Chlamydial associated syndrome of arthritis and eye involvement in young children.

The current classification of juvenile rheumatoid arthritis (JRA) consists of several distinct subsets. We describe 6 children (2 boys, 4 girls, mean age 3.7 years, range 2.0-4.9 years) with arthritis and eye involvement associated with infection with Chlamydia trachomatis. In some of the children, the clinical picture was similar to early onset pauciarticular JRA: onset within the first 4 years of life, predominance of girls, pauciarticular arthritis, subacute uveitis, and presence of antinuclear antibodies. Joint involvement was pauciarticular in 4 patients and polyarticular in 2. Two patients had clinical symptoms of Reiter's disease. Further investigations of this post chlamydial associated syndrome should be performed to establish appropriate diagnostic, therapeutic and prognostic measures.     

Antibody to streptococcal cell wall peptidoglycan-polysaccharide polymers in sera of patients with juvenile rheumatoid arthritis but absent in isolated immune complexes

Sera of 88 children with juvenile rheumatoid arthritis (JRA) (10 seropositive, polyarticular onset, 29 seronegative, polyarticular onset, 32 pauciarticular onset, and 17 systemic onset) were evaluated for the presence of serum antibodies to streptococcal cell wall peptidoglycan-polysaccharide polymers (PG-PSP). Immune complexes (IC) isolated by the antihuman IgM (HIgM) affinity column method were also evaluated for the presence of antibodies to PG-PSP. Forty-one of 88 patients with JRA (7 of 10 seropositive, polyarticular onset, 11 of 29 seronegative, polyarticular onset, 16 of 32 pauciarticular onset, and 7 of 17 systemic onset) showed elevated levels of antibodies to PG-PSP in their sera. IgM rheumatoid factors (RF) were demonstrated in 70/88 isolated IC fractions of patients with JRA and IgG RF in 7; however, none of the patients demonstrated the presence of antibodies to PG-PSP in their isolated IC fractions from the anti-HIgM affinity column. These data indicate that antibodies are produced to PG-PSP in all JRA onset types, but they are not constituents of isolated IC by the anti-HIgM affinity column method.     

Circulating immune complexes and antinuclear antibodies in juvenile rheumatoid arthritis

Materials with the Clq binding properties of soluble immune complexes (IC) were found in sera from 11 of 51 consecutive (22%) children with juvenile rheumatoid arthritis (JRA) and in 17 of 20 adults with active sero-positive rheumatoid arthritis (RA). IC appeared more frequently in children with systemic onset disease whereas antinuclear antibody (ANA) was found more frequently in sera from those with pauciarticular disease. Only 3 JRA sera contained anti-immunoglobulin (rheumatoid factor); those 3 also had high Clq binding activities. Seven of 50 patients (14%) carried HLA-B27 but B27 was not associated with high Clq binding activity or presence of ANA. The presence of free ANA more frequently in children with mild disease and IC more frequently in children with relatively severe disease suggests that children with systemic JRA may have a relative defect in antibody-forming capacity or reticuloendothelial function which results in decreased clearance of circulating IC. Alternatively, systemic, polyarticular, and pauciarticular JRA may represent a spectrum of clinically similar diseases resulting from different etiologic agents.     

Antibodies to histones H1 and H5 in sera of patients with juvenile rheumatoid arthritis

The specificity of juvenile rheumatoid arthritis (JRA) sera for histone subclasses was examined by immunoblotting. Antibodies to H1 alone were found in 4 of 21 pauciarticular-onset JRA sera, 4 of 19 polyarticular-onset JRA sera, and 2 of 11 systemic-onset JRA sera. Antibodies to H5 alone were found in 1 of 21 pauciarticular JRA sera, 1 of 19 polyarticular JRA sera, and 3 of 11 systemic JRA sera. Antibodies to both H1 and H5 were found in 4 of 21 pauciarticular JRA sera, 4 of 19 polyarticular JRA sera, and 1 of 11 systemic JRA sera. Antibodies to the core histones (H2A and H2B) were found in 1 of 21 pauciarticular JRA sera, 1 of 19 polyarticular JRA sera, and no systemic JRA sera. No reactivity to histones was observed in 30 sera from age-matched children with nonrheumatic diseases. The presence of H1 and H5 antibodies did not correlate with antinuclear antibody titers or with a homogeneous pattern of immunofluorescence. The predominance of H1 and H5 antibodies and relative absence of antibodies binding to core histones in JRA contrast with findings in adult systemic lupus erythematosus. Further, the presence of antibodies to H5 alone in some of the JRA patients indicates that the immune response in these patients is directed to determinants that are not shared by sequences of mammalian proteins.     

