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F C Breedveld

Publications and source records attributed to F C Breedveld.

At least 181 records · Page 10Linked to original sources
PubMed1998

CD28 co-stimulation is intact and contributes to prolonged ex vivo survival of hyporesponsive synovial fluid T cells in rheumatoid arthritis.

In rheumatoid arthritis (RA), T cells in the inflamed joint are considered to play a crucial role in the pathogenesis. However, despite the fact that synovial T cells have an activated memory phenotype, they are functionally suppressed upon combined CD3 and CD28 stimulation. Here, we analyzed the contribution of both CD3 and CD28 to the hyporesponsiveness of synovial T cells in RA. In contrast to the low CD3 responsiveness of synovial fluid (SF) T cells compared to peripheral blood (PB) T cells, the CD28 co-stimulatory response was observed to be unaffected. Hyporesponsiveness of SF T cells has previously been associated with decreased levels of intracellular glutathione (GSH), an antioxidant and regulator of the intracellular redox state. Treatment of SF T cells with N-acetylcysteine, an antioxidant and replenisher of GSH, selectively improved CD3-induced responses, while leaving CD28 responsiveness unaffected. These data show that the CD3 pathway is highly sensitive to intracellular GSH alterations, whereas CD28 responsiveness is relatively refractory. Furthermore, in support for a functional role of CD28 co-stimulation, it was demonstrated that CD28 ligation acted in synergy with the IL-2 receptor gamma chain signaling cytokine IL-15 in the enhancement of the ex vivo survival of SF T cells. These data indicate that CD28 co-stimulatory capacity of SF T cells, in contrast to CD3 stimulation, remains intact despite an altered intracellular redox state. Thereby, CD28 stimulation may contribute to the persistence of T cells at the site of inflammation, which might be of relevance in the pathogenesis of RA.

Arthritis, Rheumatoid↗
PubMed1998

Detection of bacterial DNA in joint samples from patients with undifferentiated arthritis and reactive arthritis, using polymerase chain reaction with universal 16S ribosomal RNA primers.

OBJECTIVE: Bacteria are considered to be important in the pathogenesis of several forms of arthritis. The goal of this study was to apply the 16S ribosomal RNA (rRNA)-polymerase chain reaction method for the detection of bacterial DNA in synovial fluid (SF) and synovial tissue (ST) from inflamed joints. METHODS: Samples from 5 patients with septic arthritis and from 7 with osteoarthritis or arthritis secondary to joint trauma were used as controls. Samples from 6 patients with spondylarthropathy (SpA) and from 20 with undifferentiated arthritis (UA) were analyzed for the presence of bacterial DNA using universal 16S rRNA primers. Automated sequencing and comparative data analysis were performed to identify the species. RESULTS: In the positive control group, the bacterial species cultured from the synovium could be identified in all cases. No bacterial DNA was detected in the SF and ST from patients in the negative control group. In 4 of 6 patients with SpA and 7 of 20 with UA, the analysis of joint samples revealed the presence of bacterial DNA. Sequence analysis indicated the presence of multiple species, which was confirmed by sequencing of cloned products. CONCLUSION: When the the above techniques were used with a stringent regimen, we were able to demonstrate that it is possible to collect and analyze joint samples without contaminating bacterial DNA. The accumulation of phagocytic cells that contain bacterial DNA of various species could play a role in the pathogenesis of both SpA and UA.

Adolescent↗
PubMed1998

Asymptomatic synovitis precedes clinically manifest arthritis.

OBJECTIVE: It has been hypothesized that asymptomatic synovitis may precede clinical manifestations of arthritis in the earliest phase of rheumatoid arthritis (RA). To obtain more insight into this disease phase, we investigated the immunohistologic features of synovial tissue (ST) from the knee joints of rhesus monkeys with induced arthritis and from RA patients with both clinically involved and clinically uninvolved knee joints. METHODS: Serial ST biopsy specimens from the knee joints of 4 rhesus monkeys that had been immunized with type II collagen and ST from 10 RA patients were investigated. Eight patients without inflammatory joint disease served as controls. RESULTS: In ST from immunized monkeys, an influx of macrophages was observed well before the occurrence of arthritis. Signs of inflammation were also demonstrated in ST from clinically uninvolved knee joints of all RA patients evaluated. The ST was characterized in particular by infiltration with macrophages and by the expression of macrophage-derived cytokines. CONCLUSION: The findings support the view that asymptomatic synovitis precedes clinically manifest arthritis in both early and established RA. This implies that the debut of RA already represents a chronic phase of the disease.

