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PubMed1989

Correlation of immunological studies and disease progression in chronic progressive multiple sclerosis.

Thirty untreated patients with clinically definite chronic progressive multiple sclerosis were matched with 10 patients with clinically stable definite multiple sclerosis and 16 patients with other neurological diseases. A group of 12 normal control (NC) volunteers was matched to these groups. All patients with chronic progressive multiple sclerosis and normal control subjects were analyzed for the concanavalin A suppressor assay, mitogen stimulation, and phenotyping of peripheral blood mononuclear cells. In addition, serum was analyzed for interleukin-2 levels. Results of mitogen stimulation studies did not distinguish the groups. Concanavalin A-induced suppression was significantly decreased in the patients with chronic progressive multiple sclerosis (p less than 0.01). Phenotyping of fresh cells showed an elevated CD4: CD8 ratio in the patients with chronic progressive multiple sclerosis. Neither phenotyping nor concanavalin A-induced suppression correlated with or predicted the degree of disability, but the serum levels of interleukin-2 correlated inversely with disability (p less than 0.01) and directly with a poor prognosis after 18 months of observation (p less than 0.05). Serum levels of interleukin-2 decreased as the disease progressed.

Adult↗
PubMed1992

Progressive abrogation of TGF-beta 1 and EGF growth control is associated with tumour progression in ras-transfected human keratinocytes.

This study examined the response of human keratinocytes in different stages of transformation to exogenous TGF-beta 1 and EGF as well as their receptor and growth-factor expression. Cells of the spontaneously immortalized HaCaT cell line and c-Ha-ras transfected clones (I-6, I-7, II-3, II-4) exhibited different tumorigenic potentials when transplanted to athymic mice. HaCaT- and I-6 cells were non-tumorigenic, I-7 cells formed persisting epidermal cysts (benign tumours) and II-3 and II-4 cells developed into invasive squamous-cell carcinomas. TGF-beta 1 inhibited thymidine uptake in a dose-dependent manner, a progressive decrease in response being associated with an increasing malignant potential (HaCaT greater than I-6 greater than I-7 = II-4). HaCaT-cells and ras-clones expressed TGF-beta 1 mRNA at similar levels, but cells of increasing malignant potential secreted markedly less receptor-binding TGF-beta (HaCaT greater than I-6 = I-7 greater than II-3 greater than II-4) into the culture medium. Whilst ras-transfected cells expressed fewer TGF-beta receptors than HaCaT cells, there was little difference between TGF-beta receptor number or affinity between the 4 transfected cell clones. The same was true for the TGF-beta receptor types, but Type-II receptors were expressed at lower levels by the malignant clones II-3 and II-4. When HaCaT and ras-transfected cells were investigated for their response to exogenous EGF, cells were refractory (I-7, II-4), partially stimulated (I-6) or fully stimulated (HaCaT). Cells with increasing malignant potential produced increasing amounts of endogenous TGF-alpha (II-4 = II-3 greater than I-7 = I-6 greater than HaCaT). All tumorigenic ras clones expressed higher mRNA levels than HaCaT-cells. Ras-transfected clones expressed fewer high- and low-affinity EGF receptors than HaCaT cells with a tendency toward increased numbers of high-affinity EGF receptors associated with increasing malignant potential (II-4 = II-3 greater than I-7 greater than I-6) but these changes were associated with a progressive decrease in receptor affinity. The results indicate that tumour progression in human epidermal keratinocytes transfected with c-Ha-ras is associated with a progressive abrogation of TGF-beta 1 and EGF growth control. They suggest that the increased autonomous growth potential associated with advanced stages of epithelial tumour progression can be defined more closely using a cellular profile of TGF-beta and EGF.

Cell Division↗
PubMed1994

Progressive loss of sensitivity to endothelium-derived growth inhibitors expressed by human melanoma cells during disease progression.

