anti-PS IgG (r = -0.734; P < 0.001) and directly with TAC (r = 0.720, P < 0.001). In conclusion PON activity is decreased in women submitted to IVF treatment and is associated with the presence of antiphospholipid antibodies. These factors might contribute to the increased oxidative status found in these patients.

Antibodies, Anticardiolipin↗
PubMed2004

The systemic lupus erythematosus Tri-nation Study: absence of a link between health resource use and health outcome.

OBJECTIVE: Health consumption and health status in SLE in three countries with different health funding structures were compared. METHODS: Seven hundred and fifteen SLE patients (Canada 231, USA 269, UK 215) were surveyed semi-annually over 4 yr for health resource utilization and health status. Cross-country comparisons of (i) cumulative health expenditure (calculated by applying 2002 Canadian prices to resources in all countries) and (ii) disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, SLICC/ACR DI) at study conclusion were performed after adjustment. Missing expenditure and damage data were managed through multiple imputation using best predictive regressions with all available data from all patients as potential covariates. RESULTS: Four hundred and eighty-five patients provided data at study entry and conclusion and at least four resource questionnaires (Canada 162, USA 157, UK 166); 41 died (Canada 13, USA 18, UK 10); 189 withdrew, were lost to follow-up or provided data at entry and conclusion but fewer than four resource questionnaires (Canada 56, USA 94, UK 39). At conclusion, after imputation, in Canada, the USA and the UK respectively, mean cumulative costs per patient over 4 yr [95% confidence interval (CI)] were $15,845 (13,509, 18,182), $20,244 (17,764, 22,724) and $17,647 (15,557, 19,737) and mean changes in SLICC/ACR DI were 0.49 (0.39, 0.60), 0.63 (0.52, 0.74) and 0.48 (0.39, 0.57). After adjustment for baseline differences, on average (95% CI), Canadian and British patients utilized 20% (8%, 32%) and 13% (1%, 24%) less resources than patients in the USA respectively, but experienced similar health outcomes. CONCLUSION: Despite patients in the USA incurring higher health expenditures, they did not experience superior health outcomes.

Adult↗
PubMed2004

Analysis of the relationship between disease activity and damage in patients with systemic lupus erythematosus--a 5-yr prospective study.

OBJECTIVE: To determine whether initial damage, disease duration, age, initial health status, average disease activity over the 5 yr or an average medication score covering the follow-up period would predict an increase in damage in patients with systemic lupus erythematosus (SLE) within the next 5 yr. METHODS: A 5-yr prospective longitudinal study of a cohort of 141 consecutive patients with SLE attending a specialist lupus out-patient clinic in London from their first assessment between July 1994 and February 1995. Disease activity was assessed using the BILAG system, initial health status by the Medical Outcome Survey Short Form 20 with an extra question about fatigue (SF-20+) and damage by the SLICC/ACR Damage Index (SDI). Damage was reassessed 5 yr later. Statistical analysis was carried out using multiple logistic regression analysis (logXact). RESULTS: One hundred and thirty-three female and eight male SLE patients (97 Caucasians, 16 Afro-Caribbeans, 22 Asians and 6 others) were included, their age at inclusion was 41.1 +/- 12.5 yr and their disease duration 10.2 +/- 6.3 yr. The mean measures at inclusion were: total BILAG 5.2 (range 0-17), total SDI 1.2 (0-7) and medication score 1.2 (0-3). Six patients were lost to follow-up because they had moved. Of the remaining 135 patients total damage had increased in 40 patients and 10 patients had died. At the end of the study, at 4.63 +/- 0.19 yr, the total SDI had increased to 1.6 +/- 1.7. Multiple logistic regression analysis revealed that death and increase in damage were strongly predicted by a high total disease activity over the entire study period (P<0.001) as we had hypothesized. When the total BILAG score was replaced by the average number of A-flares the prediction of accrual of damage during the study period was again highly significant (P = 0.004). CONCLUSIONS: In this first prospective study of its type a highly significant impact of total disease activity, as measured over 5 yr using the BILAG system, on the development of total damage was revealed. Moreover, these results provide further proof of the validity of the SDI and support the BILAG concept of the A-flares.

Adult↗
PubMed2004

Risk of coronary heart disease and stroke in a large British cohort of patients with systemic lupus erythematosus.

