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Biomedical subjects

E H Choy

Publications and source records attributed to E H Choy.

At least 19 recordsLinked to original sources
PubMed2001

Control of rheumatoid arthritis by oral tolerance.

OBJECTIVE: Previous randomized controlled trials for treatment of rheumatoid arthritis (RA) with acid-soluble chicken and bovine type II collagen (CII) have produced conflicting results. This randomized, double-blind, controlled trial examined the therapeutic effect of bovine CII tablets in RA. METHODS: CII tablets were prepared by adsorption onto a lactose base. Patients with a duration of RA of > or = 2 years and who had failed treatment with at least 1 slow-acting drug were recruited, provided that they had active arthritis. Patients were randomly assigned to receive either 0.05 mg, 0.5 mg, or 5 mg of CII or placebo daily for 6 months. All slow-acting drugs were stopped at least 4 weeks before starting CII, although prednisolone was permitted at dosages < 10 mg/day. Clinical assessments were performed at screening and at 0, 1, 4, 8, 12, 16, 20, and 24 weeks of treatment. RESULTS: Fifty-five patients were recruited. Initially, there were no significant differences in mean Disease Activity Scores between groups. At 24 weeks, there was a significant difference (P = 0.041, by Kruskal-Wallis analysis of variance); the major components of this difference were attributable to relatively large decreases in the 0.5 mg CII group (19% of initial values) and to minimal decreases in patients receiving placebo (3% of initial values). Twenty patients had American College of Rheumatology 20% responses; 11 of these were in the 0.5 mg CII group and 3 were in each of the other groups, a significant difference (chi2 = 14.6, P = 0.002). There was no significant difference in any clinical measure between the placebo, 0.05 mg CII, and 5 mg CII groups. There were no side effects associated with CII treatment. CONCLUSION: Treatment with 0.5 mg/day of bovine CII is well tolerated and produces small, but significant, disease improvement in RA. However, the therapeutic window is narrow. The difference between our results and those of other trials may relate to the dose, species, and formulation of the CII.

Administration, Oral↗
PubMed2001

Use of two-dimensional gel electrophoresis to measure changes in synovial fluid proteins from patients with rheumatoid arthritis treated with antibody to CD4.

Synovial fluid proteins from microliter volumes of synovial fluid were resolved by two-dimensional polyacrylamide gel electrophoresis and detected by silver staining to investigate the feasibility of using two-dimensional (2D) electrophoresis in the clinical research setting and provide global disease information of disease progression. Several hundred proteins could be resolved as spots, many of which displayed the characteristic pattern of plasma-derived glycoproteins. The lowest level of detection was approximately 0.2 ng from a total of 50 microg of protein loaded. Most of the proteins could be identified on the basis of pI and molecular weight when compared with plasma protein maps on the World Wide Web. Unknown proteins were characterized by mass spectrometry of tryptic digests and by comparison with peptide databases. Synovial fluids from patients with rheumatoid arthritis were analyzed using this technique. Each subject received a fixed dose of antibody to CD4 as part of a phase II clinical trial to determine the efficacy of this immunosuppressive treatment in modifying disease activity. Synovial fluid was removed at day 0, followed by administration of antibody. Subsequent removal of synovial fluid and additional administration of antibody were carried out at different times thereafter. Changes in levels of acute-phase proteins were quantified by densitometry of silver-stained 2D polyacrylamide gels. Other parameters of disease progression such as serum C-reactive protein and physician's global assessment of clinical condition were used for comparison. In this way, changes in acute-phase proteins towards normal levels, as measured by 2D polyacrylamide gel electrophoresis, could be correlated with clinical improvement and conventional clinical chemistry measurements. Thus, the system can be used for quantitative analysis of protein expression in sites of autoimmune disease activity such as the synovial fluid of rheumatoid arthritis patients.

Acute-Phase Proteins↗
PubMed2000

Pharmacokinetic, pharmacodynamic and clinical effects of a humanized IgG1 anti-CD4 monoclonal antibody in the peripheral blood and synovial fluid of rheumatoid arthritis patients.

