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Biomedical subjects

D A Isenberg

Publications and source records attributed to D A Isenberg.

At least 19 recordsLinked to original sources
PubMed2007

Development of additional autoimmune diseases in a multiethnic cohort of patients with systemic lupus erythematosus with reference to damage and mortality.

OBJECTIVES: To determine the prevalence of other autoimmune diseases (AID) in black, Caucasian and South Asian patients with systemic lupus erythematosus (SLE) compared with the prevalence of these AID in the UK population, and to assess the impact of these additional AID on damage scores and mortality. METHODS: The prevalence and chronology of development of additional AID in SLE patients was determined by case note review. Comparisons were made with prevalence data for AID in the general UK population. The impact of additional AID on mortality and damage scores at up to 10 years was determined in the index cases (patients who developed another AID either in the same year or within 5 years of onset of SLE) compared with controls matched for sex, age, ethnicity and year of onset of SLE. RESULTS: There was no significant difference in the total number of AID that developed in patients from each ethnic group but differences in the frequency of some AID were noted. Mortality and damage scores were worse at 5 years in the study cases than the controls, particularly in the peripheral vascular category. CONCLUSION: Patients with SLE might develop other AID that could complicate management of SLE by having an adverse impact on damage scores and mortality.

Adult↗
PubMed2006

Association of antinucleosome antibodies with disease flare in serologically active clinically quiescent patients with systemic lupus erythematosus.

OBJECTIVE: To identify the prevalence of serologically active clinically quiescent (SACQ) patients in a cohort of 290 patients with systemic lupus erythematosus (SLE). We investigated if the presence of anti-double-stranded DNA (anti-dsDNA) or antinucleosome (anti-NCS) antibodies during the SACQ period was associated with future flares. METHODS: SACQ patients defined as clinically inactive for 6 months (global British Isles Lupus Activity Group index [BILAG] scores <6) and serologically active (anti-dsDNA antibodies >50 units/ml on at least 2 occasions by enzyme-linked immunosorbent assay [ELISA]) were identified. Patient sera collected during the defined SACQ period were also tested for anti-NCS antibodies (ELISA). We retrospectively reviewed patient clinical details and episodes of flare using the BILAG activity index. RESULTS: Twenty-seven (9%) patients were SACQ. Seventeen (81%) patients experienced a flare (total of 91 flares, up to 12 flares per person) in the next 5 years. Median duration to first flare was 15 months (range 2-46). Time to first flare after SACQ period was significantly correlated with the presence of anti-NCS (P = 0.0012), high anti-NCS antibody titers (P = 0.0006), and anti-dsDNA titers 5 times above the normal limit (P = 0.02). Patients with higher absolute anti-NCS antibody titers showed a significant correlation with the number of flares (r = 0.57, P = 0.007). CONCLUSION: A minority of patients with SLE are SACQ. The majority of these patients experience a flare in the next 5 years and close followup is recommended. Anti-NCS antibodies may be a better predictor than anti-dsDNA antibodies for future flares.

Adult↗
PubMed2006

Incidence of cancer in a cohort of patients with primary Sjogren's syndrome.

OBJECTIVE: To compare the incidence of subsequent cancers in a cohort of patients with primary Sjögren's syndrome (pSS) with that of the general population in the same region of England. METHODS: A retrospective analysis was carried out on 112 patients who had attended the out-patients department at University College Hospital, London, from 1979 onwards. Patients were followed up from diagnosis of pSS to diagnosis of first subsequent cancer, death, loss to follow-up or 31 December 2003 (the censoring date) to determine the person-years at risk for each individual. The expected numbers of subsequent cancers were calculated from sex-/age-/period-specific rates for the general population of southeast England, derived from registrations at the Thames Cancer Registry. Standardized incidence ratios (SIRs) were then calculated as the ratio of observed to expected numbers of cancers, along with 95% confidence intervals (CIs). Separate analyses were performed for all malignant cancers combined, lymphomas and non-lymphoid cancers. RESULTS: Among the 112 patients with pSS, 25 developed cancer (either before or after development of pSS), with lymphoma occurring in 11 cases. Nine patients had two cancers. There was a significantly elevated incidence of lymphomas in pSS patients compared with the general population (SIR 37.5, 95% CI 20.7-67.6). For non-lymphoid cancer, the observed increase in incidence was small and not statistically significant (SIR 1.5, 95% CI 0.9-2.6). CONCLUSION: This study confirms that there is an increased incidence of lymphoma in patients with pSS. An increase in the incidence of other cancers was not proven but the observation that some patients developed more than one cancer raises the possibility that there may be a subgroup of patients who are at greater risk of developing cancer.

