Rheumatoid Arthritis: Choy EH

Choy EH. · No affiliation provided · Rheumatology (Oxford). · Pubmed #15226519 links to  free full text

This publication has no abstract.

Scott DL, Antoni C, Choy EH, Van Riel PC. · No affiliation provided · Rheumatology (Oxford). · Pubmed #12730547 links to  free full text

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Carville SF, Choy EH. · Sir Alfred Baring Garrod Clinical Trials Unit, Department of Academic Rheumatology, King's College London, London, UK. · J Rheumatol. · Pubmed #18792996 No free full text.

Abstract: OBJECTIVE: Fibromyalgia (FM) comprises many symptoms and features. Consequently, studies on the condition have used a wide variety of outcome measures and assessment instruments. We investigated those outcome measures and instruments in association with the OMERACT (Outcome measures in Rheumatoid Arthritis Clinical Trials) FM Workshop initiative to define core outcome measures that should be used to assess FM. METHODS: A systematic literature review up to December 2007 was carried out using the keywords "fibromyalgia," "treatment" or "management," and "trial." Data were extracted on outcome measures and assessment instruments used and the pre and post mean and standard deviation to calculate effect sizes (ES). Further sensitivity analysis was carried out according to treatment type, blinding status, and study outcome. RESULTS: The outcome domains identified fell largely within those defined by OMERACT. Morning stiffness was frequently assessed and therefore has been included here. The number of assessment instruments used was wide-ranging, so sensitivity analysis was only carried out on the top 5 within each domain. ES ranged from 0.54 to 3.77 for the key OMERACT domains. Health-related quality of life (HRQOL) was the only exception that had no instrument with moderate sensitivity. Of the secondary domains, dyscognition was lacking any sensitive instrument, as were fatigue and anxiety in pharmacological trials. CONCLUSION: Each of the key OMERACT domains has an instrument that appears to be sensitive to change, with the exception of HRQOL, which requires further research. Dyscognition, fatigue, and anxiety would all benefit from more research into their assessment instruments.

Christodoulou C, Choy EH. · Academic Department of Rheumatology, GKT School of Medicine, Weston Education Centre, London, UK. · Clin Exp Med. · Pubmed #16550339 No free full text.

Abstract: The hallmark of rheumatoid arthritis (RA) is chronic synovial inflammation resulting in progressive joint damage. Cytokines are key mediators of inflammation and can be found in abundance both in the joint and blood of patients with active disease. They are responsible not only for the destructive synovitis but also for some of the systemic features. Research over the last 2 decades has highlighted the important role of cytokines such as tumour necrosis factor alpha (TNF-alpha) and interleukins (IL) 1, 6 and 15 in the pathogenesis of RA and these are potential therapeutic targets. Inhibitors of TNF-alpha and IL-1 are already licensed treatments for RA. Novel biologic agents targeting IL-6 and -15 are currently being developed and showed promise in early clinical trials. This article reviews the role of various cytokines in the pathogenesis of RA and the therapeutic effect of inhibiting these cytokines.

Pollard L, Choy EH, Scott DL. · Department of Rheumatology, GKT School of Medicine, Weston Education Centre, Kings College, London, UK. · Clin Exp Rheumatol. · Pubmed #16273784 No free full text.

Abstract: Despite conventional treatment, RA still has many deleterious consequences. From the patients' perspective, these include persistent pain, functional disability, fatigue, and depression modified by health beliefs and underlying psychological problems. Disability is a consequence of pain, active synovitis and joint damage. It is usually assessed by self-reported questionnaire; the Health Assessment Questionnaire (HAQ) remains the dominant disability measure, although generic health measures such as Short Form-36 and Nottingham Health Profile provide similar information. Treatment with disease modifying drugs and biologic agents improves pain, fatigue and disability. We specifically evaluated the effects of both these drugs and also disease duration on disability assessed by HAQ scores, as there is most information on this topic and it is of fundamental importance to patients. In early RA HAQ gives a 'J-shaped' curve; the initial fall is due to the immediate benefits of treatment and the subsequent gradual rise due to the inability of therapy to fully suppress the disease or prevent progressive joint damage. In established RA HAQ scores increase by about 1% annually and over 25 years average HAQ scores increase by 1.0. Disease modifying drugs and biologics both significantly reduce HAQ scores and the reduction is maintained for 2-5 years. This reduction is seen in both early and established disease. Early steroid therapy has immediate symptomatic treatment, but does not have long-term benefits. Over 5 years the impact of aggressive therapy with disease modifying drugs declines and there is evidence that insufficient treatment is given to many patients with RA. The outcome of RA is greatly improved by current treatment with disease modifying drugs and biologic agents. However, more needs to be done and achieving better results is enhanced by routinely measuring the impact of the disease in routine practice.

