Patient based methods for assessing adverse events in clinical trials in rheumatology. Progress report for the OMERACT Drug Toxicity Working Party. Outcome Measures in Rheumatology.

There has been increasing recognition in recent years that the measurement of drug related toxicities in rheumatology clinical trials has been sub-optimal. The OMERACT Drug Toxicity Working Party was established to address this issue. The first task of the working party was to identify a minimum set of attributes of drug related toxicity that would be important to patients, clinicians, investigators, and policymakers.

How Canadian and US rheumatologists treat moderate or aggressive rheumatoid arthritis: a survey.

Objective: To determine which second line agents Canadian and US rheumatologists use to treat patients with active rheumatoid arthritis (RA).

Methods: A one page survey was sent by fax or mail to all 263 members of the Canadian Rheumatology Association and 320 members of the American College of Rheumatology (10% random sample weighted by region) known to practice adult rheumatology. The survey asked for first and second treatment preferences in patients with (1) aggressive RA; (2) moderate RA; and (3) aggressive RA failing a trial of methotrexate (MTX) 25 mg.

T cell receptor peptide vaccination in rheumatoid arthritis: a placebo-controlled trial using a combination of Vbeta3, Vbeta14, and Vbeta17 peptides.

Objective: Restricted T cell receptor (TCR) gene usage has been demonstrated in animal models of autoimmune disease and has resulted in the successful use of TCR peptide therapy in animal studies. This clinical trial was undertaken to determine the safety and efficacy of a combination of Vbeta3, Vbeta14, and Vbeta17 TCR peptides in Freund's incomplete adjuvant (IFA) in patients with rheumatoid arthritis (RA).

Methods: A double-blind, placebo-controlled, multicenter, phase II clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of 3 peptides derived from TCRs (Vbeta3, Vbeta14, and Vbeta17) in IFA.

Biologic agents and immunotherapy in rheumatoid arthritis. Progress and perspective.

Advances in our understanding of rheumatoid synovitis have been coupled with increasingly refined methods from biotechnology to produce promising therapeutic agents. Monoclonal antibodies (MoAbs), recombinant cytokines, cytokine receptor fusion proteins and other biologics have been elevated from the status of novel reagents applied in phase I toxicity trials to, in some cases, substantially evaluated and validated tools awaiting federal regulatory approval. Biologic agents will soon be released for the treatment of patients with RA.

Repeated exposure to an ambient level of NO2 enhances asthmatic response to a nonsymptomatic allergen dose.

We investigated the effects of NO2 and allergen on lung function in a repeated exposure model. For 4 subsequent days, 16 subjects with mild asthma and allergy to birch or grass pollen were exposed at rest to either purified air or 500 microg x m(-3) NO2 for 30 min in an exposure chamber. Four hours later, an individually determined nonsymptomatic allergen dose was inhaled.

Effect of 1 year daily treatment with 400 microg budesonide (Pulmicort Turbuhaler) in newly diagnosed asthmatics.

The aim of this study was to investigate whether treatment with a low daily dose of 400 microg inhaled budesonide (Pulmicort Turbuhaler) in newly diagnosed asthmatics could influence the course of asthma. Seventy five adult patients, mostly with mild asthma, diagnosed during the previous year and bronchial hyperresponsiveness, participated in a double-blind, randomized, parallel-group multicentre study. They were treated with budesonide 200 microg b.

Approaches to the management of systemic lupus erythematosus.

Systemic lupus erythematosus is a difficult disease to study with a variable disease course characterized by exacerbations and remissions. A variety of biologic agents are under investigation as potential treatments for systemic lupus erythematosus, either in murine disease models or in clinical trials. These products are designed to specifically interfere with the following immunologic processes: T-cell activation and T-cell-B-cell collaboration, production of anti-dsDNA antibodies, deposition of anti-dsDNA antibody complexes, complement activation, and deposition, and cytokine activation and modulation.

Recommendations for a core set of outcome measures for future phase III clinical trials in knee, hip, and hand osteoarthritis. Consensus development at OMERACT III.

Significant progress has been made in outcome measurement procedures for osteoarthritis (OA) clinical trials, and guidelines have been established by the US Food and Drug Administration, European League Against Rheumatism, the World Health Organization/International League of Associations for Rheumatology, and the Group for the Respect of Ethics and Excellence in Science. However, there remains a need for further international harmonization of measurement procedures used to establish beneficial effects in Phase III clinical trials. A key objective of the OMERACT III conference was to establish a core set of outcome measures for future phase III clinical trials.

Nitrogen dioxide exposure enhances asthmatic reaction to inhaled allergen in subjects with asthma.

We investigated whether exposure to a low level (490 micrograms/m3) of nitrogen dioxide (NO2) affects bronchial responsiveness to allergen and enhances allergen-induced increase in airway responsiveness to histamine. Eighteen subjects with asthma and allergy to pollen were exposed at rest to either purified air or NO2 for 30 min followed 4 h later by an allergen inhalation challenge. Responsiveness to histamine was measured the day after.

