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Biomedical subjects

G S Panayi

Publications and source records attributed to G S Panayi.

At least 19 recordsLinked to original sources
PubMed1995

Dysregulation of the in vivo production of interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Pathogenetic implications.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have defective hypothalamic responses to inflammation, possibly because of excessive production of cytokine inhibitor, which could blunt the effects of cytokines on the hypothalamus, or because of an imbalance between interleukin-1 beta (IL-1 beta) and interleukin-1 receptor antagonist (IL-1Ra), which could create a mainly proinflammatory state. The present study was undertaken to investigate these possibilities. METHODS: The in vivo kinetics of IL-1 beta and IL-1Ra secretion were studied in patients with RA, osteoarthritis (OA), and chronic osteomyelitis (OM), and in normal controls before and after surgery. RESULTS: The 24-hour levels of IL-1Ra were significantly increased in RA (P < 0.001), but there was no diurnal variation in any group. Preoperative levels of IL-1Ra were higher in RA and OA sera (P = 0.001). After surgery, IL-1Ra behaved like an acute-phase reactant protein in all subjects. IL-1 beta was 10-20 times higher in RA than in OM and OA patients at baseline, but the percentage increase in all groups postoperatively was the same. RA patients had an IL-1Ra:IL-1 beta ratio of 26.2 +/- 3.7 (mean +/- SEM) at baseline (OM patients 89.2 +/- 5.8 and OA patients 1,310 +/- 363); this increased to 66.5 +/- 19.8 after surgery (OM patients 120 +/- 6.7 and OA patients 325.8 +/- 106). CONCLUSION: RA patients have a dysregulation of IL-1Ra production, and it seems unlikely that the defective hypothalamic response seen in RA is due to a functional deficit of IL-1 beta.

Adult↗
PubMed1995

Hematologic and cytofluorographic analysis of patients with Felty's syndrome. A hypothesis that a discrete event leads to large granular lymphocyte expansions in this condition.

OBJECTIVE: To compare hematologic and cytofluorographic features in Felty's syndrome (FS) patients with and without the large granular lymphocyte (LGL) syndrome. METHODS: Peripheral blood cells from FS patients and from 2 control groups (rheumatoid arthritis [RA] patients and subjects without symptoms of a rheumatic disease) were analyzed by hematologic and cytofluorographic techniques. A separate assessment of disease activity was performed. RESULTS: FS patients had reduced lymphocyte and platelet counts, with a parallel reduction in lymphocyte subsets examined. CD4 counts were reduced in all FS patients, including those with the LGL syndrome. Disease activity was lower in FS patients than in RA control patients. Treatment was similar in all patient groups. No direct association was seen between LGL numbers and duration of RA or neutrophil counts in RA groups. CONCLUSION: Hematologic abnormalities in FS extend beyond neutropenia. Although similarities were seen between FS patients and FS patients with the LGL syndrome (e.g., CD4 lymphopenia), evidence for a gradation from FS to the LGL syndrome was not seen, thus favoring the hypothesis that a "transforming event" is required.

Adult↗
PubMed1995

Reduction of synovial inflammation after anti-CD4 monoclonal antibody treatment in early rheumatoid arthritis.

OBJECTIVE: To study the effect of chimeric anti-CD4 monoclonal antibody (MAb) therapy on synovial inflammation, in order to interpret the clinical experience with anti-CD4 treatment. METHODS: The immunohistologic features of synovial biopsy specimens before and 4 weeks after anti-CD4 MAb (cM-T412) therapy were studied in patients with rheumatoid arthritis. The patients received intravenous doses of either placebo (n = 1) or 10 mg (n = 4), 25 mg (n = 2), or 50 mg (n = 1) of cM-T412 daily for 5 consecutive days. RESULTS: Although the patients did not experience clinical improvement, significant decreases in the number of circulating CD4+ cells, the degree of synovial inflammatory infiltration, and the mean scores for expression of adhesion molecules were found in the 7 patients 4 weeks after receiving cM-T412. The scores for infiltration with CD4+ and other inflammatory cells were particularly reduced following treatment with either 25 mg or 50 mg cM-T412. Cytokines, such as interleukin-1 beta and tumor necrosis factor alpha, could still be detected in the synovial tissue after treatment. CONCLUSION: The decline in the numbers of inflammatory cells and adhesion molecules in synovial tissue after CD4+ cell depletion supports the view that CD4+ T cells orchestrate local cellular infiltration. The lack of clinical effect of anti-CD4 therapy might be explained by an insufficient decrease in the number of synovial CD4+ cells and by the persistence of cytokines. Determination of whether more adequate dosing would lead to a clinical improvement must await further study.