Choy EH, Smith C, Doré CJ, Scott DL. · Sir Alfred Baring Clinical Trials Unit, Academic Department of Rheumatology, GKT School of Medicine, King's College London, UK. · Rheumatology (Oxford). · Pubmed #16030080 links to  free full text

Abstract: INTRODUCTION: Combinations of disease-modifying anti-rheumatic drugs (DMARDs) are increasingly used to treat rheumatoid arthritis (RA). Early trials showed their toxicity while recent trials suggest superior efficacy. Trials of DMARD combinations have enrolled different types of patient (early or established RA), used different designs (step-up, parallel or step-down) and utilized a range of outcome measures. We undertook a systematic review of combination DMARD therapy for RA and carried out a meta-analysis to evaluate the evidence for efficacy and toxicity. METHOD: Medline, PubMed and EmBase were searched using MESH headlines 'arthritis, rheumatoid', 'drug therapy, combination' and 'randomized controlled trial' (RCT) for papers published from 1975 to April 2004. References from published articles were also searched. Three independent assessors evaluated abstracts and selected trials for detailed examination. Trials were excluded if their quality was poor, were not published in English or studied DMARDs not licensed to treat RA. Two independent assessors extracted data. Efficacy was assessed by the numbers of patients withdrawn due to lack of efficacy. Toxicity was assessed by the numbers of patients withdrawn due to adverse events. Risk ratios (RR) with 95% confidence intervals (CI) were calculated and meta-analysis was carried out based on a random effects model. Sensitivity analyses evaluated different treatment combinations, trial designs, study populations and outcome measures. RESULTS: Fifty-three potentially relevant RCTs were identified. Twelve were excluded due to: using unlicensed DMARDs (n = 3); reporting in journal supplements of RCTs already included (n = 2); follow-up of an earlier RCT, report of biological outcomes or pharmacokinetics (n = 5); and non-English language publications (n = 2). Forty-one RCTs were evaluated in detail and another five excluded (three open-labelled studies and two with high patient attrition); 36 studies were included in the meta-analysis. These comprised 13 step-up, 16 parallel and 7 step-down trials. Nine assessed early RA and 27 established RA. Seven added steroids to DMARD monotherapy and one study added steroids to DMARD combinations. Six assessed methotrexate (MTX) plus tumour necrosis factor (TNF) inhibitors. Overall, combination DMARD therapy was more effective than monotherapy (RR 0.35; 95% CI 0.28, 0.45) although the risk of toxicity was also slightly higher (RR 1.37; 95% CI 1.16, 1.62). Combinations of MTX with TNF inhibitors and MTX with sulphasalazine or anti-malarials showed good efficacy/toxicity ratios. CONCLUSIONS: DMARD combinations vary in their efficacy/toxicity ratio. MTX plus sulphasalazine and/or anti-malarials and MTX plus TNF inhibitors have particularly favourable benefit/risk ratios.

Choy EH, Panayi GS. · Department of Rheumatology, Guy's, King's, and St. Thomas' Hospitals School of Medicine, King's College, London, United Kingdom. · N Engl J Med. · Pubmed #11259725 No free full text.

This publication has no abstract.

Choy EH. · Department of Rheumatology, Guy's, King's and St Thomas' Hospitals School of Medicine, King's College Hospital, East Dulwich Grove, London, SE22 8PT, UK. · Curr Opin Investig Drugs. · Pubmed #11249596 No free full text.

Abstract: 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.

Choy EH, Kingsley GH, Khoshaba B, Pipitone N, Scott DL, Anonymous00228. · Department of Rheumatology, GKT School of Medicine, Weston Education Centre, Kings College, 10 Cutcombe Road, London SE5 9RS, UK. · Ann Rheum Dis. · Pubmed #15760929 links to  free full text

Abstract: BACKGROUND: In rheumatoid arthritis (RA), intramuscular (IM) pulsed depomedrone expedites an immediate response to disease modifying antirheumatic drugs (DMARDs). Although IM depomedrone is also widely used to treat disease flares in patients treated with DMARDs, its effect on radiological progression has not been assessed. OBJECTIVE: To evaluate the benefits of 120 mg IM depomedrone versus placebo in patients with established RA whose disease was inadequately controlled by existing DMARDs. METHODS: In a 2 year prospective randomised controlled trial patients were assessed using the ILAR/WHO core dataset, disease activity score (DAS28), x ray examination of hands and feet scored by Larsen's method, and bone densitometry. RESULTS: 291 patients with RA were screened, 166 were eligible, and 91 consented and were randomised. Disease activity improved more rapidly in the steroid treated patients than with placebo, but after 6 months no difference remained. A small but significant reduction in erosive damage in the steroid group compared with placebo was also found. More adverse reactions occurred in the steroid treated group than in the placebo patients (55 v 42), especially those reactions traditionally related to steroids (16 v 2), including vertebral fracture, diabetes, and myocardial infarction. Hip bone density fell significantly in steroid treated but not placebo patients. CONCLUSIONS: IM depomedrone improved disease activity in the short term and produced a small reduction in bone erosion at the cost of a significant increase in adverse events. Despite the initial benefit of IM depomedrone, when patients respond suboptimally to a DMARD they should not be given long term additional steroids but should be treated with alternative or additional DMARDs.

