PubMed Health⌕ Search

Biomedical subjects

P A Bacon

Publications and source records attributed to P A Bacon.

At least 19 recordsLinked to original sources
PubMed1992

Genetically determined factors as predictors of radiological change in patients with early symmetrical arthritis.

OBJECTIVE: To determine whether genetic factors associated with established rheumatoid arthritis could, in combination with rheumatoid factor, predict the development of radiological erosions in patients with early symmetrical (rheumatoid-like) arthritis. DESIGN: Prospective study. SETTING: Teaching hospital, early arthritis clinic. SUBJECTS: Forty nine patients with symmetrical polyarthritis attending the early arthritis clinic. MAIN OUTCOME MEASURES: Conserved sequence of DR beta third allelic hypervariable region, sulphoxidation capacity, rheumatoid factor, and development of radiologically determined bone erosions. RESULTS: None of the 49 patients had radiological erosions at presentation but 25 developed these by four years. Patients with the conserved class II major histocompatibility complex (third allelic hypervariable of DR beta 1) genes associated with rheumatoid arthritis had a relative risk for the development of erosions of 1.9 (95% confidence interval 0.8 to 4.5). For poor sulphoxidation the risk was 2.5 (1.1 to 5.6) and for the presence of rheumatoid factor 1.8 (0.9 to 3.7). Of the 33 patients who had two or three of these risk factors, 24 developed erosions, with a relative risk of 11.6 (1.7 to 78.5) compared with only one of the 16 individuals with no or one risk factor. CONCLUSIONS: This preliminary study shows that by using these stable markers it is possible to make clinically useful predictions of outcome in patients with early symmetrical inflammatory arthritis.

Acute-Phase Reaction↗
PubMed1992

MHC restriction of synovial fluid lymphocyte responses to the triggering organism in reactive arthritis. Absence of a class I-restricted response.

Synovial fluid mononuclear cells (SFMC) from patients with reactive arthritis (ReA) show marked proliferative responses to preparations of the organism triggering the arthritis. Initial studies with MHC-specific MoAbs have indicated that a significant element of these proliferative responses is mediated by class II MHC-restricted CD4+ T cells. It is imperative to establish the presence or absence of a class I-restricted response, for two reasons. Firstly, the association of ReA with the MHC class I molecule, HLA B27, raises the possibility of there being a B27-restricted response to the triggering organism. Secondly, a number of the organisms associated with ReA are intracellular pathogens, whose antigens might be expected to be presented by class I MHC molecules. In an effort to identify a class I MHC-restricted pathogen-specific response in the SFMC of ReA patients, we have assessed the proliferative responses of SFMC depleted of CD4+ T cells. Responses were grossly diminished by CD4+ T cell depletion. We also investigated Chlamydia-specific cytotoxicity in the SFMC of patients with sexually acquired ReA in a system using productive chlamydial infection to produce both targets and effectors. Significant antigen specific cytotoxicity was not seen. These experiments do not provide evidence to support the existence of pathogen-specific responses by CD8+, class I-restricted synovial fluid T cells in ReA.

Arthritis, Reactive↗
PubMed1992

Influence of acetylator status on sulphasalazine efficacy and toxicity in patients with rheumatoid arthritis.

The influence of acetylator status on the therapeutic efficacy and the toxicity of sulphasalazine (SASP) was assessed in 106 patients with rheumatoid arthritis (RA). Changes of indices of disease activity after 6 months, and progression of erosions after 2 years of SASP treatment were similar in fast and slow acetylators. Incidence and nature of withdrawals and side-effects, and requirement for intra-articular steroid injections or combination therapy due to poor response to SASP were almost identical in the two groups. A significant increase of the hepatic enzyme aspartate transaminase was noted mainly in slow acetylators, but was not associated with clinical disease. These results suggest that acetylator status does not relate significantly to either the efficacy or the toxicity of SASP in RA. It is possible that hepatic metabolism is affected by SASP, particularly in slow acetylators, but this does not lead to clinically identifiable problems.

Acetylation↗
PubMed1991

Clonal anergy blocks the response to IL-4, as well as the production of IL-2, in dual-producing T helper cell clones.