Tumor progression is frequently associated with changes in responsiveness of tumor cells to paracrine growth factors. A potential major source of such paracrine factors in solid tumors are endothelial cells since this type of cell can constitute a sizeable fraction of the cellular composition of solid tumors. As an initial step to examining the possible effects of endothelial cell-associated growth factors on tumor cell growth, a panel of human melanoma cell lines representative of different stages of tumor progression was employed for studies utilizing endothelial cell-derived growth modulators. Macrovascular or microvascular human endothelial cells from umbilical vein or from skin, respectively, inhibited melanoma cell growth in direct coculture experiments. The potency of this inhibitory effect diminished as a function of melanoma progression. Conditioned media from endothelial cell cultures mimicked the effect of the cell coculture experiments, suggesting the involvement of soluble growth factor(s). Approximately 50-75% of the conditioned media inhibitory effect was abrogated by addition of the neutralizing antibody to interleukin-6 (IL-6). Gel filtration chromatography revealed the presence of additional inhibitors in endothelial cell conditioned medium. Two peaks of activity were detected with apparent molecular weights of approximately 100-150 Kd and 20-30 Kd, the latter containing IL-6 activity. Whereas early-stage radial growth phase (RGP) primary tumor-derived melanoma cells were sensitive to at least three different endothelial products of high or low molecular weight (including IL-6), melanoma cells from more advanced metastatic lesions were resistant to the latter activities, and retained only partial sensitivity to the high molecular weight inhibitor. More advanced vertical growth phase (VGP) primary melanoma cell lines expressed intermediate inhibition-sensitive phenotypes. Thus human melanoma development appears to be associated with progressive loss of sensitivity to the growth inhibitory effects of IL-6 and other factors produced by endothelial cells. This is likely to be a result of a selection process when tumor cells are confronted with adjacent vasculature during the progress of tumor angiogenesis.

Cell Division↗
PubMed2005

Progression elevated gene-3 (PEG-3) induces pleiotropic effects on tumor progression: modulation of genomic stability and invasion.

Progression elevated gene-3 (PEG-3) is a novel rodent gene, identified and cloned by subtraction hybridization, that associates with transformation progression in virus- and oncogene-transformed rat embryo (RE) cells. Previous reports document that ectopic expression of PEG-3 in rodent or human tumor cells produces an aggressive transformed/tumorigenic phenotype. Moreover, PEG-3 expression in rodent tumor cells correlates directly with genomic instability, as indicated by chromosomal alterations and gene amplification, and it promotes angiogenesis. The present studies were designed to further elucidate the functional significance and role of PEG-3 in cancer progression with a specific focus on genomic instability and cancer invasion. Genomic instability was assessed by micronucleus assays and staining of centrosomes to define centrosomal amplification. Immunocytochemical observations revealed that overexpression of PEG-3 in transformed rodent cells induced a loss of chromosomes as established by the appearance of micronuclei and staining of the centrosomes with gamma-tubulin antibody, thereby confirming centrosome amplification. Overexpression of PEG-3 modulated the expression of several genes involved in centrosomal duplication, such as p21CIP1/WAF1/MDA-6, nucleophosmin (NPM), and aurora-A kinase. In vitro invasion of transformed rodent cells was augmented by PEG-3, which correlated with an increase in the transcription and activity of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), which play important roles in local invasion during cancer progression. These findings demonstrate that PEG-3 plays a central role in augmenting tumor progression by modulating several critical parameters of the carcinogenic process, such as genomic stability and local tumor cell invasion.

Animals↗
PubMed1991

Progression of coronary atherosclerosis: is coronary spasm related to progression?

A total of 239 patients undergoing serial coronary angiography with a concomitant ergonovine provocation test were studied between July 1974 and June 1987. The progression of coronary artery disease was evaluated in relation to risk factors, especially coronary artery spasm. Patients were classified into three groups: 1) new myocardial infarction group (39 patients); 2) progression without infarction group (90 patients); and 3) nonprogression group (110 patients). To assess how risk factors and coronary spasm are related to the occurrence of new myocardial infarction and progression without infarction, 11 variables in the three groups were examined: age, gender, the time interval between the studies, fasting blood sugar, systolic blood pressure, diastolic blood pressure, smoking, serum cholesterol, triglyceride, uric acid and a positive response to the ergonovine provocation test. Multiple regression analysis selected three independent predictors of progression without infarction: cholesterol (p less than 0.01), systolic blood pressure (p less than 0.05) and a positive response to the ergonovine provocation test (p less than 0.001). Multiple regression analysis also selected three independent predictors of the occurrence of new myocardial infarction: fasting blood sugar (p less than 0.01), systolic blood pressure (p less than 0.05) and a positive response to the ergonovine provocation test (p less than 0.001). A positive response to the ergonovine provocation test was the strongest factor for occurrence of both new myocardial infarction and progression without infarction. To evaluate segmental arterial changes, 3,275 coronary artery segments were analyzed in the 239 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac Catheterization↗
PubMed1995

