Biomedical subjects

F C Breedveld

Publications and source records attributed to F C Breedveld.

At least 307 records · Page 17Linked to original sources

PubMed1994

Granzyme-positive cytotoxic cells are specifically increased in early rheumatoid synovial tissue.

OBJECTIVE: To define the expression and the phenotype of granzyme (Gran) A and B positive cytotoxic cells in synovial tissue (ST) from patients with rheumatoid arthritis (RA) with respect to disease duration and activity. METHODS: Using antibodies against GranA and GranB, which serve as markers of activated natural killer (NK) cells and cytotoxic T lymphocytes, ST sections from 10 patients with early RA, 10 patients with longstanding RA, and 10 patients with osteoarthritis were examined. The phenotype of Gran+ cells was determined with double-labeling techniques. RESULTS: Gran+ cells, the majority of which were NK cells, were found in ST from patients in all groups. Several of these cells did not express the surface markers CD16, CD56, and CD57. The highest ST expression of GranB was found in patients with early RA. In RA patients, there was a positive correlation of GranB expression with serum levels of acute-phase reactants, but not with histologic scores for inflammation. CONCLUSION: Gran+ cells are mainly NK cells, a substantial proportion of which do not express conventional NK cell surface markers. GranB expression is specifically increased in the synovial tissues of patients with RA of short duration.

Aged↗

PubMed1994

Expression of granzymes A and B in synovial tissue from patients with rheumatoid arthritis and osteoarthritis.

Granzymes A and B are serine proteinases which are stored in the granules of activated cytotoxic T cells and NK cells. Expression of these granzymes by cytotoxic cells in tissues can be used as an activation marker for these cells. To investigate a possible role of cytotoxic lymphocytes in rheumatoid arthritis (RA) and osteoarthritis (OA), we assessed the expression of granzymes A and B by cytotoxic lymphocytes in synovial biopsies from five RA and five OA patients using mAb specific for these serine proteinases. In three of the five RA patients but also in two of the five OA patients granzyme A- and B-expressing lymphocytes were observed in the synovium. Double-labeling immunohistochemical techniques revealed that up to 75% of the granzyme-positive synovial lymphocytes had the CD16+ or CD56+ natural killer cell phenotype. Less than 5% were CD3+, CD8+ cytotoxic T cells, whereas in some patients the phenotype of up to 50% of these cells could not be identified. The presence of granzymes A and B in the synovium of both RA as well as OA patients was confirmed on the molecular level in a second group of 11 RA and 5 OA patients using the polymerase chain reaction. Thus, expression of granzymes A and B occurs in the synovium in patients with RA as well as those with OA. These proteins are mainly expressed by NK cells that may therefore play a role in the pathogenesis of these diseases.

Aged↗

PubMed1994

Elderly-onset rheumatoid arthritis.

Elderly-onset rheumatoid arthritis (EORA), defined as rheumatoid arthritis (RA) with onset at age 60 years or over, differs slightly at presentation from younger-onset RA (YORA) by a more equal gender distribution, a higher frequency of acute onset with systemic features, more frequent involvement of the shoulder, and higher disease activity. Longitudinal studies have showed more disease activity, radiographic damage, and functional decline in patients with EORA than in those with YORA. These differences were only found in seropositive patients. Seropositive EORA was reported to be associated with HLA-DR4, in contrast to seronegative EORA. Possible heterogeneity in the pathogenesis of seronegative EORA is supported by the recognition of subsets that overlap with the clinical manifestations of other syndromes such as polymyalgia rheumatica and remitting seronegative symmetrical synovitis with pitting edema. In addition, crystal-induced arthritis and inflammatory osteoarthritis may be difficult to distinguish from EORA. The efficacy and toxicity of second-line drugs is similar in both age groups, but in the elderly caution is needed with the use of nonsteroidal antiinflammatory drugs and prednisone.

Aged↗

PubMed1994

Inflamed joints of patients with rheumatoid arthritis contain T cells that display in vitro proliferation to antigens present in autologous synovial fluid. Functional analysis on the basis of synovial-fluid-reactive T-cell clones and lines.

