Serum p55 and p75 tumour necrosis factor receptors as markers of disease activity in juvenile chronic arthritis.

OBJECTIVE: To determine the expression of tumour necrosis factor alpha (TNF alpha) and its soluble receptors (p55 and p75) in the sera and synovial fluid of patients with juvenile chronic arthritis (JCA), and their correlation with disease activity parameters. METHODS: Ninety eight sera from 45 patients with JCA (14 systemic, 12 polyarticular, 19 pauciarticular), 20 sera from age matched healthy controls, and five synovial fluids from five antinuclear antibody (ANA) positive pauciarticular JCA patients were tested for the presence of TNF alpha, soluble TNF receptors p55 and p75 (sTNFRp55, sTNFRp75), and interleukin-6 (IL-6) by an enzyme amplified sensitivity immunoassay. Physician global estimate of disease activity, weekly fever score and joint score, C reactive protein (CRP), erythrocyte sedimentation rate (ESR), and haemoglobin concentration were evaluated as parameters of disease activity. The expression of p55 and p75 on peripheral mononuclear cells (MNCs) from five patients with systemic JCA and synovial MNCs from five ANA positive patients with pauciarticular JCA was evaluated by flow cytometry. RESULTS: TNF alpha serum concentrations did not differ significantly between the patients with active JCA and the control group. No correlation was found between TNF alpha and parameters of disease activity, but both p55 and p75 showed a significant positive correlation with the physician global estimate of disease activity (p < 0.001), ESR (p < 0.001), CRP (p < 0.001), and serum concentrations of IL-6 (p < 0.001). Serum concentrations of haemoglobin correlated inversely with the concentrations of p55 and p75 (p < 0.001). Synovial lymphocytes selectively expressed the p75 surface receptor. CONCLUSIONS: sTNFRp55 and sTNFRp75 each represent a sensitive marker of disease activity in JCA. Their increased expression in biological fluids may support the hypothesis that TNF alpha has a role in the pathogenesis of JCA.     

Autoantibodies to chromatin: prevalence and clinical significance in juvenile rheumatoid arthritis

OBJECTIVE: To determine the prevalence of anti-chromatin antibodies (Abs) in juvenile rheumatoid arthritis (JRA) and to assess any association between the presence of anti-chromatin Abs and clinical subsets of the disease. METHODS: IgG anti-chromatin Abs and anti-extractable nuclear antigens (ENA) Abs were detected by an enzyme-linked immunosorbent assay (ELISA), and antinuclear Abs (ANA) by indirect immunofluorescence in sera of 89 children with JRA. Ten children with systemic, 32 with polyarticular and 47 with pauciarticular disease onset (uveitis occurred in 17/47 children) were studied. As a control group, 12 sera of patients suffering from idiopathic uveitis and 31 age- and-sex-matched healthy children (HC) were examined. RESULTS: Abs to chromatin were detected in 14/47 (29.8%) of children suffering from pauciarticular onset JRA and in this group the higher prevalence of anti-chromatin Abs has been found in children with chronic uveitis (p = 0.002). Anti-chromatin positivity was observed in 2/10 (20%) of systemic and in 3/32 (9.3%) of polyarticular onset JRA. Furthermore, none of the patients with idiopathic uveitis and HC had Abs to chromatin. anti-chromatin Abs titers remained relatively stable over a 6-month control period. CONCLUSION: Our results confirm previous data about the presence of circulating anti-chromatin Abs in juvenile arthritis. Interestingly, anti-chromatin Abs were significantly higher in the group of patients with pauciarticular onset with past or present history of uveitis, than in patients without ocular involvement. A long-term follow-up study could be useful to demonstrate the potential utility of these autoantibodies in diagnosing, classifying and treating children affected.     

Predictive value of synovial fluid analysis in juvenile chronic arthritis.

To investigate the value of synovial fluid analysis in predicting the articular evolution of juvenile chronic arthritis, synovial fluid from 29 patients with oligoarticular onset juvenile chronic arthritis were examined prospectively. The patients were subsequently classified after a three year period of observation as having polyarticular (10 patients) or pauciarticular (19 patients) disease. The synovial fluid samples were analysed for total and differential white blood cell count, total protein, beta 2 microglobulin, and total complement activity. For comparison, synovial fluid samples from 95 patients with adult onset rheumatoid arthritis were also analysed. In patients with polyarticular disease polymorphonuclear cells and beta 2 microglobulin concentrations were higher than in the patients with pauciarticular disease (80 (29.2) v 58.1 (25.3), and 3.6 (1.2) v 2.2 (0.5) mg/l, respectively), but there was no significant difference from the patients with rheumatoid arthritis. Synovial fluid analysis may be useful in predicting the evolution of juvenile chronic arthritis and improve definition of its subtypes.     

Juvenile chronic arthritis in India: is it different from that seen in Western countries?

Medical records of 89 children with juvenile chronic arthritis attending the clinical immunology outpatient department of a tertiary care hospital were analysed. Polyarticular type of juvenile chronic arthritis was the most common, followed by pauciarticular and systemic onset types. No patient with the early onset pauciarticular disease subset, which is associated with iridocyclitis and antinuclear antibody (ANA) positivity was seen. Uveitis was observed in only one patient with late onset pauciarticular disease. The ANA positivity rate (1/89) was very low. Polyarticular onset type disease had a higher incidence of deformities.     