Choy EH, Isenberg DA, Garrood T, Farrow S, Ioannou Y, Bird H, Cheung N, Williams B, Hazleman B, Price R, Yoshizaki K, Nishimoto N, Kishimoto T, Panayi GS. · Guy's, King's, and St. Thomas' School of Medicine, King's College, London, UK. · Arthritis Rheum. · Pubmed #12483717 links to  free full text

Abstract: OBJECTIVE: To investigate the safety and efficacy of MRA, a recombinant human anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL-6, in patients with established rheumatoid arthritis (RA). METHODS: A randomized, double-blind, placebo-controlled, dose-escalation trial was conducted in 45 patients with active RA, as defined by the American College of Rheumatology (ACR) revised criteria. Patients were sequentially allocated to receive a single intravenous dose of either 0.1, 1, 5, or 10 mg/kg of MRA or placebo. The primary efficacy end point was meeting the ACR 20% response criteria at week 2 after treatment. RESULTS: Demographic features were similar between treatment groups. At week 2, a significant treatment difference was observed between the 5 mg/kg of MRA and placebo, with 5 patients (55.6%) in the MRA cohort and none in the placebo cohort achieving ACR 20% improvement. There was no statistically significant difference in the ACR 20% response between the other 3 MRA cohorts and placebo at week 2. The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 (P < 0.001 and P < 0.001 by analysis of variance), respectively. These mean scores were statistically significantly lower than those in the 0.1- and 1-mg/kg MRA and the placebo cohorts (6.4, 6.2, and 7.0, respectively). The erythrocyte sedimentation rate and C-reactive protein values fell significantly in the 5- and 10-mg/kg MRA cohorts and normalized 2 weeks after treatment. Seventeen patients (5, 4, 6, 2, and 0 patients in the placebo, 0.1-, 1-, 5-, and 10-mg/kg MRA cohorts, respectively) required corticosteroid or disease-modifying antirheumatic drug treatment because of active disease before study end. They were regarded as nonresponders from the time they received these treatments. Diarrhea was the most common adverse event, occurring in 8% of patients. Seven patients (15.6%) reported a severe adverse event (3, 1, 2, and 2 patients in the placebo, 0.1-, 1-, and 10-mg/kg MRA cohorts). There were no serious adverse events that were thought to be related to the study drug. CONCLUSION: This is the first randomized controlled trial showing that inhibition of IL-6 significantly improved the signs and symptoms of RA and normalized the acute-phase reactants. Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA.

Choy EH, Panayi GS, Emery P, Madden S, Breedveld FC, Kraan MC, Kalden JR, Rascu A, Brown JC, Rapson N, Johnston JM. · GKT School of Medicine, King's College London, London, UK. · Rheumatology (Oxford). · Pubmed #12364634 links to  free full text

Abstract: OBJECTIVE: Results of an earlier open-label pilot study showed that 4162W94 was a relatively non-depleting anti-CD4 monoclonal antibody that induced >80% down-modulation of CD4 molecules from the surface of T lymphocytes. This placebo-controlled repeat-cycle study was conducted in active rheumatoid arthritis (RA) patients to determine the duration of CD4 blockade required to achieve lasting clinical benefit. METHODS: Following DMARD washout, 48 patients (i.e. three cohorts of 16 patients) with ACR-defined RA were to be dosed with 1 (cohort 1), 2 (cohort 2) or 3 (cohort 3) cycles of 5x300 mg 4162W94 or placebo (12 and 4 patients per cohort respectively) at monthly intervals. There was at least 3 months of follow-up after dosing. Clinical outcome was assessed in evaluable patients (receiving at least 80% of each dose course) using ACR20 criteria (required on two consecutive visits). CD4 lymphocyte counts and adverse events were also monitored. RESULTS: Sixteen patients were dosed in each of the first two cohorts; however, the dose was reduced in cohort 3 after five patients had received up to two dose cycles due to accumulating evidence of a high frequency of skin rash. These patients were analysed according to the number of cycles received. A further eight patients received 5x100 mg for one to three cycles prior to stopping the study for administrative reasons. Four of 13 (P=0.119 vs placebo) and 7/13 (P=0.015 vs placebo) in cohorts 1 and 2 respectively achieved ACR20 response on at least two consecutive occasions. No patient receiving 5x100 mg/day or placebo achieved ACR20. Four patients were still responding at the end of the 3-month follow-up period. CD4 lymphocyte suppression (<0.2x10(9)/l on at least two successive occasions) occurred in 11/34 patients who received 4162W94 vs none on placebo. Rash occurred in 21/34 monoclonal antibody-treated patients, including one case of biopsy-confirmed cutaneous vasculitis and 1/11 placebo patients. CONCLUSION: 4162W94 demonstrated significant clinical efficacy in this study. However, because of unacceptable CD4 lymphopenia and rash, the original hypothesis that prolonged CD4 blockade would give lasting clinical benefit was not tested.

