The development of bone mineral lateralization in the arms.

UNLABELLED: Bone mineral content (BMC) is known to be greater in the dominant arm after the age of 8 years. We studied a group of children and found that BMC sidedness gradually increased up to the age of 6 years and then remained stable into late adolescence. INTRODUCTION: Bone mineral content (BMC) exhibits sidedness in the arms after the age of 8 years, but it is not known whether BMC is greater in the dominant arm from birth or whether lateralization develops in early childhood. To address this, we examined bone mineral status in relation to handedness and age. METHODS: Subjects (N = 158) were children recently initiating glucocorticoids for underlying disease (leukemia 43 %, rheumatic conditions 39 %, nephrotic syndrome 18 %). Handedness was determined by questionnaire and BMC by dual-energy X-ray absorptiometry. RESULTS: Median age was 7.2 years (range, 1.5 to 17.0 years), 49 % was male, and the spine BMD Z-score was -0.9 (SD, 1.3). By linear regression, BMC sidedness in the arms was significantly related to age (r = 0.294, p = 0.0005). Breakpoint analysis revealed two lines with a knot at 6.0 years (95 % CI, 4.5-7.5 years). The formula for the first line was: dominant:nondominant arm BMC ratio = 0.029 × age [in years] + 0.850 (r = 0.323, p = 0.017). The slope of the second line was not different from 0 (p = 0.332), while the slopes for the two lines were significantly different (p = 0.027). CONCLUSIONS: These results show that arm BMC sidedness in this patient group develops up to age 6 years and then remains stable into late adolescence. This temporal profile is consistent with mechanical stimulation of the skeleton in response to asymmetrical muscle use as handedness becomes manifest.

Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population.

Most of the genetic risk for rheumatoid arthritis (RA) is conferred by 'shared epitope' (SE), encoding alleles of HLA-DRB1. Specific North American Native (NAN) populations have RA prevalence rates of 2-5%, representing some of the highest rates estimated worldwide. As many NAN populations also demonstrate a high background frequency of SE, we sought to determine whether other genetic factors contribute to disease risk in this predisposed population. RA patients (n=333) and controls (n=490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL. Our findings indicate that SE is prevalent and represents a major genetic risk factor for RA in this population (82% cases versus 68% controls, odds ratio=2.2, 95% confidence interval 1.6-3.1, P<0.001). We also demonstrate that in the presence of SE, the minor allele of MMEL1-TNFRSF14 significantly reduces RA risk in a dominant manner, whereas TRAF1-C5 increases the risk. These findings point to the importance of non-HLA genes in determining RA risk in a population with a high frequency of disease predisposing HLA-DRB1 alleles.

Cytokine genotypes correlate with pain and radiologically defined joint damage in patients with juvenile rheumatoid arthritis.

OBJECTIVES: Single nucleotide polymorphisms (SNPs) in cytokine genes have been associated with risk of a number of autoimmune diseases. Moreover, some SNPs are associated with variations in rates of in vitro gene expression, and it is therefore possible that these functional polymorphisms may differentially affect inflammatory processes and disease outcome. This project's objective was to determine whether cytokine genotypes correlate with disease outcomes in patients with juvenile rheumatoid arthritis (JRA). METHODS: Genotypes of SNPs of pro-inflammatory cytokines, tumour necrosis factor-alpha -308G -->A, interleukin-6 (IL-6) -174G -->C and interferon-gamma +874G -->A, and anti-inflammatory, immunosuppressive cytokines, interleukin-10 -1082G -->A, -819C -->T and -592A -->C and transforming growth factor-beta1 (TGF-beta1) codon 10T -->C and codon 25G -->C, were determined for patients with JRA who previously participated in a long-term outcome study. Cytokine genotypes and clinical variables showing significant correlations with clinical outcomes at the alpha = 0.100 level in univariate analyses were entered in multivariate tests. RESULTS: In multivariate tests, the IL-6 genotype -174G/G was positively correlated with pain [regression coefficient B = 0.899, 95% confidence intervals (CI) 0.185, 1.612, P = 0.014]. The homozygous TGF-beta1 codon 25G/G genotype showed a protective effect against joint space narrowing on radiographs taken within 2 yr of disease onset, but confidence intervals were wide [odds ratio (OR) 0.176, 95% CI 0.037, 0.837 P = 0.029]. CONCLUSIONS: The correlation of IL-6 genotype with pain and the possible association of the TGF-beta1 codon 25 genotype with short-term radiographic damage (G/C with greater risk and G/G with decreased risk) suggests that both these polymorphisms may be useful early prognostic indicators. Further studies of the relation between cytokine genotypes and outcomes in patients with all forms of juvenile idiopathic arthritis (JIA) are warranted.

