Association of the inflammatory state in active juvenile rheumatoid arthritis with hypo-high-density lipoproteinemia and reduced lipoprotein-associated platelet-activating factor acetylhydrolase activity. (1/962)

OBJECTIVE: To investigate the relationship between the quantitative and qualitative abnormalities of apolipoprotein B (Apo B)- and Apo A-I-containing lipoproteins and between lipoprotein-associated platelet-activating factor acetylhydrolase (PAF-AH) activity in patients with juvenile rheumatoid arthritis (JRA) as a function of the inflammatory state. METHODS: Twenty-six JRA patients and 22 age- and sex-matched control subjects with normal lipid levels participated in the study. Fourteen patients had active disease, and 12 had inactive disease. Plasma lipoproteins were fractionated by gradient ultracentrifugation into 9 subfractions, and their chemical composition and mass were determined. The PAF-AH activity associated with lipoprotein subfractions and the activity in plasma were also measured. RESULTS: Patients with active JRA had significantly lower plasma total cholesterol and high-density lipoprotein (HDL) cholesterol levels as compared with controls, due to the decrease in the mass of both the HDL2 and HDL3 subfractions. Patients with active JRA also had higher plasma triglyceride levels, mainly due to the higher triglyceride content of the very low-density lipoprotein plus the intermediate-density lipoprotein subfraction. The plasma PAF-AH activity in patients with active JRA was lower than that in controls, mainly due to the decrease in PAF-AH activity associated with the intermediate and dense low-density lipoprotein subclasses. The lipid abnormalities and the reduction in plasma PAF-AH activity were significantly correlated with plasma C-reactive protein levels and were not observed in patients with inactive JRA. CONCLUSION: This is the first study to show that patients with active JRA exhibit low levels of HDL2 and HDL3 and are deficient in plasma PAF-AH activity. These alterations suggest that active JRA is associated with partial loss of the antiinflammatory activity of plasma Apo B- and Apo A-I-containing lipoproteins.  (+info)

Modular variations of the human major histocompatibility complex class III genes for serine/threonine kinase RP, complement component C4, steroid 21-hydroxylase CYP21, and tenascin TNX (the RCCX module). A mechanism for gene deletions and disease associations. (2/962)

The frequent variations of human complement component C4 gene size and gene numbers, plus the extensive polymorphism of the proteins, render C4 an excellent marker for major histocompatibility complex disease associations. As shown by definitive RFLPs, the tandemly arranged genes RP, C4, CYP21, and TNX are duplicated together as a discrete genetic unit termed the RCCX module. Duplications of the RCCX modules occurred by the addition of genomic fragments containing a long (L) or a short (S) C4 gene, a CYP21A or a CYP21B gene, and the gene fragments TNXA and RP2. Four major RCCX structures with bimodular L-L, bimodular L-S, monomodular L, and monomodular S are present in the Caucasian population. These modules are readily detectable by TaqI RFLPs. The RCCX modular variations appear to be a root cause for the acquisition of deleterious mutations from pseudogenes or gene segments in the RCCX to their corresponding functional genes. In a patient with congenital adrenal hyperplasia, we discovered a TNXB-TNXA recombinant with the deletion of RP2-C4B-CYP21B. Elucidation of the DNA sequence for the recombination breakpoint region and sequence analyses yielded definitive proof for an unequal crossover between TNXA from a bimodular chromosome and TNXB from a monomodular chromosome.  (+info)

Assessment of bone mineral density in adults with a history of juvenile chronic arthritis: a cross-sectional long-term followup study. (3/962)

OBJECTIVE: To assess bone mineral density (BMD) and bone turnover in adults with a history of juvenile chronic arthritis (JCA) or persistent JCA, and to identify predictors of reduced BMD. METHODS: Sixty-five white patients (mean age 32.2 years) with a history of JCA and 65 age-, sex-, height-, and weight-matched healthy control subjects participated in the study. Densitometry of the left hip and the lumbar spine was performed, and osteocalcin (bone formation marker) and crosslinks (bone resorption marker) were measured. In addition, bone-related clinical parameters were assessed in the JCA group. RESULTS: BMD in the hip and lumbar spine was significantly lower in the JCA group than in the controls. Levels of osteocalcin and crosslinks were significantly increased in the JCA group. According to WHO definitions, significantly more subjects in the JCA group had "osteopenia" and "osteoporosis" than would be expected in a normal population sample. Active disease at the time of the study (1996-1997), baseline erosions evaluated in 1979, Steinbrocker functional class in 1996-1997, polyarticular course of JCA, and history of systemic steroid treatment for more than 1 year were significantly associated with reduced BMD. In linear regression analysis including both the JCA and control groups, presence of JCA proved to be the factor most strongly associated with reduced BMD, explaining approximately 20% of its variation. CONCLUSION: Reduced BMD and evidence of increased bone turnover suggest that JCA patients may be at risk of developing premature osteoporosis and associated fractures later in life. The data are consistent with the concept that BMD in JCA is determined by many factors.  (+info)

Molecular fingerprinting reveals non-overlapping T cell oligoclonality between an inflamed site and peripheral blood. (4/962)

