New therapies in development for autoimmune diseases: their rationale for combination treatment.
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Adjuvants, Immunologic↗
Biomedical subjects
V Strand
Publications and source records attributed to V Strand.
Radiography of rheumatoid arthritis in the time of increasing drug effectiveness.
Recent clinical development programs for new therapeutic agents in rheumatoid arthritis have included assessment of radiographic progression comparing changes with treatment to placebo and active controls. Studies now use reliable methods of assessment and sufficient study length to detect radiographic changes. Although patient populations and characteristics differ, and radiographic scoring methods vary, the direction of a series of studies appears to indicate that leflunomide (LEF), methotrexate (MTX), sulfasalazine (SSZ), etanercept, infliximab, and IL-1ra are all effective in retarding radiographic progression, as measured by erosions and joint space narrowing. Interpretation of radiograph data in future trials will be aided by utilization of common reading methods and by continuing comparison across differing rheumatoid arthritis protocol populations.
Anti-Inflammatory Agents, Non-Steroidal↗
Monoclonal antibodies and other biologic therapies.
The treatment of systemic lupus erythematosus (SLE) presents a significant therapeutic challenge: multi-organ involvement and a variable disease course characterized by clinical exacerbations and remissions make it difficult to predict outcome. Few products have been specifically developed in this clinical indication and most accepted therapies have not been tested in randomized controlled trials in SLE. A variety of biologic agents under investigation as potential treatments for SLE are designed to interfere with specific immunologic responses, hopefully avoiding generalized immunosuppression. These include therapies to downregulate IL-10 and/or upregulate TGFb production. Agents which interfere with T cell activation and T cell-B cell collaboration, such as CTLA4-Ig and anti-CD40 ligand monoclonal antibodies, may result in long term therapeutic benefit; alone or in combination, even following brief treatment courses. Products designed to decrease production of anti-dsDNA antibodies or inhibit complement activation may prevent immune complex deposition and amerliorate organ-specific manifestations such as renal disease. More aggressive interventions include gene therapy and stem cell transplantation. As these agents enter clinical trials, efforts to develop international consensus regarding trial methodology and outcome measures will be crucial to their successful development.
Antibodies, Monoclonal↗
Looking for important change/differences in studies of responsiveness. OMERACT MCID Working Group. Outcome Measures in Rheumatology. Minimal Clinically Important Difference.
The purpose of this paper is to describe a classification system for studies of responsiveness that was designed to help organize these studies, and identify those with the potential to provide information on minimal clinically important difference (MCID). We developed a 3 dimensional cube into which studies of responsiveness can be categorized based on their evaluation of 3 attributes: 1. individual or group setting; 2. which scores are contrasted; and 3. the type of change or difference being assessed. We present and discuss examples of studies that fit into categories in the classification cube. This classification system helps to focus attention on whether the literature is able to provide information on the specific type of change a person is interested in. It reinforces that the ability of an instrument to detect a certain category of discrimination within the cube does not mean it will necessarily be responsive to another category. The cube has been shown here as a means to separate out studies that address important change. These studies can then be examined as the source of information on MCID.
Clinical Trials as Topic↗
Minimal clinically important differences: review of methods.
Determining a minimal clinically important difference to be detected in a clinical trial is a critical methodological step in the design of a study. In this review, the different methods that have been used in detecting important changes or differences are considered and categorized according to a classification system consisting of which groups are contrasted, the setting of the results, and the type of change of difference being quantified. It was found that most methods and procedures for deriving minimal clinically important differences considered important changes from the viewpoint of a group of patients. Development of methods that focus on individuals should be a goal of the future.
Clinical Trials as Topic↗
Minimal clinically important difference module: summary, recommendations, and research agenda.
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Humans↗
Recent rheumatoid arthritis clinical trials using radiographic endpoints--updated research agenda.
Recent randomized controlled trials of traditional and newly developed therapies provide evidence that we have interventions that potentially slow or prevent structural damage in active rheumatoid arthritis, as measured using radiography. These trials also provide a unique opportunity for exploratory data analysis to generate hypotheses apropos the pathogenesis and determinants of radiographic progression and functional disability; they also facilitate further study of the methodological issues regarding imaging measurement.