Aged↗
PubMed1998

Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy, pharmacokinetics, immunogenicity, and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody (cA2) (infliximab; Remicade, Centocor, Malvern, PA) given alone or in combination with low-dose methotrexate (MTX) in rheumatoid arthritis (RA) patients. METHODS: In a 26-week, double-blind, placebo-controlled, multicenter trial, 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were randomized to 1 of 7 groups of 14-15 patients each. The patients received either intravenous cA2 at 1, 3, or 10 mg/kg, with or without MTX 7.5 mg/week, or intravenous placebo plus MTX 7.5 mg/week at weeks 0, 2, 6, 10, and 14 and were followed up through week 26. RESULTS: Approximately 60% of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20% Paulus criteria for response to treatment, for a median duration of 10.4 to >18.1 weeks (P < 0.001 versus placebo). Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 (median duration 2.6 weeks; P=0.126 versus placebo). However, coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic, prolonging the duration of the 20% response in >60% of patients to a median of 16.5 weeks (P < 0.001 versus placebo; P=0.006 versus no MTX) and the 50% response to 12.2 weeks (P < 0.001 versus placebo; P=0.002 versus no MTX). Patients receiving placebo infusions plus suboptimal low-dose MTX continued to have active disease, with a Paulus response lasting a median of 0 weeks. A 70-90% reduction in the swollen joint count, tender joint count, and C-reactive protein level was maintained for the entire 26 weeks in patients receiving 10 mg/kg of cA2 with MTX. In general, treatment was well tolerated and stable blood levels of cA2 were achieved in all groups, except for the group receiving 1 mg/kg of cA2 alone, at which dosage antibodies to cA2 were observed in approximately 50% of the patients. CONCLUSION: Multiple infusions of cA2 were effective and well tolerated, with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60% of patients with active RA despite therapy with low-dose MTX. When cA2 at 1 mg/kg was given with low-dose MTX, synergy was observed. The results of the trial provide a strategy for further evaluation of the efficacy and safety of longer-term treatment with cA2.

Adult↗
PubMed1998

No increased risk of malignancies and mortality in cyclosporin A-treated patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the cyclosporin A (CSA)-attributed risk of developing malignancies in general and malignant lymphoproliferative diseases (LPDs) and skin cancers in particular, as well as the CSA-attributed incidence of mortality in patients with rheumatoid arthritis (RA). METHODS: In a retrospective, controlled cohort study, the incidence of malignancies and mortality was evaluated in 208 CSA-treated patients with RA compared with 415 matched control patients with RA between 1984 and 1995. Patients were followed up for a median of 5.0 years (range 1.4-12.0). RESULTS: Forty-eight cases of malignancy (8 in the CSA group and 40 in the control group; relative risk [RR] 0.40, 95% confidence interval [95% CI] 0.19-0.84) were identified, of which 8 were malignant LPDs (2 CSA versus 6 control; RR 0.67, 95% CI 0.14-3.27) and 14 were skin cancers (2 CSA versus 12 control; RR 0.33, 95% CI 0.08-1.47). Seventy-three patients died (16 CSA versus 57 control; RR 0.56, 95% CI 0.33-0.95) due primarily to cardiovascular diseases (4 CSA versus 22 control; RR 0.36, 95% CI 0.13-1.04) or a malignancy (3 CSA versus 8 control; RR 0.67, 95% CI 0.18-2.43). Proportional hazards regression analysis with correction for potential confounding factors did not significantly change the results. CONCLUSION: The study findings suggest that CSA treatment in RA patients does not increase the risk of malignancies in general or the risk of malignant LPDs or skin cancers in particular. Moreover, the incidence of mortality in CSA-treated RA patients was comparable to that in matched control RA patients.