Adult↗
PubMed2006

B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles.

OBJECTIVE: Autoantibody production in patients with systemic lupus erythematosus (SLE) is associated with abnormalities of B cell function and phenotype. Clinical responses to B cell depletion therapy (BCDT), based on rituximab, are encouraging. Therefore, we undertook this study to investigate the effect of BCDT on antibody profiles. METHODS: Serial sera from 16 patients with active, refractory SLE were assayed for antinucleosome antibodies, anti-double-stranded DNA (anti-dsDNA), anti-extractable nuclear antigen, anti-tetanus toxoid, and antibodies to pneumococcal capsular polysaccharide for at least 1 year following BCDT. Anti-dsDNA antibodies derived from the V(H)4.34 immunoglobulin germ line gene (9G4+) were also measured. RESULTS: All patients achieved peripheral B cell depletion and improved clinically for at least 3 months. Antinucleosome and anti-dsDNA antibodies decreased to a mean +/- SD of 64 +/- 37% and 38 +/- 33% of baseline values, respectively, by 6-8 months post-BCDT. Levels of other autoantibodies and antimicrobial antibodies were generally unchanged. In the 9 of 16 patients who were still well at 1 year, anti-dsDNA antibodies fell to 42 +/- 36% of baseline values at 6-8 months and to 37 +/- 33% at 10-14 months. In patients who had disease flares within 1 year of BCDT, levels of these antibodies decreased to 60 +/- 40% and 83 +/- 93% of baseline values at 6-8 months and at 10-14 months, respectively. Circulating anti-dsDNA antibodies were positive for 9G4 expression in 4 of 6 patients tested, and flares in 2 of these patients were accompanied by rises in 9G4+ anti-dsDNA antibodies. CONCLUSION: These observations suggest that B cell clones committed to producing antinucleosome and anti-dsDNA antibodies, including the V(H)4.34 subpopulation of anti-dsDNA antibodies, have a relatively rapid turnover compared with B cell clones producing other antibodies. There was also a trend toward a greater and more sustained decrease in anti-dsDNA antibodies in patients with clinical benefit lasting >1 year.

Adolescent↗
PubMed2006

Treatment of inflammatory myopathies.

Idiopathic inflammatory myopathies, notably polymyositis and dermatomyositis are comparatively uncommon diseases and few randomised, double blind placebo controlled trials have been done. Final validation of measures to assess outcome and response to treatment is awaited. Corticosteroids are an effective initial treatment, although rarely tested in randomised controlled trials. Unfortunately, not all patients respond to them and many develop undesirable side effects. There is thus a need for second line agents notably immunosuppressives or intravenous immunoglobulin. There are no defined guidelines or best treatment protocols agreed internationally and so the medical approach must be individualised, based on the severity of clinical presentation, disease duration, presence of extramuscular features, and prior therapy and contraindications to particular agents. There is still a significant percentage of non-responders (around 25%) and clinical relapses. Novel therapeutic approaches are now directed towards cytokine modulation and the use of monoclonal antibodies targeting B and T cells.

Adrenal Cortex Hormones↗
PubMed2006

Immunizing patients with systemic lupus erythematosus: a review of effectiveness and safety.

Concerns regarding the safety and efficacy of immunization in patients with SLE have persisted for over 60 years, despite the increased risk of infection in these patients. There are many anecdotal case reports of SLE induction or exacerbation following immunization, but overall, these events seem to be very rare. Evidence from prospective trials suggests that inactivated and component vaccines are probably safe in patients with SLE. Live vaccines are contraindicated in patients on immunosuppressive agents or high dose steroids (prednisone 20 mg/day or greater). There is limited evidence regarding efficacy of vaccination in patients with SLE. Studies assessing serological response to vaccination have generally shown that the majority of patients have an appropriate response, but a significant minority do not. Response to hepatitis B vaccination may be impaired and serological responses should be assessed post vaccination. It is not clear if disease activity or immunosuppressive medications are risk factors for a poor response, rather than intrinsic abnormalities of immune function in patients with SLE. The majority of patients appear to have a reasonable serological response to vaccination.