BACKGROUND: CD4(+) T cells are important mediators in the pathogenesis of rheumatoid arthritis (RA). In this open-label, dose-escalating study, we examined the pharmacokinetic (PK), clinical, biological and immunological effects of a humanized IgG1 anti-CD4 monoclonal antibody (mAb), 4162W94, in the peripheral blood (PB) and synovial fluid (SF) of RA patients. METHOD: Twenty-four patients in four cohorts (six patients in each cohort) were allocated to be treated with five consecutive daily doses of 4162W94 (10, 30, 100 or 300 mg i.v.). Disease activity was measured by the American College of Rheumatology (ACR) criteria and disease activity score (DAS). We also measured 4162W94 concentration, the percentage of 4162W94-coated CD4(+) lymphocytes, percentage down-modulation of CD4, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFalpha) levels in the PB and SF. RESULTS: A direct relationship between 4162W94 dose, biological response and clinical outcome was seen. Treatment with 10 and 30 mg of 4162W94 for 5 consecutive days resulted in transient coating and down-modulation of CD4(+) lymphocytes, with little effect observed beyond the final dose. However, treatment with 100 and 300 mg resulted in sustained coating and/or down-modulation for 3 weeks and 4 weeks, respectively, in PB and >4 weeks in SF in one patient from the 300 mg cohort. There was a dose-related moderate but transient depression in the CD4(+) lymphocyte count in most patients, with all but three returning to >0.40 x 10(9)/l or >75% baseline by the end of the study period. Significant clinical improvement (ACR 20%) was seen in only 1/6 patients in each of the 10- and 30-mg cohorts; however, 3/6 and 5/5 patients in the 100 and 300-mg cohorts, respectively, were ACR 20% responders. In addition, there were significant reductions in PB acute phase reactants as well as SF IL-6 and TNFalpha concentrations in parallel to clinical improvement. CONCLUSION: Data from this pilot study suggest that 4162W94 is a clinically active novel immunotherapeutic agent that may suppress inflammation in RA.

Adult↗
PubMed2000

Oral toleragens in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common inflammatory and destructive arthropathy. Its precise pathogenesis remains unknown but there is evidence to suggest it is an autoimmune disease. Recently, a number of candidate autoantigens have been identified in RA. Modulating the immune response to the autoantigens by oral tolerance may lead to safer and more effective treatment. Oral tolerance is a state of systemic immune suppression to an antigen induced by oral feeding of the same antigen. In animal models, oral feeding with pathogenic antigens prevents and reduces the severity of autoimmune diseases. Even in diseases where the pathogenic autoantigens are unknown, bystander suppression can be induced using antigens present in the anatomical vicinity. Hence, oral tolerance has been advocated as a treatment strategy for autoimmune diseases including RA. Clinical trials of chicken and bovine type II collagen, a major constituent of articular cartilage, produced conflicting results in RA. This review examines the scientific basis of oral tolerance, discusses the apparent discrepancy in clinical trial results and looks at the future prospect.

Animals↗
PubMed1999

The engineered human anti-tumor necrosis factor-alpha antibody CDP571 inhibits inflammatory pathways but not T cell activation in patients with rheumatoid arthritis.