Estrogen replacement therapy and progression of intimal-medial thickness in the carotid arteries of postmenopausal women. ACAPS Investigators. Asymptomatic Carotid Atherosclerosis Progression Study.

The effect of estrogen replacement therapy (ERT) on 3-year changes in carotid intimal-medial thickness (IMT) was explored using serial B-mode ultrasound measurements collected during 1989-1993 as part of the Asymptomatic Carotid Atherosclerotic Progression Study (ACAPS). Eligibility included increased IMT and elevated low density lipoprotein cholesterol. Of the 186 postmenopausal ACAPS women randomly assigned to receive either placebo or lovastatin, 34% reported use of ERT. Users tended to be younger than nonusers by an average of 3 years, to have more favorable high and low density lipoprotein cholesterol levels, and to be more likely to have had hysterectomies. Baseline blood pressure, body mass index, and cross-sectional IMT were similar among ERT users and nonusers. In the placebo group, IMT tended to progress among ERT nonusers but to regress among ERT users: Mean covariate-adjusted progression rates were 0.015 +/- 0.007 mm/year versus -0.012 +/- 0.012 mm/year, respectively (p = 0.05). This difference appeared to be independent of lipoprotein concentrations. Lovastatin was associated with an approximately 25% lowering of low density lipoprotein cholesterol among both ERT users and nonusers and had a marked impact on IMT progression (p = 0.004) in these women. ERT appeared to have little additional effect on IMT in women assigned to lovastatin. ERT may reduce or halt the progression of early atherosclerosis in women not receiving active lipid-lowering medication.

Adult↗
PubMed1998

Psychological functioning in primary progressive versus secondary progressive multiple sclerosis.

Psychological functioning in two types of multiple sclerosis (MS) patients is assessed: primary progressive (PP) and secondary progressive (SP) patients. On the basis of differences in clinical course and underlying pathology we hypothesized that primary progressive patients and secondary progressive patients might have different psychological functioning. Seventy patients treated in an MS centre were examined cross-sectionally. Forty had an SP course of MS and 30 a PP course. The 33 male and 37 female patients had a mean age of 48.4 years (SD 11.2) and mean age of onset of MS of 30.7 years (SD 11.1). Patients completed questionnaires measuring among others the following aspects of psychological functioning: depression (BDI, SCL-90), anxiety (STAI, SCL-90), agoraphobia (SCL-90), somatic complaints (SCL-90), hostility (SCL-90) and attitude towards handicap (GHAS). Patients with a PP-MS scored significantly better on 5 out of 14 subscales than patients with SP-MS (p < .05). On the basis of our operationalizations of psychological functioning, the findings support the conclusion that on average 18 years after diagnosis of MS, amongst patients attending an MS unit, primary progressive patients were found to have better psychological functioning.

Adaptation, Psychological↗
PubMed1996

Comparative evaluations of neuroperformance and clinical outcome assessments in chronic progressive multiple sclerosis: I. Reliability, validity and sensitivity to disease progression. Multiple Sclerosis Study Group.