Slow acting antirheumatic drugs in patients with juvenile rheumatoid arthritis--evaluated in a randomized, parallel 50-week clinical trial

Seventy-two consecutive patients with pauciarticular and polyarticular juvenile rheumatoid arthritis (JRA) were randomized into a parallel 50-week open, controlled, comparative trial of hydroxychloroquine (HC), gold sodium thiomalate (GSTM) and D-penicillamine (PEN). Similar improvement of disease activity measurements and reduction of the erythrocyte sedimentation rate were seen in all 3 groups. No HC treated, 3 GSTM treated and 6 PEN treated patients were withdrawn because of adverse reactions. The results of our study indicate that HC is better tolerated than GSTM and especially PEN, but that the drugs are comparable with regard to efficacy in patients with pauciarticular and polyarticular JRA.     

Autoantibodies to chromatin components in juvenile rheumatoid arthritis

Objective. To characterize autoantibodies to chromatin components in patients with juvenile rheumatoid arthritis (JRA). Methods. The sera of 50 children with JRA were analyzed for antinuclear antibodies (ANA) by immunofluorescence and enzyme-linked immunosorbent assay (ELISA) techniques. Results. By immunofluorescence, ANA and antibodies to high-mobility group proteins or to DNA-free histones were common in patients with pauciarticular JRA and rheumatoid factor–positive polyarticular JRA. However, reactivity with histone–DNA complexes was rare. Conclusion. Because antihistone antibodies detected by ELISA failed to bind chromatin or other histone–DNA complexes, they are not likely to represent the immunofluorescent ANA activity in serum.     

DNA analysis of HLA-DR, DQ, and DP alleles in children with polyarticular juvenile rheumatoid arthritis.

HLA-DR, DQ and DP alleles were determined by restriction fragment length polymorphism analysis and oligonucleotide probe hybridization of polymerase chain reaction amplified genomic DNA in 94 Caucasian children with polyarticular juvenile rheumatoid arthritis (JRA) [13 rheumatoid factor (RF)+ and 81 RF-] and 100 healthy controls. HLA-DRw8, DQw4, DQA1*0401, DQB1*0402 were increased in frequency in those patients with RF seronegative disease, with highest frequencies seen in patients with young age at onset (< 5 years of age). These findings were similar to what we observed in children with pauciarticular JRA, especially those with young age at onset. DPB1*0301 was also found in increased frequency in the RF- group, and in particular those seronegative for antinuclear antibody. In contrast to what is observed in patients with pauciarticular JRA, the frequency of DPB1*0201 was not increased in any polyarticular JRA patient group. These data suggest that polyarticular JRA shares many genetic features with pauciarticular JRA.     

Autoantibodies in chronic arthritis of childhood: relations with each other and with histocompatibility antigens.

BACKGROUND: Studies have shown the presence of either antibodies to histone or anticardiolipin antibodies in some forms of childhood chronic arthritis. The relation between these autoantibodies has not been previously reported, however, and the immunogenetics of their association with childhood arthritis has not been studied. METHODS: The interrelation of fluorescent antinuclear antibodies, antibodies to histone, and anticardiolipin antibodies and their associations with histocompatibility antigens (HLA) were studied in 114 children with chronic arthritis (45 children with pauciarticular onset juvenile chronic arthritis (JCA), 22 with polyarticular onset JCA, 13 with systemic onset JCA, and 34 with juvenile psoriatic arthritis (JPsA). Antibodies to histone and anticardiolipin antibodies were determined in 108 children. HLA antigens (A, B, C, and DR) were studied in the 83 white children. RESULTS: Antibodies to histone occurred in 0% (systemic onset JCA) to 42% (uveitis negative, pauciarticular onset JCA), and anticardiolipin antibodies in 26% (JPsA) to 55% (polyarticular onset JCA) of patients. Only 12 patients (11%) had both antibodies to histone and anticardiolipin antibodies. Neither antibodies to histone nor anticardiolipin antibodies associated with the type of arthritis. Neither of these antibodies alone associated with uveitis. Antibodies to histone were associated with HLA-A2, probably reflecting the known association of HLA-A2 with pauciarticular onset JCA. There was no other HLA association. Fluorescent antinuclear antibodies occurred most often in patients with uveitis; however, the occurrence of fluorescent antinuclear antibodies in patients with pauciarticular onset JCA (the group most at risk for uveitis) was not significantly greater in children with uveitis than in those without uveitis (100 and 88% respectively). CONCLUSIONS: Although antibodies to histone and anticardiolipin antibodies often occur in serum samples from patients with JCA and JPsA, they rarely occur together. Their presence does not associate with uveitis. This study did not show any strong evidence that production of either antibodies to histone or anticardiolipin antibodies in patients with JCA or JPsA is under the control of the histocompatibility locus.     

