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Biomedical subjects

V Strand

Publications and source records attributed to V Strand.

At least 73 records · Page 4Linked to original sources
PubMed1996

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.m-3 (0.26 ppm) NO2 for 30 min during intermittent exercise. Airway responsiveness to histamine, specific airway resistance (sRaw) and thoracic gas volume (TGV) were measured 30 min, 5 h, 27 h and 7 days after exposure. Peripheral blood inflammatory mediators and the expression of an adhesion molecule, (Mac1) on granulocytes, were analysed 30 min and 27 h after exposure. Bronchial responsiveness to histamine was significantly increased 5 h after NO2 exposure when compared to air (median provocative dose of histamine required to cause 100% increase of sRaw ((PDsRaw,100%) 110 micrograms after NO2 exposure vs 203 micrograms on air). There was a tendency for an increase after 30 min, which was nonsignificant (median PDsRaw,100% 100 vs 153 micrograms). NO2 exposure did not affect sRaw, but TGV was significantly reduced after exposure. We found an increased expression of Mac-1 on granulocytes 30 min after NO2 exposure when compared to pre-exposure values. No effect was seen on tryptase, eosinophil cationic protein (ECP), or myeloperoxidase (MPO). These results suggest that exposure to an ambient level of NO2 causes a delayed effect on bronchial responsiveness in asthmatics. The increased expression of an adhesion molecule in peripheral blood may indicate a NO2-induced priming of human granulocytes.

Adult↗
PubMed1996

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. Although combinations of biologic agents have yet to be used in human disease, successful examples employing immunosuppressive agents exist: cyclosporin (CsA) with methotrexate in patients with persistent active RA, as well as azathioprine and/or mycophenolate mofitil with CsA in organ transplantation and acute graft rejection. There are many arguments against the use of combination biologic therapies including acute infusion related toxicities, infection, malignancy, autoimmune manifestations, and expense. While caution dictates that phase I-II clinical trials be performed in patients with longstanding, refractory disease, subsequent trials should be conducted in patients with earlier, more responsive disease. Successful combination biologic therapies must afford sufficient duration of benefit (at least 6, preferably 12 months), cost comparable to approved 2nd line agents, ease of treatment, and an acceptable safety profile.

Animals↗
PubMed1995

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. The goal of this study was to promulgate a single definition for use in RA trials. METHODS: Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3-step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement. RESULTS: The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved. CONCLUSION: We present a definition of improvement which we hope will be used widely in RA trials.

Adult↗
PubMed1995

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. Most are immunologically active; early trials are performed in patients with disease, rather than normal volunteers. This poses multiple challenges: access to an appropriate patient population, as well as effecting immunomodulation without interfering with normal immune surveillance. Species-specificity of the agent may limit the use of preclinical animal models, and the duration of toxicology studies. Immunogenicity may preclude regular re-administration, necessitating prolonged benefit after single or limited treatment courses. Parenteral administration requires more careful monitoring, limits access to the agent, is associated with more expense, and may contribute to the high observed placebo response following treatment with biological agents. Requirements, and our expectations, for clinical benefit are therefore higher with these products than with traditional pharmaceuticals. Despite a scientific rationale and the use of biological markers, it is unlikely that development of a biological agent for the treatment of a chronic auto-immune disease can progress significantly faster than for a traditional pharmaceutical product. It is therefore important, particularly in the treatment of chronic RA, to develop a careful and rational step-by-step clinical development programme and to define the goals of the therapy: anti-inflammatory or symptom modification versus disease modification. Some biological agents may be expensive but safe NSAIDs. Others may treat disease flares. After 'induction therapy', utilizing a biological agent, followed by 'maintenance therapy' with a traditional DMARD agent, we may envisage 'combination chemotherapy', employing multiple biological products targeting different specific immunological aspects of the disease. We must therefore develop biological agents utilizing rigorous clinical trial principles, and follow suggested guidelines.

Animals↗
PubMed1995

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 < 0.01) during and immediately after treatment. A sustained decrease in the number of CD3, CD4, CD5, and CD8 bearing lymphocytes persisted for 2 months after treatment (p < 0.05). After 3 months a mild decrease in the number of these lymphocyte populations persisted, but when compared to baseline values, the differences were not found to be statistically significant. Phytohemagglutinin induced PBMC proliferation was decreased at the 3-month followup (p < 0.05). Evaluations of mitogen induced cytokine and immunoglobulin production, immunoglobulin level, autoantibody, and in vivo antibody response to tetanus toxoid did not show any consistent change from baseline. CONCLUSION: Anti-CD5 treatment of RA appears to be associated with a decrease in the population of cells bearing CD5, but does not appear to induce any persistent immunologic abnormalities.