There remains controversy regarding the most sensitive and valid outcome assessments to use in multiple sclerosis (MS) clinical trials. A double blind, placebo controlled, parallel group multicenter clinical trial to evaluate the clinical efficacy of cyclosporine A in chronic progressive MS incorporated several major clinical and performance outcome assessment modalities and a large sample size, both of which provide a unique opportunity to explore the relationship among MS disease status and the various outcome measures over time. The measures included a structured neurological examination, the Kurtzke Functional System scales and Expanded Disability Status Score, and the Incapacity Status Scale from the MS Minimal Record of Disability, the Harvard Ambulation Index, and neuroperformance testing. A test-retest reliability index, principal component analyses and a signal-to-noise ratio metric were used to comparatively evaluate the reliability, validity and sensitivity to disease progression of the various outcome assessments. The goal was to provide a rational basis for selection of behavioral outcome assessments in future MS clinical trials by identifying the primary dimensions of MS measured by the candidate outcome assessments and providing an objective basis for selecting tests that are most sensitive to MS disease and its progression over a two year trial period. We conclude that the components of the major clinical and performance measures show excellent reliability and cross validation. Principal component analyses of all outcome assessments yielded six primary underlying factors for describing disease status in chronic progressive MS that included lower extremity/pyramidal dysfunction, cerebellar/brainstem and upper extremity dysfunction, somatosensory dysfunction, visual dysfunction, mental or intellectual dysfunction and bowel/bladder problems. Signal-to-noise ratios indicated that upper and lower extremity composites of neuroperformance test items provided the most sensitive indicators of MS disease progression in the placebo group over the 2 year trial period.

Activities of Daily Living↗
PubMed1990

Measurement of progress against cancer. Extramural Committee to Assess Measures of Progress Against Cancer.

The questions of the extent of progress against cancer and how to measure it have stimulated attention among scientists and in Congress. In this presentation, we summarize a report requested by the Senate Appropriations Committee to address the adequacy of the existing measures of progress against cancer. The report was prepared by an extramural committee convened by the National Cancer Institute at the request of Congress. It includes extensive findings and recommendations on the existing measures of progress against cancer, the systems used to develop the data reported through the measures, the frequency and content of reports addressing progress, and the need for analytic research on this topic. Although the Extramural Committee To Assess Measures of Progress Against Cancer found the measures and systems to be generally adequate, they also found that modification or expansion of the information base is needed in many areas.

Health Policy↗
PubMed2000

The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. European Study Group on Interferon beta-1b in secondary progressive multiple sclerosis.

The recently completed European trial of interferon beta-1b (IFNbeta-1b) in patients with secondary progressive multiple sclerosis (SP multiple sclerosis) has given an opportunity to assess the impact of treatment on cerebral atrophy using serial MRI. Unenhanced T(1)-weighted brain imaging was acquired in a subgroup of 95 patients from five of the European centres; imaging was performed at 6-month intervals from month 0 to month 36. A blinded observer measured cerebral volume on four contiguous 5 mm cerebral hemisphere slices at each time point, using an algorithm with a high level of reproducibility and automation. There was a significant and progressive reduction in cerebral volume in both placebo and treated groups, with a mean reduction of 3.9 and 2.9%, respectively, by month 36 (P = 0.34 between groups). Exploratory subgroup analyses indicated that patients without gadolinium (Gd) enhancement at the baseline had a greater reduction of cerebral volume in the placebo group (mean reduction at month 36: placebo 5.1%, IFNbeta-1b 1.8%, P < 0.05) whereas those with Gd-enhancing lesions showed a trend to greater reduction of cerebral volume if the patient was on IFNbeta-1b (placebo 2.6%, IFNbeta-1b 3.7%; P > 0.05). These results are consistent with ongoing tissue loss in both arms of this study of secondary progressive multiple sclerosis. This finding is concordant with previous observations that disease progression, although delayed, is not halted by IFNbeta. The different pattern seen in patients with and without baseline gadolinium enhancement suggests that part of the cerebral volume reduction observed in IFNbeta-treated patients may be due to the anti-inflammatory/antioedematous effect of the drug. Longer periods of observation and larger groups of patients may be needed to detect the effects of treatment on cerebral atrophy in this population of patients with advanced disease.

Adult↗
PubMed2003

Pick Complex: an integrative approach to frontotemporal dementia: primary progressive aphasia, corticobasal degeneration, and progressive supranuclear palsy.