We have demonstrated a stable expansion of CD8+ T cells in the peripheral blood of a child with chronic arthritis. The expanded TCRBV family (TCRBV14) was enriched for CD57hiCD28- T cells. Sequencing of the TCRBV14 amplification products showed a TCR sequence which contributed 32% of the total TCR in the CD8+TCRBV14 population. Using the modified heteroduplex technique, the CD8+TCRBV14 cells showed a clonal pattern and these bands were restricted to the CD28- population. This method also detected multiple other clones within the CD8+ population but few in the CD4+ cells. The dominant TCRBV14+ clone was not detectable in synovial fluid T cells from two inflamed joints by CDR3 length analysis or heteroduplex probing, suggesting that this long-lived clone is excluded from inflammatory sites. Synovial fluid T cells showed an unexpected discordance of the CD28 and CD57 phenotype compared to peripheral blood mononuclear cells. T cells from both inflamed joints both showed marked oligoclonality in all TCR families and had almost identical heteroduplex patterns. Taken together these data suggest that some clones are actively excluded from inflamed sites in juvenile chronic arthritis, yet the pattern of restricted T cell expansion is shared between sites of inflammation.  (+info)

Absence of association between interleukin 1 alpha and oligoarticular juvenile chronic arthritis in UK patients. (5/962)

OBJECTIVE: To determine whether interleukin 1 alpha (IL-1alpha) polymorphisms are associated with UK oligoarticular juvenile chronic arthritis (JCA). PATIENTS AND CONTROLS: A well-characterized population of 164 UK Caucasian oligo-JCA patients and a control panel of 173 unrelated healthy UK Caucasian individuals. METHODS: The IL-1alpha promoter mutation at -889 was examined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The cases and controls were also genotyped for an IL-1alpha intronic microsatellite repeat. RESULTS: No association was observed between IL-1alpha polymorphisms and UK oligoarticular JCA patients. In particular, no association between IL-1alpha polymorphisms and chronic anterior uveitis was found. CONCLUSIONS: IL-1alpha is not associated with oligoarticular JCA in UK patients. This differs markedly to findings for IL-1alpha in Norwegian JCA patients.  (+info)

Responsiveness of outcome measures in juvenile chronic arthritis. Italian Pediatric Rheumatology Study Group. (6/962)

OBJECTIVE: To examine the responsiveness of the disease activity measures more commonly used in juvenile chronic arthritis (JCA) clinical trials. METHODS: Data were obtained from an open-label, non-controlled, multicentre trial designed to investigate the efficacy of methotrexate (MTX) in children with JCA. Outcome measures, including physician and parent global assessments, functional ability measures, articular variables, and laboratory indicators of systemic inflammation, were assessed at baseline and after 6 months of MTX treatment in 132 patients. Responsiveness of endpoint variables was evaluated by assessing the effect size (ES) and the standardized response median (SRM). RESULTS: Physician and parent global assessments were the more responsive instruments, showing ES and SRM above 1.0. Erythrocyte sedimentation rate, C-reactive protein, functional status measures and articular variables showed intermediate responsiveness. Morning stiffness, haemoglobin and platelet count were the least responsive instruments. CONCLUSION: The results of our analysis indicate that subjective estimations of the disease activity, either by the physician or parents, are the most responsive instruments in the assessment of the therapeutic response in children with JCA. The responsiveness of outcome measures in JCA should be further investigated in prospective controlled studies.  (+info)

Assessment of mutilans-like hand deformities in chronic inflammatory joint diseases. A radiographic study of 52 patients. (7/962)

OBJECTIVES: To evaluate patients with mutilans-like hand deformities in chronic inflammatory joint diseases and to determine radiographic scoring systems for arthritis mutilans (AM). METHODS: A total of 52 patients with severe hand deformities were collected during 1997. A Larsen hand score of 0-110 was formed to describe destruction of the hand joints. Secondly, each ray of the hand was assessed individually by summing the Larsen grade of the wrist and the grades of the MCP and PIP joints. When the sum of these grades was > or = 13, the finger was considered to be mutilated. A mutilans hand score of 0-10 was formed according to the number of mutilans fingers. Surgical treatment and spontaneous fusions were recorded. RESULTS: The study consisted of 22 patients with juvenile rheumatoid arthritis (JRA), nine with rheumatoid factor (RF) positive and 13 with RF negative arthritis, 27 patients with RF positive RA, and three adult patients with other diagnoses. The mean age of patients with adult rheumatic diseases was 27 years at the onset of arthritis. The mean disease duration in all patients was 30 years. The mean Larsen hand score was 93. Four patients had no mutilans fingers and in 15 patients all 10 fingers were mutilated. The Larsen hand score of 0-110 and the mutilans hand score of 0-10 correlated well (rs = 0.90). Fourteen patients showed spontaneous fusions in the peripheral joints. A total of 457 operations were performed on 48 patients. CONCLUSION: Both the Larsen hand score of 0-110 and the mutilans hand score of 0-10 improve accuracy in evaluating mutilans-like hand deformities, but in unevenly distributed hand deformities the mutilans hand score is better in describing deformation of individual fingers.  (+info)

Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. (8/962)

OBJECTIVE: To determine the distribution of the interleukin-10 (IL-10) 5' flanking region haplotypes in children with arthritis and in controls, and to investigate the functional significance of each haplotype. METHODS: Sequence-specific oligonucleotide probing was used to determine haplotype frequency. Transient transfection studies were used to investigate the transcription of reporter genes driven by each haplotype. Whole blood cultures were performed to assess IL-10 production by each genotype. RESULTS: Patients with arthritis involving >4 joints were more likely to have a genotype with an ATA haplotype than those whose arthritis remained restricted to <4 joints. This ATA haplotype was associated with lower transcriptional activity than the GCC haplotype (P = 0.02), and the ATA/ATA genotype was associated with lower IL-10 production under lipopolysaccharide stimulation than other genotypes (P < 0.02). CONCLUSION: The results of this study demonstrate the functional significance of the ATA haplotype and reveal a significant association of genotypes containing this haplotype with extended oligoarthritis.  (+info)