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Biomedical subjects

F C Breedveld

Publications and source records attributed to F C Breedveld.

At least 127 records · Page 7Linked to original sources
PubMed2000

HLA class II association with rheumatoid arthritis: facts and interpretations.

We have reviewed the literature on the association of HLA class II with rheumatoid arthritis (RA). Strong linkage disequilibrium among DQB1, DQA1 and DRB1 alleles makes it difficult to evaluate the individual contribution of each locus. Nonetheless, there is a strong case for the role of DQB1*03 and *04 combined with DQA1*03 in susceptibility to severe RA while DQB1*0501 combined with DQA1*0101 and *0104 weakly predisposes to a mild form of RA. However, it is also clear that DRB1*0401 has a particular role in predisposition to the most severe form of the disease while other DRB1 alleles might provide protection. We would like to propose that in RA, as in type I diabetes, both DQ and DR loci contribute to predisposition to the disease.

Alleles↗
PubMed2000

Double-blind, placebo-controlled study of oral calcitriol for the treatment of localized and systemic scleroderma.

BACKGROUND: Various treatments including corticosteroids, nonsteroidal anti-inflammatory drugs, D-penicillamine, interferon gamma, cyclosporine, and cytostatic drugs have been used with limited success in both morphea and systemic sclerosis (SSc). OBJECTIVE: We investigated the effect of treatment with oral calcitriol in patients with localized or systemic scleroderma. METHODS: A randomized, double-blind, placebo-controlled study of 9 months' duration with a 6-month follow-up was performed at the Department of Dermatology. A total of 27 patients (7 patients with SSc and 20 with morphea) were selected on a minimal skin score of 3 for patients with morphea and 12 for those with SSc. Each patient received calcitriol (0.75 microg/day for 6 months plus 1.25 microg/day for 3 months) or placebo for 9 months. Efficacy parameters included skin score, measurement of serum markers of collagen synthesis and degradation and, additional for the patients with SSc, oral aperture measurements, lung function studies, and esophagus motility. RESULTS: The skin score in patients with morphea after 9 months' treatment showed no significant difference between the placebo and calcitriol groups (mean percentage reduction [SD] in skin score in the placebo group was -29.3 [57.9]; in the calcitriol group it was -19.4 [46.6]). The small group of patients with SSc was inadequate to allow us to draw any conclusions regarding efficacy. No significant change was found in the serum markers of collagen metabolism. CONCLUSION: In this study calcitriol was not more effective than placebo in patients with morphea. Because of the small group of patients with SSc treated, no conclusions regarding efficacy in SSc can be drawn.

Administration, Oral↗
PubMed2000

Quantification of the cell infiltrate in synovial tissue by digital image analysis.

OBJECTIVE: The experience with digital image analysis (DIA) in the assessment of synovial inflammation is limited. In this study we compared DIA with two currently applied methods for the evaluation of the synovium. METHODS: Synovial tissue (ST) specimens were obtained by arthroscopy from knee joints of rheumatoid arthritis (RA) patients with variable disease expression and in control subjects. CD68+ macrophages and CD3+ T-cells were detected by immunohistochemical staining using two different labelling techniques. The labelled ST sections were quantified using three different analysis techniques: manual cell counting (MC), semi-quantitative analysis (SQA) and DIA. RESULTS: We observed strongly positive correlations between the three methods when examining T-cell infiltration: between MC and SQA: sigma=0.91 (P<0. 0001), between MC and DIA: sigma=0.95 (P<0.0001), and between SQA and DIA: sigma=0.83 (P<0.0001). Similarly, for the analysis of synovial intimal macrophages, positive correlations were noted between MC and SQA (sigma=0.62; P=0.002), MC and DIA (sigma=0.56; P<0.01), and SQA and DIA (sigma=0.79; P<0.0001). Finally, the analysis of synovial sublining macrophages revealed positive correlations between MC and SQA (sigma=0.95; P<0.0001), MC and DIA (sigma=0.64; P=0.001) and SQA and DIA (sigma=0.69; P<0.0001). CONCLUSION: These three different methods generated similar results. DIA offers the opportunity of a reliable and time-efficient analysis of the synovial infiltrate.

Aged↗
PubMed2000

HLA association with autoimmune disease: a failure to protect?