BACKGROUND: Frontotemporal dementia (FTD) is a new label for clinical Pick's disease (PiD) because the eponymic term is increasingly restricted to the pathologic finding of Pick bodies. This restriction created the impression that PiD is rare and that is it difficult to diagnose. FTD is also a term most often used for behavioral and personality alterations. Primary progressive aphasia (PPA) and corticobasal degeneration (CBD), formerly the extrapyramidal variety of PiD, are also part of the syndrome. Recently, chromosome 17 localization and tau mutations were discovered in familial forms of the disease. REVIEW SUMMARY: FTD consists of behavioral and personality changes, often beginning with apathy and disinterest, which may be mistaken for depression. Disinhibition and perseverative, compulsive behavior often appear at the same time. A quantifiable frontal behavioral inventory is useful in the diagnosis beyond a checklist. The second type of presentation is progressive language loss (PPA). A less common variety is semantic dementia: the meaning of nouns and objects is lost. As the disease progresses, all components tend to overlap. CBD and progressive supranuclear palsy (PSP), although described as distinct entities, show a great deal of clinical, pathologic, genetic, and biochemical overlap. The evidence suggests they also belong to the complex. The association of motor neuron disease (MND) with FTD and other varieties of the complex is also reviewed. CONCLUSIONS: Clinical Pick's disease or Pick Complex includes the overlapping syndromes of FTD, PPA, CBD, PSP, and FTD-MND. The neuropathological and genetic spectrum should be viewed with emphasis on the commonalities rather than the differences, allowing the recognition of the relatively high frequency of this presenile syndrome.

Aphasia, Primary Progressive↗
PubMed2003

Clinical presentation of primary progressive multiple sclerosis 10 years after the incidental finding of typical magnetic resonance imaging brain lesions: the subclinical stage of primary progressive multiple sclerosis may last 10 years.

BACKGROUND: Subclinical multiple sclerosis (MS) has been identified incidentally at autopsy; apparently unaffected individuals with an affected twin have demonstrated magnetic resonance imaging (MRI) changes consistent with MS, and 'MRI relapses' are several times more common than clinical relapses. CASE DESCRIPTION: A 39-year-old, right-handed man underwent MRI and PET scanning in 1986 as a 'normal' control in a Parkinson's disease study, where his father was the proband. MRI indicated multiple areas of abnormal signal intensity in a periventricular and grey-white matter junction distribution. Repeated clinical evaluations over the next 10 years were unchanged until 1996, when he complained of progressive weakness of the right foot and clumsiness in the right hand. MRI now indicated a further area of high signal intensity in the right posterior cord at the level of C5/C6. There was mild pyramidal distribution weakness in the right leg with an extensor plantar response on the same side. Over the next five years there has been mild progression in weakness and fatigue and intermittent Lhermitte's phenomenon. At no stage has there been a history of relapse, cerebrospinal fluid examination was normal and evoked responses (visual and somatosensory) are normal. CONCLUSION: This case demonstrates the phenomenon of subclinical MS, unusually supported by prolonged clinical and MRI follow-up. The patient eventually became symptomatic nine years after MRI diagnosis and is following a primary progressive course. Although MRI is known to be sensitive in identifying subclinical 'attacks', the pattern illustrated here may actually be quite typical of primary progressive MS and is compatible with the later onset seen in this subgroup of patients.

Adult↗
PubMedDate not supplied

Intravenous immunoglobulin and mitoxantrone stop the progression of secondary progressive multiple sclerosis in a patient with interferon intolerance.

A 36 year-old female patient with secondary progressive multiple sclerosis accompanied by neuropsychiatric depression and history of intolerance to beta-interferon was treated with mitoxantrone (MX) and intravenous immunoglobulin (IVIG) for 2 years. Both clinical response and magnetic resonance imaging were performed at the end. With a combination of MX and IVIG long-term treatment, her disabilities improved as measured by the Expanded Disability Status Scale (EDSS). The combination therapy was well-tolerated. It represents an alternative to treat patients who do not respond well to cytostatics alone, or in those in whom intolerance to interferons may also occur. Immunomodulation with intravenous immunoglobulin stopped the progression of the disease and avoided subsequent exacerbations during 24 months. The role of high doses of immunoglobulins in the treatment of patients with secondary progressive MS deserves clinical trials to evaluate the stopping of progression of the disease in comparison to remissions induced by cytostatics, interferons and steroids.

Adult↗
PubMed2005

Proteomic profiling for cancer progression: Differential display analysis for the expression of intracellular proteins between regressive and progressive cancer cell lines.

