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David Isenberg

Publications and source records attributed to David Isenberg.

14 recordsLinked to original sources
PubMed2006

Arginine residues are important in determining the binding of human monoclonal antiphospholipid antibodies to clinically relevant antigens.

In the antiphospholipid syndrome (APS), antiphospholipid Abs (aPL) bind to anionic phospholipids (PL) and various associated proteins, especially beta(2)-glycoprotein I (beta2GPI) and prothrombin. In the present study, we show that altering specific Arg residues in the H chain of a human pathogenic beta2GPI-dependent aPL, IS4, has major effects on its ability to bind these clinically important Ags. We expressed whole human IgG in vitro by stable transfection of Chinese hamster ovary cells with expression plasmids containing different V(H) and V(L) sequences. V(H) sequences were derived from IS4 by altering the number of Arg residues in CDR3. V(L) sequences were those of IS4, B3 (anti-nucleosome Ab), and UK4 (beta2GPI-independent aPL). Binding of the expressed H/L chain combinations to a range of anionic, neutral, and zwitterionic PL, as well as prothrombin, beta2GPI, dsDNA, and chicken OVA, was determined by ELISA. Of four Arg residues in IS4VH CDR3 substituted to Ser, two at positions 100 and 100g, reduced binding to all Ags, while two at positions 96 and 97 reduced binding to beta2GPI but increased or decreased binding to different PL. Eleven of 14 H/L chain combinations displayed weak binding to OVA with Arg to Ser replacements of all four Arg residues enhancing binding to this Ag. Only one H/L chain combination bound neutral PL and none bound dsDNA; hence, these effects are particularly relevant to Ags important in antiphospholipid syndrome. We hypothesize that these four Arg residues have developed as a result of somatic mutations driven by an Ag containing both PL and beta2GPI.

Amino Acid Substitution↗
PubMed2006

Systemic lupus erythematosus--2005 annus mirabilis?

We are about to enter a new era in the treatment of patients with systemic lupus erythematosus (SLE). For the past 40 years hydroxychloroquine sulfate and corticosteroids, together with varying combinations of immunosuppressive drugs, have been the main treatments for SLE. Although effective for many patients, some patients fail to respond to these drugs and even more suffer from major side effects due to the generalized nature of the immunosuppression. In this article we review the remarkable confluence of new therapies ranging from newer immunosuppressive drugs with fewer side effects, such as mycophenolate mofetil, to the more targeted approaches offered by biological agents. These agents have been designed to block molecules such as CD20, CD22 and interleukin-10 that are thought to have an integral part in the development of SLE. This wolf might not yet be about to become extinct but its survival is increasingly under threat!

Clinical Trials as Topic↗
PubMed2005

Imaging in CNS lupus.

The diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) is complex not only on account of the heterogeneous nature of neurological presentation but also because of the difficulty of differentiating lupus-related pathology from other neuropsychiatric diseases. Magnetic resonance imaging (MRI) remains the gold standard for the non-invasive assessment of NPSLE but there are problems, both with sensitivity and specificity. Both T(2) quantitation and the use of gadolinium have shown promise in differentiating acute from chronic lesions. Nonetheless, the lack of sensitivity of conventional MRI has led to the exploration of other MR-based techniques. Magnetic resonance spectroscopy (MRS) allows the measurement of brain metabolites, whereas diffusion weighted imaging and diffusion tensor imaging allow assessment of white matter structure and integrity. MRS studies in NPSLE have consistently shown a reduction in N-acetyl aspartate (a neuronal marker). Diffusion weighted imaging has had only limited application in lupus and the results to date have shown abnormal diffusivity in lupus patients consistent with inflammation and loss of white matter structure. These techniques remain research tools at this early stage. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) have also been explored as functional imaging tools in lupus and both appear to be more sensitive in detecting subtle brain changes in NPSLE but there are issues with specificity which deter their use in the clinical setting.

Diagnostic Imaging↗
PubMed2005

Mixed connective tissue disease: still crazy after all these years.