The immunopathology of inflamed joints in patients with RA is thought to result from an antigen-driven T-cell response. The antigen(s) responsible for the activation of synovial T cells, however, are as yet unidentified. In this study, we tested SF as a potential source of (auto)antigen(s). Five of 15 IL-2-expanded T-cell lines generated from SF cells of RA patients displayed a proliferative response to autologous SF. Five CD4+CD8-alpha beta TCR+SF-reactive T-cell clones obtained from responder T-cell lines were studied in more detail. Three T-cell clones from one RA patient were found to recognize epitopes in autologous SF in the context of DR4(Dw4), and two T-cell clones of another RA patient responded to autologous SF in the context of the HLA-DPB1*0401 gene product. The two DP-restricted clones and one of the DR-restricted clones did not proliferate to 50 SF samples of other RA patients, whereas the remaining DR-restricted clones responded to one allogeneic sample. Sequence analysis demonstrated that the latter clones expressed identical V beta 6.9 + TCR beta chains. This was also found for the (V beta 19+) DP-restricted clones. Proliferation of SF-reactive T cells was not only obtained with SF of the joint that had contained the T cells, but also with autologous SF of other affected joints. Together, these findings indicate that epitopes able to stimulate synovial T cells differ among RA patients, but may be similar within multiple joints of an individual patient. The presence of T cells able to respond to SF antigens in inflamed joints suggests that these T cells play an active role in the pathogenesis of RA.

Amino Acid Sequence↗

PubMed1994

Tumor necrosis factor alpha-308 gene variants in relation to major histocompatibility complex alleles and Felty's syndrome.

The location of the human TNF genes within the MHC complex has prompted much speculation about the role of TNF alleles in the etiology of MHC-associated autoimmune diseases. On sequencing the 5' regulatory region of the human TNFA gene a G (TNFA-308G) to A (TNFA-308A) transition polymorphism at position -308 was discovered. We have developed a simple PCR assay to facilitate the screening of the -308 polymorphism at the DNA level. In view of the possible linkage between the TNFA-308A allele and a certain MHC type, TNFA-308 genotypes in HLA-typed healthy individuals (n = 88) were determined. A statistically significant association between the TNFA-308A allele and HLA-DR3, DQB1*0201, DQA1*0501, A1, B8, and the NcoI 5.5-kb RFLP of the TNFB gene was observed. In addition, we determined the frequency of the TNFA-308A allele in patients with FS (n = 13), an HLA-DR4-associated disease. In this study, no association was found of Felty's syndrome with the TNFA-308A allele, indicating that this allele does not appear to be a susceptibility factor for FS.

Alleles↗

PubMed1994

Evidence for selective in vivo expansion of synovial tissue-infiltrating CD4+ CD45RO+ T lymphocytes on the basis of CDR3 diversity.

In this study we have analyzed the TCR V alpha and V beta regions at the DNA level in the CD4+CD45RO+ memory T cell population of synovial tissue infiltrating T lymphocytes of three rheumatoid arthritis (RA) patients and one patient with chronic arthritis. Cell lines of CD4+CD45RO+, CD4+CD45RO-, CD8+CD45RO+ and CD8+CD45RO- T lymphocyte populations were generated following FACS cell sorting of freshly isolated synovial tissue mononuclear cell infiltrates (STMC) and of freshly isolated peripheral blood mononuclear cells (PBMC) of these patients. The phenotypic and molecular analyses have revealed the following. (i) The TCR repertoires of tissue infiltrating T lymphocytes in the various subsets were extensive on the basis of TCR V gene family usage. (ii) Furthermore, each patient displayed individual specific TCR V gene expression patterns in the various STMC and PBMC derived T cell subsets. However, the majority of these arthritis patients manifested increased expression of multiple TCR V gene families in the synovial tissue derived CD4+CD45RO+ T cell population when compared with the peripheral blood derived CD4+CD45RO+ subset. Of these gene families, we found enhanced expression of the TCR V alpha 7 and V beta 11 gene segments in synovial tissue to be shared by all four patients analyzed. (iii) Nucleotide sequence analysis of the CDR3 regions of a number of TCR V regions in the CD4+CD45RO+ T cell subsets has revealed that the CDR3 regions comprised within synovial tissue derived TCR V regions differed from those found in peripheral blood derived TCR V regions. These differences in CDR3 diversity might be the consequence of a specific interaction with particular MHC-peptide complexes expressed at the site of inflammation. (iv) The CDR3 region analysis also showed individual specific amino acid motifs within the N-D-N regions of all analyzed TCR V beta genes derived from PBMC as well as STMC.

Amino Acid Sequence↗

PubMed1994

Early agalactosylation of IgG is associated with a more progressive disease course in patients with rheumatoid arthritis: results of a follow-up study.