Arthritis, Rheumatoid↗
Minimal clinically important difference in plain films in RA: group discussions, conclusions, and recommendations. OMERACT Imaging Task Force.
Analysis of progression of structural damage on an individual patient level in randomized controlled trials provides extra information in addition to the analysis on a group level. A cutoff level is required to define which patients show progression and which patients do not. The objective of the mimimal clinically important difference (MCID) module for plain films was to elaborate the various concepts to determine a MCID for plain films, and if possible, to define a MCID for specific scoring methods. The module comprised preconference reading material, a plenary session, small group discussions, and a plenary report of the group sessions, combined with interactive voting. The following conclusions and recommendations were made: the smallest detectable difference (SDD) beyond measurement error is a good starting point to define MCID; SDD is study-specific; SDD should be reported for all radiographic endpoints used in a trial as a quality control; the expert panel approach is a reasonable method to define MCID, but defined in this way MCID may be smaller than current SDD; more research is needed to validate expert panel based MCID in different datasets and with different experts; a predictive, data driven MCID is the ultimate goal, but is not yet available; the SDD can be used as a proxy for MCID until a data driven MCID is available; analysis at the group level (comparison of means or medians) should remain primary in studies that include progression of joint damage as outcome measure; the proportion of patients showing more progression than the SDD is a secondary outcome measure.
Arthritis, Rheumatoid↗
Standardizing assessment of adverse effects in rheumatology clinical trials. Status of OMERACT Toxicity Working Group March 2000: towards a common understanding of comparative toxicity/safety profiles for antirheumatic therapies.
This paper describes the background and current status of an OMERACT facilitated effort to improve the consistency of adverse event reporting in rheumatology clinical trials. The overall goal is the development of an adverse event assessment tool that would provide a basis for use of common terminology and improve the consistency of reporting severity of side effects within rheumatology clinical trials and during postmarketing surveillance. The resulting Rheumatology Common Toxicity Criteria Index encompassed the following organ systems: allergic/immunologic, cardiac, ENT, gastrointestinal, musculoskeletal, neuropsychiatric, ophthalmologic, pulmonary and skin/integument. Before this tool is widely accepted, its validity, consistency, and feasibility need to be assessed in clinical trials.
Antirheumatic Agents↗
A proposal for developing a large patient population cohort for longterm safety monitoring in rheumatoid arthritis. OMERACT Drug Safety Working Party.
This paper proposes the creation of an objectively acquired reference database to more accurately characterize the incidence and longterm risk of relatively infrequent, but serious, adverse events. Such a database would be maintained longitudinally to provide for ongoing comparison with new rheumatologic drug safety databases collecting the occurrences and treatments of rare events. We propose the establishment of product-specific registries to prospectively follow a cohort of patients with rheumatoid arthritis (RA) who receive newly approved therapies. In addition, a database is required of a much larger cohort of RA patients treated with multiple second line agents of sufficient size to enable case-controlled determinations of the relative incidence of rare but serious events in the treated (registry) versus the larger disease population. The number of patients necessary for agent-specific registries and a larger patient population adequate to supply a matched case-control cohort will depend upon estimates of the detectability of an increased incidence over background. We suggest a system to carry out this proposal that will involve an umbrella organization, responsible for establishment of this large patient cohort, envisioned to be drawn from around the world.
Adverse Drug Reaction Reporting Systems↗
Patient based method of assessing adverse events in clinical trials in rheumatology: the revised Stanford Toxicity Index.
We describe the progress towards developing a patient rated toxicity index that meets all of the patient-important attributes defined by the OMERACT Drug Safety Working Party. These attributes are frequency, severity, importance to patient, importance to the clinician, impact on economics, impact on activities, and integration of adverse effects with benefits. The Stanford Toxicity Index (STI) has been revised to collect all attributes with the exception of impact on activities. However, since the STI is a part of the Health Assessment Questionnaire (HAQ), impact on activities is collected by the HAQ. In particular, a new question asks patients to rate overall satisfaction, taking into consideration both benefits and adverse effects. The next step in the development of this tool is to ensure that the STI meets the OMERACT filter of truth, discrimination, and feasibility. Although truth and feasibility have been confirmed by comparisons within the ARAMIS database, discrimination needs to be assessed in clinical trials.