That certain HLA specificities are associated with predisposition to autoimmune disease does not necessarily imply that self-reactive T cells restricted to particular HLA alleles are eliciting the disease. In the present essay, we argue that HLA can be a major genetic factor in the development of autoimmune diseases without T cells being primarily involved in its initiation or perpetuation. There is now ample evidence that self-reactive, regulatory T cells can protect against pernicious autoimmunity. Hereafter, we propose that extended HLA haplotypes, such as DQ3-DR4, DQ3-DR9, DQ5-DR1 and DQ5-DR10 in the case of rheumatoid arthritis, predispose to impaired T-cell-mediated immune regulation. The haplotypes associated with impaired regulation are the combination of certain class II alleles and a yet unknown 'amplifier'. In this model, products of the HLA class II region are not involved in the presentation of particular organ-specific autoantigens. Therefore, HLA does not predispose to autoimmune disease per se, but rather fails to provide efficient protection.

Animals↗
PubMed2000

Are differences in interleukin 10 production associated with joint damage?

OBJECTIVE: Constitutive differences between individuals in cytokine production may determine the variation in the course of inflammatory arthritis. METHODS: The association between interleukin 10 (IL-10) production and joint destruction was studied by comparing IL-10 mRNA content in synovial biopsies from seven patients with destructive joint disease and six patients with non-destructive joint disease. The IL-10 mRNA content was 0.4 +/- 0.6 arbitrary units in erosive joints compared with 2.3 +/- 1.2 arbitrary units in non-erosive joints (P: < 0.03, Mann-Whitney U:-test). As this difference suggested that IL-10 production was associated with joint destruction, we tested whether the IL-10 locus determined the extent of joint damage. RESULTS: Innate differences in IL-10 production are locus-dependent. In line with these data, we showed that innate differences in IL-10 protein production were also present as differences in IL-10 mRNA levels. We tested if polymorphisms in the promoter of IL-10 were associated with the extent of joint damage. DISCUSSION: In a cohort study of female rheumatoid arthritis patients followed for 12 yr, the extent of joint destruction differed significantly between patients with different IL-10 genotypes. In patients with the -1082AA genotype who were studied prospectively, the mean increase in radiographic damage score (modified Sharp score of X-rays of hands and feet) during the first 6 yr was 9 +/- 9 per yr vs 19 +/- 16 per yr for patients with the genotype -1082GG (P: < 0.02). In line with these data, cultures of endotoxin-stimulated whole blood from 158 donors showed that the presence of the allele associated with less joint destruction correlated with slightly higher IL-10 production. CONCLUSIONS: Both the immunogenetic and the synovial biopsies suggest that a variation in IL-10 production is associated with joint destruction.

Adult↗
PubMed2000

Cellular immune response to human cartilage glycoprotein-39 (HC gp-39)-derived peptides in rheumatoid arthritis and other inflammatory conditions.

OBJECTIVE: To study the specificity of the peripheral blood mononuclear cell (PBMC) response to peptides derived from human cartilage glycoprotein-39 (HC gp-39) in patients with rheumatoid arthritis (RA) and the correlation between this response and disease activity. METHODS: RA patients, patients with systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) or osteoarthritis (OA) and healthy controls were studied. All individuals were typed for HLA-DRB1 and their disease activity score was documented. Proliferation of PBMC was measured following incubation with five different HC gp-39-derived peptides, selected by the use of a DR4 (DRB1*0401) binding motif. RESULTS: A proliferative response to one of the five peptides (peptide 259-271 at 10 microg/ml) was more often observed in RA patients than in healthy controls (P=0.001). RA patients who expressed DRB1*0401 more often showed a response against this peptide than RA patients who did not express this RA-associated haplotype. This response was not RA-specific since patients with IBD or OA also showed a response significantly more frequently than healthy controls (P:=0.02 and P=0.03 respectively). However, the level of the response against peptide 259-271 correlated with disease activity in RA patients but not in patients with IBD or SLE. Increased responses to HC gp-39 263-275 were found in patients with IBD or OA; a trend towards such a response failed to reach significance in RA patients in this study. CONCLUSION: In RA patients as well as in patients with other inflammatory conditions, HC gp-39-derived peptides may be targets of the T-cell-mediated immune response. In the RA patient group the immune response to HC gp-39-derived peptide 259-271 correlated with disease activity.