The clinical significance of the percentage agalactosyl IgG oligosaccharides [%G(O)] was investigated in serum of a well-characterized cohort of 127 female RA patients who were followed for a mean duration of 6 yr. The %G(O) was determined in the first available serum sample which was obtained at a mean of 3.4 yr after symptom onset. It could be shown that patients with a %G(O) more than 2 S.D. above the mean level of controls (n = 34), had significantly more erosions, disease activity, and were treated with more second-line drugs, than patients without an increased %G(O) (n = 93), both at the time the serum sample was obtained, and during follow-up. These findings suggest that G(O) may serve as an indicator for the disease course in patients with RA.

Adult↗

PubMed1994

Joint scintigraphy for quantification of synovitis with 99mTc-labelled human immunoglobulin G compared to late phase scintigraphy with 99mTc-labelled diphosphonate.

The ability of scintigraphy with technetium 99m-labelled polyclonal human immunoglobulin G (99mTc-IgG) to detect and quantify arthritis activity was studied in 24 patients with RA and in 10 patients with OA. The results of 99mTc-IgG scintigraphy were compared with those of scintigraphy with 99mTc-labelled hydroxymethylene-diphosphonate (HDP). The mean joint scores of 99mTc-IgG scintigraphy in RA patients with active disease were significantly higher (P < 0.001) than the mean scores in patients with inactive disease. The mean joint scores were also higher in patients with erosions compared to those in patients without erosions (P < 0.05). For 99mTc-HDP scintigraphy no significant differences were found between the mean joint scores of these patient groups. Comparison of scintigraphic results between patients with RA and OA revealed that the mean joint score of 99mTc-IgG scintigraphy was significantly (P < 0.001) higher in the patients with RA than in patients with OA, whereas for 99mTc-HDP scintigraphy this difference was not significant. These results show that 99mTc-IgG scintigraphy, when compared to 99mTc-HDP scintigraphy, is a more specific method of detecting synovitis and, also, shows differentiation between different degrees of arthritis activity in RA.

Adult↗

PubMed1994

Treatment of rheumatoid arthritis with a chimeric CD4 monoclonal antibody (cM-T412): immunopharmacological aspects and mechanisms of action.

To investigate the mechanisms of action underlying the therapeutic effect of CD4 monoclonal antibody therapy in rheumatoid arthritis (RA), clinical responses were compared with several laboratory parameters. Twenty-nine RA patients received either 10 mg, 50 mg or 100 mg of cM-T412, a chimeric CD4 MoAb, for 7 days. The CD4 binding sites on circulating lymphocytes were saturated directly with cM-T412 and serum levels of unbound cM-T412 accumulated towards day 7 of treatment only in the patients treated with 50 and 100 mg. The treatment induced an instant and prolonged depression of the number of circulating CD4+ cells, similar for all dosages. Clinical improvement was observed predominantly in the patients treated with 50 or 100 mg cM-T412 daily and did not correlate with changes in counts of circulating leucocyte subsets nor with changes in serum cytokine levels. An antiglobulin response against cM-T412 developed in a majority of the patients. Side effects on the first day of treatment were correlated with an increase of serum IL-6 levels. This study indicates that a favourable clinical effect of cM-T412 administration was associated with the presence of unbound cM-T412 in the circulation of RA patients. Therefore penetration of unbound cM-T412 into the site of inflammation might determine the therapeutic effect in RA.

Adult↗

PubMed1994

Antinuclear antibodies in psychiatric patients.

To investigate whether unrecognized systemic lupus erythematosus (SLE) might occur more frequently among psychiatric patients than expected on clinical examination, sera of 100 patients from a psychiatric hospital were tested for the presence of antibodies against nuclear antigens (ANA) and antibodies against DNA. The occurrence of sera positive for ANA was compared with the test results of serum samples of 859 individuals randomly selected from the general population. Positive tests for ANA were found in 7% of the psychiatric patients and 4% of the individuals selected from the population. Antibodies against dsDNA were not found in sera of the psychiatric patients. After categorizing both groups for age and sex, no difference was found as for the frequency of ANA positive sera between both groups, indicating that on the basis of serology, no evidence exists that SLE might be underestimated among psychiatric patients.

Adult↗

PubMed1994

Sociodemographic factors and the outcome of rheumatoid arthritis in young women.