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) are at increased risk of myocardial infarction and stroke. We sought to determine how much of this risk was dependent on recognized cardiovascular risk factors. METHODS: Initially a software package 'Cardio-Risk-Manager', which utilizes Framingham data, was used to calculate a 10-yr risk of coronary heart disease (CHD) and stroke for 202 patients with SLE (Group 1) in comparison with hypothetical age- and sex-matched comparators. Subsequently 47 patients who had been followed since 1991 (Group 2) were studied to compare their predicted risks in 1991 with the actual number of cardiovascular events that occurred during the subsequent decade. RESULTS: Patients in Group 1 had a higher predicted 10-yr risk of stroke (P<0.0001), but not of CHD, than their comparators. However, following age stratification, traditional risk factors predicted a higher risk of CHD (P<0.0001) and of stroke (P<0.0001) in patients under 40 with SLE compared with age-matched comparators. The predicted 10-yr risks of CHD and stroke for patients aged 40 and above were not significantly different from those of their comparators. Predicted risks, however, were lower than the true 10-yr event rate for CHD and stroke in patients in Group 2. In this group, during the 10 yr of follow-up four patients (8.5%) suffered a CHD event and five patients (10.6%) had a stroke, significantly more than were predicted by the presence of conventional risk factors (P<0.001 for CHD and P<0.001 for stroke, respectively). CONCLUSIONS: Conventional risk factors predicted an increased risk of stroke and CHD in younger patients. They do not, however, fully explain the high risk of cardiovascular disease in patients with SLE. Although it is important to address the management of orthodox risk factors for cardiovascular disease in patients with SLE, other causes must be sought to explain the increased incidence of CHD and stroke, especially in those aged over 40.

Adult↗
PubMed2004

Effect of neutralizing antibodies to IL-10 and C5 on the renal damage caused by a pathogenic human anti-dsDNA antibody.

OBJECTIVES: There is considerable evidence suggesting that anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibodies are involved in the pathogenesis of lupus nephritis. It was shown previously using severe combined immune deficient (SCID) mice that when the hybridomas secreting human immunoglobulin G (IgG) anti-dsDNA antibodies, RH14 and DIL-6, were implanted intraperitoneally the antibodies produced by RH14, but not DIL-6, deposited in the kidneys, caused pathological changes in the renal tissues and induced proteinuria. In this study we have further analysed the effect of activated terminal complement proteins and interleukin-10 (IL-10) in the pathogenesis of glomerulonephritis caused by the RH-14. METHODS: SCID mice implanted with RH-14 or DIL-6 cell lines were treated with neutralizing antibodies to IL-10 (mAb B-S10) or anti-complement factor 5 (anti-C5) (mAb BB5.1) intraperitoneally. Control groups received either an isotype control antibody (135.8) or phosphate-buffered saline (PBS). Serum human IgG levels and proteinuria were estimated and the extent of renal involvement was examined by histopathological and electron microscopic techniques. RESULTS: While there was a tendency to reduce proteinuria in the anti-IL-10 injected group the anti-C5 injected group showed a significant reduction in proteinuria (P<0.01) compared with the groups injected with either the control mAb or PBS. There was a considerable reduction in the serum human IgG levels in the anti-IL-10 but not in the anti-C5 treated animals. Both anti-IL-10 and anti-C5 treated groups showed significantly reduced renal impairment as revealed by histopathological examination and proteinuria assessment. CONCLUSION: The findings, while confirming the role of IL-10 and activated terminal complement component in the production of antibody at the cellular level and at the site of glomerular immune deposition in this model, respectively, also suggest the beneficial effect of a combined therapy using both anti-IL-10 and anti-C5 mAb to prevent or reduce the effect of the humoral immune response in lupus disease.

Animals↗
PubMed2004

EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis.

OBJECTIVE: To compare the efficacy and side effects of intermittent pulse cyclophosphamide plus methylprednisolone with continuous oral cyclophosphamide plus prednisolone, followed by azathioprine, in patients with proliferative glomerulonephritis caused by systemic lupus erythematosus (SLE). METHODS: A multicentre randomised controlled trial was conducted between June 1992 and May 1996 involving eight European centres. All patients satisfied the American College of Rheumatology criteria for SLE and had biopsy proven proliferative lupus nephritis. All received corticosteroids in addition to cytotoxic drugs, as defined in the protocol, for two years. The trial was terminated after four years as recruitment was disappointing. RESULTS: 32 SLE patients with lupus nephritis were recruited: 16 were randomised to intermittent pulse cyclophosphamide and 16 to continuous cyclophosphamide plus azathioprine. Mean duration of follow up was 3.7 years in the continuous group (range 0 to 5.6) and 3.3 years in the pulse group (range 0.25 to 6). Three patients were excluded from the pulse therapy group as they were later found to have pure mesangial glomerulonephritis. Two patients in the continuous therapy group developed end stage renal failure requiring dialysis, but none in the intermittent pulse therapy (p = 0.488; NS). There were similar numbers of side effects and withdrawals from treatment in both groups. There were three deaths: two in the intermittent pulse therapy group and one in the continuous therapy group. CONCLUSIONS: There was no statistically significant difference in efficacy and side effects between the two regimens. Infectious complications occurred commonly, so careful monitoring is required during treatment.

Administration, Oral↗
PubMed2004

Antibodies to mannose binding lectin in patients with systemic lupus erythematosus.