Comparative epidemiology of the rheumatic diseases in children.

Publications from different countries collectively confirm distinctions in the occurrence of pediatric rheumatic diseases among different populations. In part, this heterogeneity is due to differences in the distribution of human leukocyte antigen alleles. The epidemiology of the various forms of pediatric chronic arthritis has been studied most extensively. However, it is clear that these are complex conditions involving multiple genes as well as environmental and probably developmental factors. Other publications during the past year have updated the epidemiology of Kawasaki disease, Behcet disease, and acute rheumatic fever.

Primary antiphospholipid syndrome with moyamoya-like vascular changes.

We describe a young girl with antiphospholipid syndrome (APS) and moyamoya-like cerebrovascular changes which reversed after anticoagulation. Although there was a risk of hemorrhage from collateral vessels, we speculate that this treatment may have prevented progression of the vascular abnormalities, while resolution of the thrombus resulted in improved cerebrovascular circulation.

HLA associations of seropositive rheumatoid arthritis in a Cree and Ojibway population.

OBJECTIVE: To determine the HLA associations of seropositive rheumatoid arthritis (RA) in a Cree and Ojibway population; to determine whether specific alleles distinguish juvenile or adult onset. METHODS: HLA-A, B, C, and DRB1 alleles were analyzed in 23 Ojibway and Cree patients with RA seen in a single tertiary care center. Comparisons were made with published results of controls and with results of 18 patients with rheumatoid factor (RF) positive polyarticular juvenile rheumatoid arthritis (JRA) from the same population. RESULTS: Comparisons among patients with RA, patients with RF positive polyarticular JRA, and controls showed increased frequencies of the RA shared epitope in patients with RA and of DRB1*0901 in patients with seropositive polyarticular JRA, while the frequency of DRB1*08 alleles was decreased in patients with RF positive polyarticular JRA. CONCLUSION: In this population, DRB1*0901 may promote while DRB1*08 alleles may protect against a juvenile onset of RA specifically. In contrast, the RA shared epitope may have a greater effect on the risk of adult onset seropositive RA. Due to the small patient numbers, these results require confirmation.

Juvenile rheumatoid arthritis in a Canadian First Nations (aboriginal) population: onset subtypes and HLA associations.

OBJECTIVE: To determine onset subtypes and HLA associations of juvenile rheumatoid arthritis (JRA) in a First Nations (aboriginal) population; to determine whether population frequencies of HLA antigens may explain the distribution of subtypes of JRA in this population. METHODS: All patients were children from Manitoba and Northwestern Ontario seen in a single pediatric rheumatology clinic between 1975 and 1996. Patients were identified from a clinic registry. Controls were adults of Algonkian Cree and Ojibway heritage. Class I and II major histocompatibility (HLA) typing was performed for First Nations patients and controls. RESULTS: There were a total of 74 First Nations patients with JRA. The relative frequency of rheumatoid factor (RF) positive polyarticular JRA was higher and that of pauciarticular JRA was lower in First Nations compared with Caucasian patients (42 versus 3% and 22 versus 58%, respectively; p = 0.00000). HLA-DRB1*04 (63%), 08 (43%), and 1402 (25%) were the most common DRB1 antigens among controls. The main subtypes of DRB1*04 were 0404 (33% of controls) and 0407 (23%). HLA typing was performed for 39 First Nations patients; 27 were Cree or Ojibway, 4 were from other tribes, and 8 were part First Nations. Among Cree and Ojibway, 59% of controls and 63% of patients with RF positive polyarticular JRA (n = 16) had HLA-DRB1 antigens bearing the rheumatoid arthritis (RA) shared epitope (OR 1.16, 95% CI: 0.38, 3.48). The OR for polyarticular RF positive JRA in those with DRB1*0802 and 0901 were 0.15, 95% CI: 0.02; and 1.24 and 5.83, 95% CI: 1.58, 28.38, respectively. CONCLUSION: There was a high frequency of the RA shared epitope represented by both HLA-DRB1*0404 and 1402 in this Algonkian population. This high frequency may explain the high frequency of RF positive polyarticular JRA. DRB1*0802 may be protective, whereas DRB1*0901 may increase the risk for this subtype of JRA.

Epidemiology of chronic arthritis in childhood.