Tumor development and progression consist of a series of complex processes involving multiple changes in gene expression (Paolo et al. Physiol. Rev., 1993, 73, 161-195; Lance et al. Cell., 1991, 64, 327-336). Tumor cells acquire an invasive and metastatic phenotype that is the main cause of death for cancer patients. Therefore, for early diagnosis and effective therapeutic intervention, we need to detect the alterations associated with transition from benign to malignant tumor cells on a molecular basis. To unravel alterations concerned with tumor progression, the proteomic approach has attracted great attention because it can identify qualitative and quantitative changes in protein composition, including post-translational modifications. In this study, we performed proteomic differential display analysis for the expression of intracellular proteins in the regressive cancer cell line QR-32 and the inflammatory cell-promoting progressive cancer cell line QRsP-11 of murine fibrosarcoma by two-dimensional gel electrophoresis and mass spectrometry using an Agilent 1100 LC/MSD Trap XCT. We found 11 protein spots whose expression was different between QR-32 and QRsP-11 cells and identified nine proteins, seven of which, calreticulin precursor, tropomyosin 1 alpha chain, annexin A5, heat shock protein (HSP)90-alpha, HSP90-beta, PEBP, and Prx II, were over-expressed, and two, Anp32e and HDGF, which were down-regulated. The results suggest an important complementary role for proteomics in identification of molecular abnormalities in tumor progression.

Animals↗
PubMed2003

A cost-utility analysis of mitoxantrone hydrochloride and interferon beta-1b in the treatment of patients with secondary progressive or progressive relapsing multiple sclerosis.

BACKGROUND: Information on the cost utility of interferon beta-1b and mitoxantrone hydrochloride, 2 disease-modifying agents approved by the US Food and Drug Administration for the treatment of secondary progressive (SP) multiple sclerosis (MS), is limited. OBJECTIVE: The aim of this study was to compare the cost utility of i.v. mitoxantrone hydrochloride administered every 3 months, s.c. interferon beta-1b administered every other day, and routine supportive care from the perspectives of both the insurer and society. METHODS: We used a Markov model with health states based on the Kurtzke Expanded Disability Status Scale (EDSS) scores from both an insurer's and a societal perspective (including direct and total costs, respectively). Theoretical patients entered the model with an EDSS score of 3; their progression was followed for 10 years. Transition probabilities were derived from clinical trial data. Cost and utility inputs were taken from the literature. Sensitivity analyses were conducted on all variables. RESULTS: From the insurer's perspective, the incremental cost-utility ratio of mitoxantrone hydrochloride therapy compared with routine supportive care was 58,272 dollars per quality-adjusted life year (QALY) gained. From a societal perspective, mitoxantrone hydrochloride was more effective and less costly than supportive care. From the perspectives of insurers and society, the cost-utility ratios of interferon beta-1b compared with routine supportive care were 338,738 dollars and 245,700 dollars per QALY gained, respectively. When compared with mitoxantrone hydrochloride, interferon beta-1b had an incremental cost-utility ratio of 741,331 dollars and 658,402 dollars per QALY from the insurer's and society's perspectives, respectively. Cost-utility ratios for mitoxantrone hydrochloride were sensitive to acquisition and administration costs of therapy and to effectiveness at slowing disease progression. Cost-utility ratios for interferon beta-1b were not sensitive to any of the variables included in the model. CONCLUSIONS: Mitoxantrone hydrochloride is likely to be a cost-effective treatment for patients with SPMS or progressive relapsing MS from an insurer' perspective and is cost saving from a societal perspective. Interferon beta-1b is not likely an efficient treatment using conventional comparisons for cost-effectiveness. This analysis has potentially important implications for policy implementation; however, decisions about which agent to use for each patient should consider the treatment's adverse-event profile, the method of administration, and the patient's preferences for these factors.

Adjuvants, Immunologic↗
PubMed1996

Progression of ulcerative proctosigmoiditis: incidence and factors influencing progression.

