Search PubMed⌕ Search

Biomedical subjects

C H Polman

Publications and source records attributed to C H Polman.

At least 145 records · Page 8Linked to original sources
PubMed1997

Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial.

We report the results of a randomized, double-blind, placebo-controlled exploratory trial of the chimeric monoclonal anti-CD4 antibody cM-T412 in 71 patients suffering from active relapsing-remitting and secondary progressive multiple sclerosis. Infusion of the antibody produced frequent but usually minor side effects and resulted in a long-lasting reduction of circulating CD4-positive T cells. There was no significant effect on the primary measure of efficacy, the number of active lesions on monthly gadolinium-enhanced MRI over 9 months. Further statistical evaluation provided evidence that the degree of depletion of CD4-positive cells was important with regard to treatment efficacy; using CD4 counts as a covariate there was a statistically significant effect on the number of active lesions over 18 months (p = 0.04). There was a statistically significant reduction of 41% in the number of clinical relapses (a secondary efficacy parameter) after 9 months (p = 0.02), which was still present after 18 months, but this finding may be partly due to physician unblinding. Other secondary efficacy parameters (Expanded Disability Status Scale progression, number of courses of methylprednisolone) were not influenced by anti-CD4 treatment. We conclude that intravenous treatment with the monoclonal antibody cM-T412 in the dosage we used results in a substantial and sustained reduction of the number of circulating CD4-positive cells, but is not able to reduce MS activity as measured by monthly gadolinium-enhanced MRI, and is therefore unlikely to have a beneficial effect on the clinical disease course. We found preliminary evidence suggesting that more aggressive depletion of CD4-positive cells might lead to a more substantial reduction in MRI activity.

Adult↗
PubMed1997

Other immunomodulatory therapies in multiple sclerosis.

This short review concentrates on immunomodulatory disease-modifying approaches that are under development for the treatment of multiple sclerosis based on present concepts of the immunopathogenesis of the disease that especially involve T-cells and macrophages as being prominently involved in inducing tissue destruction and on the advances that have been made in recent years by studying other treatment interventions that have been applied and that have been shown to be either successful (interferon beta, copolymer-1) or unsuccessful (many others).

Adjuvants, Immunologic↗
PubMed1997

Single-dose gadolinium with magnetization transfer versus triple-dose gadolinium in the MR detection of multiple sclerosis lesions.

PURPOSE: To compare the efficacy of single-dose gadolinium with magnetization transfer contrast (MTC) with that of triple-dose gadolinium in detecting enhancing multiple sclerosis lesions. METHODS: Twenty-one patients with multiple sclerosis were examined with MR imaging first with 0.1 mmol/kg gadolinium (single dose) and then, after 24 to 72 hours, with 0.3 mmol/kg gadolinium (triple dose). T2-weighted fast spin-echo and T1-weighted spin-echo MR images with and without MTC were obtained before contrast administration followed by either T1-weighted spin-echo images with MTC (single dose) or conventional T1-weighted spin-echo images (triple dose), starting 5, 17, and 29 minutes after contrast administration. All images were evaluated in a blinded fashion and scored in random order by two readers. Outcome parameters included number of enhancing lesions, number of active MR examinations (those containing at least one enhancing lesion), contrast ratio (signal intensity of enhancing lesion divided by signal intensity of normal-appearing white matter), and size of enhancing lesions. RESULTS: Eighty-one percent more enhancing lesions and 49% more active MR examinations were detected when a triple dose of gadolinium was used as compared with a single dose. The level of agreement between readers as to the number of enhancing lesions was significantly higher for triple-dose than for single-dose gadolinium. With triple-dose gadolinium, contrast ratios and areas of enhancement increased by 10% and 33%, respectively. Delayed imaging increased the size of the lesion by 11% on single-dose MTC images and by 18% on triple-dose images. CONCLUSION: Triple-dose gadolinium is more effective (higher sensitivity and interobserver agreement) than single-dose gadolinium in combination with MTC in detecting enhancing multiple sclerosis lesions.

Adult↗
PubMed1996

Quality of life in multiple sclerosis: the disability and impact profile (DIP).