Choy EH, Hazleman B, Smith M, Moss K, Lisi L, Scott DG, Patel J, Sopwith M, Isenberg DA. · Academic Department of Rheumatology, GKT School of Medicine, King's College London, King's College Hospital, London, UK. · Rheumatology (Oxford). · Pubmed #12364632 links to  free full text

Abstract: OBJECTIVE: Biological products that neutralize tumour necrosis factor alpha (TNF-alpha) are beneficial in rheumatoid arthritis (RA). We studied the effects of CDP870, a novel anti-TNF-alpha antibody fragment modified to obtain a prolonged plasma half-life ( approximately 14 days). METHODS: Thirty-six patients were randomized in a double-blind, ascending-dose group study to a single intravenous infusion of placebo (n = 12) or 1, 5 or 20 mg/kg CDP870 (each n = 8). The patients were predominantly female (30/36), had a mean age of 56 yr and a mean duration of RA of 13 years. They had received a mean of five DMARDs or experimental therapies (with 1 month washout before the study started) and had active disease. Continuation of NSAIDs and up to 7.5 mg prednisolone daily was allowed. Following the blinded dosing period, 32 patients received a single open-label infusion of either 5 or 20 mg/kg CDP870. RESULTS: In the blinded dosing period, 6/12 placebo patients withdrew from the study (for deteriorating RA < or =4 weeks after dosing). Two of 24 CDP870-treated patients withdrew, both in the 1 mg/kg group (for deteriorating RA or lost to follow up >4 weeks after dosing). The proportion of patients with ACR20 improvement for the per-protocol population with the last observation carried forward was 16.7, 50, 87.5 and 62.5% after 0, 1, 5 and 20 mg/kg CDP870 respectively (combined treatment effect, P = 0.012, primary analysis) at 4 weeks and 16.7, 25, 75 and 75% (P = 0.032) at 8 weeks. The proportion of patients with ACR50 improvement for the per-protocol population with the last observation carried forward was 0, 12.5, 12.5 and 50% after 0, 1, 5 and 20 mg/kg CDP870 respectively (combined treatment effect, P = 0.079) at 4 weeks and 0, 12.5, 12.5 and 50% (P = 0.079) at 8 weeks. Following the open-label dose of CDP870, similar beneficial effects were achieved. CONCLUSION: CDP870 is effective, was very well tolerated in this small study, and has an extended duration of action following one or more intravenous doses.

Choy EH, Scott DL, Kingsley GH, Williams P, Wojtulewski J, Papasavvas G, Henderson E, Macfarlane D, Erhardt C, Young A, Plant MJ, Panayi GS. · Academic Department of Rheumatology, GKT School of Medicine, London, UK. · Clin Exp Rheumatol. · Pubmed #12102471 No free full text.