In this report we extend the in vitro clonal anergy model to examine the regulation of proliferation in T cells that secrete both IL-2 and IL-4. Newly cloned Ag-specific murine T cells are shown to depend on both IL-2 and IL-4 synthesis for maximal proliferation. Whereas IL-2 responsiveness is constitutive in these cells, IL-4 responsiveness develops only after Ag and APC stimulation. Remarkably, proliferation of these cells to Ag is sensitive to inhibition by clonal anergy, even though IL-4 synthesis remains inducible. Anergy in these cells is associated with an inability to respond to IL-4, in addition to the development of an IL-2 production defect. The results suggest that anergy induction may be capable of preventing the clonal expansion of autoreactive T cells producing both IL-2 and IL-4 in vivo.

Animals↗
PubMed1991

Isolation of Yersinia-specific T cell clones from the synovial membrane and synovial fluid of a patient with reactive arthritis.

Synovial fluid (SF) mononuclear cells from patients with reactive arthritis (ReA) proliferate in vitro when challenged with ReA-associated bacteria, the maximal response being for the organism causing the triggering infection. We report the results of a study of the antigenic specificity of synovial T lymphocytes from an HLA-B27 positive ReA patient whose SF mononuclear cells responded preferentially to Yersinia antigens. This is the first report of the isolation of Yersinia-specific T cell clones from synovial membrane (obtained by closed-needle synovial biopsy). We present a detailed analysis of these clones, together with others obtained from the SF.

Adult↗
PubMed1991

Primed and naive helper T cells in labial glands from patients with Sjogren's syndrome.

This study has investigated the presence and distribution of B cells, T cells and T-cell subsets within labial glands of patients with primary Sjogren's syndrome (n = 9) and secondary Sjogren's syndrome associated with rheumatoid arthritis (n = 8) using a sequential double immunoperoxidase technique and true colour image analysis. The composition of the inflammatory infiltrates was similar in glands from both patient groups. B cells were normally present within large foci with few detected in diffuse infiltrates such that the ratio of T:B cells in foci (2.4:1) was significantly lower than in diffuse infiltrates (7.3:1; P less than 0.001). In all infiltrates helper T cells (CD8-, CD3+) predominated over suppressor/cytotoxic cells (CD8+, CD3+; 2.7:1). Analysis of primed (CD45RA-, CD45RO+) and naive (CD45RA+, CD45RO-) CD8- T cells showed that the ratio of the primed to naive subset was significantly higher in focal (4.2:1) compared to diffuse (1.5:1; P less than 0.001) areas of lymphoid infiltration. These results indicate that the focal lymphocytic infiltrates characteristic of Sjogren's syndrome contain B cells associated with a T-cell population consisting predominantly of primed CD8- helper T cells. This latter population may be responsible for upregulating glandular B-cell activity in Sjogren's syndrome.

Antigens, CD↗
PubMed1991

Epitope specificity and MHC restriction of rheumatoid arthritis synovial T cell clones which recognize a mycobacterial 65 kDa heat shock protein.

CD4+ T cell clones specific for the mycobacterial hsp 65 were obtained from synovial fluid of a DR4 homozygous rheumatoid arthritis (RA) patient. A stimulatory epitope was defined using both deletion mutants of the mycobacterial hsp 65 and synthetic peptides and proved to be in a highly conserved region of the molecule. Despite this, however, there was no recognition by these clones of either the recombinant human homologue of mycobacterial hsp 65, P60, nor of a synthetic peptide containing an amino acid sequence from P60 corresponding to the epitope defined in the mycobacterial hsp 65. When the pattern of HLA restriction shown by the hsp-65-specific T cell clones was investigated, all clones tested proved to be restricted by HLA-DP rather than the more usual HLA-DR. Inhibition experiments suggested that this restriction also applied to the polyclonal synovial T cell response to hsp 65, but not to other antigens. Exclusive restriction of T cell recognition of an antigen by HLA-DP has not been reported previously, and strongly suggests that in this case the T cell repertoire for recognizing hsp 65 in the context of DR4 is deficient. Such an association between DR4 and the inability to respond to an immunodominant bacterial antigen may have implications for the pathogenesis of RA.

Amino Acid Sequence↗
PubMed1991

Immunodeficiencies associated with sulphasalazine therapy in inflammatory arthritis.