Adult↗
PubMed1998

Functional analysis of rheumatoid factor-producing B cells from the synovial fluid of rheumatoid arthritis patients.

OBJECTIVE: To understand the regulation of rheumatoid factor (RF) production in rheumatoid arthritis (RA), we studied IgM-RF production by B cells isolated from the synovial fluid (SF). METHODS: Highly purified SF and peripheral blood (PB) B cells were isolated by negative selection in a fluorescence-activated cell sorter (FACS) and then cultured with either L cells, CD40 ligand (CD40L)-transfected L cells, or type B synoviocytes in the presence or absence of interleukin-2 (IL-2), IL-4, or IL-10. Total IgM and IgM-RF were detected after 14 days by enzyme-linked immunosorbent assay. Enzyme-linked immunospot assays were performed to detect cells that spontaneously produced immunoglobulin. SF B cells were also phenotypically characterized by FACS analysis. RESULTS: Terminally differentiated CD20-,CD38+ synovial plasma cells (PC) present in the SF of RA patients secreted IgM-RF in the absence of a stimulus. IgM-RF production markedly increased when SF B cells were cultured in the presence of type B RA synoviocytes together with IL-10, but independently of CD40-CD40L interaction. Although CD20-,CD38+ PC could also be demonstrated in SF B cells from patients with other forms of arthritis, IgM-RF production was restricted to the SF B cell cultures of patients with seropositive RA. The frequency of IgM-RF-producing cells among IgM-producing PC in patients with seropositive RA was estimated to be as much as 50%. CONCLUSION: These data demonstrate that terminally differentiated CD20-,CD38+ IgM-RF-producing B cells are specifically present in the inflamed joints of patients with seropositive RA. There is evidence that the local environment in the rheumatoid joint favors RF production. The relatively high frequency of IgM-RF PC in the SF B cell population provides evidence of a dominant RA-specific antigen-driven response in the development of the synovial PC repertoire.

ADP-ribosyl Cyclase↗
PubMed1998

Poor expression of T cell-derived cytokines and activation and proliferation markers in early rheumatoid synovial tissue.

We compared the state of activation and proliferation of T cells in synovial tissue (ST) from rheumatoid arthritis (RA) patients in early and late stages of the disease to find out whether T-cell-driven immune responses vary during the course of the disease. ST was obtained from 12 patients with early RA (< 1 year) and 12 patients with longstanding RA (> 5 years). T cells and interferon-gamma (IFN-gamma)-positive cells were detected in ST using immunohistologic methods. To determine the percentage of T cells expressing the interleukin-2 receptor, IFN-gamma, or the proliferation associated antigen Ki-67, immunofluorescence double-staining techniques were used. The scores for the number of T cells and for the expression of IFN-gamma as well as the percentages of T cells expressing CD25, IFN-gamma, or Ki-67 in rheumatoid synovium were not dependent on disease duration. These results do not support the assumption that the responsiveness of T cells in ST of RA patients differs between early and late stages of the disease. The data indicate that at present no arguments exist that the effect of T-cell-directed interventions on synovial inflammation might vary in different stages of the disease.

Adult↗
PubMed1998

Flexion contractures associated with a malignant neoplasm: 'A paraneoplastic syndrome?'.

A 71-year-old man developed polyarthritis and, subsequently, severe flexion contractures of multiple joints, particularly the joints of the hands. Eighteen months after developing this disease a parailiacal lymph node metastasis of an unknown primary cancer was found. We suggest that this patient's history, dominated by contractures that resembled the 'palmar fasciitis and polyarthritis syndrome', should be considered as a paraneoplastic syndrome.

Aged↗
PubMed1998

Cigarette smoking and pulmonary diffusion defects in rheumatoid arthritis.

The pathogenesis of lung disease in rheumatoid arthritis (RA) has still to be defined. Risk factors associated with lung involvement in RA were investigated by means of pulmonary function studies in 40 RA patients without apparent lung disease. A decreased carbon monoxide (CO) diffusion capacity indicative of interstitial lung disease (ILD) was the main pulmonary function defect found in the first 20 patients. The occurrence was associated with current cigarette smoking. This association was confirmed in a case control study performed subsequently. These data suggest that ILD in RA is stimulated by smoking and provide an additional argument that modification of smoking behaviour in RA patients might lead to less severe complications.