This study was performed to review reports of the descriptive epidemiology of chronic arthritis in childhood and to analyze the factors that may explain differences in its reported frequency. Articles were retrieved by searching MEDLINE and EMBASE under the following index terms: juvenile rheumatoid arthritis (JRA), juvenile chronic arthritis (JCA), spondyloarthropathy, epidemiology, prevalence, and incidence. For reports published between 1977 to 1982, the Index Medicus was used. All original articles that provided prevalence or incidence rates, population size, or number of cases, were reviewed and entered into the analysis. Variables analyzed were disease prevalence and incidence. Modifier variables investigated were diagnostic criteria, source population, geographic origin of the report (Europe or North America), duration of the study, and race of the population studied. Diagnostic criteria had no effect on reported prevalence or incidence rates. Prevalence per 100,000 at risk obtained from population studies (132, 95% CI: 119, 145) was significantly higher than values derived from practitioner- (26, 95% CI: 23, 29) or clinic-based studies (12, 95% CI: 10, 15) (P = .02). North American clinic-based studies had higher prevalence values compared with European reports (32, 95% CI: 26, 38 versus 8, 95% CI: 5, 11, P = .009). None of the factors analyzed accounted for the variability in reported incidence rates. An effect of race was detected only in the distribution of patients among onset subsets. Thus, the percentage of patients with pauciarticular JRA was highest in series of North American and European caucasian patients (58, 95% CI: 56, 60) compared with series of East Indian (25, 95% CI: 20, 31), native North American Indian (26, 95% CI: 15, 37), or other races (31, 95% CI: 28, 35) (P = .001). In contrast, the percentage of patients with polyarticular JRA was lowest in the former (27, 95% CI: 25, 28) compared with the other racial groups (East Indian, 61, 95% CI: 55, 66; native North American Indian, 64, 95% CI: 53, 76; other races, 34, 95% CI: 30, 38) (P = .004). Although an effect of source population on reported prevalence was confirmed, the effect of geographic origin suggests that environmental or ethnic differences also may influence the prevalence of chronic arthritis in children. Differences in the percentages of patients with pauciarticular and polyarticular JRA may reflect racial differences in the prevalence of these conditions.

Seasonal onset of systemic-onset juvenile rheumatoid arthritis.

OBJECTIVE: This study was undertaken to investigate the recent finding of a seasonal difference in the onset of systemic-onset juvenile rheumatoid arthritis (SoJRA). We hypothesized that a seasonal onset pattern might implicate on infectious agent as a cause of SoJRA. METHODS: The date of onset was collected from the records of all patients with SoJRA from 1980 to 1992 at presentation to pediatric rheumatology clinics across Canada. The onset pattern of SoJRA was then compared with incidence data on viral infections obtained for the same period. RESULTS: Across Canada the onset of SoJRA was constant across the seasons. However, in the Prairie region there was a statistically significant seasonal pattern, with peaks in autumn and early spring. We could find no evidence that viral incidence correlated with disease incidence either throughout Canada or in the Prairie region. CONCLUSIONS: If a seasonal infectious agent causes SoJRA, then it is likely only one of several causes and may act only in certain regions. Future studies should be carried out in those areas where SoJRA does have a seasonal onset pattern.

Epidemiology of juvenile rheumatoid arthritis in Manitoba, Canada, 1975-92: cycles in incidence.

OBJECTIVE: To determine the yearly incidence of juvenile rheumatoid arthritis (JRA) and to seek correlations between this and cyclic infections occurring in the province of Manitoba, Canada, during the same period. METHODS: An estimate of the incidence of JRA in Manitoba was determined from a disease registry of the Pediatric Rheumatology Clinic, Children's Hospital, Winnipeg. The numbers of confirmed Mycoplasma pneumoniae and viral respiratory infections were determined from annual reports of Cadham Provincial Laboratory. Both facilities provide centralized services for the province. RESULTS: Between 1975 and 1992 the onset of JRA occurred in 261 patients (136 with pauciarticular, 91 polyarticular, and 34 systemic onset). The average annual incidence of JRA for this period was 5.34/100,000. However, a cyclic incidence was apparent with peaks in 1979, 1982, 1986, and 1990-91. Increases in confirmed M. pneumoniae infections were concurrent with peaks in the incidence of JRA. A significant correlation was found between the incidence of JRA and the number of M. pneumoniae infections detected in the province between 1985 and 1992 (R = 0.76, p = 0.044). In contrast, there was no consistent variation in the incidence of seronegative spondyloarthropathies in children (n = 103 patients). CONCLUSION: These data suggest the need for further study of a possible infectious etiology for JRA.

Adhesion of peripheral blood lymphocytes of children with arthritis to human umbilical vein endothelial cells.