Abnormalities in serum immunoglobulin levels (Igs) are documented in a series of 350 patients with rheumatoid arthritis (RA) and other inflammatory joint diseases treated with sulphasalazine (SASP) for up to 10 years. Low Ig levels occurred in just over 10% of patients after therapy. Three per cent developed selective IgA deficiency between 8 and 20 weeks after starting SASP. Low IgG levels occurred in 2% at 4-52 weeks and low IgM levels in 5% after 3-7 months. One per cent developed panhypogammaglobulinaemia (hypo gamma) 3-7 months after commencing therapy. Most immunodeficiencies were not accompanied by other toxic reactions and SASP was continued in all but one patient with a rash and thrombocytopenia. A good clinical response was observed in most patients particularly those with selective IgA deficiency and hypo gamma. Two patients with hypo gamma developed chest infections which responded to antibiotics. A low level of individual Igs is not usually an indication to stop SASP unless accompanied by other reactions. Panhypo gamma is potentially serious and should be monitored carefully and replacement therapy should be considered in these patients if infections occur.

Adolescent↗
PubMed1991

Vasculitic syndromes associated with other rheumatic conditions and unclassified systemic vasculitis.

Markers for systemic vasculitis may be useful in both assessment of disease activity and ascribing pathogenesis. Endothelial cell damage may be assessed by Factor VIII-related antigen and perhaps fibrinolysis (plasmin inhibitor/plasmin complex). Antibodies to endothelial cells potentially combine both assessment and pathogenesis. Complement fixing antibodies to endothelial cells, previously reported in systemic lupus erythematosus and Kawasaki syndrome, are also elevated in rheumatoid vasculitis. Their relationship to vascular endothelial cell antibodies, reported in a wide spectrum of systemic vasculitis, is not clear. A direct role for neutrophils in some forms of vasculitis is supported by the overlap of rheumatoid vasculitis with Sweet's syndrome, previously associated with both Behçet's and Crohn's syndrome. An indirect role of persistent neutrophil inflammation at mucosal surfaces is suggested by the vasculitis with antineutrophil cytoplasmic antibodies seen in cystic fibrosis. In other cases, vasculitis may be triggered by direct viral infection such as cytomegalovirus. Experimental models may clarify the confusion. In the MRL mouse, vasculitis appears independent of the B-cell hyperactivity. Experimental models of uveitis also support a role for T cells in the induction of vasculitis.

Animals↗
PubMed1991

Assessment of rheumatoid arthritis.

Accurate assessment of disease activity and progression is essential in diseases with marked chronicity such as rheumatoid arthritis. It is not surprising that rheumatologists continue to seek improvement in old indices and to develop new ones. In the field of clinical indices, selection of data that contribute independently to the overall value of a compound assessment index will simplify trial methodology considerably. The trend is to reduce the number of tests done, but there is still a need to include functional indices and perhaps psychologic ones, because disability and self-image clearly affect prognosis. In the laboratory area, the trend is to develop methods to specifically assess different aspects of inflammation rather than to rely on overall nonspecific measures such as acute-phase proteins. Radiographs remain the simplest method for detecting scars of previous disease and the potential exists to improve and perhaps mechanize the reading of such films. Magnetic resonance imaging has the potential for assessment of the current state of inflammation if newer methodologies are used. Radionuclides may also have much to offer in joint assessment in the 1990s.

Arthritis, Rheumatoid↗
PubMed1990

Recognition of a mycobacteria-specific epitope in the 65-kD heat-shock protein by synovial fluid-derived T cell clones.

Adjuvant arthritis in rats is induced by a T cell clone specific for amino acids 180-188 of the mycobacterial 65-kD heat-shock protein, and synovial T cell responses to this same Ag have been noted in human arthritis. We have isolated 65-kD Ag-specific T cell clones from synovial fluid mononuclear cells of a patient with acute arthritis, which, unlike the corresponding PBMC, showed a marked proliferative response to the 65-kD Ag. Using synthetic peptides corresponding to the whole sequence of the 65-kD Ag, all the clones were shown to recognize an epitope present in the first NH2-terminal peptide (amino acids 1-15), with no response to the adjacent peptide (amino acids 6-22) or to any other peptide. The complete dominance of this epitope in the response to the 65-kD Ag was shown by documenting responses to the peptide in PBMC obtained after recovery from the arthritis. This epitope, like that recognized by the rat arthritogenic T cell clone, is in a portion of the 65-kD sequence that is not conserved between bacteria and eukaryotes, so that in this case, joint inflammation could not be attributed to bacteria-induced T cell clones cross-reacting with the self 65-kD Ag.

Antigens, Bacterial↗
PubMed1990

Etodolac: efficacy in osteoarthritis and effects on chondrocyte function.