Adult↗
PubMed1998

Monoclonal antibodies to CD4.

Animal models of human autoimmune disease suggest that it should be possible to reinduce self-tolerance in these conditions by the use of T-cell directed therapies, in particular with anti-CD4 monoclonal antibodies (CD4-mAb). Many studies have shown that CD4-mAb can prevent and in a treatment setting suppress activity of these disease models, including collagen-induced arthritis.

Animals↗
PubMed1998

Laboratory screening for side effects of disease modifying antirheumatic drugs in daily rheumatological practice.

To observe the actual laboratory screening for side effects of disease modifying antirheumatic drugs (DMARDs) in daily rheumatological practice, a retrospective multi-center cohort study was performed on the laboratory tests in DMARD treated rheumatoid arthritis (RA) patients. RA patients were investigated by chart review if they started with a DMARD (cohort 1) or were treated with a DMARD for at least one year (cohort 2). Hematological, hepatic, and renal tests were collected. In cohort 1 and 2, 513 and 1209 patients were included, respectively. A fairly outlined screening profile was observed for each DMARD studied. Except for antimalarials, the testing frequency decreased with time in cohort 1. For all DMARDs the testing frequency in cohort 1 was higher than in cohort 2. In general, rheumatologists requested laboratory tests less frequently than is internationally recommended. This discrepancy raises questions about the relation between the efficacy and costs of laboratory screening for side effects of DMARDs in patients with RA.

Adolescent↗
PubMed1998

Tranexamic acid, an inhibitor of plasminogen activation, reduces urinary collagen cross-link excretion in both experimental and rheumatoid arthritis.

The plasminogen activation system is one of the enzyme systems held responsible for bone and cartilage degradation in rheumatoid arthritis (RA). In this study, we evaluated the effect of tranexamic acid (TEA), an inhibitor of plasminogen activation, on urinary collagen cross-link excretion and radiological joint damage in rat adjuvant arthritis (AA) and on urinary collagen cross-link excretion in patients with RA. In the animal study, adjuvant arthritis was induced in male Lewis rats. From day 7 onward, high-dose TEA (500 mg/kg body weight, once daily) or placebo was administered orally. Study groups consisted of TEA-treated normal rats (C + TEA), placebo-treated normal rats (C + plac), AA rats treated with TEA (AA + TEA) or with placebo (AA + plac). To monitor joint destruction, urinary collagen cross-link excretion (pyridinoline, HP; deoxypyridinoline, LP) was measured by high-performance liquid chromatography at days 14 and 21. Radiological evaluation of joints was performed at day 21. In the patient study, TEA was administered to nine patients with RA as adjuvant medication (approximately 20 mg/kg body weight, three times daily) for 12 weeks. Urinary HP and LP excretion levels were measured before and during TEA treatment, and 4 weeks after the cessation of TEA treatment. In AA + TEA rats, a significant reduction of HP and a tendency towards a reduction of LP excretion were found compared with AA + plac rats (P < 0.05), at day 14, whereas the HP/LP ratio did not change. No difference was observed in HP, LP excretion, HP/LP ratio and radiological damage score between the TEA- and placebo-treated AA rats at day 21. In RA patients, a significant reduction of HP and LP excretion was found during the TEA treatment period (P < 0.05). After the cessation of TEA treatment, HP and LP excretion increased towards baseline levels. No effect on disease activity was observed. The plasmin antagonist TEA reduced the excretion of collagen pyridinoline cross-links in both experimental and rheumatoid arthritis. As such, this study not only supports the involvement of the plasminogen activation system in the destructive phase of arthritis, but also suggests a beneficial effect of therapeutic strategies directed against inhibition of matrix proteolysis.

Amino Acids↗
PubMed1998

Diagnosis and course of early-onset arthritis: results of a special early arthritis clinic compared to routine patient care.