Bacterial Infections↗
PubMed2005

Repeated B cell depletion in treatment of refractory systemic lupus erythematosus.

OBJECTIVES: To report the clinical outcome and safety profile of repeated B cell depletion in seven patients with refractory systemic lupus erythematosus (SLE). METHODS: Since June 2000, seven patients with refractory SLE had repeated cycles of B cell depletion (18 cycles in total, up to three cycles per patient) because of disease relapse. The clinical response (assessed by the British Isles Lupus Activity Guide (BILAG) activity index), duration of B cell depletion, and adverse events in these patients was reviewed. RESULTS: Four patients (Nos 1, 2, 3, 6) had three cycles of treatment and three (Nos 4, 5, 7) had two cycles. Four of the seven patients (Nos 1, 3, 5, 6) improved. The mean global BILAG scores dropped from 15 to 6 at 5-7 months. The median duration of clinical response and B cell depletion was 13 months and 6 months, respectively. After the third cycle, 2/4 patients (Nos 1 and 2) improved. The median duration of clinical benefit was 12 months. Most patients tolerate re-treatment very well. CONCLUSION: Re-treatment with B cell depletion of patients with severe SLE is safe and may be effective for 6-12 months on average.

Adult↗
PubMed2005

A statistical analysis of the interrelationships between disease activity in different systems in systemic lupus erythematosus.

OBJECTIVES: To develop models for disease activity in patients with systemic lupus erythematosus (SLE) and to examine the hypothesis that possible subsets exist within the disease, notably renal disease and little else, mucocutaneous and musculoskeletal disease in isolation and more multisystem disease. METHODS: Four hundred and forty patients with SLE were followed for a period of 10 yr. Socio-demographic data were obtained at the first visit with disease activity being recorded at subsequent visits and damage scores at 6-monthly intervals. Prognostic factors for active disease in each of the mucocutaneous, musculoskeletal and renal systems were examined statistically. The results were then validated using data collected over 5 yr on a further 295 SLE patients from a different centre. RESULTS: Logistic regression analyses indicated that for all three systems studied a patient known to have an involvement in that system is more likely to present with active disease in that same system than a patient with no known prior involvement. Patients with a higher frequency of clinic visits with active disease in a system are more likely to represent with active disease than those with fewer visits. The results suggest that renal disease is most likely to occur on its own. Associations between activity in the mucocutaneous and musculoskeletal systems support the suggestion that patients with musculoskeletal and mucocutaneous disease alone represent a possible subset of SLE. None of the associations identified were modified by the medication a patient received. CONCLUSIONS: Previous disease history and involvement of other systems determine a patient's chance of developing further episodes of active disease in SLE.

Adolescent↗
PubMed2005

B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients.

OBJECTIVES: To assess the clinical and basic serological consequences of B-cell depletion with rituximab in the treatment of patients with systemic lupus erythematosus (SLE) who have failed conventional immunosuppression. METHODS: An open study of 24 patients with severe SLE followed for a minimum of 3 months is reported. In the majority of patients (19 out of 24), 6 months follow-up data are described. Disease activity in these patients was assessed every 1-2 months using the British Isles Lupus Assessment Group (BILAG) system and estimates of anti-double-stranded DNA antibodies and serum C3 levels. During the follow-up period, significant side-effects were sought and the reduction in oral prednisolone was recorded. It was our general practice to stop concomitant immunosuppression (e.g. azathioprine, mycophenolate) when B-cell depletion was given (in most cases in the form of two 1 g intravenous infusions of rituximab 2 weeks apart accompanied by two 750 mg intravenous cyclophosphamide infusions and two methylprednisolone infusions of 250 mg each). RESULTS: Twenty-two patients were female and two male. At the time of B-cell depletion, the mean age was 28.9 yr (range 17-49) and the mean disease duration was 7.9 yr (range 1-18). The global BILAG score (P < 0.00001), serum C3 (P < 0.0005) and double-stranded DNA binding (P < 0.002) all improved from the time of B-cell depletion to 6 months after this treatment. Only one patient failed to achieve B-lymphocyte depletion in the peripheral blood. The period of B-lymphocyte depletion ranged from 3 to 8 months except for one patient who remains depleted at more than 4 yr. Analysis of the regular BILAG assessments showed that improvements occurred in each of the eight organs or systems. The mean daily prednisolone dose fell from 13.8 mg (s.d. 11.3) to 10 mg (s.d. 3.1). CONCLUSION: In this open study of patients who had failed conventional immunosuppressive therapy, considerable utility in the use of B-cell depletion has been demonstrated. Our data provide strong support for the performance of a full double-blind control trial.