Adipokines↗
PubMed2000

The diagnostic value of streptococcal serology in early arthritis: a prospective cohort study.

OBJECTIVE: To evaluate the diagnostic value of streptococcal serology in adult early arthritis patients in discriminating between post-streptococcal reactive arthritis (PSRA) and arthritis with other causes. METHODS: The antistreptolysin-O (ASO) and anti-DNase B tests were performed at baseline in 366 consecutive, newly referred early arthritis patients. After 1 yr of follow-up the patients were classified according to international classification criteria and were evaluated for the presence of persistent arthritis. The outcome measures were the predictive value of streptococcal serology for the diagnosis of PSRA and the ability of this serology to discriminate at the first visit between the self-limiting and persistent forms of arthritis. RESULTS: With a positive serological result, the probability of having PSRA increased from 2 to 9%, whereas the probabilities of having rheumatoid arthritis or undifferentiated arthritis continued to be high (23 and 29%). The serological tests did not discriminate between the self-limiting and persistent forms of arthritis. The major Jones criteria apart from arthritis were not observed. CONCLUSION: Streptococcal serology has no diagnostic value in adult early arthritis patients in whom major Jones criteria other than arthritis are not present.

Adult↗
PubMed2000

A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis.

OBJECTIVE: To compare the clinical efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis (RA). METHODS: In this multicentre, double-blind trial, 999 subjects with active RA were randomized to leflunomide (n = 501; loading dose 100 mg/day for 3 days, maintenance dose 20 mg/day) or methotrexate (n = 498; 10-15 mg/week) for 52 weeks. After 1 yr the subjects could choose to stay for a second year of double-blind treatment. The primary end-points were tender and swollen joint counts and overall physician and patient assessments. Analyses were of the intent-to-treat group. RESULTS: After 1 yr, the mean changes in the leflunomide and methotrexate groups, respectively, were -8.3 and -9.7 for tender joint count; -6.8 and -9.0 for swollen joint count; -0.9 and -1.2 for physician global assessment; -0.9 and -1.2 for patient global assessment; -14.4 and -28.2 for erythrocyte sedimentation rate. Improvements seen with methotrexate were significantly greater than those with leflunomide. No further improvement occurred after the second year of treatment and the distinction between the two treatments in terms of tender joint count and patient global assessment was lost. During the first year of treatment, a small and equivalent degree of radiographically assessed disease progression was seen with both drugs. After 2 yr, disease progression was significantly less with methotrexate. The most common treatment-related adverse events in both groups were diarrhoea, nausea, alopecia, rash, headache, and elevated plasma liver enzyme levels. Over 2 yr, 21 subjects receiving methotrexate were withdrawn due to elevated plasma liver enzymes vs eight subjects taking leflunomide. Two drug-related deaths from pulmonary causes were recorded with methotrexate vs no drug-related deaths among the subjects receiving leflunomide. CONCLUSIONS: Both leflunomide and methotrexate are efficacious for prolonged treatment of RA. At the doses used, some clinical benefit of methotrexate over leflunomide was observed in the first year of treatment. This benefit must be weighed against the potential toxicity of this drug when used without folate supplementation.

Adolescent↗
PubMed2000

Radiographic damage of large joints in long-term rheumatoid arthritis and its relation to function.

OBJECTIVE: To describe the extent of radiographic damage of large joints in long-term rheumatoid arthritis (RA) and its relationship to small joint involvement and physical function. METHODS: After 12 yr of follow-up, radiographs of all large joints (Larsen large joint score 0-60) of 105 recent RA patients were assessed. Correlations were evaluated between the Larsen large joint score and radiographic damage of the hands and feet as measured by the van der Heijde modification of the Sharp score (SHS) and the health assessment questionnaire (HAQ). We determined the relative contributions of radiographic damage of small and large joints, disease activity and psychological function to the HAQ. RESULTS: The median Larsen large joint score was 3. In 54% of the patients at least one large joint was erosive. The correlation of the Larsen score with the SHS and HAQ scores was 0.76 and 0.60, respectively. Disease activity and radiographic damage of the large joints were the major determinants of the HAQ score. CONCLUSION: Large joint involvement after 12 yr of follow-up is extensive and is associated with functional disability. Large joint involvement is closely associated with small joint involvement.

Adult↗
PubMed2000

Leflunomide: mode of action in the treatment of rheumatoid arthritis.

