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Biomedical subjects

R N Maini

Publications and source records attributed to R N Maini.

338 records · Page 19Linked to original sources
PubMedDate not supplied

Combination therapy with DMARDs and biological agents in collagen-induced arthritis.

There is increasing interest in the use of combination therapy for rheumatoid arthritis and in the possibility of combining the conventional drug approach with newer biological therapies. Animal models of arthritis provide important tools for evaluating novel forms of therapy and for eludicating mechanisms of drug action. In this paper, we review the results of our own research into combination therapy in collagen-induced arthritis using biological therapies such as anti-tumor necrosis factor alpha, anti-CD4, and anti-interleukin 12 monoclonal antibodies, and small molecular weight compounds such as cyclosporin and the phosphodiesterase IV (PDE IV) inhibitor rolipram.

Animals↗
PubMedDate not supplied

The Consensus Workshops for the Detection of Autoantibodies to Intracellular Antigens in Rheumatic Diseases: 1989-1992.

The European Consensus Study Group for Autoantibodies was formed in 1988 to examine test systems for the detection of autoantibodies found in patients with rheumatic and related conditions. In the last four years it has organised an annual exercise to examine the sensitivity and reproducibility of different methodologies for the detection of these antibodies, and the concordance obtained between leading laboratories in Europe. The results of these exercises show an improvement in detection rates. In addition, the group has produced a methodology handbook, containing recommended methods as used by expert laboratories, and has made recommendations on the performance of assays for the detection of autoantibodies.

Antigens↗
PubMedDate not supplied

HLA-B40: a marker for susceptibility to lung disease in rheumatoid arthritis.

We have compared the frequency of HLA antigens in groups of patients with rheumatoid arthritis (RA) who had pulmonary manifestations, other extra-articular features or articular disease alone. There was a significantly increased frequency of the antigen HLA-B40 in patients with lung involvement compared to other forms of extra-articular RA (relative risk 40.54), and when compared to the total RA group (relative risk 4.94). In contrast there was little variation in the frequency of HLA-DR4, which was significantly increased in all patient groups. These data suggest that HLA-B40 is a marker of increased susceptibility to lung disease in patients with rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMedDate not supplied

Anti-La (SS-B): a diagnostic criterion for Sjögren's syndrome?

We examined the diagnostic sensitivity and specificity of antibodies to Ro (SS-A) and La (SS-B) in Sjögren's syndrome (SS) by counterimmunoelectrophoresis and immunodiffusion. Anti-Ro was found in 56% and anti-La in 42% of patients with SS and in 38% and 6% respectively in SLE. Anti-La was rare (less than 1%) in other connective tissue diseases. As a more stringent test of diagnostic specificity, 88 patients whose sera contained anti-La and/or anti-Ro were carefully examined for evidence of Sjögren's syndrome. Of 35 patients whose sera contained anti-La, 29 (83%) fulfilled criteria for SS, and four out of 6 of the remainder showed some evidence of early disease. Of 53 patients with anti-Ro (without anti-La), only 42% had Sjögren's syndrome, 45% had SLE and 13% other connective tissue diseases. These data confirm that anti-La, but not anti-Ro, has a high diagnostic specificity for Sjögren's syndrome and merits inclusion as separate diagnostic criterion for the disease.

Adult↗
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Clinical, serological, and HLA phenotype subsets in Sjögren's syndrome.

The clinical and laboratory features of 89 patients with Sjögren's syndrome (SS) have been reviewed. Forty-eight of the patients had primary SS, of whom 27 had antibodies to Ro and/or La. The anti-Ro/La antibody positive patients showed a higher frequency of systemic clinical features, as well as high IgG levels and rheumatoid factors compared to those without the antibodies. Patients with SS-SLE developed symptoms of SS at the same age as those with primary SS but facial rashes, photosensitivity, and serositis were more common. Otherwise the clinical and laboratory features were indistinguishable from primary SS with anti-Ro/La. The frequency of HLA DR3 and HLA DRW 52 in European Caucasians with primary SS was 67% and 82% (92% in those with anti-Ro/La) respectively. DRW 53 occurred in 94% of all patients with SS-RA.

Adult↗
PubMedDate not supplied

Targeting TNF alpha for the therapy of rheumatoid arthritis.

Our pre-clinical studies have demonstrated a pathogenic role for TNF alpha in RA. Firstly, TNF alpha and its receptors are upregulated and co-expressed in the synovium and cartilage-pannus junction of RA joints. Secondly, mononuclear cells from RA joints maintained in culture produce many cytokines with pro-inflammatory activity, including TNF alpha. Neutralizing TNF alpha antibodies in vitro reduces the production of these pro-inflammatory cytokines, including IL-1, IL-8, and GM-CSF. Thirdly, when injected into arthritic DBA/l mice with collagen-induced arthritis, monoclonal anti-TNF antibodies decrease inflammatory damage of joints. Clinical trials employing cA2, a monoclonal chimeric anti-TNF alpha antibody, in open-label and randomized placebo-controlled studies have demonstrated a dose-dependent efficacy with impressive improvement in disease activity and acute phase responses lasting several weeks. We conclude that TNF alpha is a critical mediator of inflammation in RA and is an important therapeutic target in this disease.