Adult↗
PubMed1995

The pathogenesis of rheumatoid arthritis and the development of therapeutic strategies for the clinical investigation of biologics.

This review discusses current concepts of the pathogenesis of rheumatoid arthritis. It is proposed that RA is a T cell mediated disease following which a large number of subsequent inflammatory events are unleashed. Many of the pathogenetic steps are targets for new therapies including biologics. Laboratory, clinical and radiological methods of assessing disease activity are sufficiently sensitive and reproducible to permit their use in multicentre studies capable of detecting a biologic with disease modifying activity. The clinical assessment of the efficacy and toxicity of biologics poses unique problems. These have been illustrated by the example of 3 monoclonal antibodies directed against ICAM-1, CD4 and TNF alpha. The main role of most biologics may be to pinpoint important therapeutic targets which can be attacked by more easily administered and less costly xenobiotic drugs.

Antibodies, Monoclonal↗
PubMed1995

Hormonal control of rheumatoid inflammation.

As other contributors to this volume have discussed, the genetic basis of rheumatoid arthritis (RA) is multifactorial. One aim of this chapter is to propose that perhaps an additional, non-MHC genetic factor contributing to the pathogenesis of RA may reside in a defective response of the neuroendocrine system to inflammatory stimuli. This proposal is based on work carried out in patients with RA and on lessons learned from animal models of chronic inflammatory disease. This chapter will not consider the effect of sex hormones on the pathogenesis of RA because the data are often contradictory and have yet to crystallize into a coherent hypothesis with testable predictions.

Acute Disease↗
PubMed1995

The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody (CDP571) in rheumatoid arthritis.

Pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF alpha) have been implicated in the pathogenesis of rheumatoid arthritis (RA), and have therefore become therapeutic targets. An engineered human antibody, CDP571, that neutralizes human TNF alpha was administered intravenously in single doses of 0.1, 1.0 or 10 mg/kg to patients with active RA (n = 24). The effects of the antibody were compared in a double-blind fashion with those of placebo (n = 12). In an open continuation phase patients were given either 1.0 or 10 mg/kg. We found that CDP571 was well tolerated and caused reductions in markers of disease activity such as erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP): this was confirmed by a reduction in the disease activity score (DAS). There was a reduction in the number of tender joints, maximal in degree and duration after 10 mg/kg. Patients also documented a reduction of pain and relief of arthritis symptoms. The effects of 10 mg/kg CDP571 on ESR, CRP, tender joints, pain and symptom relief compared to placebo were statistically significant at weeks 1 or 2. The continuation phase, although open, confirmed both the safety and the beneficial effects of CDP571 in active RA. In conclusion CDP571, an engineered human anti-TNF alpha antibody, is well tolerated and, after a single dose of 10 mg/kg, provides improvements in symptoms, signs and serological markers of disease activity in patients with active RA.

Adolescent↗
PubMed1995

Therapeutic monoclonal antibodies.

Monoclonal antibodies have been used extensively over the last few years in clinical trials of rheumatoid arthritis (RA). Not only are they potential therapeutic agents, but they are also useful probes into the immunopathogenesis of RA. Anti-tumour necrosis factor alpha (TNF alpha) monoclonal antibodies have been shown to be clinically efficacious. Although they produced rapid disease amelioration, the duration of clinical improvement was limited to 4-6 weeks. Re-treatments were again effective but long-term studies are required to assess their therapeutic role in RA. So far, the therapeutic effects of lymphocyte-depleting antibodies have been disappointing. From the data, it is clear that synovial lymphocytes are more difficult to eliminate than peripheral blood lymphocytes and it is likely that in order to delete all synovial lymphocytes, high doses of depleting antibodies will be required which could lead to severe immunosuppression. Hence, lymphocyte depletion may not be a feasible therapeutic strategy. However, there are a number of clinical trials currently underway attempting to inhibit CD4 lymphocyte function by non-depleting antibodies. In animal models of RA, such antibodies have been shown to induce long-term disease remission. Another possibility is to combine several monoclonal antibodies in order to induce disease remission in RA. This strategy has been used in murine collagen-induced arthritis in which a combination of anti-CD4 and anti-TNF alpha monoclonal antibodies was shown to be synergistic.

Antibodies, Monoclonal↗
PubMed1995

Large granular lymphocyte expansions in patients with Felty's syndrome: analysis using anti-T cell receptor V beta-specific monoclonal antibodies.

