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Biomedical subjects

G Panayi

Publications and source records attributed to G Panayi.

At least 19 recordsLinked to original sources
PubMed2005

Adalimumab in clinical practice. Outcome in 70 rheumatoid arthritis patients, including comparison of patients with and without previous anti-TNF exposure.

OBJECTIVE: To assess the efficacy and safety of the fully human recombinant monoclonal anti-TNF antibody adalimumab in routine clinical practice, including comparison of patients with and without previous anti-TNF exposure. METHODS: We prospectively studied the outcome of 70 rheumatoid arthritis patients treated with adalimumab in normal clinical practice. The primary outcome measures were Disease Activity Score 28 (DAS28), EULAR (European League Against Rheumatism) response and Health Assessment Questionaire (HAQ). RESULTS: Seventy-seven per cent achieved a EULAR response (26% good, 51% moderate) and 19% were in remission. The mean decrease in DAS28 was 2.1 (6.3-4.2; P<0.001). The mean decrease in HAQ score was 0.34 (2.07-1.73; P<0.001), 66% achieving a clinically significant decrease of greater than 0.22. Twenty-three per cent stopped treatment because of side-effects (7%) or failure to respond (16%). Of the 26 patients who had previously tried 29 biologicals, 65% responded to adalimumab. There was no significant difference in the change in mean DAS (P = 0.69) or HAQ (P = 0.88) between groups with and without previous anti-TNF exposure. Of the 13 patients with previous secondary failure to infliximab, 77% responded to adalimumab. Patients with previous secondary failure had significantly better improvement in DAS (P = 0.023) than patients with previous primary failure. CONCLUSION: Our clinical experience confirms that adalimumab is effective and safe in the treatment of RA. It also shows adalimumab is effective in patients with previous biological failures, particularly patients with secondary failure to infliximab.

Adalimumab↗
PubMed2001

The glucocorticoid inhibition of LFA-1 and CD2 expression by human mononuclear cells is reversed by IL-2, IL-7 and IL-15.

Glucocorticoids are agents endowed with powerful immunosuppressive and anti-inflammatory properties partially related to the inhibition of adhesion-related processes. We have previously demonstrated that glucocorticoids inhibit LFA-1 and CD2 expression in human peripheral blood mononuclear cells (PBMC) by down-regulating mRNA steady-state levels. In this study, we investigated whether glucocorticoids could also act indirectly by modulating the effect/function of cytokines whose expression are known to inhibit. To test this hypothesis, we replenished the following cytokines IL-2, IL-7, IL-15, TNF-alpha, IL-1beta, IL-4 and IL-10, in an in vitro PBMC culture system. Our results indicate that only the IL-2Rgamma-chain-dependent cytokines IL-2, IL-7 and IL-15, among the cytokines of this panel, could reverse the inhibition of glucocorticoids on PBMC adhesion molecule expression and the related functions of intercellular aggregation and proliferation. Furthermore, we also demonstrated that IL-2, IL-7 and IL-15 could induce de novo the synthesis of LFA-1 and CD2. Taken together, these data suggest that glucocorticoids inhibit PBMC LFA-1 and CD2 expression not only directly by modulating transcriptional events, but also indirectly through the inhibition of IL-2Rgamma-dependent cytokines.

CD2 Antigens↗
PubMed2000

Are differences in interleukin 10 production associated with joint damage?

OBJECTIVE: Constitutive differences between individuals in cytokine production may determine the variation in the course of inflammatory arthritis. METHODS: The association between interleukin 10 (IL-10) production and joint destruction was studied by comparing IL-10 mRNA content in synovial biopsies from seven patients with destructive joint disease and six patients with non-destructive joint disease. The IL-10 mRNA content was 0.4 +/- 0.6 arbitrary units in erosive joints compared with 2.3 +/- 1.2 arbitrary units in non-erosive joints (P: < 0.03, Mann-Whitney U:-test). As this difference suggested that IL-10 production was associated with joint destruction, we tested whether the IL-10 locus determined the extent of joint damage. RESULTS: Innate differences in IL-10 production are locus-dependent. In line with these data, we showed that innate differences in IL-10 protein production were also present as differences in IL-10 mRNA levels. We tested if polymorphisms in the promoter of IL-10 were associated with the extent of joint damage. DISCUSSION: In a cohort study of female rheumatoid arthritis patients followed for 12 yr, the extent of joint destruction differed significantly between patients with different IL-10 genotypes. In patients with the -1082AA genotype who were studied prospectively, the mean increase in radiographic damage score (modified Sharp score of X-rays of hands and feet) during the first 6 yr was 9 +/- 9 per yr vs 19 +/- 16 per yr for patients with the genotype -1082GG (P: < 0.02). In line with these data, cultures of endotoxin-stimulated whole blood from 158 donors showed that the presence of the allele associated with less joint destruction correlated with slightly higher IL-10 production. CONCLUSIONS: Both the immunogenetic and the synovial biopsies suggest that a variation in IL-10 production is associated with joint destruction.