To determine whether adhesion of peripheral blood lymphocytes (PBL) of patients with juvenile rheumatoid arthritis (JRA) may be enhanced, adhesion of PBL of children with JRA, children with seronegative spondyloarthropathies (SSA), age-appropriate and adult controls, to human umbilical vein endothelial cells (HUVEC) was assessed in vitro. B and CD4 T lymphocytes in initial, adherent, and non-adherent cell fraction were identified by flow cytometry. B lymphocytes of all the younger subjects combined had a higher adherence to activated HUVEC compared with B lymphocytes of the adult donors. Except for greater adherence of HLA-DR+ CD4 T cells, lymphocytes of children with JRA showed no enhanced adhesion to either unactivated or activated HUVEC. The percentage of B cells adherent to activated HUVEC in each of the subject groups was 1.5-3.6-fold higher than adherent CD4 T lymphocytes. Surface analyses indicated higher percentages of CD49d (alpha 4)+ and CD29 (beta 1)+ CD4 T lymphocytes in adherent cells, but less of a differential in CD49 (alpha 4)+ and no difference in CD29 (beta 1)+ B lymphocytes. There were fewer Leu-8 (L-selectin)+ B and Leu-8+ CD4 T cells among adherent cells. The data suggest a greater adhesive capacity of B lymphocytes compared with CD4 T lymphocytes which is unrelated to disease, and the possibility that B lymphocytes may utilize adhesion molecules distinct from those of CD4 T lymphocytes. Only a small subset of T cells of patients with JRA may have an enhanced capacity for adhesion to endothelium.

Interleukin 6 and autoantibodies in juvenile rheumatoid arthritis.

OBJECTIVE: To assess whether interleukin 6 (IL-6) may influence autoantibody production, the correlation of rheumatoid factors (RF) and antitype II collagen antibodies with IL-6 was determined in children with juvenile rheumatoid arthritis (JRA). METHODS: IL-6 was measured by proliferation of the B-9 cell line or by ELISA: IgG, IgA, and IgM RF were measured by ELISA: RESULTS: Plasma IL-6 levels were higher in patients with polyarticular JRA than controls. In serial studies, the presence of a greater number of RF isotypes and IgG antinative type II collagen antibodies correlated with higher IL-6 levels [1650 x divided by 3.4 vs 831 x divided by 4.4, p < 0.01 (geometric mean x divided by SD); and 1828 x divided by 5.9 vs 646 x divided by 4.1, p < 0.005, respectively]. The change in RF isotype expression most often involved IgG or IgA RF. In vitro IgG RF production increased in one and became detectable in another 2 cases upon the addition of IL-6 to B cell cultures. CONCLUSION: Our results suggest that IL-6 may promote the production of IgG and IgA RF and IgG antinative type II collagen antibodies.

SEA syndrome revisited: a longterm followup of children with a syndrome of seronegative enthesopathy and arthropathy.

Thirty-six of the 39 children originally described with the syndrome of seronegative enthesopathy and arthropathy, followed for a mean of 11 years after symptom onset, were found to have had a widely varied clinical course. Twelve of the 23 patients (52%) who originally did not have a seronegative spondyloarthropathy developed definite (6) or possible (6) seronegative spondyloarthropathies. The development of a seronegative spondyloarthropathy was associated with HLA-B27 (p = 0.0004) and the presence of arthritis (rather than arthralgia only) at the time of the original report (p = 0.05). For patients with arthritis, the development of a seronegative spondyloarthropathy was associated with arthritis onset after 5 years of age (p = 0.01).

Immunoglobulin and cytokine production by neonatal lymphocytes.

Growth and differentiation of cord blood B cells were studied using T cell-depleted populations. In the absence of in vitro activation, cord blood B cells proliferated in response to cytokines including interleukin-2 (IL-2) and interleukin-4 (IL-4); anti-mu-stimulated cord B cells had a lesser response to IL-2 than adult cells. IgM synthesis by cord blood B cells was enhanced by interleukin-6 (IL-6) and decreased by IL-2. In cultures activated by Staphylococcus aureus Cowan I (SAC), cord blood B cells produced lesser increases in IgM than adult B cells regardless of the cytokine added. Cord blood B cells produced no IgG or IgA with any cytokine preparation with or without SAC activation. Supernatants of cord blood T cells pulse-stimulated with phytohaemagglutinin and phorbol myristate acetate contained less IL-2 and IL-6 and had less growth and differentiation activity than adult T cell supernatants. The results confirm a limited cord blood B cell response and also suggest a limitation in production of B cell stimulatory lymphokines by cord blood T cells.

Growth and differentiation of B lymphocytes of patients with juvenile rheumatoid arthritis.