Leflunomide is a selective inhibitor of de novo pyrimidine synthesis. In phase II and III clinical trials of active rheumatoid arthritis, leflunomide was shown to improve primary and secondary outcome measures with a satisfactory safety profile. The active metabolite of leflunomide, A77 1726, at low, therapeutically applicable doses, reversibly inhibits dihydroorotate dehydrogenase (DHODH), the rate limiting step in the de novo synthesis of pyrimidines. Unlike other cells, activated lymphocytes expand their pyrimidine pool by approximately eightfold during proliferation; purine pools are increased only twofold. To meet this demand, lymphocytes must use both salvage and de novo synthesis pathways. Thus the inhibition of DHODH by A77 1726 prevents lymphocytes from accumulating sufficient pyrimidines to support DNA synthesis. At higher doses, A77 1726 inhibits tyrosine kinases responsible for early T cell and B cell signalling in the G(0)/G(1) phase of the cell cycle. Because the immunoregulatory effects of A77 1726 occur at doses that inhibit DHODH but not tyrosine kinases, the interruption of de novo pyrimidine synthesis may be the primary mode of action. Recent evidence suggests that the observed anti-inflammatory effects of A77 1726 may relate to its ability to suppress interleukin 1 and tumour necrosis factor alpha selectively over their inhibitors in T lymphocyte/monocyte contact activation. A77 1726 has also been shown to suppress the activation of nuclear factor kappaB, a potent mediator of inflammation when stimulated by inflammatory agents. Continuing research indicates that A77 1726 may downregulate the glycosylation of adhesion molecules, effectively reducing cell-cell contact activation during inflammation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Raised human cartilage glycoprotein-39 plasma levels in patients with rheumatoid arthritis and other inflammatory conditions.

OBJECTIVE: To evaluate plasma human cartilage glycoprotein (HC gp-39) as a possible marker for the presence and/or activity of rheumatoid arthritis (RA) and other inflammatory conditions. BACKGROUND: HC gp-39 is a secretory product of chondrocytes, synovial cells, macrophages, and neutrophils. HC gp-39, also described as YKL-40, was found to be a marker of joint disease and tissue injury in RA and various other diseases. METHODS: Levels of HC gp-39 were determined by a sandwich enzyme linked immunosorbent assay (ELISA) in 47 patients with RA, 47 with osteoarthritis (OA), 24 with systemic lupus erythematosus (SLE), 24 with inflammatory bowel disease (IBD), and in 47 healthy controls. A disease activity score was assessed in the patients with RA, SLE, and IBD. RESULTS: The plasma level of HC gp-39 in the RA patient group was significantly higher than in the other patient groups and healthy controls. The level in patients with OA, SLE, and IBD was also significantly higher than the HC gp-39 level found in the healthy control group. HC gp-39 levels in patients with RA correlated positively with the ESR and IgM rheumatoid factor level but not with other variables of disease activity. In the patients with SLE and IBD no correlation was found with the disease activity score. CONCLUSION: The plasma level of HC gp-39 is increased in inflammatory conditions with and without joint disease (SLE, IBD, OA, and RA). Thus increased levels of HC gp-39 do not only reflect joint disease but also reflect inflammation or tissue degradation in various conditions. Notably, the highest level of HC gp-39 was found in patients with RA. Only in the RA patient group was a correlation between HC gp-39 plasma levels and some laboratory variables of disease activity found.

Adipokines↗
PubMed2000

Increased cellularity and expression of adhesion molecules in muscle biopsy specimens from patients with rheumatoid arthritis with clinical suspicion of vasculitis, but negative routine histology.