Seventy-three Dutch and Flemish patients with definite multiple sclerosis (MS) were assessed by means of the Disability and Impact Profile (DIP), which is a 2 x 39 item, self-administered questionnaire with parallel questions about disabilities and their importance for or impact on the patient, resulting in a profile of weighted scores. It was designed as a tool for clinical assessment of quality of life (QoL) domains in MS patients. Group data showed more than 50% loss on weighted scores for "walk", "clean home", "work" and "worry about deterioration". In individual patients a median of 7 (range 0-23) major disruptions of quality of life (MD-QoL: loss on weighted score more than 50%) was found. Prevalence of MD-QoL in more than 10% of the patients was found for as many as 31 disabilities and > 50% for 3 ("clean home", "work" and "worry about deterioration"). Results in the MS group were compared with available data from 25 patients with rheumatoid arthritis (RA) and 25 patients with a spinal cord lesion (SCl). Weighted scores of "read", "memory" and "concentration" were significantly lower in the MS group than in the RA and SCl groups. Significantly lower weighted scores in both the MS and RA groups were found for "worry about deterioration", "physical endurance", "clean home", "work", "see" and "write". In conclusion, major disruptions in many domains of QoL were found in MS patients. Weighted score profiles for MS were in accordance with clinical manifestations. Unlike Kurtzke's Extended Disability Status Scale, DIP assesses a wide range of potentially MS-affected human activities, and also takes into account the subjective perception of disabilities.

Adult↗
PubMed1996

The effect of the 21-aminosteroid U74006F on the clinical course of acute experimental allergic encephalomyelitis.

We evaluated the clinical effect of several doses of the 21-aminosteroid U74006F in acute experimental autoimmune encephalomyelitis (EAE) and compared it with the administration of methylprednisolone (MP). There was no significant change in the clinical course of EAE with the dosages we used, whereas the effect of MP was unquestionably beneficial. Based on these results U74006F does not seem to be a promising drug for the treatment of exacerbations of multiple sclerosis.

Acute Disease↗
PubMed1996

A pilot study investigating the effects of orally administered pentoxifylline on selected immune variables in patients with multiple sclerosis.

Multiple sclerosis is probably mainly mediated by T-helper 1 (TH1)-lymphocytes. TH1-function can be down-regulated in vitro and in animal experiments by pentoxifylline. Therefore, we included 20 multiple sclerosis patients in an open label pilot trial of pentoxifylline. Outcome parameter was the effect of treatment on levels of various cytokines and adhesion molecules in cerebrospinal fluid and serum, on production of TH1- and TH2-cytokines using cell stimulation assays, as well as on measures of T-cell activation and proliferation. Kurtzke's EDSS was a secondary efficacy parameter. A convincing and consistent effect of pentoxifylline could not be demonstrated.

Administration, Oral↗
PubMed1996

Recombinant interferon-beta blocks proliferation but enhances interleukin-10 secretion by activated human T-cells.

Results from recent clinical trials have indicated that recombinant interferon-beta (rIFN-beta) is a promising drug for the treatment of Multiple Sclerosis (MS), a disease of supposed autoimmune etiology. To gain insight into the immunoregulatory properties of this cytokine, we analyzed effects of interferon-beta (IFN-beta) on T-cell functions in vitro. Interferon-beta inhibited T-cell proliferation, as well as T-cell-dependent immunoglobulin secretion, in a dose-dependent manner. IFN-beta did not inhibit upregulations of CD40L on activated T-cells, but blocked induction of CD25 on stimulated T- and B-lymphocytes. Secretion of interferon-gamma (IFN-gamma), tumour necrosis alpha (TNF-alpha) and IL-13 was inhibited by the addition of IFN-beta, whereas IL-4 secretion was unaffected. Interestingly, IFN-beta enhanced secretion of IL-2 about two-fold and secretion of IL-10 nearly four-fold. In summary, these findings suggest that IFN-beta may exert direct effects on T- and beta-cell function in vivo. In addition, enhanced secretion of IL-10 by activated T-cells may interfere with newly initiated and ongoing inflammatory immune reactions.

B-Lymphocytes↗
PubMed1996

Disappearance of multiple sclerosis lesions with severely prolonged T1 on images obtained by a FLAIR pulse sequence.

Although the superiority of FLAIR over conventional T2-weighted spin-echo (SE) is still unclear, one potential advantage would be its use in quantitative lesion load measurements. We have observed a potential pitfall regarding the use of FLAIR in image quantification. We report a case where a part of the hyperintense lesions on T2 SE, which was hypointense on T1 SE, subsequently was found to be isointense to brain on FLAIR images. Therefore, quantification of lesion load by means of FLAIR might underestimate the "true" lesion load, as seen on T2 SE.