OBJECTIVE: We investigated the effect of an engineered human anti-tumor necrosis factor-alpha antibody, CDP571, on immune functions as well as bone and cartilage turnover in patients with rheumatoid arthritis (RA) in a placebo controlled trial. We also assessed the effects of repeated treatment with CDP571 in an open label continuation study. METHOD: Thirty-six patients were treated with either placebo or 0.1, 1, or 10 mg/kg of CDP571 given as an intravenous infusion. The followup period was 8 weeks. Lymphocyte phenotype, soluble CD4 (sCD4), soluble interleukin 2 receptor (sIL-2R), IL-6, and stromelysin levels in the blood were measured before and after treatment; bone and cartilage markers (pyridinoline, deoxypyridinoline, N-terminal telopeptide) were similarly assessed in the urine. Patients who completed a placebo controlled trial of CDP571 were offered further treatment with CDP571. They received a maximum of 2 further doses of 1 mg/kg (7 patients) or 10 mg/kg (9 patients) in an open study. RESULTS: Plasma IL-6 level was statistically significantly reduced in the 1 and 10 mg/kg groups. In the 10 mg/kg group, there were also reductions in plasma stromelysin and urine bone markers, although there was no change in sCD4 and sIL-2R levels. Repeat doses of CDP571 were well tolerated and continued to suppress the acute phase response and disease activity. CONCLUSION: Treatment with 10 mg/kg of CDP571 reduced IL-6 and surrogate markers of bone turnover in RA, suggesting that CDP571 might prevent joint damage in RA. Since there was no effect on lymphocyte markers despite the marked reduction in inflammation, CDP571 appears to have no effect on ongoing CD4 T cell activation.

Antibodies↗
PubMed1998

Monoclonal antibody therapy in rheumatoid arthritis.

Monoclonal antibodies bind to their targets with high specificity and therefore have excellent potential as therapeutic agents. Biotechnological advances have allowed the production of large quantities of engineered monoclonal antibodies for therapeutic use. Recent research in rheumatoid arthritis has identified important mediators of synovitis. Monoclonal antibodies targeting these have been tested in clinical trials over the last decade. Anti-cytokine therapies, in particular anti-tumour necrosis factor alpha monoclonal antibodies, suppressed inflammation and produced rapid symptomatic improvement. Anti-lymphocyte monoclonal antibodies produced long-lasting disease suppression in animal models of rheumatoid arthritis. The use of depleting anti-lymphocyte monoclonal antibodies in rheumatoid arthritis had been disappointing as they did not penetrate the synovial joint in sufficient quantity to suppress disease without producing severe and protracted peripheral blood lymphopenia. Consequently, their use in rheumatoid arthritis had been abandoned. In contrast, clinical trials of non-depleting anti-CD4 monoclonal antibodies in rheumatoid arthritis showed that they could suppress synovitis. However, it remains unclear whether they could lead to prolonged disease improvement.

Animals↗
PubMed1998

Clinical pharmacology and therapeutic potential of monoclonal antibody treatment in rheumatoid arthritis.

Many monoclonal antibodies (mAb) have been tested in rheumatoid arthritis (RA). Murine antibodies were antigenic and caused human antimouse responses in the recipients. As a result, re-treatments were less effective and were associated with an increased risk of anaphylaxis. Advances in biotechnology have allowed us to develop chimaeric and humanised mAb that are less antigenic than their murine equivalents. The specificity of mAb allows targeting of particular inflammatory mediators that are thought to be pathogenic in RA. In clinical trials, anti-cytokine antibodies such as anti-tumour necrosis factor-alpha mAb reduced inflammation rapidly and produced marked symptomatic improvement. The clinical improvement was related to the dosage and plasma concentration of the antibody. When depleting anti-lymphocyte mAb were used in RA, they produced variable clinical responses. One of the explanations for this is the poor penetration of anti-lymphocyte antibodies into the synovial joint. Therefore, depletion of lymphocytes was much greater in the blood than in the synovial joints. Consequently this approach has been abandoned and, recently, nondepleting anti-CD4 mAb have been tested in RA. When sufficient dosages were given, they produced clinical improvement, but more studies are required to assess whether they can lead to long term disease suppression.

Antibodies, Monoclonal↗
PubMed1997

Nickel contamination of gold salts: link with gold-induced skin rash.