We studied growth and differentiation of B lymphocytes of patients with juvenile rheumatoid arthritis (JRA) using B cell enriched populations. Mitogen stimulation led to similar proportionate increases in proliferation and immunoglobulin (Ig) secretion in cultures of patient and control lymphocytes. While there was no increase in proliferation, IgG secretion was increased in the absence of mitogen. Nonmitogen activated Ig synthesis could be reduced by replacing culture medium with fresh medium after 16-20 h in culture. It was partly reconstituted by addition of recombinant cytokines, interleukin (IL), IL-2, IL-4, or IL-6. Our results suggest there may be a population of B circulating B cells in patients with JRA and other rheumatic diseases which is sufficiently mature to differentiate and secrete Ig in response to cytokines alone.

Variation in the CD4/non-T cell autologous mixed lymphocyte reaction with disease activity and rheumatoid factor titer in patients with juvenile rheumatoid arthritis.

Variation in the CD4/non-T autologous mixed lymphocyte reaction (AMLR) with disease activity in juvenile rheumatoid arthritis (JRA) was evaluated by repeated study of 5 patients with rheumatoid factor (RF) negative and 8 patients with seropositive polyarticular onset. Results of repeated studies of adult controls fell within the limits of 1 SD from the previously established normal mean. In contrast, greater variation occurred in results of patients with JRA. Patients with RF negative JRA showed no correlation with disease activity but in seropositive patients stimulation indices in the AMLR improved with a reduction in disease activity and RF titer.

IL-2 production in the autologous mixed lymphocyte reaction of patients with juvenile rheumatoid arthritis.

Interleukin 2 (IL-2) production in the CD4/non-T cell autologous mixed lymphocyte reaction (AMLR) was estimated for patients with juvenile rheumatoid arthritis (JRA). A cellular IL-2 assay (CILA) consisting of co-cultures of indicator cells, CTLL-2, added to CD4/non-T cell AMLR cultures was used. As both CD4 and CTLL-2 cell proliferation are IL-2 dependent, results of the CILA assay were taken as a reflection of the total IL-2 in the co-culture. By this assay most patients with JRA had normal IL-2 production. However, five patients with polyarticular disease had both a low AMLR and low levels of IL-2 production. Three of those tested showed little improvement in the AMLR on addition of recombinant IL-2, suggesting decreased responsiveness to IL-2 as well.

In vitro immunoglobulin production by lymphocytes of patients with juvenile rheumatoid arthritis: effects of Staphylococcus aureus Cowan I stimulation and monocyte depletion.

Pokeweed mitogen (PWM) and Staphylococcus aureus Cowan I (SAC) were used to stimulate in vitro IgG and IgM production by lymphocytes of 27 patients with juvenile rheumatoid arthritis (JRA). Twelve had reduced stimulation indices for PWM stimulated cultures of T and non-T cells. Stimulation with SAC resulted in increased IgM production in half (5/10); and partial removal of monocytes resulted in improved PWM induced IgM production in 5/7. IgG production was less easily improved. The results of our study suggest that while PWM induced Ig production may be reduced, B cells responding to SAC may function normally in some patients with JRA. In others, monocyte mediated suppression may account for reduced responses to PWM.

T/non-T and CD4/non-T cell autologous mixed lymphocyte reactions in juvenile rheumatoid arthritis.

Proliferation of T and CD4 cells in the autologous mixed lymphocyte reaction (AMLR) was determined for children with juvenile rheumatoid arthritis (JRA) and children with other rheumatic and connective tissue diseases. Children with musculoskeletal symptoms but no rheumatic disease and healthy adults served as controls. Patients with polyarticular rheumatoid factor (RF) positive JRA had a diminished CD4/non-T cell AMLR, whereas those with RF negative polyarticular and pauciarticular onsets had normal results.

Activation of OKT4 suppressor cells in the autologous mixed lymphocyte reaction of patients with juvenile rheumatoid arthritis.

Activation of suppressor cells by the autologous mixed lymphocyte reaction (AMLR) was studied in patients with juvenile rheumatoid arthritis (JRA). Isolated OKT4 cells were used as responders and irradiated whole non-T cell preparations, non-adherent non-T cells (B and null cells), adherent non-T cells (monocytes), and B cells preactivated by Staphylococcus aureus Cowan I, as stimulators in the AMLR. Suppression was assessed by a reduction of pokeweed mitogen stimulated immunoglobulin synthesis by lymphocytes of healthy donors upon addition of AMLR-activated OKT4 cells. The results of this study suggest normal activation of OKT4 suppressor cells in the AMLR of patients with JRA.