OBJECTIVE: To investigate the impact of sociodemographic factors on the outcome of rheumatoid arthritis (RA). METHODS: A group of 138 women with RA of recent onset and a mean duration of follow up of 5.8 years was studied. Additional information on sociodemographic variables at disease onset (level of formal education, marital status and employment status) was related to the initial disease severity and various outcome measures. RESULTS: Patients with lower levels of education showed a trend towards a worse outcome, according to Health Assessment Questionnaire (HAQ) score, erosion score and the patient's and physician's assessment of outcome at the last visit. However, we also found a trend towards an association between lower levels of education and more severe disease at onset, as measured by HAQ score, erosion score and the number of painful and swollen joints. The association between lower levels of education and poorer outcome of RA was weakened after correction for the initial disease severity. Results of other sociodemographic variables were equivocal. CONCLUSIONS: Differences in severity of RA between patients with different levels of education develop or are present in the early stages of the disease.

Adult↗

PubMed1994

Musculoskeletal disorders and disability in persons aged 85 and over: a community survey.

OBJECTIVES: To study the prevalences of musculoskeletal disorders and disability in the elderly, and the relationship between them. METHODS: A community sample of 73 females and 32 males aged 85 and over underwent a standardised examination at home. Musculoskeletal disorders were classified according to published clinical criteria. The relative effects on disability (a walking distance of < 500 m or dependency in activities of daily living (ADL)) of musculoskeletal disorders and comorbidity were analysed by logistic regression. RESULTS: Musculoskeletal pain was reported by 57% of those interviewed. A major restriction of joint movement range was frequent in the shoulder but uncommon in other joints. A shoulder disorder was found in 27% of subjects, rheumatoid arthritis in 1% and osteoarthritis (OA) of the hand, hip, and knee in five, seven, and 18% of subjects, respectively. Disability was frequent: a walking distance of < 500 m was found in 60% and ADL dependency in 40% of the group. Factors related to one or both of these disability measures included female gender, hip and knee OA, impaired vision, cognitive impairment and neurological disease. CONCLUSION: Musculoskeletal pain and disorders, in addition to disability were frequent in this very elderly population. However, as a cause of disability, other disorders were at least as important as musculoskeletal disorders.

Aged↗

PubMed1994

Gastric outlet obstruction as a presenting manifestation of systemic lupus erythematosus.

A patient with nausea and vomiting who subsequently proved to have systemic lupus erythematosus is described. Although gastrointestinal involvement is common in systemic lupus erythematosus it is rare as an initial manifestation. Gastric outlet obstruction was shown on the air contrast examination while the mucosa at endoscopy was normal. The gastric symptoms regressed after treatment with high dose corticosteroids and a repeat air contrast examination of the stomach was normal. This stricturing process may have been caused by a local peritonitis.

Adult↗

PubMed1994

Antiendothelial cell antibodies in systemic lupus erythematosus: enhanced antibody binding to interleukin-1-stimulated endothelium.

IgG antiendothelial antibodies (IgG AEA), as measured by enzyme-linked immunosorbent assay, could be detected in serum samples of 38 out of 41 patients with systemic lupus erythematosus. Incubation of endothelial cells (EC) with interleukin-1 alpha (IL-1 alpha), in contrast to incubation with interferon gamma or tumor necrosis factor alpha, resulted in an enhanced IgG AEA binding. Immunoblotting revealed reactivity of AEA against a variety of EC antigens. The upregulation of IgG-AEA-binding reactivity to IL-1 alpha-stimulated EC was due to binding to antigens that were already expressed by unstimulated EC. The IgG-binding reactivity to both IL-1 alpha-stimulated and unstimulated EC was significantly higher in the serum of patients with joint or skin abnormalities as compared with patients without these manifestations. These data suggest that upregulated binding of IgG to EC induced by IL-1 alpha may play a role in immune vascular damage.

Adult↗

PubMed1994

The severity of rheumatoid arthritis: a 6-year followup study of younger women with symptoms of recent onset.

OBJECTIVE: In rheumatoid arthritis (RA), not only outcome measurements taken at a single point in time, but also the severity during the entire disease period is important. In this investigation we measured severity in terms of the course of disease activity. It is the activity of the disease which leads to most suffering in the patient, and which we try to alleviate. METHODS: Patterns of disease activity were investigated in 132 female patients who were followed yearly from an early phase of the disease for a mean duration of 6 years. RESULTS: Sixty-seven patients (50.8%) continuously had < or = 4 swollen joints (low activity), 23 patients (17.4%) continuously had > or = 4 swollen joints (high activity), in 10 patients (7.6%) disease activity decreased from high to low, in 8 patients (6.1%) disease activity increased from low to high, and 24 patients (18.2%) had fluctuating levels of disease activity. The outcome of the disease as measured by the functional ability, the radiological abnormalities, and number of prescribed 2nd line drugs, was best in patients with continuously low levels of disease activity, and worst in patients with continuously high or increasing levels of disease activity. CONCLUSION: For about half of the female patients presenting to a rheumatology outpatient clinic, the severity of RA after 6 years of disease duration is characterized by continuous but low disease activity, and sufficient preservation of functional ability. For the other half of the patients RA is a progressive and disabling disease.