Mixed connective tissue disease (MCTD) remains a controversial diagnosis. The classification criteria have changed significantly from the original description by Sharp and colleagues in 1972 after follow-up of the original and other MCTD patients. In this article we review the clinical, serologic, and genetic studies of MCTD published in the last 10 years and ask if this term is appropriate.

Autoantibodies↗
PubMed2004

The critical role of arginine residues in the binding of human monoclonal antibodies to cardiolipin.

Previously we reported that the variable heavy chain region (VH) of a human beta2 glycoprotein I-dependent monoclonal antiphospholipid antibody (IS4) was dominant in conferring the ability to bind cardiolipin (CL). In contrast, the identity of the paired variable light chain region (VL) determined the strength of CL binding. In the present study, we examine the importance of specific arginine residues in IS4VH and paired VL in CL binding. The distribution of arginine residues in complementarity determining regions (CDRs) of VH and VL sequences was altered by site-directed mutagenesis or by CDR exchange. Ten different 2a2 germline gene-derived VL sequences were expressed with IS4VH and the VH of an anti-dsDNA antibody, B3. Six variants of IS4VH, containing different patterns of arginine residues in CDR3, were paired with B3VL and IS4VL. The ability of the 32 expressed heavy chain/light chain combinations to bind CL was determined by ELISA. Of four arginine residues in IS4VH CDR3 substituted to serines, two residues at positions 100 and 100 g had a major influence on the strength of CL binding while the two residues at positions 96 and 97 had no effect. In CDR exchange studies, VL containing B3VL CDR1 were associated with elevated CL binding, which was reduced significantly by substitution of a CDR1 arginine residue at position 27a with serine. In contrast, arginine residues in VL CDR2 or VL CDR3 did not enhance CL binding, and in one case may have contributed to inhibition of this binding. Subsets of arginine residues at specific locations in the CDRs of heavy chains and light chains of pathogenic antiphospholipid antibodies are important in determining their ability to bind CL.

Amino Acid Sequence↗
PubMed2004

Anti B cell therapy (rituximab) in the treatment of autoimmune diseases.

B cells play an important role in the pathogenesis of many autoimmune diseases. Selective targeting of these cells has been recently achieved using a chimeric monoclonal antibody against the pan B cell surface marker CD20 (rituximab). This antibody was originally developed for the treatment of non-Hodgkin's lymphoma. It was found to be effective, well tolerated and had a very good safety profile. Recent studies have demonstrated the efficacy of rituximab in several refractory autoimmune disorders including rheumatoid arthritis, systemic lupus erythematosus, immune thrombocytopenic purpura, chronic cold agglutinin disease, IgM-mediated neuropathies and mixed cryoglobulinemia.

Antibodies, Monoclonal↗
PubMed2003

B cell depletion in autoimmune disease.

The CD20 cell marker appears early in the process of B cell development. In this review we focus on the results of attempts to utilize B cell depletion based on the use of a chimeric monoclonal antibody (MAb) specific for human CD20, rituximab, for the treatment of patients with autoimmune diseases. In 1997, rituximab was approved for the treatment of low-grade B cell non-Hodgkin's lymphoma. Following these encouraging results, rituximab started to be used experimentally in other diseases presumed to be due to B cell pathology. The first autoimmune disease to be treated effectively was chronic idiopathic thrombocytopaenia. More recent success has been demonstrated in patients with rheumatoid arthritis and systemic lupus erythematosus.

Antibodies, Monoclonal↗
PubMed2003

Defining Clinical Improvement in Adult and Juvenile Myositis.