Some nonsteroidal anti-inflammatory drugs (NSAIDs) used in the treatment of osteoarthritis (OA) may damage articular cartilage. This damage may be caused by suppression of proteoglycan synthesis or by altered collagen synthesis in the presence of prostaglandin E2 (PGE2) induced by interleukin-1 (IL-1). The clinical and biochemical effects of etodolac, a new NSAID, on the symptoms of OA and on cartilage metabolism are reviewed. Clinically, etodolac (200-600 mg/day) was more effective than placebo, and as effective as aspirin (3200-4800 mg/day), piroxicam (20 mg/day), naproxen (1000 mg/day), and diclofenac (150 mg/day) in relieving the symptoms of OA. In in vitro studies, proteoglycan synthesis was not affected by the presence of etodolac when human chondrocytes were grown in a three-dimensional culture. Etodolac preserved collagen phenotype in human chondrocytes cultured in a monolayer in the presence of IL-1. In contrast, the collagen phenotype of cells cultured in the presence of indomethacin and IL-1 changed. Under those conditions, less type II and type IX collagen were synthesized and more type I and type III collagen were synthesized. These findings suggest that etodolac, an effective agent in the treatment of OA, has the potential advantage of not damaging articular cartilage in vivo.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Azathioprine, cyclophosphamide and chlorambucil.

Immunosuppressive agents serve a major role in the management of once-fatal conditions such as the systemic necrotizing vasculitides, but they are also being used in more common, chronic inflammatory disorders such as rheumatoid arthritis. The drugs are all capable of reducing cell division but they differ in their modes of action. This is in keeping with their differing rates of action, and different indications. Azathioprine is a valuable alternative to slow-acting antirheumatic drugs in older patients with rheumatoid arthritis. Cyclophosphamide has transformed the outlook of many forms of vasculitis. Chlorambucil is particularly useful in improving the prognosis for children with amyloidosis secondary to juvenile chronic arthritis. We have tried to highlight the role of these drugs in a number of rheumatic diseases. We have emphasized their clinical applications, with some laboratory evidence for their effects. The major side-effects are reviewed. Finally, we have discussed their possible mechanisms of action.

Arthritis, Rheumatoid↗
PubMed1990

Sulphasalazine in psoriatic arthritis: a double-blind placebo-controlled study.

Sulphasalazine (SASP) is now accepted as an effective slow-acting antirheumatic drug for treating active rheumatoid arthritis (RA), but has not been previously evaluated in psoriatic arthritis. An earlier open study suggested that it was well tolerated and potentially beneficial. The present double-blind placebo-controlled trial of 30 patients has now confirmed its efficacy. Greater improvement occurred in those patients on active treatment than on placebo, with more benefit being detected in those patients with the symmetrical polyarticular but seronegative pattern of arthritis associated with a high acute-phase response. SASP was stopped in 26% because of side-effects but these were mild. No exacerbation or remission of psoriasis was observed. Further studies are in progress to determine the degree of efficacy of SASP in different clinical subgroups of psoriatic arthritis.

Arthritis↗
PubMed1990

Synovial fluid antigen-presenting cells unmask peripheral blood T cell responses to bacterial antigens in inflammatory arthritis.

We and others have previously shown that synovial fluid (SF) mononuclear cells (MC) from patients with both reactive arthritis and other inflammatory arthritides proliferate in vitro in response to bacteria clinically associated with the triggering of reactive arthritis. In all cases, such SFMC responses are greater than the corresponding peripheral blood (PB) MC responses, often markedly so, and the mechanism for this is unclear. We have investigated this phenomenon by comparing the relative abilities of irradiated non-T cells derived from PB and SF to support autologous T cell responses to ReA-associated bacteria. Seven patients whose SFMC had been shown previously to respond to bacteria were studied. We demonstrate antigen-specific responses of PB T cells to bacteria in the presence of SF non-T cells which are in marked contrast to the minimal responses of either unfractionated PBMC or PB T cells reconstituted with PB non-T cells. We also show that PB, but not SF T cells respond strongly to autologous SF non-T cells in the absence of antigen or mitogen. These findings demonstrate that SF antigen-presenting cells (APC) are potent activators of PB T cells. We conclude that the contrasting responses of SFMC and PBMC to bacterial antigens may be accounted for at least in part by an enhanced ability of SF APC to support T cell proliferative responses.

Antigen-Presenting Cells↗