Adult↗
PubMed1997

Corticosteroids inhibit lymphocyte binding to endothelium and intercellular adhesion: an additional mechanism for their anti-inflammatory and immunosuppressive effect.

Glucocorticosteroids (GCS) are potent anti-inflammatory and immunosuppressive agents widely used in the treatment of many medical conditions, but their mechanism of action is not yet fully understood. Some of the anti-inflammatory effects of GCS have been attributed to the synthesis of lipocortins, whereas the immunosuppressive effects are thought to be mediated through the inhibition of several immune functions through a down-regulation of cytokine gene expression. Another important mechanism of action of GCS may relate to their ability to interfere with the phenomena of adhesion and migration of inflammatory cells. In this study, the direct effects of GCS on lymphocyte adhesion capacity in vitro were investigated. We demonstrate that GCS inhibit lymphocyte adhesion to endothelium through the down-modulation of lymphocyte adhesion molecules. We also provide evidence that GCS inhibit cell aggregate formation induced by TCR ligation, which directly correlates with the down-modulation of LFA-1 and CD2, but not LFA-3 or ICAM-1. Such down-modulation was paralleled by a decrease in the steady state mRNA level of LFA-1 and CD2 gene products, which suggests a direct GCS control of the expression of these genes. Finally, we show that GCS effects are mediated through the GCS receptor, since they can be completely reversed by the GCS-R antagonist RU-486. This study supports the concept that some of the immunosuppressive and anti-inflammatory effects of GCS are likely to be exerted by the inhibition of adhesion-dependent lymphocyte functions.

Adrenal Cortex Hormones↗
PubMed1994

Adhesion molecules in rheumatoid arthritis: role in the pathogenesis and prospects for therapy.

The essential role played by cell adhesion and migration in the generation of chronic synovitis is now beyond doubt. Some of the beneficial effects of currently used drugs may be related to their ability to interfere with these mechanisms. The complexity of the process, however, means that there are many potential targets for therapeutic intervention and therefore further studies of the basic mechanisms are necessary to identify those which are most important.

Arthritis, Rheumatoid↗
PubMed1994

Adverse interaction between intramuscular methylprednisolone and sulphasalazine in patients with early rheumatoid arthritis. A pilot study.

A defective hypothalamic-pituitary-adrenal axis has been associated with susceptibility to arthritis in rats and with rheumatoid arthritis in humans. The effect of corticosteroid supplementation in early RA has not been tested previously. We undertook a double-blind placebo-controlled study of sulphasalazine plus either corticosteroid or placebo. No early benefit was demonstrated as 7 of 11 of the corticosteroid supplemented group had withdrawn by 1 year. The addition of corticosteroids to sulphasalazine in patients with early disease did not appear to offer any benefit.

Adult↗
PubMed1992

Cellular responses to human chondrocytes: absence of allogeneic responses in the presence of HLA-DR and ICAM-1.

To assess the accessory cell function of human articular chondrocytes, we assessed the ability of human chondrocytes to stimulate allogeneic peripheral blood mononuclear cells (PBMC) and to support phytohaemagglutinin (PHA)-induced proliferation of highly purified T cells. We also examined the surface expression of HLA-DR and ICAM-1 on the chondrocytes both unstimulated and stimulated with cytokines in vitro. Chondrocytes failed to stimulate allogeneic PBMC despite the constitutive expression of MHC class I molecules and the cytokine-induced expression of class II molecules but were able to support T cell proliferation to PHA, IFN-gamma and to a limited extent, IL-1 beta, induced class II expression on chondrocytes. ICAM-1 was present on 94-99% of freshly isolated cells; this declined with culture (17-59%; P < 0.005) but was readily induced by IFN-gamma, IL-1 beta, and tumour necrosis factor-alpha. Alloreactivity and, presumably, autoreactivity to chondrocytes requires factors in addition to the surface expression of DR and ICAM-1. However the presence of these molecules suggests a capacity for cell-cell interactions in inflammatory sites such as the cartilage pannus junction.

Antigen-Presenting Cells↗
PubMed1992

Serial estimation of interleukin 6 as a measure of systemic disease in rheumatoid arthritis.