Felty's syndrome (FS), the association of rheumatoid arthritis (RA) and idiopathic neutropenia, remains an unexplained phenomenon. HLA-DR4 is found in over 90% of cases. Patients with FS may have a T cell lymphocytosis of CD3+CD8+CD57+ large granular lymphocytes (LGL syndrome). In this study of 47 patients with FS, 19% had clear evidence for LGL expansions, while in total 42% had variable evidence for the LGL syndrome using currently available techniques. Of these T cell expansions, 76% were clonal, as demonstrated by Southern blotting and analysis with T cell receptor (TCR) beta chain constant region probes. This technique may fail to detect clonal populations in some patients. Cytofluorographic analysis using antibodies specific for TCR V beta chains identified patients with clonal LGL expansions with results comparable to those obtained with Southern blotting. No evidence for shared V beta usage among expansions from different patients was seen. The role of LGL in RA and FS is currently unclear, but this technique offers a practical and accessible means of identifying patients with LGL expansions, as a starting point for further investigation.

Adult↗
PubMed1995

Cytokine and adhesion molecule expression in the minor salivary glands of patients with Sjögren's syndrome and chronic sialoadenitis.

OBJECTIVE: To investigate the role of cytokines and cell adhesion molecules in the pathogenesis of Sjögren's syndrome (SS). METHODS: Using an indirect immunoperoxidase technique we assessed the expression of the cytokines interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-8 (IL-8), transforming growth factor beta (TGF beta) and granulocyte macrophage colony stimulating factor (GM-CSF), of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), lymphocyte function associated antigen-1 (LFA-1), the activated molecular form of LFA-1 (NKI-L16), CD2, and LFA-3, and of a panel of cellular markers in the minor salivary glands. RESULTS: In SS and chronic sialoadenitis (CS), the ductal epithelial cells and acini expressed all the cytokines examined. The percentage of glandular mononuclear cells which stained positive for cytokines did not differ significantly between SS and CS. NKI-L16 was detected on 33.6 (SD 10.1)% and 15.3 (4.3)% of LFA-1 cells in SS and CS, respectively (p < 0.002). CONCLUSION: SS and CS did not differ in the pattern of cytokines examined. The characteristic cell clustering seen in the salivary glands in SS may be caused by the upregulation of NKI-L16.

Adult↗
PubMed1995

Peripheral blood and synovial fluid monocyte expression of interleukin 1 alpha and 1 beta during active rheumatoid arthritis.

OBJECTIVE: To investigate the mononuclear cell (MNC) types from peripheral blood (PB) and synovial fluid (SF) of patients with rheumatoid arthritis (RA) expressing interleukin-1 beta and -1 alpha (IL-1 beta, IL-1 alpha). METHODS: PB and SF MNC from 16 patients with classical or definite RA and controls were analyzed by flow cytometry for IL-1 beta and IL-1 alpha staining. RESULTS: MNC from normal individuals do not stain for either IL-1 beta or IL-1 alpha. By contrast, PB and SF CD14+ monocytes from patients with active RA show significant staining for surface and intracellular IL-1 beta and IL-1 alpha. Furthermore, the erythrocyte sedimentation rate (ESR) correlates with the surface expression of IL-1 alpha (r = 0.52, p < 0.05) while the number of active joints (i.e., tender and/or swollen) correlate with the intracellular expression of IL-1 beta (r = 0.58, p < 0.03) in CD14+ monocytes. CONCLUSION: The analysis of IL-1 beta and IL-1 alpha expression on CD14+ monocytes from peripheral blood by flow cytometry could be a potential immunological marker of disease activity in RA and its variation could be used to monitor the effects of therapy.

Antigens, CD↗
PubMed1995

The value of percentage of CD8+ T lymphocyte levels in distinguishing polymyalgia rheumatica from early rheumatoid arthritis.

OBJECTIVE: To determine whether the low absolute numbers and percentages of CD8 positive T cells in the circulation of patients with polymyalgia rheumatica (PMR) could be used as a new diagnostic criterion for the disease. METHODS: The % CD4 and CD8 positive T lymphocyte sub-populations were measured in 37 patients with PRM before treatment and during steroid treatment over the subsequent 2 years, in 21 patients with rheumatoid arthritis (RA), and in 27 normal (N) control subjects. RESULTS: During the study, 10 patients, who were initially diagnosed as PMR, were reclassified as having had a myalgic onset of RA (PMR-RA), according to the American College of Rheumatology criteria for the diagnosis of RA. No decreased %CD8+ T lymphocyte subset had been observed in these patients at presentation, before steroid therapy, or during treatment with steroids when compared with the RA and N groups. CONCLUSION: The measurement of %CD8+ T cell subset may provide a simple method for determining whether patients presenting with myalgia are "true" PMR or are destined to develop RA.

Adult↗
PubMed1994

Association of TAP2 polymorphism with rheumatoid arthritis is secondary to allelic association with HLA-DRB1.