Abstract: BACKGROUND: Current disease management in rheumatoid arthritis (RA) has moved towards "inverting the therapeutic pyramid" by introducing disease-modifying anti-rheumatic drugs (DMARDs) early. Despite the logic of early DMARD therapy, there is a dearth of supportive evidence for this approach. We report a randomised controlled trial comparing sulphasalazine monotherapy with diclofenac monotherapy in early RA. The primary aim was to provide unequivocal evidence that early DMARDs prevent erosive damage. The secondary aim was to evaluate if sulphasalazine used alone has comparable symptomatic benefits to NSAIDs. METHODS: 117 patients with RA for under 12 months of diagnosis (mean 2 months) were randomised (62 sulphasalazine; 55 diclofenac). Sulphasalazine patients comprised 76% women, and 58% were rheumatoidfactor positive. Diclofenac patients comprised 74% women, and 54% were seropositive. 36% completed 12 months of therapy (16 sulphasalazine; 26 diclofenac); sulphasalazine was given for a mean period of 21 weeks and diclofenac for a mean period of 33 weeks. Results were analysed on an intention to treat basis. RESULTS: After 12 months the mean number of new erosions in patients randomised to receive sulphasalazine was 2.0 (95%CI 0.9, 3.1) and in patients randomised to receive diclofenac was 7.5 (95%CI 4.1, 10.9; p = 0.002 by Student's unpaired t-test). An analysis of valid compliant completers showed the mean number of new erosions in patients who received 12 months therapy with sulphasalazine was 2.3 (95%CI 0.6, 4.0) and in patients who received 12 months diclofenac was 10.5 (95%CI 5.0, 15.9; p = 0.018 by Student's unpaired t-test). The Ritchie articular index, swollen joint counts and pain scores decreased with both sulphasalazine and diclofenac, with mean falls in both groups of 15-20% at 2 weeks and 30-40% at 4 and 8 weeks. There were no differences between treatments. Disease activity scores showed similar highly significant mean decreases within both treatment groups (P < 0.001 in all cases) of 0.5 at 2 weeks and 1.0 at 4 weeks; at 12 and 26 weeks they were significantly lower with sulphasalazine (p = 0.036 and 0.045). 75% of the patients given sulphasalazine and 65% of those given diclofenac had one or more adverse events with no major differences between treatments. CONCLUSIONS: These results show that an accelerated dosing schedule of sulphasalazine has identical effects to diclofenac in reducing symptoms, indicating it is a rapidly effective DMARD. They also provide unequivocal evidence, analysed on an intention to treat basis, that early treatment with sulphasalazine significantly reduces the extent of radiological progression in active RA.

Choy EH, Scott DL, Kingsley GH, Thomas S, Murphy AG, Staines N, Panayi GS. · Guy's Kings, Hospital School of Medicine, King's College, London, UK. · Arthritis Rheum. · Pubmed #11592359 links to  free full text

Abstract: 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.

Choy EH, Connolly DJ, Rapson N, Jeal S, Brown JC, Kingsley GH, Panayi GS, Johnston JM. · Department of Rheumatology, Guy's, King's College and St Thomas Hospitals School of Medicine, King's College London, UK. · Rheumatology (Oxford). · Pubmed #11035136 links to  free full text

Abstract: 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.

Choy EH, Rankin EC, Kassimos D, Vetterlein O, Garyfallos A, Ravirajan CT, Sopwith M, Eastell R, Kingsley GH, Isenberg DA, Panayi GS. · Department of Clinical and Molecular Rheumatology, The Guy's Hospital Medical and Dental School, London, United Kingdom. · J Rheumatol. · Pubmed #10555883 No free full text.

Abstract: 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.

Choy EH. · Consultant Rheumatologist at King's College Hospital and Director of the Sir Alfred Baring Garrod Clinical Trials Unit, London, UK. · Clin Exp Rheumatol. · Pubmed #19604448 No free full text.

Abstract: Disease-modifying antirheumatic drug therapy, including biological treatments that act via tumour necrosis factor (TNF)-alpha blockade, have benefited numerous patients suffering from rheumatoid arthritis (RA). However, a portion of the patient population is unresponsive to initial therapy, experience a decline in response over time or may develop side effects to treatment. These factors illustrate the requirement for additional therapy options, with novel modes of action, in order to treat this chronic and disabling disease. Activated T cells predominate in the disease processes of RA. Therefore, one rational approach to therapy is to modulate or target T cells. Abatacept is a first-in-class agent that targets T-cell modulation via the co-stimulatory CD80/CD86:CD28 pathway. Preclinical studies and clinical trials have demonstrated both the rationale and efficacy of using T-cell modulation as a therapeutic approach and, as a result, abatacept is currently approved in the European Union for the treatment of RA in adults with moderately to severely active disease who have not responded to TNF-alpha antagon-ist therapy. This review will highlight abatacept as an important treatment option in the therapeutic repertoire for RA that selectively modulates T-cell co-stimulation.

Ravindran V, Rachapalli S, Choy EH. · Academic Department of Rheumatology, Sir Alfred Baring Garrod Clinical Trials Unit, Weston Education Centre, King's College London, London, UK. · Rheumatology (Oxford). · Pubmed #19447767 No free full text.