Deficiency of mannose binding lectin (MBL), a C-type lectin with structural similarities to C1q, has been shown to predispose to the development of systemic lupus erythematosus (SLE). Some patients have low serum MBL levels which cannot be explained by either structural gene mutations or promoter polymorphisms. The objective of this study was to detect the presence of autoantibodies against MBL and to evaluate their relationship to serum MBL levels. Anti-MBL antibodies of IgM and IgG classes from consecutive SLE patients (n = 135) and healthy subjects (n = 50) were measured by an in-house ELISA. Using the 90th percentile of controls as a cutoff, more SLE patients [23.7% (32/135)] were found to have IgG anti-MBL antibodies than normal controls [10.0% (5/50)] (P = 0.04). The same trend was observed when ethnicity was taken into account by analysing Caucasians alone (n = 90). IgM anti-MBL antibodies were only found in two SLE patients (2/22, 9.1%) who had no concomitant IgG anti-MBL antibodies. Serum levels of IgG anti-MBL antibodies were found to correlate with serum MBL levels (r = 0.55, P = 0.049). However, the levels of anti-MBL antibodies did not correlate with overall disease activity. Thus the production of anti-MBL antibodies is likely to be a specific antigen-driven process. Its role in lupus pathogenesis remains to be elucidated.

Adult↗
PubMed2003

International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease.

OBJECTIVE: To devise new tools to assess activity and damage in patients with idiopathic myopathies (IIM). METHODS: An international multidisciplinary consensus effort to standardize the conduct and reporting of the myositis clinical trials has been established. Two tools, known as the myositis intention to treat index (MITAX) and the myositis disease activity assessment visual analogue scale (MYOACT), have been developed to capture activity in patients with IIM. In addition, the myositis damage index (MDI) has been devised to assess the extent and severity of damage developing in different organs and systems. These measures have been reviewed by the myositis experts participating in the International Myositis Assessment and Clinical Studies (IMACS) group and have been found to have good face validity and to be comprehensive. The instruments were assessed in two real patient exercises involving patients with adult dermatomyositis and inclusion body myositis. RESULTS: The reliability of MITAX, MYOACT and MDI, measured by the intraclass correlation coefficient among the physicians, and the inter-rater reliability, as assessed by variation in the physicians' rating of patients, was fair to good for most aspects of the tools. Reliability and inter-rater agreement improved at the second exercise after the participants had completed additional training. CONCLUSIONS: The MITAX, MYOACT and MDI tools, which are now undergoing validity testing, should enhance the consistency, comprehensiveness and reliability of disease activity and damage assessment in patients with myositis.

Acute Disease↗
PubMed2003

Definition and treatment of lupus flares measured by the BILAG index.

OBJECTIVES: The BILAG index is a clinical measure of lupus disease activity. It is valid, reliable and sensitive to change. Scoring in the BILAG index is based upon the physician's intention to treat. A flare of active lupus is defined as a new A or B score in at least one system. The main aim of this study was to determine whether patients with a lupus flare are treated as expected from the principles upon which the scoring system was devised. Secondly we wanted to establish whether patients with a new B score preceded by a C should be considered to have flared, as with patients scoring B following a D or E score. METHODS: Over a 12-month period, 250 patients regularly attending lupus clinics in Birmingham and London were assessed using the BILAG index at each visit. RESULTS: A new A or B score was observed in 154 (61.6%) patients. An A flare was observed in 26 (10.4%) patients. A B flare (in which the B score was preceded by a D or E score) was observed in 65 (26.0%) patients. There were 63 (25.2%) patients in whom there was a B score in a system in which a C score was previously recorded. Steroids were started or increased in 20 (77%) patients with an A flare. Almost all (92%) patients with a new A score had some increase in therapy. For the patients with new B scores, 53 (41%) had some increase in therapy, but multiple reasons were found for no change in therapy in 75 (59%) of these patients. There was no difference in the treatment of new B scores arising after a previous C score compared with previous D or E scores. Non-Caucasians were more likely to have a lupus flare than Caucasians. CONCLUSIONS: These results are consistent with the principles upon which the BILAG index was devised and suggest that a moderate disease flare can be defined as a new B score following a C, D or E score according to the BILAG index.

Adolescent↗
PubMed2003

Pregnancy outcome in adult-onset idiopathic inflammatory myopathy.

OBJECTIVES: To assess the prevalence of pregnancy in 28 females with dermatomyositis (DM) and polymyositis (PM), assess the outcome in those who became pregnant after the onset of the disease and review the literature of all published cases. METHOD: Fifty-four patients with myositis have been under long-term follow-up from 1976-2001 (28 female, nine male). RESULTS: Twenty-eight female patients were divided into 15 with pure DM/PM (seven PM, eight DM) and 13 with an overlap syndrome. The majority of patients had the onset of the disease after childbearing years (mean age of 32 yr for the overlap group and 41 for the DM/PM group). Only four of our patients (14.3%) have been pregnant after the onset of the disease. One patient had a spontaneous abortion, but was on methotrexate and had active disease; one had a late pregnancy loss, but had active disease; and the other two had uneventful pregnancies during a time when the disease was in remission. CONCLUSION: Fetal prognosis in the main reflects the level of maternal disease. The more active the myositis during the pregnancy, the greater the chance of fetal loss.

Adult↗