The lack of consensus regarding outcome measures and trial design issues in the idiopathic inflammatory myopathies (IIM) is inhibiting the conduct and interpretation of clinical trials. To begin to address these problems, a multispecialty group of over 70 adult and pediatric neurologists, rheumatologists, rehabilitation medicine physicians, statisticians, and patient support group leaders, called the International Myositis Outcome Assessment Collaborative Study Group (IMACS), is engaged in developing consensus on the assessment of disease activity and damage for myositis clinical trials. As part of this ongoing international effort, members of this group met in November 2001 at a work-shop entitled "Defining Clinical Improvement in Adult and Juvenile Myositis." A goal of the work-shop was to review current data on the validity and responsiveness of the recently published proposed preliminary core set measures for disease outcome assessment in clinical trials for myositis and to define the degree of change in each core set measure that is clinically meaningful. Despite differences in the clinical presentations, natural history and responses to therapy between adult onset and juvenile onset myositis, expert specialists in these diseases came to a consensus that the amount of improvement that is clinically meaningful in each core measure is the same for adult and juvenile myositis. For the domains of muscle strength and physical function, a minimum of 15% improvement is clinically significant, whereas for the physician and patient global assessments, as well as the extramuscular assessment, a minimum of 20% improvement is considered clinically meaningful, and for serum levels of muscle associated enzymes, at least 30% improvement is needed to be clinically important. This workshop is the first of several planned to develop multidisciplinary, international consensus on the conduct and reporting of IIM clinical trials.

Adult↗
PubMed2002

The rate and pattern of organ damage in late onset systemic lupus erythematosus.

OBJECTIVE: To compare the extent and type of damage in patients with late onset and earlier onset systemic lupus erythematosus (SLE) using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). METHODS: A total of 86 SLE patients with disease onset after the age of 54 years were matched for center, sex, and ethnic origin with 155 SLE patients with disease onset before the age of 40 years. SDI scores were obtained at one year and 5 years after the diagnosis of SLE. Analysis was based on conditional logistic regression. RESULTS: SDI scores were higher in the late onset group than in younger patients at both one [mean 0.7 (range 0-3) vs 0.3 (range 0-3); p < 0.001] and 5 years [mean 1.6 (range 0-8) vs 0.9 (range 0-7); p < 0.001] after diagnosis. There was also a difference in the pattern of organ damage. While damage to the skin, kidneys, and central nervous system occurred with similar frequency, late onset disease was characterized by significantly more cardiovascular (OR 14.13, p < 0.001), ocular (OR 9.38, p = 0.001), and musculoskeletal (OR 2.68, p = 0.016) damage and malignancy (OR 7.04, p = 0.046). CONCLUSION: The occurrence of organ damage assessed by the SDI is greater in patients with late onset SLE than in younger patients and, by this criterion, lupus cannot be judged to be more benign in this age group. Also, the pattern of damage is different, but whether this reflects age per se or the effect of the disease in the elderly remains to be established.

Adult↗
PubMed2002

Serial analysis of Ro/SSA and La/SSB antibody levels and correlation with clinical disease activity in patients with systemic lupus erythematosus.

OBJECTIVE: To investigate the temporal correlation between anti-Ro/SSA and anti-La/SSB antibody levels and compare them with variation in clinical disease activity in patients with systemic lupus erythematosus (SLE). METHODS: Sequential serum samples collected over 18-44 months from 18 anti-Ro/SSA positive patients with systemic lupus erythematosus were analysed by ELISA with recombinant Ro60, Ro52 and La antigens. Disease activity was assessed by the BILAG index. RESULTS: Limited antibody level variation over time was found in most patients, but a subset displayed more changes and a co-variation between the levels of separate specificities was found in 40% of patients. In two patients antibody levels fluctuated with the global score. Antibodies also correlated with separate organ/systems involvement in individual patients. CONCLUSION: The Ro60, Ro52 and La antibody profile is fixed at an early stage of disease and in most patients hardly changes. Patients with fluctuating levels tend to have a co-ordinated expression of these autoantibodies.

Adult↗
PubMedDate not supplied

Working together to improve rheumatology services.

The fast-moving changes in the NHS, particularly with respect to patients with chronic diseases, are a challenge and will have major financial and practical costs. For these changes to be successful the potential threat posed by PBR, PBC and CAB for smaller acute hospitals needs to be evaluated. Most importantly, bridging the primary and secondary care interface will be essential for the 'new' NHS to be successful. The shape of rheumatology in the future is also likely to depend on the national musculoskeletal strategy due to be published in the coming weeks.

Arthritis, Rheumatoid↗