Intramuscular chrysotherapy is a well-established treatment for rheumatoid arthritis. Its therapeutic use has been limited by the high incidence of dermatological side-effects. The pathogenic mechanisms of these are unknown, but could include allergic reactions to gold or to nickel contaminating the gold. In order to investigate these mechanisms further, 15 patients, who developed cutaneous eruptions after chrysotherapy, were assessed using skin biopsy and lymphocyte transformation stimulated by gold and nickel salts in vitro. Chrysotherapy induced two main cutaneous eruptions: lichenoid reactions and non-specific dermatitis. Peripheral blood mononuclear cells from patients with lichenoid reaction proliferated to gold salts in vitro, while those who developed non-specific dermatitis responded mainly to nickel. Nickel was a significant contaminant of the gold preparation (sodium aurothiomalate, Myocrisin, Rhone-Poulenc Ltd), amounting to a total of 650 ng after 6 months treatment. We suggest that a significant percentage of skin reactions during chrysotherapy are due to nickel contamination of the gold preparation.

Adult↗
PubMed1997

Chronic sialadenitis in patients with nodal osteoarthritis.

Amongst the patients attending our combined oral medicine/rheumatology clinic, we have identified a subset presenting with xerostomia due to non-specific sialadenitis, who also suffer from generalized nodal osteoarthritis (NOA). We have called this combination SOX syndrome: sialadenitis, osteoarthritis and xerostomia. In this study, we have examined the characteristics of these patients clinically and histologically, and then determined the prevalence of SOX syndrome in patients with NOA compared to healthy age-matched controls. Patients were obtained from rheumatology clinics and a local old people's home. The series consisted of 35 patients with NOA and 18 age- and sex-matched controls without evidence of NOA or inflammatory rheumatic disease. There was no significant difference in age and sex between the two groups. None were on drugs known to induce xerostomia. The subjects were assessed for whole salivary, parotid saliva and lacrimal flow, autoantibodies, rheumatoid factor (RF) and erythrocyte sedimentation rate (ESR). The whole saliva flow (mean +/- 95% CI) was 0.32 +/- 0.07 ml/min for the NOA group and 0.54 +/- 0.17 ml/min for the control group. The difference is statistically significant (P < 0.05, two-tailed Student's t-test). No statistically significant difference was found in the parotid and lacrimal flow rates of NOA and controls. Nine of the 35 NOA patients had reduced whole salivary flow (normal range > 0.02 ml/min) compared with only one out of 18 in the control group (P > 0.05, chi 2 test). All NOA patients with xerostomia and reduced whole salivary flow were RF, anti-Ro and anti-La negative, and had a normal ESR. Thus, 25% of subjects with NOA had clinical and laboratory features of SOX syndrome, suggesting that this is a defined disease entity.

Adult↗
PubMed1997

Drug treatment of rheumatic diseases in the 1990s. Achievements and future developments.

There have been several advances in the therapy of arthritis. These are based on better understanding of the pathogenesis of rheumatic diseases, re-evaluation of previous therapeutic concepts such as combination therapy, and developments within biotechnology. There are 4 main areas of development, mainly involving the treatment of inflammatory synovitis. The first is with anti-inflammatory drugs, where there has been a focus on reducing gastrointestinal toxicity through the use of combination preparations such as diclofenac-misoprostol, and the introduction of drugs with more selectivity for cyclo-oxygenase-2 inhibition such as meloxicam. An additional approach has been the development of anti-inflammatory drugs such as tenidap which also control cytokine metabolism. The second area is slow-acting antirheumatic drugs with the introduction of cyclosporin as a single agent or in combination with methotrexate, the development of immunomodulating drugs such as leflunomide, and the demonstration that some antibiotics such as minocycline have slow-acting effects. The third area is the use of corticosteroids including the development of deflazacort as a bone sparing agent, the greater use of intramuscular depot steroids and the validation of low-dose oral corticosteroids in early rheumatoid arthritis. Finally, there have been advances in the biotechnology area with the demonstration that cytokine immunotherapy such as antibodies to tumour necrosis factor can rapidly improve the symptoms of rheumatoid arthritis, and that T cell immunotherapy with antibodies to the CD4 receptor may be effective in reducing synovitis. Many of these agents have not yet been introduced into clinical practice but they show the diversity of drug development and suggest the likelihood of major therapeutic benefits in the next few years.

Antirheumatic Agents↗
PubMed1996

Percentage of anti-CD4 monoclonal antibody-coated lymphocytes in the rheumatoid joint is associated with clinical improvement. Implications for the development of immunotherapeutic dosing regimens.