Antibodies, Monoclonal↗
PubMedDate not supplied

TNF-alpha in rheumatoid arthritis and prospects of anti-TNF therapy.

Our work has shown that TNF alpha is produced by cultured mononuclear cells from rheumatoid arthritis joints and appears to regulate the production of IL-1. Immunohistochemical examination has shown the presence of TNF alpha in the synovium, e.g. in the lining layer, some endothelial cells and most importantly, in the cells in the cartilage pannus junction. TNF receptors (both p55 and p75) have a similar distribution, thereby suggesting that TNF has the potential for autocrine and paracrine activity in the joint. The concept that TNF alpha is pathogenic in inflammatory arthritis has been validated by showing that neutralizing monoclonal anti-TNF antibodies significantly attenuate collagen-induced arthritis in mice. In preliminary trials in rheumatoid patients anti-TNF appears to have an impressive effect on indices of disease activity including C-reactive production and serum amyloid-A production. TNF alpha appears to be a relevant therapeutic target in rheumatoid disease.

Animals↗
PubMedDate not supplied

Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti TNF-alpha antibody with the interleukin-1 receptor antagonist.

While there is an extensive literature on cytokine regulation in vivo using human cell lines or peripheral blood monocytes, very little is known about cytokine regulation within the multicellular environment of inflammatory sites in vivo. We have previously shown that in rheumatoid synovial membrane cultures, a complex, but pathophysiologically relevant mixture of cells, the addition of a neutralizing anti TNF-alpha antibody inhibits the production of IL-1 and GM-CSF, indicating the presence of a cytokine 'cascade' in this inflammatory tissue. In this paper we demonstrate that the interactivities between cytokines in rheumatoid arthritis also extends to other cytokines, such as IL-6 and IL-8, and that within the IL-1 family it is IL-1 beta in particular which is downregulated by neutralizing TNF-alpha activity. The cytokine interactions are unidirectional, in that neutralization of TNF-alpha reduced IL-1 beta, IL-6 and IL-8 production, whereas treatment of the rheumatoid synovial membrane cells with a neutralizing concentration of the IL-1 receptor antagonist (IL-1ra) reduced IL-6 and IL-8 production but not TNF-alpha production. These results suggest a rationale for the profound anti-inflammatory effects and consequent clinical benefit noted in RA patients treated recently in clinical trials with a chimeric anti-TNF-alpha antibody in vivo.

Antibodies, Blocking↗
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A perspective on anti-cytokine and anti-T cell-directed therapies in rheumatoid arthritis.

Clinical trials have provided a unique opportunity to test the consequences of specific interactions between biologically therapeutic modalities--mainly monoclonal antibodies (mabs) and recombinant proteins--and molecular targets in RA. Biological agents directed against T cell surface markers effectively deplete CD4+ lymphocytes, in some instances for prolonged periods. To date such therapies have shown promising results in 'open label' trials, but in those instances in which randomized placebo-controlled trials have been undertaken, there has been a failure to demonstrate significant benefit over placebo. In contrast, randomized clinical trials with a single cycle of neutralizing anti-TNF alpha mabs have shown substantial benefit in the majority of patients, with marked reduction in CRP lasting several weeks. IL-1 blockade with IL-1 ra and soluble IL-1 R showed possible efficacy in early trials but their performance is much less striking when compared with anti-TNF alpha therapy. Overall the results of trials with anti-T cell and cytokine blockade may reflect on the biological properties of the agents chosen for trial, rather than giving a conclusive answer on the relative merits of targeting these molecules in RA. Nevertheless, promising new directions for therapy and concepts of disease pathogenesis are emerging from the new era of hypothesis testing by specific biological therapies.

Antibodies, Monoclonal↗
PubMedDate not supplied

Cytokine expression and networks in rheumatoid arthritis: rationale for anti-TNF alpha antibody therapy and its mechanism of action.

The cloning of cytokine cDNAs has permitted the analysis of cytokine expression in diseased sites such as rheumatoid joints. A very wide range of cytokines were detected, mostly with proinflammatory activities. From the analysis of cytokine regulation in rheumatoid joint cell cultures using neutralizing anti-cytokine antibodies, it was found that blockade of TNF alpha reduced the production of other proinflammatory cytokines. Hence TNF alpha was a potential therapeutic target. This concept was tested successfully in collagen induced arthritis in mice and led to clinical trials of anti-TNF alpha antibody in rheumatoid arthritis (RA) in humans. The mechanism of action of anti-TNF alpha will be discussed.

Animals↗