Brain↗
PubMed1996

A phase II trial of anti-CD4 antibodies in the treatment of multiple sclerosis.

In multiple sclerosis (MS) myelin damage is the result of a chronic inflammatory process mediated by CD4 positive T helper/effector cells. In experimental allergic encephalomyelitis (EAE), the animal model of MS, treatment with anti-CD4 antibodies can prevent the onset of disease. Natural history studies have demonstrated that gadolinium enhanced magnetic resonance imaging (MRI) of the brain is more sensitive and objective in assessing inflammatory disease activity in MS than clinical monitoring, so that less patients and shorter studies suffice to reach the same statistical power as compared to trials using clinical outcome parameters. In this paper we describe the design of an exploratory trial of chimeric monoclonal anti-CD4 antibodies in the treatment of MS. For this study we chose the number of active MS lesions on monthly gadolinium enhanced MRI scans as the primary outcome measure.

Adolescent↗
PubMed1996

Accumulation of hypointense lesions ("black holes") on T1 spin-echo MRI correlates with disease progression in multiple sclerosis.

MRI findings are increasingly used as outcome measures in therapeutic trials in MS. The discrepancy between the extent of the lesions on conventional T2 images and the clinical condition of the patient is one of the problems encountered in such studies. This clinical-radiological paradox prevents the use of MRI data as surrogate markers of disability in MS. A recent pilot study suggested a relationship between hypointense lesions on T1 MRI and disability. To assess in more detail the correlation of changes in hypointense lesion load on T1-weighted spin-echo MR images ("black holes") with changes in disability in MS, we studied 46 patients with clinically definite MS at baseline and after a median follow-up of 40 months. There was a significant correlation between baseline disability and hypointense lesion load (Spearman rank correlation coefficient [SRCC] = 0.46, p = 0.001). In secondary progressive patients, the rate of accumulation of these "black holes" was significantly related to progression rate (SRCC = 0.81, p < 0.0001). We speculate that the appearance of hypointense lesions is the MRI equivalent of a failure of remission. Overall, T1 lesion load measurements correlated better with clinical assessments than T2 lesion load measurements. Quantification of hypointense lesion load on T1-weighted spin-echo MRI helps to resolve the clinical-radiological paradox between disability and MRI and has the potential to be a surrogate marker of disability in MS.

Adult↗
PubMed1996

Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2.

There is evidence that treatment with an antibody to tumor necrosis factor alpha (TNF alpha) improves an animal model of multiple sclerosis (MS) and is beneficial in two systemic inflammatory disease in humans, but there are no reports about anti-TNF treatment of MS. Therefore, we treated two rapidly progressive MS patients with intravenous infusions of a humanized mouse monoclonal anti-TNF antibody (cA2) in an open-label phase I safety trial and monitored their clinical status, gadolinium-enhanced brain magnetic resonance imaging (MRI), and peripheral blood and cerebrospinal fluid (CSF) immunologic status. We did not notice any clinically significant neurologic changes in either patient. The number of gadolinium-enhancing lesions increased transiently after each treatment in both patients. CSF leukocyte counts and IgG index increased after each treatment. The transient increase in the number of gadolinium-enhancing lesions that followed each infusion of cA2 together with the increase in cells and immunoglobulin in the CSF of each patient suggest that the treatment caused immune activation and an increase in disease activity. These results suggest that further use of cA2 in MS is not warranted and that studies of other agents that antagonize TNF alpha should be carried out with frequent monitoring of gadolinium-enhanced MRIs.

Adult↗
PubMed1996

Magnetic resonance imaging of epilepsy in multiple sclerosis: a case control study. Implications for treatment trials with 4-aminopyridine.