Abstract: OBJECTIVE: Several randomized controlled trials (RCTs) and meta-analyses have confirmed clinical efficacy of glucocorticoids in RA. Concerns regarding safety associated with medium- to long-term use in RA have limited their use in clinical practice. In this meta-analysis, we assessed the toxicity related to medium- to long-term (defined as 1 year or longer) glucocorticoid therapy in RA. METHODS: MEDLINE, EMBASE and CINAHL databases were searched for RCTs of glucocorticoids in RA. RCTs fulfilling the following criteria were included: double-blinded, placebo-controlled, lasted 1 year or longer, used prednisolone (or equivalent) and in English. Toxicity was assessed by number of the patients withdrawn for adverse events (AEs), and the numbers of serious adverse events (SAEs) and AEs. RCTs were compared by meta-analysis using odd ratios (OR) with 95% CIs. RESULTS: Six RCTs with total of 689 patients met the inclusion criteria. All RCTs lasted >or=2 years. All studies allowed concomitant use of NSAIDs and DMARDs. Toxicity of glucocorticoid therapy based on number of patients withdrawn was limited (OR = 1.09; 95% CI 0.52, 2.25). Using number of AEs per patient-year (OR = 1.19; 95% CI 0.91, 1.57) and SAEs (OR = 1.06; 95% CI 0.67, 1.67) produced similar results. Efficacy/toxicity ratio was good for glucocorticoid therapy (number needed to harm/number needed to treat = 0.25). CONCLUSION: Medium- to long-term glucocorticoid therapy in RA is associated with limited toxicity compared to placebo.

Choy EH, Khoshaba B, Cooper D, MacGregor A, Scott DL. · Sir Alfred Baring Garrod Clinical Trials Unit, Academic Department of Rheumatology, King's College London, London, UK. · Arthritis Rheum. · Pubmed #18240256 links to  free full text

Abstract: OBJECTIVE: Assessor-based disease activity measures such as the Disease Activity Score in 28 joints (DAS28), although widely used in rheumatoid arthritis (RA), have high interobserver variability. We developed and validated a patient-based disease activity score (PDAS) as an alternative assessment. METHODS: Patients' assessments of swollen or tender joints, visual analog scales for pain and general health, the Health Assessment Questionnaire, and erythrocyte sedimentation rate (ESR) were used to develop the PDAS. In a developmental cohort (204 patients), regression analyses determined the best fit with the DAS28. A validation cohort (322 patients) subsequently evaluated criterion and construct validity against a range of outcome measures, including the Nottingham Health Profile (NHP) and Short Form 36 (SF-36). Sensitivity to change was assessed in 56 patients after 6 months of treatment with disease-modifying antirheumatic drugs or biologics. RESULTS: In the developmental cohort, the PDAS with ESR (PDAS1) and without ESR (PDAS2) achieved excellent fit with the DAS28 (r = 0.88 and 0.74, respectively). In the validation cohort, the PDAS showed high criterion validity by correlation with the DAS28 (PDAS1: r = 0.89, PDAS2: r = 0.76). Construct validity was demonstrated by high correlations with a range of disease activity measures (r > or = 0.45), whereas low correlations (r < 0.45) with mental and social components of the SF-36 and NHP indicated divergent validity. The PDAS and DAS28 had similar sensitivity to change, determined using effect sizes (DAS28 = 1.03, PDAS1 = 1.02, PDAS2 = 0.77) or standardized response means (DAS28 = 0.79, PDAS1 = 0.77, PDAS2 = 0.73). CONCLUSION: The PDAS1 and PDAS2 are valid and sensitive tools to assess disease activity in RA. They appear suitable for clinical decision making, epidemiologic research, and clinical trials.

Ravindran V, Seah MA, Elias DA, Choy EH, Scott DL, Gordon PA. · Department of Clinical & Academic Rheumatology, King's College Hospital, Denmark Hill, London, UK. · Clin Rheumatol. · Pubmed #17932617 No free full text.

Abstract: The objective of this study was to determine whether radiographic damage is different in British black African patients with rheumatoid arthritis compared to Caucasian patients. Data on demographics, disease- and disability-related variables were obtained from all black African patients and their age-, gender- and disease-duration-matched Caucasian controls. After all features identifying the patients were concealed, X-rays of hands and feet were scored by using the Sharp/van der Heijde method. Data were analysed using Mann-Whitney U test, t test and chi (2) test. Sixty-four patients (32 in each ethnic group) were studied. The median age was 52 years and median disease duration 6 years. Seventy-two percent of patients were female. Black Africans and Caucasians did not differ significantly in rheumatoid factor positivity, disease-modifying anti-rheumatic drugs and biological treatment use. British black African patients had significantly more tender joints and disability. Joint space narrowing was significantly greater in Caucasian patients [48 (27-85) vs 56 (34-107), p = 0.01]. Caucasian patients had more number of erosions (172 vs 220) and higher erosion score; however, the difference in the erosion scores was not statistically significant [2 (0-48) vs 4.5 (0-46), p = 0.17]. Radiographic damage was less severe in black African patients with rheumatoid arthritis compared to their age-, gender- and disease-duration-matched Caucasian controls. A large prospective study is required to confirm the findings of this study and to establish the factors which might be accountable for any differences in the expression of rheumatoid arthritis in this ethnic group.