Adolescent↗
PubMed1995

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. Often the duration of benefit is brief; although they may effectively serve as "induction therapy." For example, we have a "wonderful new biologic agent," judged effective by the ACR preliminary index for improvement, which after 2 treatment courses at +1500 (US) each, offers a year of "clinically meaningful" improvement with an acceptable safety profile in most patients. How will we convince our regulatory authorities and health services agencies that it should be approved and added to our formularies? It will be necessary to prospectively collect information about its costs (both direct and indirect) and the costs of alternative treatments. In the multicenter clinical trials for approval, patients' opinions about their health status, quality of life, and the treatment itself must be sought. In addition to a disease specific measure of function/disability, a generic measure of health status/quality of life should be included. Use of a health utilities instrument will allow comparison of different therapeutic interventions. The promise of specifically targeting disregulated immune responses without altering underlying normal immune function makes biologic agents uniquely attractive for use in an early disease population. It will therefore be important to identify those indirect costs saved or gained by maintaining function and work capacity, as well as the direct (and indirect) costs incurred by treatment associated toxicities.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Products↗
PubMed1995

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. Participants had little personal experience with these instruments. After inspection, many voiced strong concerns over comprehensiveness and responsiveness. Many dimensions of health relevant for patients with this group of diseases were felt to be underrepresented. The dimension of adverse effects was universally absent, although this is more a problem of state of the art in trial methodology than a problem of these measures. Although there is little data, the small number of response categories in the dimensions covered, plus the lack of comprehensiveness, make it likely that responsiveness will be low. Further research, especially the adoption of one or more generic measures alongside specific measures, both in trials and in observational studies, is necessary to validate and improve the current generic measures. Until that time, valid conclusions and health policy regarding musculoskeletal diseases cannot be based on generic measures of health status.

Health Status↗
PubMed1994

Administration of an anti-CD5 immunoconjugate to patients with rheumatoid arthritis: effect on peripheral blood mononuclear cells and in vitro immune function.

OBJECTIVE: An immunoconjugate, CD5 Plus, composed of ricin A chain and murine IgG1 anti-CD5 monoclonal antibody is under investigation for treatment of rheumatoid arthritis. To understand better the mechanism of action of this agent, alterations in immune function and lymphocyte subpopulations were assessed in a subset of patients consecutively enrolled in 2-phase II clinical trials. METHODS: Flow cytometric and in vitro functional analyses of peripheral blood mononuclear cells from 12 patients receiving 5 daily intravenous infusions of CD5 Plus at doses of 0.20 or 0.33 mg/kg were performed before, during and after treatment. RESULTS: Peripheral CD3+ T cells were significantly depleted (p < 0.01) during treatment on Days 2 and 5 and returned towards baseline on Days 15 to 29; changes in CD5+ B cells occurred in parallel. There was no significant treatment effect on monocytes. All T cell subsets examined, including CD4, CD8, CD45RA, CD45RO, HLA-DR+, TCR-alpha beta and TCR-gamma delta, were affected equally through Day 15. On Day 29, the median CD4:CD8 ratio, elevated before treatment, was significantly decreased (p < 0.01), approaching the ratio observed in healthy controls. Proliferative responses to antigenic, allogeneic and mitogenic stimuli in vitro were depressed but detectable during the time of maximal T cell depletion and normalized to baseline values with recovery of T cell number. Spontaneous and pokeweed mitogen induced immunoglobulin secretion were unaffected in these patients. CONCLUSION: Treatment associated effects of CD5 Plus were observed for both T and B cell populations which bear the CD5 antigen, and were reversible, as measured by in vitro assays of immune cell function, phenotype and number.

Adult↗
PubMed1994

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 0.1 mg/kg was administered intravenously on 5 consecutive days. A second course of immunoconjugate was given to patients who failed to show any clinical response one to 2 months later. RESULTS: Six patients (4 with glomerulonephritis and 2 with thrombocytopenia) were studied. Improvement was documented in 2 patients with nephritis; no effect on thrombocytopenia was observed. Adverse effects were mild and transient. Relative to pretreatment lymphocyte counts, the mean reduction in CD3+ T cell count was 69% at 2 weeks, 32% at one month, and 34% at 6 months following initial treatment. A comparable decrease in all subpopulations of mature T cells was noted, using a variety of surface markers, including CD4 and CD8. The mean percentage of T cells expressing the activation markers HLA-DR and interleukin 2R (IL-2R) was high before treatment, and remained so. There was a transient decrease in CD5+ B cells, but no persistent depletion of total B cell numbers. There was no consistent change in natural killer cell populations. CONCLUSION: Anti-CD5 ricin A chain immunoconjugate is well tolerated in patients with SLE, causes modest T cell depletion which may persist for months, and may have some clinical efficacy in lupus nephritis.

Antibodies, Monoclonal↗
PubMed1994

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. The disease controlling antirheumatic therapy (DC-ART) classification with its requirement for longterm efficacy poses problems for the biological agents, which, in general, have demonstrated short term benefit. They may be best accommodated in a new "remission induction" category or, alternatively, as part of longterm combination therapy either with pharmaceuticals or with other biologicals to fulfill DC-ART requirements.