OBJECTIVE: To assess the changing distribution of disease within the large bowel in patients presenting with ulcerative proctitis or proctosigmoiditis. To evaluate the influence of clinical exacerbations, smoking, parity and family history in disease extension. DESIGN: Retrospective single-centre study in a university hospital. METHODS: Case records of patients presenting over a 40-year period were examined to evaluate the clinical course and disease distribution from initial presentation to final follow-up. For each patient whose disease extended to the more proximal colon, an age- and sex-matched control patient was identified whose disease remained confined to the original site. Patients completed a questionnaire to provide information on family history, smoking and parity. The differences in clinical exacerbations, family history, smoking and parity were then compared between the two groups. RESULTS: Among 145 patients presenting with proctitis or proctosigmoiditis followed prospectively for a median period of 10.9 years, the disease extended in 53 patients. Using actuarial methods the disease progressed beyond the rectosigmoid area in 16% of patients at 5 years and 31% at 10 years. Among the patients whose disease progressed, progression was preceded in 68% of cases by a clinical exacerbation of the colitis. When patients whose disease progressed were compared with those whose disease remained confined to the original site, no differences were detected in the number of clinical exacerbations, smoking habit, family history or parity. CONCLUSIONS: The factors that are associated with the extension of colitis are probably different from those that predisposed an individual to develop inflammatory bowel disease initially.

Adult↗
PubMed2006

Effect of rat kidney fraction 3 (rKF3) antigen and specific IgM antibody against rKF3 on the progression of slowly progressive Heymann nephritis.

The aim of the present study was to find out if specific IgM (M) antibody (directed against rat kidney fraction 3 (rKF3)) or rKF3 antigen were able to influence disease progression in an experimental autoimmune kidney disease called slowly progressive Heymann nephritis (SPHN). The level of circulating autoantibodies (aabs) and the morphological and functional changes to the kidney were studied in six groups of rats. All of the treatment components (except post-treatment with M) used in the SPHN pre- and post-treated rats and post-treated-only rats had measurable beneficial effects (even during restimulation with the chemically modified renal antigen, 22 weeks after the induction of the disease) as demonstrated by diminished pathogenic IgG aab production, less severe kidney lesions, and proteinuria reductions. The injected rKF3 minimized progression best in this experiment, especially when administered in a pre- and post-treatment regimen. It is thought that the effect of rKF3 in the reduced progression of SPHN was due to increased production of specific IgM aabs, which in turn limited pathogenic aab production and continuous buildup of immune complexes in the glomeruli by facilitating removal or blockage of nephritogenic autoantigens from the circulation.

Animals↗
PubMed2006

Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA Class II-defined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-up treatment.

MBP8298 is a synthetic peptide with a sequence corresponding to amino acid residues 82-98 of human myelin basic protein (DENPVVHFFKNIVTPRT). It represents the immunodominant target for both B cells and T cells in multiple sclerosis (MS) patients with HLA haplotype DR2. Its administration in accordance with the principle of high dose tolerance results in long-term suppression of anti-myelin basic protein (MBP) autoantibody levels in the cerebrospinal fluid (CSF) of a large fraction of progressive MS patients. MBP8298 was evaluated in a 24-month placebo-controlled double-blinded Phase II clinical trial in 32 patients with progressive MS. The objective was to assess the clinical efficacy of 500 mg of MBP8298 administered intravenously every 6 months, as measured by changes in Expanded Disability Status Scale (EDSS) scores. Contingency analysis for all patients at 24 months showed no significant difference between MBP8298 and placebo-treatments (n = 32, P = 0.29). Contingency analysis in an HLA Class II defined subgroup showed a statistically significant benefit of MBP8298 treatment compared with placebo in patients with HLA haplotypes DR2 and/or DR4 (n = 20, P = 0.01). Long-term follow-up treatment and assessment of patients in this responder group showed a median time to progression of 78 months for MBP8298 treated patients compared with 18 months for placebo-treatment (Kaplan-Meier analysis, P = 0.004; relative rate of progression = 0.23). Anti-MBP autoantibody levels in the CSF of most MBP8298 treated patients were suppressed, but antibody suppression was not predictive of clinical benefit. Anti-MBP autoantibodies that reappeared in the CSF of one patient at 36 months, whilst under treatment with MBP8298, were not reactive with the MBP8298 peptide in vitro. The identification of a responder subgroup (62.5% of the patients in this study) enables a more efficient design of a large confirmatory clinical trial of MBP8298. The probability that patients with other less common HLA-DR haplotypes will respond to this treatment should not be ignored.

Adult↗