Adolescent↗
PubMed2005

Human monoclonal IgG anticardiolipin antibodies induce nitric oxide synthase expression.

OBJECTIVE: Antiphospholipid antibodies are associated with increased risk of thrombosis, particularly as in antiphospholipid syndrome. This study aims to determine the acute effects of anticardiolipin antibodies on nitric oxide production and vascular function. METHODS: Ex vivo aortic rings from male Sprague Dawley rats were incubated with IgG monoclonal anticardiolipin antibody (IS4) or a non-specific IgG control. In organ baths, response to phenylephrine and acetlycholine was determined alone and with nitro-L-arginine methyl ester (L-NAME), 1,400 W, D-arginine, L-arginine, sodium nitroprusside and cardiolipin. In vivo antibodies were injected into anaesthetised, spontaneously breathing male Sprague Dawley rats. Haemodynamic variables and serum nitric oxide were measured. Immunohistochemistry for iNOS and eNOS was performed in kidney vessels. RESULTS: Phenylepherine contraction was decreased in the IS4 group compared to controls (p < 0.001). L-NAME, 1,400 W and cardiolipin, abolished this effect. L-Arginine caused significant relaxation in the IS4 group (p = 0.005). Mean arterial pressure in rats injected with IS4 was reduced compared to IgG and saline controls (p < 0.001). NO in plasma increased significantly after IS4 administration (p < 0.001). Immunohistochemistry showed increased iNOS expression in kidney arteries in the IS4 group, with no change in eNOS. CONCLUSION: Anticardiolipin antibodies induce NO production acutely via increased expression of iNOS in both ex vivo and in vivo models.

Animals↗
PubMed2005

Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model.

OBJECTIVE: Oxidative stress contributes to atherosclerosis, and evidence of enhanced oxidative stress exists in antiphospholipid syndrome (APS). In a non-lupus murine model, we evaluated whether anticardiolipin (aCL) antibodies could affect the oxidant/antioxidant balance as an early biochemical step of APS. METHODS: Hybridomas producing human and murine aCL and anti-beta(2)-glycoprotein I (abeta2-GPI) monoclonal antibodies were injected into three groups of five female BALB/c severe combined immunodeficiency (SCID) mice. Corresponding hybridomas secreting non-antiphospholipid antibodies of the same isotype were employed as controls. Sera and organs were collected after 30 days. Paraoxonase (PON) activity, peroxynitrite, superoxide, nitric oxide (NO) and nitrotyrosine were measured in plasma. Expression of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) was assessed by western blot and immunohistochemistry. RESULTS: PON activity and NO (sum of nitrate and nitrite) levels were reduced in the human aCL IgG group (P<0.002 and P<0.04, respectively), whilst peroxynitrite and superoxide and expression of total antioxidant capacity of plasma were increased (P<0.01). PON and NO were decreased in the murine abeta2-GPI IgG and IgM aCL groups (P<0.03 and P<0.05, respectively). Nitrotyrosine was elevated in the human aCL IgG group (P<0.03). Western blotting showed reduced iNOS expression in the hearts of the IgG aCL group, confirmed by immunostaining. PON inversely correlated with IgG aCL titres (P<0.001), superoxide (P<0.008) and peroxynitrite levels (P<0.0009). Peroxynitrite and total IgG aCL were independent predictors of PON (P<0.0009 and P<0.02, respectively). Superoxide was the only independent predictor of NO (P<0.008) and of nitrotyrosine (P<0.002). CONCLUSION: aCL antibodies are associated with the decreased PON activity and reduced NO that may occur in the preclinical phase of APS.

Animals↗
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↗
PubMed2005

The systemic lupus erythematosus tri-nation study: longitudinal changes in physical and mental well-being.