Disease activity in rheumatoid arthritis (RA) is frequently associated with a marked acute phase response, thrombocytosis, hypergammaglobulinemia and the presence of rheumatoid factors (RF). Interleukin 6 (IL-6) is a cytokine that stimulates hepatocytes to produce acute phase reactants and B lymphocytes to produce immunoglobulin. We measured serum IL-6 in patients with active RA during induction of intramuscular gold therapy. Levels of IL-6 correlated strongly with the erythrocyte sedimentation rate and RF titers and to a lesser degree with platelet counts. It may, therefore, be responsible for many of the systemic manifestations of RA and its measurement in the serum may be a convenient and reproducible variable for the assessment of disease activity in this very common disease.

Arthritis, Rheumatoid↗
PubMed1992

Antigenic responses in reactive arthritis.

In this article, the mechanisms by which infection at a distant site could lead to ReA and whether they could explain the association of ReA with HLA-B27 have been discussed. We propose that ReA synovitis is primarily due to specific synovial T-cell proliferation to fragments of the triggering bacterial found in the joint. Nonspecific T cells amplify synovitis with antibodies playing only a secondary role. First, we have shown that the triggering bacterial antigen is present in a nonviable form in ReA synovium and that this, not cross-reactive joint autoantigen, stimulates the specific synovial immune response. Second, the studies of the humoral immune response in ReA have been reviewed. Further evidence of bacterial persistence in the joint comes from work demonstrating intrasynovial bacteria-specific antibody synthesis. Continuing maturation of the antibody response also points to persisting antigen. In enteric but not genitourinary ReA, the humoral response is mainly IgA, implying chronic stimulation of the gut mucosa. Analysis of the molecules against which the humoral response is directed has shown no difference between yersinia arthritis and yersiniosis, but in CTA, the response to the 57kD and 59kD antigens differs from CT urethritis suggesting they may be arthritogenic. Finally, the antibody response may be absent in ReA patients rendering antibody titres diagnostically less useful and confirming their secondary role in the pathogenesis of synovitis. Third, studies of cellular response in ReA have been analyzed. We show there is a specific synovial MNC proliferative response to fragments of the triggering bacteria found in the joint, which is potentially of diagnostic use. The proliferation is due to CD4+ and CD8+ T cells and restricted by MHC class I and II antigens. This antigen-specific T-cell response is accompanied by an antigen-independent recruitment of nonspecific T cells, which may contribute to the amplification of synovitis. The importance of the synovial APC in determining the synovial immune response is unarguable but the exact mechanisms are unclear. Further details on the possible role of HLA-B27 in the presentation of arthritogenic peptides and on the exact identity of the antigenic epitopes recognized in ReA must await analysis of a large panel of T-cell clones. Finally, it is hoped that advances in this field will lead to specific and effective immunologic therapies or vaccines for this currently untreatable disease.

Antibody Formation↗
PubMed1991

The T-cell-receptor repertoire in the synovial fluid of a patient with rheumatoid arthritis is polyclonal.

We have analyzed the T-cell-receptor repertoire expressed in the synovial fluid of a patient with rheumatoid arthritis by using an inverse polymerase chain reaction. Total RNA was isolated from Ficoll-purified mononuclear cells and converted into circularized double-stranded cDNA. Specific amplification of alpha- and beta-chain variable regions (V alpha and V beta) was achieved with inverted alpha- and beta-chain constant region (C alpha and C beta) primer pairs, and the amplification products were cloned into phage vectors. A total of 78 alpha and 76 beta clones were sequenced, and 67 and 72 productively rearranged alpha and beta genes were identified, respectively. Thirty-one V alpha, 33 alpha-chain joining region (J alpha), 29 V beta, and 12 beta-chain joining region (J beta) gene segments were found in the productively rearranged clones, indicating that the T-cell repertoire expressed in the synovial fluid of this RA patient is highly heterogenous and polyclonal. Comparison of peripheral blood and synovial fluid repertoires showed that the most abundant V beta sequences, V beta 2.1 and V beta 3.1, were enriched in the inflamed joint by a factor of 2 to 3. It is possible that T cells expressing these V beta gene segments, which recognize bacterial superantigens, play a role in the disease.

Amino Acid Sequence↗
PubMed1991

Immunotherapy of rheumatic diseases--practice and prospects.

Present treatments for rheumatic diseases are both toxic to patients and largely ineffective in modifying the disease process. This report, based on a meeting recently held in London, investigates how far recent molecular and immunological advances can be converted into more effective, less toxic and, above all, more specific therapies.

Cytokines↗