A case-control study of epilepsy in multiple sclerosis (MS) is presented using magnetic resonance (MR) imaging to semiquantitatively assess cortical-subcortical lesion load. In this sample of 13 pairs of cases with MS and epilepsy and controls with MS without epilepsy we found statistically higher cumulated cortical-subcortical lesion loads in the cases than in the controls (Wilcoxon, P = 0.036). Total lesion loads (cortical-subcortical plus deep white matter loads) did not differ significantly (P > 0.1) between cases and controls. The relative risk for seizures as determined by the odds ratio of a cortical-subcortical lesion load of > or = 20 was 8.8 (chi 2 = 5.23, P 0.025), the odds ratio of a large (> 1 cm) cortico-subcortical lesion was 4.7 (chi 2 = 4.9, P < 0.05), while the 2 MR criteria combined show an odds ratio of 19.2 (chi 2 = 8.0, P < 0.005). We conclude that: first, the presence of cortical-subcortical lesions in part accounts for the occurrence of seizures in MS patients; second, due to the substantial overlap of MR imaging scores between cases and controls the ultimate use of these MR imaging findings in the management of individual patients or in the organizations of trials should depend on the expected benefit of the treatment. If the benefit is only moderate or not known a cautious approach with exclusion of cases showing a substantial cortical-subcortical lesion load on MR imaging seems appropriate in trials with drugs, like 4-aminopyridine, that lower the epileptic threshold.

4-Aminopyridine↗
PubMed1995

The small heat-shock protein alpha B-crystallin as candidate autoantigen in multiple sclerosis.

The identification of key antigens in human autoimmune diseases is a crucial step towards the development of specific intervention. The autoantigen(s) relevant to multiple sclerosis (MS) probably reside in myelin of the central nervous system, the target of the disease. Here we examine proliferative responses of human peripheral blood T cells to the complete collection of myelin proteins fractionated by reversed-phase high-performance liquid chromatography. Myelin isolated from MS-affected brain contained a single protein fraction to which T cells from MS patients and from healthy controls showed dominant responses. This highly immunogenic protein was identified as alpha B-crystallin, a small heat-shock protein. Immunohistochemical examination of MS lesions revealed the presence of oligodendrocytes and astrocytes with raised alpha B-crystallin expression, which were not found in unaffected myelin. Our findings indicate that alpha B-crystallin serves as immunodominant myelin antigen to human T cells when expressed at the elevated levels found in active MS lesions.

Astrocytes↗
PubMed1995

Analysis of CD27 surface expression on T cell subsets in MS patients and control individuals.

Within the peripheral blood, CD4+CD27- T cells only reside within the CD45RA- (memory or primed) T cell subset. Cells with this phenotype have characteristics of specialized effector T cells according to their cytokine secretion profiles and the expression of tissue-specific adhesion molecules. This subset was previously found to be increased in certain diseases that are associated with immune activation. Therefore we analyzed CD27 expression of peripheral blood and CSF T cells in MS patients. Within the CD4+ T cell subset no differences were seen between MS patients and controls in proportions of CD45RA-CD27- cells. However, when the CD3+ T cell compartment was analyzed, CD27- cells were also found within the CD45RA+ subset. These cells, most likely CD8+, are significantly reduced in PBL and CSF of MS patients as compared with OND patients. In MS and OND groups the level of CD27- cells in peripheral blood correlated significantly with that in CSF, indicating a balanced migration of CD27- cells between the two compartments. In OIND patients, however, this equilibrium was lost. The correlation of the level of CD27+ cells with the amount of intrathecally produced IgG in MS patients may suggest that CD27+ cells are responsible for B cell help in this disease.

Adult↗
PubMed1995

The treatment of multiple sclerosis: current and future.

During the past year observations have been published that might lead to further improvement in the design of future clinical trials. At the same time, results of clinical trials have become available that suggest that a number of treatments could be of benefit in the care of patients in the various phases of multiple sclerosis. Future multiple sclerosis clinical trials should involve a blinded investigator restricted to assessing the clinical outcome variables, and because current evidence suggests that magnetic resonance imaging gives an objective and sensitive reflection of the biological evolution of the disease, such scanning should also be included. The use of a composite outcome variable in a trial of chronic progressive multiple sclerosis should also be considered in order to increase the percentage of patients reaching the clinical endpoint. In 1994 recommendations were published for the selection of relapsing-remitting patients for treatment with interferon beta-1b; furthermore, large and well performed clinical trials demonstrated that interferon beta-1a and copolymer-1 are also partially effective, though not curative, for these patients. Two smaller studies suggested that low-dose methotrexate and cladribine might have a beneficial effect on the course of the disease in patients with secondary chronic progressive multiple sclerosis, the former drug probably being less toxic. Unfortunately, therapeutic perspectives for patients with primary progressive multiple sclerosis are less promising at present. Several studies suggest that 4-aminopyridine and tizanidine have therapeutic potential for symptomatic treatment; the former by improving neurological deficits, the latter by relieving troublesome spasticity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