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Biomedical subjects

V Strand

Publications and source records attributed to V Strand.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1981

Concomitant renal and hepatic failure treated by polyacrylonitrile membrane hemodialysis.

A patient with fulminant hepatic encephalopathy and acute renal failure progressively deteriorated following daily hemodialysis with a hollow fiber artificial kidney improved dramatically after an initial dialysis with a polyacrylonitrile membrane system. Following repetitive dialysis with this system the patients continued to improve and is well many months following discharge. His course during hemodialysis with membrane systems having different clearances for substances of various molecular weights suggests the hypothesis that a substance(s) with a molecular weight between 1,500 and 15,000 daltons is involved in the pathogenesis of hepatic encephalopathy and offers and additional therapeutic modality for his devastating disease.

Acrylic Resins↗
PubMedDate not supplied

Ganciclovir treatment of life- or sight-threatening cytomegalovirus infection: experience in 314 immunocompromised patients.

A total of 314 immunocompromised patients with serious cytomegalovirus (CMV) infection treated with ganciclovir administered intravenously were studied. Rates of favorable clinical response among evaluatable patients were 91 (84%) of 108 for CMV retinitis, 35 (83%) of 42 for gastrointestinal CMV infection, and 26 (72%) of 36 for CMV pneumonia. Of 167 treated patients who had AIDS, improvement or stabilization of CMV disease occurred in 83% as compared with 13% of 39 untreated, historical control patients with AIDS and similar CMV disease (P less than or equal to .004). Virologic response was noted in 111 (92%) of 121 patients who had sequential cultures of blood, urine, or throat washings for CMV. In an attempt to prevent relapse of CMV disease after discontinuation of ganciclovir, maintenance treatment was evaluated in a group of 61 patients with AIDS and CMV retinitis who had received an initial dosage of greater than or equal to 7.5 mg/(kg.d) for greater than or equal to 10 days. Median time to relapse of retinitis was 47 days in patients not receiving maintenance treatment as compared with 105 days in patients treated with 25-35 mg/(kg.w) (P = .0002). Adverse effects of treatment included neutropenia (42%), thrombocytopenia (19%), central nervous system effects (18%), nausea (6%), fever (6%), rash (6%), vomiting, diarrhea, infusion site reactions, and anemia (4% each). It was concluded that ganciclovir has clinical efficacy against CMV disease, as well as an in vivo antiviral effect, and that this agent reduces morbidity of serious CMV infections in immunocompromised patients.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Combination biologic therapy.

Biologic therapies refer to genetically engineered treatments such as monoclonal antibodies and receptor-immunoglobulin fusion proteins. Following many disappointments, the introduction of anti-tumor necrosis factor (anti-TNF alpha) therapies into the clinic has clearly demonstrated the exciting potential of biologic agents. Many of these have been designed to modulate a specific aspect of the underlying autoimmune process, thus avoiding generalized immunosuppression. They include products which interfere with the trimolecular complex of major histocompatibility complex II-Antigen-T cell receptor interaction; others designed to block the secondary signals for T cell activation and T cell interaction with antigen-presenting cells; and cytokine agonists as well as antagonists. Whilst reducing the degree of global immunosuppression associated with therapy, this targeted specificity may reduce the likelihood that a single therapeutic agent will provide long-term disease control. On the other hand, animal models have demonstrated synergy of combination biologic therapy, particularly for the re-induction of self-tolerance. As our knowledge of immune physiology and, particularly, immune regulation improves, it can be expected that many combination biologic therapies will be tested in the clinic. Pilot studies of combined anti-CD4 and TNF alpha blockade are underway; combination use of TNF alpha and interleukin-1 beta inhibitors are expected. This article reviews the potential for combination biologic therapy, including likely adverse effects, for the treatment of rheumatoid arthritis and other autoimmune diseases.

Animals↗
PubMedDate not supplied

Low dose glucocorticoids in early rheumatoid arthritis.

The use of glucocorticoid therapy in the treatment of rheumatoid arthritis [RA] remains controversial. There has been much data accumulated over the years describing both the risks and benefits of acute and chronic glucocorticoid therapy. Initially there was significant enthusiasm for this type of therapy given the extent of the anti-inflammatory effects. However, use was then modified as chronic therapy with higher doses was associated with frequent reports of important safety concerns. More recently low dose glucocorticoid therapy (e.g. < or = 5 mg prednisone per day) is being reconsidered in particular for patients with early disease. This paper will review the historical experience with higher dose therapy along with the evolving evidence of an improved benefit to risk ratio with the advent of concomitant therapies to minimize some of the more problematic adverse events associated with chronic use of even low dose glucocorticoid therapy. It is suggested that with appropriate monitoring and careful concomitant prophylactic therapy to prevent osteoporosis, adjunctive therapy using low dose glucocorticoids along with the appropriate disease modifying anti-rheumatic drug may be a reasonable treatment plan for select patients.

Arthritis, Rheumatoid↗
PubMedDate not supplied

Longer term benefits of treating rheumatoid arthritis: assessment of radiographic damage and physical function in clinical trials.

Evidence from randomized controlled trials with newly approved DMARD therapies have proven efficacy by American College of Rheumatology [ACR] response criteria, Disease Activity Scores [DAS] and radiographic measures of disease progression. Treatment over 2 years duration results in clinically meaningful improvements in physical function, by the Health Assessment Questionnaire [HAQ] and health related quality of life [HRQOL], using the medical outcomes short form 36 [SF-36]. Changes in HAQ are evident within one month, maximal at 3-6 months, and sustained over 24 months, reflected by improvements in social functioning, role emotional and the general health profile as well as physical domains of SF-36. Trials with the new DMARDs, as well as MTX, indicate that long term benefits in radiographic damage and physical function can be inferred from treatment data over 12 months. "Successful" patients who continue to do well will derive benefit from treatment for as long as 3 to 5 years. Recent RCTs indicate that combination therapy, initiated together, offers more improvement in radiographic progression and physical function than monotherapy, although the trial data cannot yet tell us which DMARD may be most beneficial in a given patient. Once treatment with any one agent--biologic or synthetic--is initiated, the addition of a second agent should occur rapidly, if for example active disease persists 8 or 12 weeks later, without waiting for documented treatment failure. If this treatment paradigm is followed, along with regular assessments of radiographic damage and physical function, then patients may more likely derive long term clinical benefit than with traditional approaches.

Antirheumatic Agents↗