Use of the HEp-2 cell substrate in the detection of antinuclear antibodies in juvenile rheumatoid arthritis

Presence and titer of antinuclear antibodies (ANA) were determined in 217 juvenile rheumatoid arthritis (JRA) patients, by indirect immunofluorescence using HEp-2 cells as substrate. Positive ANA titers (greater than or equal to 1:40) were present in 131 (60%) of the JRA patients. All 3 JRA onset types demonstrated increased percentages of ANA positivity compared with healthy children. Sixty-seven percent of the patients in the polyarticular onset group had positive titers; titers were positive in 62% of the pauciarticular onset group and in 32% of the systemic onset group. ANA were also found in 45% of control patients with other connective tissue diseases. In JRA patients, the speckled pattern occurred most commonly (72%). Fourteen patients (8 with pauciarticular onset and 6 with polyarticular onset) had iridocyclitis; all of them had high titers (greater than or equal to 1:80) of ANA. The use of HEp-2 cells provided a sensitive substrate for detecting ANA in JRA. It proved to be of value in differentiating JRA patients from healthy controls, but not from patients with other connective tissue diseases.     

Prevalence and concentration of IgM rheumatoid factor in polyarticular onset disease as compared to systemic or pauciarticular onset disease in active juvenile rheumatoid arthritis as measured by ELISA

The prevalence and concentration of IgM rheumatoid factor (RF) in children with juvenile rheumatoid arthritis (JRA) and its major disease onset groups remains uncertain. In our study enzyme linked immunoabsorbent assay (ELISA) of 68 children with active JRA showed IgM RF in the area of 67% (16/24) of those with polyarticular onset disease, 26% (7/27) of those with systemic onset disease, and 6% (1/17) of those with pauciarticular onset disease. The median IgM RF concentration was 50-fold higher in polyarticular disease compared to systemic disease. The prevalence of IgM RF in polyarticular disease was greater in those with severe disease (functional classes and 3 and 4), with 90% (9/10) seropositive. By agglutination assay, the prevalence of IgM RF in JRA was significantly less than by ELISA, with 33% of the polyarticular group positive for IgM RF, and none of the systemic group positive, Relatively low concentration IgM RF similar to that seen in systemic JRA was also found in high prevalence in the area of children with non-JRA, systemic rheumatic disease (n = 8). In summary, our study shows by ELISA that high concentrations of IgM RF are found essentially only in the sera of children with polyarticular onset JRA and especially in those with severe disease.     

Clinical relevance of IgA rheumatoid factor (RF) in children with juvenile rheumatoid arthritis

This study proposed to investigate the prevalence and clinical relevance of serum immunoglobulin A (IgA) rheumatoid factor (RF) in juvenile rheumatoid arthritis (JRA) as published reports vary in their conclusion. Sera of 82 children with JRA and 25-age and sex-matched healthy children were measured for IgA RF by an enzyme linked immunoassay using human IgG as the antigen. Forty-three percent of the disease population were positive and the prevalence in pauciarticular, polyarticular and systemic onset was 9/18 (50%), 21/47 (44.7%) and 5/17 (27.7%) respectively when mean + 2SD of normal was taken as the cut-off value. By defining the upper limit of normal as mean + 6SD, 16/47 (34%) were positive in the polyarticular as compared to 2/18 (11.1%) in pauciarticular and 1/17 (5.8%) of systemic onset disease groups. The prevalence in the polyarticular subset with the upper cut-off limit was significantly higher than the pauciarticular and the systemic onset group (P < 0.05). Furthermore, the mean level of IgA RF was significantly higher in the polyarticular group compared to the mean level in the systemic onset group (P < 0.05). The mean level of IgA RF was also significantly higher (P < 0.05) in 61 children with active diseases. Received: 29 January 1999 / Accepted: 10 August 1999     

Rheumatoid arthritis, juvenile arthritis, iridocyclitis and the Epstein-Barr virus.