Choy EH, Smith CM, Farewell V, Walker D, Hassell A, Chau L, Scott DL, Anonymous00454. · Sir Alfred Baring Garrod Clinical Trials Unit, Academic Department of Rheumatology, King's College School of Medicine, Weston Education Centre, Cutcombe Road, London SE5 9RJ, UK. · Ann Rheum Dis. · Pubmed #17768173 No free full text.

Abstract: OBJECTIVE: Treating early active rheumatoid arthritis (RA) with disease modifying antirheumatic drug (DMARD) monotherapy achieves incomplete outcomes and intensive treatment seems preferable. As the relative benefits of combining two DMARDs, one DMARD with glucocorticoids and two DMARDs with glucocorticoids are uncertain we defined them in a factorial trial. METHODS: A 2-year randomised double-blind factorial trial in patients with RA within 2 years of diagnosis treated with methotrexate studied the benefits of added ciclosporin, 9 months intensive prednisolone or both (triple therapy). The primary outcome was the number of patients with new erosions. Secondary outcomes included Larsen's x-ray scores, disability, quality of life and adverse events. Findings: 1391 patients were screened and 467 randomised. Over 2 years 132 (28%) changed therapy and 88 (19%) were lost to follow-up. The number of patients with new erosions was reduced by nearly half by adding ciclosporin or prednisolone (p = 0.01 and 0.03); both treatments reduced increases in Larsen's x-ray scores by over 2 units (p = 0.008 and 0.003). A further reduction in erosive damage was seen with combined use of both treatments. Their effects on erosive damage appeared independent. Triple therapy reduced disability and improved quality of life compared with methotrexate; ciclosporin and prednisolone acted synergistically. More patients withdrew because of adverse events with triple therapy, without an increase in serious adverse effects. CONCLUSIONS: This study confirms the existence of a "window of opportunity" in early RA, when intensive combination therapy produces sustained benefits on damage and disability. Although methotrexate-prednisolone combinations reduce erosive damage, the synergistic effect of two DMARDs is needed to improve quality of life.

Scott DL, Khoshaba B, Choy EH, Kingsley GH. · Department of Rheumatology, King's College London School of Medicine, Weston Education Centre, King's College, Cutcombe Road, London SE5 9RS, UK. · Ann Rheum Dis. · Pubmed #17660223 No free full text.

Abstract: OBJECTIVES: There is growing emphasis on the cost-effectiveness of treating rheumatoid arthritis. Few trials directly record the health utility measures, like EuroQol, needed for economic analyses. Consequently linear regression methods have been used to transform Health Assessment Questionnaire (HAQ) scores into utility measures. The authors examined whether this is justified. METHODS: The authors compared HAQ and EuroQol in cross-sectional and treatment change observational studies of rheumatoid arthritis patients; they also measured SF-36 and Nottingham Health Profiles. RESULTS: In the cross-sectional study, HAQ and EuroQol scores were moderately inversely correlated (Spearman rank correlation, r = 0.76). HAQ showed a Gaussian distribution whereas EuroQol was bimodal. In the treatment change study, changes in HAQ and EuroQol were unrelated (r = 0.08); the changes showed similar Gaussian and bimodal distributions. CONCLUSIONS: Not all patient-based measures are analogous, and evidence of clinical equivalence, especially in treatment response, is needed before data transformation is considered. Specifically, as HAQ and EuroQol are demonstrably not equivalent, economic evaluations of treatment cost effectiveness should not be based on EuroQol data transformed from HAQ. The use of such transformed data by regulatory bodies which determine drug availability means that the issue is no longer only of academic interest but a real clinical concern.