Peripheral neutrophils after allergic asthmatic reactions.

The response of peripheral neutrophils was studied in 16 patients with allergic asthma after challenge with birch/grass pollen allergen, in order to identify inflammatory markers associated with only the early asthmatic reaction and those associated with both early and late asthmatic reactions. The allergen challenge proceeded until the patients had an early asthmatic reaction with 100% increase in specific airway resistance. Bronchoconstriction after allergen challenge was monitored hourly over 9 h and finally after 18 h, by measurement of the forced expiratory volume in 1 s.

A double-blind, placebo-controlled study of anti-CD5 immunoconjugate in patients with rheumatoid arthritis. The Xoma RA Investigator Group.

Objective: To evaluate the efficacy of an anti-CD5 ricin-linked immunoconjugate (CD5-IC) in patients with rheumatoid arthritis (RA).

Methods: A total of 104 evaluable patients were enrolled in a multicenter, double-blind, multiple-dose, placebo-controlled study of CD5-IC.

Results: Treatment with CD5-IC in doses up to 8 mg/m2/day for 4 days in 1 month failed to produce marked or prolonged T cell depletion and was no more effective than placebo in ameliorating disease manifestations.

Immediate and delayed effects of nitrogen dioxide exposure at an ambient level on bronchial responsiveness to histamine in subjects with asthma.

The time-kinetics of NO2 induced effects on bronchial responsiveness are poorly known as most observations have been made shortly after exposure. The aim of this study was to measure nonspecific bronchial responsiveness, lung function and inflammatory markers at different times after NO2 exposure in asthmatics. Nineteen subjects with mild asthma were exposed to either purified air or 488 micrograms.

The future use of biologic therapies in combination for the treatment of rheumatoid arthritis.

The complexity of the immune system, exemplified by the pleiotropic effects of many cytokines and the redundancy of regulatory networks controlling immune responses, suggests that single therapeutic interventions will offer transient or less than clinically meaningful benefit. Theoretically, combination therapy using 2 or more biologic agents will modulate important symptomatic and objective manifestations of rheumatoid arthritis (RA). Data from animal models suggest that use of biologic agents in combination can be synergistic and may alter the severity and course of disease.

Biologic agents for the treatment of rheumatoid arthritis.

Substantial progress has been made in our understanding of the immune system and immunopathogenesis of rheumatoid arthritis. This knowledge, combined with advances in biotechnology, has resulted in the development of biologic agents to selectively target elements of the immune system participating in the inflammatory response. This article reviews the available data from clinical trials of biologic agents for the treatment of rheumatoid arthritis.

Innovative treatment approaches for rheumatoid arthritis. Issues in clinical trials of biological agents.

Biological agents have pointed out directions for future research, although none yet are therapies to be employed in the clinic. To date we have administered them at pharmacological; even industrial-strength doses, without demonstrating the desired cell- or diseased-specific effects. There are many issues specific to the clinical development of biological agents which distinguish them from pharmaceutical products.

OMERACT II: the biologics perspective.

The development of biologic agents for the treatment of rheumatic diseases will necessitate inclusion of pharmacoeconomic analyses in the phase III trials. These products are expensive to manufacture, administer, and monitor. Typically, they require parenteral administration and regular monitoring.

American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis.

Objective: Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials.

Health status instruments / utilities.

Rheumatologists and other interested professionals at the OMERACT II conference formed small groups to discuss whether it was sensible to use a generic health status instrument in musculoskeletal disease trials. These instruments promise the possibility of comparison of health status between disease states. However, data is lacking on validity of the current generation of instruments to support their use.

Immunologic assessment during treatment of rheumatoid arthritis with anti-CD5 immunoconjugate.

Objective: To determine if sustained immunologic effects occurred after treatment of patients with rheumatoid arthritis (RA) with an immunoconjugate of murine anti-CD5 monoclonal antibody with ricin A chain (anti-CD5).

Methods: We measured lymphocyte populations, mitogen induced peripheral blood mononuclear cell (PBMC) stimulation, cytokine levels, immunoglobulin levels, in vivo immune function, and clinical outcomes in 9 patients with RA treated with anti-CD5.

Results: The treatment of patients with RA with anti-CD5 was associated with marked acute depletion of peripheral blood lymphocytes (p < 0.

A pilot study of anti-CD5 ricin A chain immunoconjugate in systemic lupus erythematosus.

Objective: To determine the safety and clinical and biological effects of a murine monoclonal anti-CD5 ricin A chain immunoconjugate (CD5 Plus) in patients with systemic lupus erythematosus (SLE).

Methods: An open label phase I study of CD5 Plus. A dose of 0.

Are there special considerations relevant to trials of biologic agents?

Although biologic agents have been developed to effect change in observed or hypothesized pathogenic pathways, discrepancies between biological and clinical effects are well recognized. In trials of these agents, biological and clinical effects need to be evaluated. While the biological effects require assessment to test the proposed primary effect and significant influences, clinical evaluation should use the same set of assessment procedures as pharmacological agents.