In order to examine the relation of Epstein-Barry virus (EBV) infection to chronic arthritis in children antibodies to EB virus capsid antigen (EBVCA) and rheumatoid arthritis nuclear antigen (RANA) were analysed in sera from 133 patients classified as juvenile rheumatoid arthritis (JRA) or pauciarticular, polyarticular, or systemic juvenile chronic arthritis. Except for an increased frequency in the systemic subgroup, the prevalence of antibodies to EBVCA and titres of anti-RANA antibodies was similar in patients and controls. These data do not support an aetiological role for EBV in chronic arthritis in children, including JRA, and suggest that the mechanisms which may account for the higher titres of anti-RANA antibodies in adult RA do not occur in children.     

High prevalence of iga rheumatoid factor in severe polyarticular-onset juvenile rheumatoid arthritis,but not in systemic-onset or pauciarticular-onset disease

The presence of IgA rheumatoid factor (IgA-RF) has been correlated with severe joint disease in adult rheumatoid arthritis (RA), but IgA-RF has not been reported in juvenile rheumatoid arthritis (JRA). In the present study, IgA-RF was assayed by an enzyme-linked immunosorbent assay and was found in the sera of 14 of 24 children (58%) with active polyarticular JRA. The presence of IgA-RF correlated with the degree of functional disability. In contrast, IgA-RF was not found in the sera of systemic-onset disease patients, regardless of the degree of dysfunction. IgA-RF was detected in only 1 patient with pauciarticular disease, despite the fact that several patients in this group had severe disease. The presence of IgA-RF in polyarticular JRA did not correlate with serum IgA levels, but did correlate with the presence and the level of serum IgM-RF. Thus, the presence of IgA-RF appears to be specific for polyarticular JRA, and shows a correlation with severe disease in this group.     

Serum IgM rheumatoid factor by enzyme-linked immunosorbent assay (ELISA) delineates a subset of patients with deforming joint disease in seronegative juvenile rheumatoid arthritis

Using human IgG as an antigen in an enzymelinked immunosorbent assay (ELISA), we looked for the presence of IgM rheumatoid factor (RF) in the sera of 74 children with juvenile rheumatoid arthritis (JRA). Nine children had RF detectable by both latex agglutination and ELISA. Forty-five percent (26 of 65) of the children who were seronegative by latex agglutination were found to be positive for IgM RF by ELISA. The prevalence of IgM RF was higher in patients with polyarticular onset disease (57.4%) than in those with pauciarticular onset (38.5%) or systemic onset (27.2%) disease. The prevalence of RF was higher in sera from patients with deforming joint disease than those without deformities (P<0.01).     

The immunogenetics of juvenile rheumatoid arthritis.

Recent major advances in understanding the genetic structure of the human leukocyte antigen (HLA) region and how HLA molecules contribute to immune responses have been paralleled by more precise identification of specific HLA genes conferring susceptibility to the various forms of juvenile rheumatoid arthritis (JRA). This article presents current models for HLA-associated autoimmune disease susceptibility and summarizes the HLA Class II alleles currently known to be associated with JRA: primarily DR8, DR5, DR6, and DPw2.1 in pauciarticular onset JRA; and DR4 in rheumatoid factor-positive polyarticular onset JRA. Rheumatoid factor-negative polyarticular onset JRA and systemic onset JRA are variously associated with several of these same genes. Gene interactions and the clinical utility of HLA typing in this disease are also discussed.     

Analysis of the HLA-DR gene frequencies in Japanese cases of juveniles rheumatoid arthritis and rheumatoid arthritis by oligonucleotide DNA typing

Summary HLA-DR gene frequencies in 59 Japanese children with juvenile rheumatoid arthritis (JRA) and 62 Japanese adults with rheumatoid arthritis (RA) were analyzed by oligonucleotide DNA typing. As in other studies, the frequency of DRB1*0405 in RA patients was significantly higher than in the Japanese controls. In a comparison of non-calssified JRA patients with Japanese controls, no significant differences were observed in the frequency of DR types. However, when the JRA patients were classified into four clinical types, i.e., a rheumatoid factor-positive [RF(+)] polyarticular type, a rheumatoid factor-negative [RF(-)] polyarticular type, a pauciarticular type, and a systemic onset type, DRB1*0405 was found to be significantly higher in the RF(+) polyarticular JRA patients than in the controls (P>0.05). Thus, the RF(+) polyarticular type of JRA had the same HLA association as RA. This result is consistent with the fact that both RF(+) polyarticular JRA and RA cases have a similar clinical course.     

Increased circulating vascular endothelial growth factor is correlated with disease activity in polyarticular juvenile rheumatoid arthritis.