Pollard LC, Murray J, Moody M, Stewart EJ, Choy EH. · Sir Alfred Baring Garrod Clinical Trials Unit, Academic Department of Rheumatology, King's College London, London SE5 9RJ, UK. · Ann Rheum Dis. · Pubmed #17114190 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis (RA) tends to remit during pregnancy, with more patients achieving remission in the third trimester, coinciding with an increase in levels of alpha-fetoprotein (AFP). In vitro and animal studies have shown that AFP has immunomodulatory properties. MM-093 is a non-glycosylated, recombinant version of human AFP. OBJECTIVE: To assess the safety, tolerability and clinical effects of MM-093 during a 12-week, randomised, double-blind, placebo-controlled study. METHODS: 12 patients with RA, who had active disease and were on stable doses of methotrexate, received weekly subcutaneous injections of placebo or 21 mg of MM-093. Assessments were carried out at baseline and weekly thereafter. RESULTS: Baseline characteristics were similar in both groups. There was one dropout in the placebo group, due to flare of disease. Treatment with MM-093 was well tolerated. No serious adverse event was observed. By day 85, MM-093 produced a significant mean improvement from baseline in Disease Activity Score 28 (DAS28; 0.913 vs 0.008, p = 0.033) and patient's global assessment (28.9% vs -36.3%, p = 0.02) compared with placebo. CONCLUSION: This is the first randomised, controlled trial of MM-093, a recombinant version of human AFP, in patients with RA. MM-093 was well tolerated. Evidence of efficacy was observed, suggesting that MM-093 may have therapeutic potential in RA.

Pollard LC, Choy EH, Gonzalez J, Khoshaba B, Scott DL. · Department of Rheumatology, King's College London, Weston Education Centre, Denmark Hill, 10 Cutcombe Road, London SE5 9RJ, UK. · Rheumatology (Oxford). · Pubmed #16449363 links to  free full text

Abstract: OBJECTIVE: We determined the amount of fatigue experienced by patients with RA, and its relationship to synovitis, pain and other common clinical features. We also examined to what extent RA fatigue is improved by disease-modifying antirheumatic drugs (DMARDs) and anti-tumour necrosis factor (TNF) therapy. METHODS: We studied two cohorts of 238 and 274 RA patients cross-sectionally and examined treatment responses in 30 RA patients starting anti-TNF and 54 starting DMARDs followed for 3 and 6 months. We measured fatigue using visual analogue scores (VAS) and Medical Outcomes Study Short Form 36 (SF-36) vitality scores. We recorded the disease activity score for 28 joints and its components (tender/swollen joint counts, patient global assessment, ESR), morning stiffness, health assessment questionnaire, physician global assessment, erosive disease, nodules, rheumatoid factor, concomitant medications and illnesses, and the SF-36 questionnaire. RESULTS: Fatigue was common in RA patients; over 80% had clinically relevant fatigue (VAS > or =20 mm), over 50% had high levels (VAS > or =50 mm). It was associated with pain and changes in mental health, particularly depression. In each of the two cross-sectional cohorts, this relationship was similar whichever measures of fatigue and mental health were used. Fatigue fell with DMARDs and anti-TNF: before treatment, 87% of patients had high fatigue, after treatment this fell to 50%. These treatment effects were mainly linked to improvements in pain. CONCLUSIONS: High fatigue levels characterize RA and are mainly linked to pain and depression. The association with disease activity is secondary. Fatigue falls with DMARD and anti-TNF therapy. The balance of evidence suggests that fatigue is centrally mediated in established RA.

Kingsley GH, Khoshaba B, Smith CM, Choy EH, Scott DL. · Department of Rheumatology, GKT School of Medicine, Weston Education Centre, Kings College, Cutcombe Road, London SE5, UK. · Rheumatology (Oxford). · Pubmed #15705630 links to  free full text

Abstract: OBJECTIVE: Trials of disease-modifying anti-rheumatic drugs (DMARDs) enrol active rheumatoid arthritis patients identified using standard criteria (three out of four of: >/=6 tender joints, >/=6 swollen joints, ESR >/= 28 mm/h, >/=45 min morning stiffness). Concern has been expressed about generalizability, as many patients in routine practice have less active disease. Furthermore, these criteria do not map onto standard disease activity and treatment response measures. We examined how many routine patients were sufficiently active to meet trial recruitment criteria and whether alternative definitions of active disease were more appropriate. METHODS: We studied 504 patients in a cross-sectional study, 156 in a longitudinal study and 94 starting new DMARDs or biologics. Patients were classified as 'trial active' (met entry criteria), in remission or 'intermediately active' (between the two). We also evaluated the effect of amendments to criteria. RESULTS: Cross-sectionally only 38% patients were 'trial active', but longitudinally 68% were 'trial active' at least once. Thus, many clinic patients do have disease activity below the level required for trial entry, but over time most reach eligibility levels. More (62%) of the cohort starting new treatment were 'trial active', suggesting that recruitment criteria relate to clinical decisions. Criteria omitting morning stiffness and a disease activity score (DAS28) >/=5.4 replicated the classification given by current criteria. CONCLUSIONS: Trial results can be generalized to routine practice because most clinic patients are 'trial active' when their therapy is changed and most become 'trial active' over time. As DAS-based criteria are simpler and relate directly to response measures, their use should be considered in future.