Adverse Drug Reaction Reporting Systems↗
[Inaccuracy about telepathology from the Radiumhospital].
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Diagnosis, Computer-Assisted↗
Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Leflunomide Rheumatoid Arthritis Investigators Group.
OBJECTIVE: To determine whether treatment with leflunomide (LEF), methotrexate (MTX), or sulfasalazine (SSZ) for 6-12 months retards progression of radiographic damage and to identify clinical variables that correlate with radiographic progression. METHODS: Radiographs of the hands and feet were performed at baseline and at the end of study or early exit in 3 randomized controlled trials. Protocol US301 was a 12-month controlled trial of LEF or MTX treatment compared with placebo in 482 patients randomized in a 3:3:2 ratio. Protocol MN301 compared 6 months of LEF or SSZ treatment with placebo in 358 patients, randomized in a 3:3:2 ratio, with continued blinded treatment in the active control arms for 12 months. Protocol MN302 compared 12 months of LEF treatment with MTX in 999 patients. Radiographs were blinded for sequence and treatment and were scored for erosions and joint space narrowing. All analyses were by intent-to-treat. Sensitivity analyses were performed to account for missing data. RESULTS: LEF, MTX, and SSZ treatment resulted in statistically significantly less radiographic progression compared with placebo at 6 and 12 months: for protocol US301, LEF versus placebo P = 0.0007 and MTX versus placebo P = 0.0196; for protocol MN301, LEF versus placebo P = 0.0004 and SSZ versus placebo P = 0.0484. The effect of LEF treatment was similar to that of MTX and SSZ. CONCLUSION: These are the first 6- and 12-month randomized placebo- and active drug-controlled trials to demonstrate retardation of radiographic progression by a new disease-modifying antirheumatic drug (DMARD), LEF, as well as 2 commonly used DMARDs, MTX and SSZ.
Anti-Inflammatory Agents, Non-Steroidal↗
Clinical improvement as reflected in measures of function and health-related quality of life following treatment with leflunomide compared with methotrexate in patients with rheumatoid arthritis: sensitivity and relative efficiency to detect a treatment effect in a twelve-month, placebo-controlled trial. Leflunomide Rheumatoid Arthritis Investigators Group.
OBJECTIVE: To examine correlations between clinical improvement as defined by the American College of Rheumatology (ACR) responder analysis and clinical improvement as determined by 4 function and/or health-related quality of life measures, and to estimate the sensitivity and relative efficiency of these measures compared with changes in the tender joint count in patients with rheumatoid arthritis (RA). METHODS: A 52-week, multicenter, double-blind controlled trial was conducted to compare treatment with leflunomide (n = 182), methotrexate (n = 180), or placebo (n = 118) in patients with active RA. ACR response rates and improvement in scores on the Health Assessment Questionnaire (HAQ), Problem Elicitation Technique (PET), and Medical Outcomes Survey Short Form 36 (SF-36) were compared in 438 of the patients. RESULTS: In comparing leflunomide with placebo, the patient global assessment, HAQ disability index, and SF-36 bodily pain scale were most responsive to treatment group differences. The modified HAQ (M-HAQ), PET Top 5, SF-36 physical component score, physician global assessment, pain intensity scale, and SF-36 physical functioning scale were more responsive to treatment group differences than was the tender joint count. In comparing methotrexate with placebo, the patient and physician global assessments were most responsive. These 2 measures, as well as the pain intensity scale and the C-reactive protein level, were more responsive to treatment group differences than was the tender joint count, while the SF-36 mental health component score was least responsive. A close correlation between changes in the M-HAQ and HAQ scores indicated that the M-HAQ was similarly responsive to change over time. Improvements in the PET, SF-36 physical component score, bodily pain, and physical functioning scales correlated with the ACR responder status. CONCLUSION: Both disease-specific and generic measures of function and health-related quality of life detect improvements in RA patients. Using both types of measures for evaluating therapies will identify discernible changes that are important to patients, and will facilitate comparisons across different disease states.