Adult↗

PubMed1994

Cyclosporine in common clinical practice: an estimation of the benefit/risk ratio in patients with rheumatoid arthritis.

OBJECTIVE: To investigate in common clinical practice the toxicity/efficacy ratio of low dose cyclosporine A (CsA) in patients with advanced rheumatoid arthritis (RA) after 12 months CsA administration. METHODS: One hundred and two patients with RA were included in the study. The initial dose of CsA was 2.5 mg/kg/day, the mean maximum dose was 3.2 mg/kg/day and the dose at 12 months was 2.8 mg/kg/day. RESULTS: Sixty-nine (68%) patients completed 12 months of treatment. Seventeen (17%) patients discontinued for lack of efficacy and 16 (16%) for toxicity (of which 50% for gastrointestinal intolerance). The clinical efficacy variables improved significantly by 36-42% between entry and Month 6 and remained stable thereafter. The C-reactive protein decreased from 43 U/ml at entry to 22 U/ml (p < 0.0001) at 12 months. Forty-four percent of the patients and 47% of the physicians judged the efficacy as good or very good. The median number of adverse events/patient was 3 but most adverse events were either not clinically important or disappeared after dose reduction. Gastrointestinal (GI) intolerance and nephrotoxicity (> 30% increase in serum creatinine) each occurred in 50% of the patients. GI intolerance was transient in 80% of the patients but accounted for 50% of the premature discontinuations for toxicity. Nephrotoxicity persisted in the 50% of the patients in whom it occurred, despite dose reduction. The mean serum creatinine rose from 70 (13) mumol/l at entry to 86 (23) mumol/l at 12 months (23% increase; p < 0.0001), and this increase had been entirely reached after 3 months. Variables that could significantly predict the occurrence of nephrotoxicity could not be identified. CONCLUSION: CsA can be safely and effectively administered to patients with RA for a duration of at least 12 months. An acceptable renal function at entry, close monitoring of the serum creatinine concentration and dose reductions when appropriate are prerequisities.

Adolescent↗

PubMed1994

Clinical and biochemical response to single infusion of pamidronate in patients with active rheumatoid arthritis: a double blind placebo controlled study.

OBJECTIVE: To assess the effects of 3-amino-1-hydroxypropylidine-1,1-bisphosphonate (pamidronate) in rheumatoid arthritis (RA). METHODS: Thirty patients with active RA were randomly allocated to receive a single intravenous infusion of placebo, 20 mg pamidronate, or 40 mg pamidronate. RESULTS: Pamidronate treatment resulted in a rapid and sustained reduction in urinary calcium and hydroxyproline excretions. A sustained reduction in serum corrected calcium was only noted in the group treated with 40 mg pamidronate. In both groups treated with pamidronate a temporary increase in serum parathyroid hormone was noted. Compared to the placebo group clinical variables of disease activity improved significantly in both groups treated with aminohydroxypropylidine bisphosphonate. The erythrocyte sedimentation rate and serum C-reactive protein levels improved significantly in patients treated with 40 mg pamidronate. No serious side effects were documented. CONCLUSION: A single infusion of pamidronate in patients with RA is safe, suppresses bone resorption, and reduces disease activity. It is suggested that the effect on disease activity is dose dependent.

Adult↗

PubMed1994

Oral calcitriol as a new therapeutic modality for generalized morphea.

BACKGROUND: None of the commonly used drugs for the treatment of scleroderma appears to significantly influence the fibrotic stage of this disorder. Recently, a beneficial effect of the treatment with oral calcitriol (1,25 dihydroxyvitamin D3) in 10 patients with systemic sclerosis and four patients with morphea was described. This fact could be ascribed to the immunoregulatory effects of calcitriol observed in vitro and to inhibition of fibroblast growth. We treated three patients with extensive morphea with remarkable results. OBSERVATION: Three patients with generalized morphea were treated with calcitriol in an oral daily dose of 0.50 to 0.75 microgram. After 3 to 7 months of treatment, the mobility of the joints improved and the skin extensibility increased. No adverse effects were observed. The improvement persisted after discontinuation of therapy during a follow-up period of 1 to 2 years. CONCLUSION: Calcitriol showed a beneficial effect in generalized morphea during an open study. Double-blind, placebo-controlled trials are needed to assess its therapeutic value.

Administration, Oral↗