OBJECTIVE: Histological analysis of random quadriceps muscle biopsy specimens can be used to detect vasculitis in patients with rheumatoid arthritis (RA). This study aimed at determining the immunohistological features in patients with clinical suspicion of rheumatoid vasculitis, but without a transmural infiltrate or fibrinoid necrosis of the vessel wall on routine histology. METHODS: Three groups of patients with RA were studied: (a) without clinical signs of vasculitis (n=6); (b) with recent onset of extra-articular features and a clinical suspicion of vasculitis but normal routine histology (n=11); and (c) with recent onset of extra-articular features and vasculitis, histologically proved either in muscle or other biopsy specimens (n=14). A control group of patients with osteoarthritis was also included (n=5). Frozen sections from quadriceps muscle biopsy specimens were analysed with monoclonal antibodies to detect CD3, CD4, CD8, CD68, ICAM-1, VCAM-1, and HLA-DR. The slides were evaluated using a semiquantitative scoring system (0-4). RESULTS: The mean scores gradually increased from group 1 to 3, leading to significant differences between groups 1 and 2, but not between groups 2 and 3 for most markers (p< 0.05). Thus the pathological changes were similar for the two groups with clinical signs of vasculitis, even when the conventional histological evaluation was negative. Higher immunohistological scores were associated with perivascular infiltrates on routine histology. CONCLUSION: The pathophysiological events leading to vasculitis are reflected by the changes in the quadriceps muscle biopsy specimens. The data indicate that the sensitivity of examination of muscle biopsy specimens for the diagnosis of rheumatoid vasculitis can be increased by the use of new criteria.

Aged↗
PubMed2000

Effect of intensive exercise on patients with active rheumatoid arthritis: a randomised clinical trial.

OBJECTIVE: To investigate the effects of a dynamic, intensive exercise regimen on pain, disease activity, and physical functioning in active rheumatoid arthritis (RA). METHODS: 64 patients with RA with a mean age of 60 (13) years and mean disease duration of 8 (8) years, admitted to hospital because of active disease, were randomly assigned to an intensive exercise programme or to a conservative exercise programme during their period in hospital with a mean length of 30 (14) days. The intensive exercise programme consisted of knee and shoulder dynamic and isometric muscle strengthening exercises against resistance five times a week and conditioning bicycle training three times a week and was supplemental to the conservative exercise programme of range of motion and isometric exercises. Indices of disease activity, pain, muscle strength, and functional ability were assessed at 0, 3, 6, 12, and 24 weeks by a blinded observer. RESULTS: The medical treatment during the study was the same in both groups. Both groups improved in measures of disease activity, differences between groups were not statistically significant. The mean improvement in disease activity score at 24 weeks in the intensive and conservative exercise group was -1.4 (1. 5) and -0.7 (1.4), respectively. Measures of physical functioning improved significantly for patients in the intensive exercise group, and differences between groups were statistically significant for measures of muscle strength. CONCLUSION: A short term intensive exercise programme in active RA is more effective in improving muscle strength than a conservative exercise programme and does not have deleterious effects on disease activity.

Adult↗
PubMed2000

Influence of blood and synovial fluid immune complexes of patients with rheumatoid arthritis on production of nitric oxide and growth and viability of chondrocytes.

OBJECTIVE: To determine whether blood and synovial fluid (SF) immune complexes (IC) of patients with rheumatoid arthritis (RA) influence the production of nitric oxide (NO) and growth and viability of chondrocytes. METHODS: IC were precipitated and IgM and IgG were determined in the precipitates by ELISA and nephelometry, respectively. Primary cultures of bovine articular chondrocytes were incubated with the IC precipitates. After 48 h NO was determined as nitrite. After 7 days, growth was determined by incorporation of tritiated thymidine and viability was detected by neutral red uptake. RESULTS: Patient sera were positive in 8/12 for IgM IC and 9/12 for IgG IC, and 1/8 control sera was slightly positive for IgM IC. Seven of 12 SF samples were IgM IC and 10/12 IgG IC positive. With and without additional interleukin 1alpha (IL-1alpha) stimulation, NO production by chondrocytes was significantly higher with SF IC precipitates than with control serum precipitates (p = 0.03, p = 0.04, respectively). NO production by chondrocytes that were not stimulated with IL-1alpha was significantly increased with SF IC precipitates compared to RA serum IC precipitates (p = 0.03). SF IC significantly inhibited growth compared to control serum precipitates (p = 0.04) and RA serum IC (p = 0.012). Neutral red uptake by chondrocytes was significantly decreased when incubated with RA serum IC in comparison with control serum IC (p = 0.012) and SF IC (p = 0.006). With and without additional IL-1alpha stimulation, NO production by chondrocytes after incubation with SF derived IC was positively correlated to the Ritchie score (r = 0.8, r = 0.7, respectively) and the number of swollen joints (r = 0.8, r = 0.6, respectively). CONCLUSION: These results support the hypothesis that, especially in active RA, SF derived IC stimulate NO production and inhibit chondrocyte growth.

Antigen-Antibody Complex↗