Antirheumatic Agents↗
PubMed1993

Effects of administration of an anti-CD5 plus immunoconjugate in rheumatoid arthritis. Results of two phase II studies. The CD5 Plus Rheumatoid Arthritis Investigators Group.

OBJECTIVE: To evaluate the safety and activity of an immunoconjugate of ricin A chain and anti-CD5 monoclonal antibody (anti-CD5 IC), with and without concomitant methotrexate and/or azathioprine, in the treatment of rheumatoid arthritis (RA). METHODS: Seventy-nine patients with active RA were enrolled in 2 prospective open-label protocols. RESULTS: Using composite criteria, response rates were 50-68% at 1 month and 22-25% at 6 months. Transient depletion of CD3/CD5 T cells was observed on days 2 and 5 of treatment, with reconstitution on day 15 or day 29. Treatment-associated adverse effects were common but resolved rapidly without sequelae. CONCLUSION: These findings suggest activity of anti-CD5 IC in active RA and warrant confirmation in a multicenter randomized study (currently underway).

Adult↗
PubMed1993

In vivo T cell depletion in rheumatoid arthritis is associated with increased in vitro IgM-rheumatoid factor synthesis.

T cell depletion has been demonstrated to have therapeutic potential in patients with rheumatoid arthritis and several agents which deplete or inactivate T cells are currently being evaluated in clinical trials. We treated six patients with active rheumatoid arthritis with one such agent, the murine IgG1 anti-CD5 immunoconjugate CD5 Plus, as part of a multicenter trial. Measurement of in vitro synthesis of IgM and IgM-rheumatoid factor by peripheral blood mononuclear cells obtained from patients before, during, and after treatment, was performed using enzyme-linked immunoassays. Subsets of T and B lymphocytes were measured by flow cytometry. Significant T cell depletion was observed on Days 2 and 5 during the treatment period and was associated with increased in vitro rheumatoid factor (RF) production on Days 5 and 8 in 4 of the 5 patients with significant pretreatment levels of RF synthesis. No apparent relationship to serum RF levels or clinical responses was noted. These results implicate a role for T cells in the control of IgM-RF production in patients with rheumatoid arthritis.

Adult↗
PubMed1992

The emerging role of biologics in rheumatic disease.

Biologically based therapeutics may be classified as agents which (1) restore altered immunoregulatory, hematopoietic or other disease resistant functions, (2) modulate immunologic effector mechanisms (immunomodulators), or (3) upregulate or downregulate a specific cell function. There are several characteristics which differentiate biologic agents from more traditional pharmaceutical drugs. Administered parenterally, they often generate systemic effects, and may be associated with a higher placebo response. Many are administered not at pharmacologic, but "industrial strength" doses. The specific desired effect may be obscured by cytokine and other immunoregulatory networks. A host immune response typically occurs with repetitive administration; this may alter the pharmacokinetics of the agent but not necessarily the biologic or clinical effects. The use of biologic markers, both disease specific and agent specific, may allow more efficient clinical development of these agents. A variety of biologic agents are in clinical trials for the treatment of autoimmune diseases. These include interferon gamma, the IL-1 receptor antagonist and monoclonal antibodies to the T cell surface antigens CD4 and CD7. Two immunotoxins, CD5-ricin A chain, and diphtheria AB toxin-IL-2 are undergoing evaluation in rheumatoid arthritis. Data regarding these agents will be reviewed. Issues specific to their use in pediatric clinical applications will be discussed.

Adolescent↗
PubMed1983

Natural killing activity in Sjögren's syndrome. An analysis of defective mechanisms.

Natural killing (NK) by peripheral blood mononuclear cells (PBMC) against K562 cells was examined in 27 patients with Sjögren's syndrome and 17 normal controls. NK activity in the patients was significantly reduced compared with normal controls (34.6 +/- 3.4% versus 52.2 +/- 3.4%, P less than 0.001). Patients with secondary Sjögren's had lower cytotoxicity compared with those who had primary Sjögren's (28.5 +/- 5.5% versus 37.3 +/- 4.2%, P less than 0.01). The proportion of PBMC with characteristics of NK cells was not decreased in the patients. NK by normal PBMC was diminished both in the presence of sera from patients with reduced NK and when the effector cells were pretreated with the sera. Pretreatment of target K562 cells did not alter NK activity. Suppression of NK by sera from patients did not correlate with levels of immune complexes or with antilymphocyte antibodies. Some patients had adherent cells which inhibited NK function. Addition of either indomethacin or catalase partially restored NK activity in such patients, indicating that both prostaglandins and hydrogen peroxide play a role in suppression. These data suggest that multiple mechanisms are involved in the defective NK activity seen in patients with Sjögren's syndrome. The reduction of NK activity in Sjögren's syndrome may contribute to the increased incidence of lymphoid malignancy.

Adult↗