Anti-Inflammatory Agents, Non-Steroidal↗
Folic acid supplementation and methotrexate efficacy: comment on articles by Schiff, Emery et al, and others.
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Arthritis, Rheumatoid↗
New therapies for systemic lupus erythematosus.
New therapies for the treatment of SLE have gained increased attention, as demonstrated by a growing number of new modalities being studied. These modalities include novel biologic agents that target specific immunologic responses and more traditional pharmaceutical agents. This article summarizes these new therapies and briefly discusses their mechanisms of action and the most recent research performed to characterize their safety and efficacy.
Antigen-Antibody Complex↗
Short-term exposure to air pollution in a road tunnel enhances the asthmatic response to allergen.
The aim of this study was to assess whether air pollution in road tunnels would promote asthmatic reactions in persons with mild allergic asthma. Twenty volunteers with mild allergic asthma were exposed, inside a car, for 30 min in a Stockholm city road tunnel. As a control, the subjects were exposed to much lower pollution levels in a suburban area. Four hours after the exposure, the subjects inhaled a low dose of allergen. Asthmatic reaction during the early phase was measured as the increase in specific airway resistance 15 min after allergen inhalation and during the late phase as the decrease in lung function forced expiratory volume in one second 3-10 h after allergen inhalation. Asthma symptoms and drug use were monitored up to 18 h after allergen inhalation. The median nitrogen dioxide level during exposure was 313 microg x m-3 (range 203-462). The median levels of particles with 50% cut-off aerodynamic diameters of 10 (PM10) and 2.5 microm (PM2.5) were 170 (range 103-613) and 95 (range 61-218) micro x m-3, respectively. Subjective symptoms during tunnel exposure were not pronounced. However, subjects exposed to tunnel N02 levels of > or = 300 microg x m-3 had a significantly greater early reaction, following allergen exposure, as well as lower lung function and more asthma symptoms during the late phase, compared to control. Also, subjects with PM2.5 exposure > or = 100 microg x m-3 had a slightly increased early reaction compared to control. In conclusion, exposure to air pollution in road tunnels may significantly enhance asthmatic reactions to subsequently inhaled allergens.
Adult↗
Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs.
OBJECTIVE: To summarize the evidence on treatment withdrawal rates reported in observational studies and randomized controlled trials (RCTs) of methotrexate (MTX), parenteral gold (GST), sulphasalazine (SSZ) and hydroxychloroquine (HCQ) among patients with rheumatoid arthritis (RA). METHODS: Two independent Medline searches were used to retrieve relevant studies published between 1966 and 1997. Those which disclosed information on the number of patients withdrawing from the drug were retained. Cumulative probabilities of survival on treatment were then computed using actuarial survival estimates, and differences were tested using log-rank, Wilcoxon and Cox proportional hazards tests. RESULTS: A total of 159 studies provided withdrawal information, and the numbers of patients who withdrew, in general or because of inefficacy or toxicity, could be abstracted from 110 studies contributing 142 treatment arms (MTX, 48; GST, 56; SSZ, 22; HCQ, 16). Data for HCQ were available only up to 24 months, but combined percentages of patients estimated to have continued MTX, GST or SSZ, respectively, for 60 months were 36, 23 and 22% when all failures were considered, 75, 73 and 53% when withdrawals due to lack of efficacy alone were considered, and 65, 36 and 48% when only withdrawals due to toxicity were taken into account. The Cox proportional hazards test performed on all withdrawals, after adjusting for year of publication and type of study, revealed that patients remained on MTX significantly longer than they did on the other three agents; however, the patients stayed significantly longer on GST than MTX when withdrawals for inefficacy were analysed separately. No significant differences in withdrawal rates were noted between observational studies and RCTs. CONCLUSION: Patients with RA stay significantly longer on MTX than on other disease-modifying anti-rheumatic drugs. Higher withdrawal rates among those given GST are mainly due to high toxicity, whereas the majority of withdrawals from SSZ and HCQ result from lack of efficacy. Withdrawal rates in observational studies are similar to those reported in RCTs.
Antirheumatic Agents↗