OBJECTIVE: To study polymorphisms of the newly described TAP2 locus in rheumatoid arthritis (RA) and to analyze their relationship with HLA-DRB1 alleles previously implicated in the development of the disease. METHODS: TAP2 polymorphic residues at 3 sites, Val/Ile-379, Ala/Thr-565, and Ala/Thr-665, were characterized by amplification refractory mutation system polymerase chain reaction in 185 RA patients and 48 HLA-DR4 positive healthy controls. HLA-DR4 subtypes were determined by sequence-specific priming and oligonucleotide hybridization. RESULTS: The frequencies of Ile-379, Thr-565, and Thr-665 were significantly increased in DR4 positive versus DR4 negative RA patients. TAP2 genotype distributions also differed between the patient groups stratified by DR4 status. However, no significant differences in TAP2 polymorphisms were observed between DR4 positive RA patients and DR4 positive controls, although relationships between specific DR4 subtypes and TAP2 variants were identified. CONCLUSION: Particular TAP2 polymorphisms are associated with distinct HLA-DR specificities in both normal and RA populations. Thus, the prevalence of specific TAP2 residues and genotypes in RA appears to be secondary to the HLA-DR frequencies and genotypic combinations that are typical of RA.

Adult↗
PubMed1994

The large granular lymphocyte syndrome with rheumatoid arthritis. Immunogenetic evidence for a broader definition of Felty's syndrome.

OBJECTIVE: To assess whether the HLA-DR4 association found in rheumatoid arthritis (RA) is also seen in the large granular lymphocyte (LGL) syndrome. METHODS: HLA-DR genotyping was performed using restriction fragment length polymorphism and polymerase chain reaction analysis. RESULTS: LGL syndrome patients with RA showed the same HLA-DR4 association seen in RA/Felty's syndrome (FS), while LGL syndrome patients without arthritis did not. CONCLUSION: It is proposed that FS and the LGL syndrome represent different variants of a broader syndrome comprising RA, neutropenia, LGL expansions, HLA-DR4 positivity, and splenomegaly.

Adult↗
PubMed1994

Evidence for the continuous recruitment and activation of T cells into the joints of patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) synovial fluid (SF) T cells express the activation markers CD69, HLA-DR and very late antigen (VLA)-1, but surprisingly few bear interleukin-2 receptors (CD25). This unusual activation state is commonly assumed to be due to stimulation by local antigen, yet T cells activated in vitro express activation antigens in the clearly defined sequence: CD69, CD25, HLA-DR and finally VLA-1. Two possible explanations for the activation state of SF cells are: first, they comprise several subpopulations each expressing different activation antigens or, second, activation markers are up-regulated by mechanisms other than antigen stimulation. To examine these hypotheses, double- and triple-color immunofluorescence techniques were applied to four T cell populations: normal peripheral blood T cells activated in vitro, RA SF T cells, T cells from an in vivo model of migration [tuberculin purified protein derivative (PPD)-induced skin blisters] and T cells co-cultured with endothelial cells (EC). The results confirmed that in vitro activated T cells expressed activation markers in the sequence described above, with significant CD25 expression and few cells co-expressing CD69 with HLA-DR or VLA-1. In contrast, almost half the SF T cells were CD69+HLA-DR+ but CD25-; a significant minority were CD69+VLA-1+. T cells from PPD-induced skin blisters were already HLA-DR+ and VLA-1+ at 24 h, although, in vitro, PPD-activated T cells up-regulated HLA-DR and VLA-1 only after 1 week, suggesting that pre-activated T cells were preferentially recruited into the blisters. Finally, T cells were found to up-regulate CD69 and, to a lesser extent, HLA-DR after adhering to EC in vitro. In summary, the paradoxical activation state of SF T cells cannot be explained solely by single or multiple rounds of activation in situ. At least two other mechanisms, the preferential recruitment of pre-activated T cells and the induction of HLA-DR and especially CD69 by endothelial contact during migration, may also play a role.

Adult↗
PubMed1994

Immunology of psoriasis and psoriatic arthritis.

Psoriasis and psoriatic arthritis are diseases of unknown aetiology characterized by chronic immune-mediated lesions in the skin and synovial joints respectively. The lesions are remarkably similar in appearance and in functional terms. The main differences reside in the fact, first, that the main antigen-presenting cell in the skin is the Langerhans' cell while in the joint it is probably the dendritic antigen-presenting cell and, second, that the main mesenchymal cell in the skin is the keratinocyte while in the joint it is the synoviocyte. Whether these differences merely reflect tissue-specific characteristics or are important in aetiopathogenesis is not known at present. However, the similarity in pathogenesis does mean that similar immunotherapeutic approaches can be used for their treatment.

Arthritis, Psoriatic↗