OBJECTIVE: Early arthritis patients referred to an Early Arthritis Clinic (EAC) (n = 233) were compared to 241 patients from the routine out-patient clinic with respect to lag time between the onset of symptoms and the visit to the rheumatologist, clinical presentation and the consistency of the diagnosis after 1 yr. RESULTS: The reduction in median lag time for the EAC patients was at least 3 months. An insidious onset of symptoms was found more often in the rheumatoid arthritis (RA) patients in the routine clinic. In 70% of all cases, a diagnosis could be made after 2 weeks and, if the clinical diagnosis was definite RA, this hardly changed during the following year. Early erosions were seen in 25% of RA patients and were associated with a positive rheumatoid factor (OR 2.08, 95% CI 0.95 4.59). CONCLUSION: An early diagnosis of RA at the EAC is possible and reliable; the high frequency of erosions illustrates the need for early treatment.

Adolescent↗
PubMed1998

Distribution of T cells and signs of T-cell activation in the rheumatoid joint: implications for semiquantitative comparative histology.

A prerequisite for comparative histology of synovial tissue by means of biopsies is insight into the distribution of a marker under study. This investigation focuses on the variation in the presence of T cells and signs of T-cell activation within the rheumatoid joint. For this purpose, multiple slides from several pieces of synovial tissue from different parts of a joint were stained and scored for the expression of CD3, CD25, HLA-DR, Ki67 and interferon-gamma. The variation in scores for the presence of T cells and markers of activation was more pronounced in slides prepared from different pieces of tissue than in slides from one piece of tissue. Based on multiple analysis of variance, methods are suggested to establish a reliable overall score for the expression of a certain marker within a joint. Following validation, such methods may prove to be useful by allowing semiquantitative histology of synovial tissue for studies on arthritis.

Arthritis, Rheumatoid↗
PubMed1998

Methotrexate reduces inflammatory cell numbers, expression of monokines and of adhesion molecules in synovial tissue of patients with rheumatoid arthritis.

Methotrexate (MTX) is one of the most widely prescribed drugs in the treatment of rheumatoid arthritis (RA). The mechanism by which MTX exerts its anti-rheumatic effect has not yet been defined. The aim of the present study was to investigate the effect of MTX treatment (7.5-15 mg/week) on synovial tissue in RA. For this purpose, synovial biopsies were taken from 11 RA patients before and 16 weeks after initiation of MTX therapy. Immunohistochemistry was performed using monoclonal antibodies (MAb) specific for CD3, CD4, CD8, CD22, CD25, CD38, CD68, MAb67, Ki67, interferon gamma (IFN-gamma), interleukin (IL)-1alpha, IL-1beta, tumour necrosis factor alpha (TNF-alpha), E-selectin, ICAM-1 and VCAM-1. All parameters for disease activity improved during the period of treatment. Immunohistochemical analysis revealed a statistically significant decrease in scores for CD3, CD8, CD38, CD68, Ki67, IL-1beta, TNF-alpha and the adhesion molecules E-selectin and VCAM-1. The observed decrease in synovial scores for inflammatory cells, monokines and adhesion molecules suggests that the anti-inflammatory effect of MTX is, in part, dependent on a reduction in monokine-inducible vascular adhesion molecules and subsequent reduction of cell traffic into joints.

Antibodies, Monoclonal↗
PubMed1998

Female sex hormones at the onset of systemic lupus erythematosus affect survival.

Female sex hormones affect susceptibility to systemic lupus erythematosus (SLE). To determine the effect of female sex hormones at onset of SLE on the survival of these patients, a retrospective survey was performed. The charts of 168 female SLE patients were evaluated to study the disease course, in particular the presence and kind of SLE criteria. Patients were classified as either belonging to the 'high female sex hormone at onset (HH)' or 'low female sex hormone at onset (LH)' group according to age at diagnosis. The statistics of the Dutch population, matched for age, were used to control for differences in life expectancy in these groups. A Cox regression model revealed that the relative mortality risk of HH patients vs HH controls was 4.2 times higher than the relative mortality risk of LH patients compared to LH controls. No differences in the frequency of SLE criteria between HH and LH patients were found that could explain the observed difference in mortality risk.

Adolescent↗