OBJECTIVE: We have shown that SLE patients in Canada and the UK incurred 20% and 13% lower health costs than those in the US, respectively, but did not experience worse outcomes as expressed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. We now compare change in quality of life in these patients. PATIENTS AND METHODS: Seven hundred and fifteen SLE patients (Canada 231, US 269, UK 215) completed the SF-36 annually over four years. The annual change in the SF-36 Physical and Mental Component Summary (PCS and MCS) scores over the course of the study were summarized by estimating a linear trend for each individual patient using hierarchical modelling. Cross-country comparison of the slopes in the PCS and MCS scores was then performed using simultaneous regressions. RESULTS: The estimated mean annual changes (95% credible interval [CrI]) in the PCS scores in Canada, the US, and the UK were 0.18 (-0.07, 0.43), -0.05 (-0.27, 0.17), and 0.03 (-0.20, 0.27), respectively; the mean annual changes in the MCS scores were 0.15 (-0.04, 0.34), 0.23 (0.09, 0.37), and 0.08 (-0.10, 0.27), respectively. Regression results showed that the mean annual changes in PCS and MCS scores did not substantially differ across countries. CONCLUSION: Quality of life remained stable across countries. Despite Canadian and British patients incurring lower health costs, on average, patients experienced similar changes in physical and mental well-being.

Adult↗
PubMed2005

Elevated expression of the Brn-3a and Brn-3b transcription factors in systemic lupus erythematosus correlates with antibodies to Brn-3 and overexpression of Hsp90.

OBJECTIVE: Important developmental and antiapoptotic roles have been described for the Brn-3 family of transcription factors in mammalian cells. Following a report of pathogenic autoantibody-inducing T cell reactivity to the Brn-3 transcription factors in murine lupus, we undertook this study to investigate serum levels of antibodies to Brn-3 and levels of expression of Brn-3 in peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE). METHODS: Serum and PBMC samples were obtained from 87 SLE patients and 30 normal control subjects. Serum antibodies to the Brn-3a and Brn-3b transcription factors were measured by enzyme-linked immunosorbent assay. Levels of Brn-3a and Brn-3b messenger RNA (mRNA) in PBMCs were measured by reverse transcription and real-time quantitative polymerase chain reaction. RESULTS: Elevated serum levels of antibodies to Brn-3a and Brn-3b were found in 43% and 32%, respectively, of SLE patients. This elevation paralleled enhanced expression of Brn-3a and Brn-3b in PBMCs of 44% and 31%, respectively, of SLE patients. Furthermore, we observed a significant correlation (P = 0.002) between elevated levels of anti-Brn-3b antibodies and elevated levels of Brn-3b mRNA in individual patients. A preliminary analysis of possible target genes for Brn-3a and Brn-3b revealed a significant correlation (P = 0.01) between the level of Brn-3a mRNA and the level of Hsp90 protein (90-kd heat-shock protein, which is overexpressed in SLE) in PBMCs of SLE patients. In addition, we observed that overexpression of Brn-3a and Brn-3b in cultured cells enhanced expression of Hsp90 protein and transcription of Hsp90 promoter-reporter constructs. Finally, we observed an association between elevated levels of Brn-3a mRNA and active SLE (P = 0.002). CONCLUSION: Expression of both Brn-3a and Brn-3b was found to be enhanced in SLE, and this correlated with enhanced levels of autoantibodies to these proteins and with the previously reported overexpression of Hsp90, which was shown to be a novel gene regulated by Brn-3a and Brn-3b. The overexpression of Brn-3a correlated with active disease, suggesting that it may play a role in the disease process via its targeting by the immune system and its ability to induce the expression of specific genes.

Adolescent↗
PubMed2005

New therapies for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease, which continues to cause significant morbidity in affected persons. In the past few years, a number of new exciting therapeutic options have become available. These reflect the application of knowledge obtained from advancements in understanding of disease pathogenesis and underlying molecular mechanisms. A number of these therapies are outlined in the following review, including the various biological modifiers, in particular, anti-tumour necrosis factor-alpha agents and interleukin-1 (IL-1) receptor antagonists, which have been developed in recognition of the role of pro-inflammatory cytokines in RA. Also notable, is the current interest centring on the development and trials with B cell depletion therapies, specifically rituximab, in patients with RA. This demonstrates acknowledgment for a more significant role for B cells in the aetiology of RA, in contrast to the long held view that RA was a predominantly T cell mediated disease. To evaluate this therapeutic option for RA, salient features from recent rituximab trials have been collated. Finally, a selection of other therapeutic alternatives, including anti-IL-6 receptor monoclonal antibody and tacrolimus, and newer anti-rheumatic therapies presently in development are summarized.

Antirheumatic Agents↗