OBJECTIVE: To investigate the relevance of vascular endothelial growth factor (VEGF) in the pathogenesis of juvenile rheumatoid arthritis (JRA). METHODS: Serum VEGF levels in 58 patients with JRA (systemic in 17, polyarticular in 29, pauciarticular in 12) were measured by ELISA and compared with those of 21 patients with infectious diseases and 50 healthy children. Correlations of VEGF levels with number of joints with active arthritis, erythrocyte sedimentation rate (ESR), and hyaluronic acid (HA) were examined. RESULTS: Serum levels of VEGF in patients with JRA were significantly higher than in healthy controls. Patients with systemic and polyarticular JRA showed statistically higher levels of VEGF than those with infectious diseases. VEGF levels correlated statistically with C-reactive protein (CRP) in patients with both infectious diseases and polyarticular JRA, but the regression slope (VEGF/CRP) was much steeper in polyarticular JRA than in infectious diseases. Serum VEGF levels correlated with disease activity variables such as the number of joints with active arthritis, ESR, and serum HA levels in polyarticular JRA. CONCLUSION: The correlation of serum VEGF levels and disease activity in polyarticular JRA suggests that VEGF may take an active part in joint inflammation.     

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.     

Early predictors of longterm outcome in patients with juvenile rheumatoid arthritis: subset-specific correlations

OBJECTIVE: To determine early predictors of longterm outcome in juvenile rheumatoid arthritis (JRA) in a multicenter cohort. METHODS: Patients were selected if they were > or = 8 years of age; the onset of arthritis occurred > or = 5 years before study; and a diagnosis of JRA was made at a participating center. Outcome variables were scores on self-administered Childhood Health Assessment Questionnaires (CHAQ) and active disease duration. Possible explanatory variables assessed included characteristics present at onset, HLA alleles, in particular the rheumatoid arthritis associated shared epitope (RASE), and radiographic indicators of joint damage within 2 years of onset. Data for 393 patients were available. Multivariate analyses were performed for the total group and for each onset subtype. RESULTS: Male sex correlated with worse disability in systemic onset JRA but less disability in RF negative, and a shorter active disease duration in RF positive polyarticular onset JRA. Positive antinuclear antibody correlated with a longer active disease duration in patients with pauciarticular onset JRA. Younger age at onset predicted longer active disease duration in pauciarticular and RF negative polyarticular, and a shorter active disease duration in systemic onset JRA. Residence on a reserve, rather than native North American race, correlated with worse disability. The RASE correlated with less disability in systemic JRA; but no correlation with outcome was evident for patients with rheumatoid factor positive polyarticular JRA. CONCLUSION: Variables predictive of longterm outcome in JRA are specific for each onset subtype. The most important early predictors were age at onset and sex of the patient. Place of residence may have a greater effect on disability than race. RASE may associate with a more favorable outcome in systemic onset disease.     

Growth patterns in juvenile rheumatoid arthritis

OBJECTIVE: To define patterns of growth in juvenile rheumatoid arthritis (JRA) and to evaluate possible associated clinical and laboratory correlates. METHODS: The study population comprised 67 children with JRA who had been followed for 5 years or longer and whose follow-up period did not extend beyond 18 years of age. Height and weight z scores were calculated with reference to age-related standards for each of the annual follow-up intervals and correlated with JRA subtype, the presence of rheumatoid factor (RF), the erythrocyte sedimentation rate (ESR), alkaline phosphatase level (ALP) and medication history. RESULTS: Initial height-for-age (HAZ) scores for pauciarticular, polyarticular and systemic JRA onset groups (PaJRA, PoJRA and SJRA respectively) were +0.27, -0.07 and +0.40 respectively. A significantly lower HAZ score in the SJRA population compared to the PaJIA population first became apparent at year 2 and the difference was maintained throughout the 9-year follow-up period. A significantly lower HAZ score in the SJRA population compared to the PoJRA population first became apparent at year 6 and the difference was maintained until the ninth year. During the 9-year follow-up period, RF-positive children tended to have negative HAZ scores whereas RF-negative children tended to have positive HAZ scores. The SJRA onset group displayed significantly lower HAZ scores, as compared to the HAZ score at onset, for 7 of the 9 subsequent follow-up intervals. Only 2 patients had heights < 2SD below the mean at final determination. Delay in generalized linear growth occurred predominantly in the SJRA population and to a lesser degree in those with PoJRA associated with RF positivity. CONCLUSIONS: Delay in linear growth occurs in some children with JRA. Patients with pauciarticular and RF-negative polyarticular disease can have growth patterns similar to normal children. Children with RF-positive polyarticular and systemic JRA have more significant growth retardation that occasionally can be sustained and extreme.