OBJECTIVE: We assessed the effect of a daily dosing schedule of the chimeric anti-CD4 monoclonal antibody (MAb), cM-T412, in rheumatoid arthritis (RA) patients, and compared lymphocyte changes in the peripheral blood (PB) and synovial fluid (SF) of these patients. METHODS: Twelve patients received 50 mg/day of cM-T412 for 5 days, followed by a maintenance treatment of 50 mg/week for 5 weeks (6 patients), or a retreatment course of 50 mg/day for 5 days after 5 weeks (6 patients). Paired PB and SF samples were obtained during treatment for analysis. RESULTS: Changes in lymphocyte count and coating with the MAb in PB did not reflect changes in the SF. After 5 daily treatments, the percentage of cM-T412-coated CD4+ lymphocytes in SF correlated with the degree of clinical improvement seen in patients at 2 weeks after the initiation of therapy (r = 0.75, P < 0.05). CONCLUSION: These results demonstrate the importance of antibody dosage and treatment regimen in determining clinical benefit. Our findings suggest that the percentage of cM-T412-coated CD4+ lymphocytes in SF may be a predictor of clinical outcome.

Adult↗
PubMed1996

Standardising joint assessment in rheumatoid arthritis.

Evaluating joint involvement in rheumatoid arthritis in a key clinical assessment. We investigated the extent of variation in measurement of joint swelling and tenderness and evaluated the impact of training to standardise methods. Eight observers (medical and nursing staff) examined eight rheumatoid patients for joint swelling and tenderness before and after training in clinical methods. The EULAR handbook for joint evaluation was used for training and assessments were based on the 28 joint count. There was extensive variability in both numbers of swollen and tender joints. Coefficients of variation for articular indices recorded by the 8 observers in individual patients were often high (up to a maximum of 204%), indicating considerable differences between observers. Training had an impact on the assessment of the numbers of swollen joints which increased by a mean of 32% (P < 0.05) and the number of tender joints which increased by 41% (p < 0.01). Training had only a limited impact on the variation among observers in determining the number of swollen and number of tender joints. After training, the mean coefficients of variation were still 59% for swollen joints and 65% for tender joints. These results highlight the extent of variation in clinical assessment of rheumatoid arthritis and show the advantages of training. It leads to increased sensitivity of measurement. Standardisation appears essential for clinical studies.

Analysis of Variance↗
PubMed1996

Endogenous opioid tone in patients with rheumatoid arthritis.

We have previously shown that there is deficient hypothalamic-pituitary-adrenal (HPA) responsiveness in rheumatoid arthritis (RA) patients. The basis for this deficient response is not known. The purpose of the project was to investigate whether the defective HPA response in RA patients is the result of increased endogenous opioid tone secondary to chronic pain which can suppress corticotrophin-releasing hormone (CRH) production. We conducted a double-blind placebo-controlled cross-over trial to study the effect of the opiate antagonist, naloxone, on psychometric function together with plasma adrenocorticotrophic hormone (ACTH), cortisol and prolactin. Seven RA patients with active and established disease and eight healthy controls were studied. Each received either a bolus i.v. infusion of 20 mg naloxone or normal saline. After at least 72 h, they received naloxone if they had previously received normal saline or vice versa. The pain score was statistically significantly higher at baseline in the RA group compared with controls (5.7 +/- 3.25 vs 0.35 +/- 0.21, P < 0.001). No difference was found in the other psychometric assessments throughout the study. Patients receiving normal saline did not show any significant change in cortisol or ACTH. Cortisol and ACTH showed a sharp and significant rise after naloxone treatment in both RA and normal subjects (P < 0.001 and P < 0.01), but no difference was observed between the two groups. The mean prolactin level showed no significant change in both groups after any treatment. We conclude that endogenous opioid tone does not appear to be a major contributor to the HPA defect in RA. However, the number of patients studied was small and this result will require confirmation from larger trials.

Adrenocorticotropic Hormone↗