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.     

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     

IgG-anti-IgG antibodies in juvenile chronic arthritis

IgG antiglobulins were measured in 117 children with seronegative juvenile chronic arthritis (JCA). 100 had active disease, and these had significantly higher levels of IgG antiglobulins (mean 0.45 +/- 0.16 micrograms/ml) than the control group (mean 0.25 +/- 0.16 micrograms/ml (p less than 0.01]. The inactive group of patients had a mean of 0.14 +/- 0.06 micrograms/ml, comparable to a group of cord bloods from normal births (mean 0.14 +/- 0.05 micrograms/ml). In the active patients there was no difference when subdivision was made according to their mode of onset into pauciarticular, polyarticular, or systemic.     

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.     

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.     

Evaluation of ILAR classification criteria for juvenile idiopathic arthritis in Spanish children.

OBJECTIVE: To evaluate the proposed International League of Associations for Rheumatology (ILAR) classification criteria for juvenile idiopathic arthritis in a cohort of Spanish children. METHODS: One hundred twenty-five patients with chronic arthritis were categorized according to one of the traditional classifications and the proposed ILAR classification system after at least 6 months of disease. The traditional classifications included the European League Against Rheumatism (EULAR) criteria for pauciarticular, polyarticular rheumatoid factor (RF) negative, and systemic juvenile chronic arthritis (JCA), as well as for RF+ polyarthritis; the Vancouver criteria for juvenile psoriatic arthritis (JPsA); and the European Spondylarthropathy Study Group (ESSG) preliminary criteria for juvenile spondyloarthropathy (JSpA). RESULTS: The ILAR criteria classified 106/125 patients (84.8%). All patients with systemic and polyarticular JCA, RF+ polyarthritis, and definite juvenile psoriatic arthritis were reclassified in the corresponding ILAR category. In contrast, only 80% of pauciarticular JCA and 47% of JSpA patients could be allocated to the ILAR oligoarthritis (47/59 patients, 35 persistent and 12 extended) and enthesitis related arthritis (ErA. 8/17 patients) categories. Two children with probable PsA were reclassified in the RF- polyarthritis category. Nineteen patients (15.2%) were allocated to the ILAR "other arthritis" group, 13/19 because they did not fulfill criteria for any of the other categories (12 due to family history of psoriasis and one because of family history of HLA-B27 associated disease). The remaining 6 patients met criteria for 2 categories, RF- polyarthritis and either ErA (n = 5) or PsA (n = 1). No differences other than family history of psoriasis were found in any of the variables studied between pauciarticular JCA patients classified in the oligoarthritis (n = 47) and those in the "other arthritis" (n = 11) ILAR categories. CONCLUSION: The proposed ILAR criteria allocated 84.8% of the patients classified by traditional criteria. Family history of psoriasis (n = 12) and polyarticular onset of disease in patients with ErA (n = 5) were responsible for most of the exclusions from other ILAR categories.     

HLA antigens in juvenile arthritis. Pauciarticular and polyarticular juvenile arthritis are immunogenetically distinct

Using DNA techniques, we investigated the role of HLA-DR, DQ, and DP alleles in susceptibility to juvenile arthritis (JA). We studied 2 groups of patients with JA having a different disease prognosis and course. The pauciarticular form is usually benign, while the polyarticular disease frequently leads to joint destruction and disability. Persistent pauciarticular disease developed preferentially in patients having HLA-DRw13-Dw18 and DQw6-Dw18, but these antigens did not confer susceptibility in patients whose disease converted to the polyarticular form. HLA-DPw2.1 was an additional susceptibility factor for patients with JA of pauciarticular onset. In the polyarticular form of JA, HLA-DPw3 was the major factor for susceptibility, giving a relative risk of 10.3 (P less than 0.0001). In addition, we found that DRw8.1 and DQw4 were increased, and HLA-DR4 was markedly decreased, in patients with pauciarticular and polyarticular disease. These results indicate that in addition to some shared factors, distinct HLA class II alleles are important in pauciarticular or polyarticular JA. We conclude that typing with oligonucleotide probes may be useful in predicting the outcome in some children with arthritis.     

Expression of the rheumatoid factor cross-reactive idiotype in JRA: association with disease onset subtype, disease activity and disease severity.

We previously reported that approximately one-third of patients with juvenile rheumatoid arthritis (JRA) express high concentrations of antibodies marked by the rheumatoid factor cross reactive idiotype (RCRI) in their sera (6). In order to determine if an expression of RCRI is associated with certain clinical features of the disease, we prospectively studied 49 patients with JRA over a six month period, and determined serum RCRI concentrations by inhibition ELISA. RCRI concentrations correlated significantly with the duration of morning stiffness (r = .3866, p less than .01), and the functional class (p less than .001), but not with the number of active joints. Expression of RCRI was higher in patients with systemic onset disease (p less than .03), compared to patients with pauciarticular or polyarticular disease. In patients studied on more than one occasion, the RCRI expression was relatively constant despite changes in disease activity. A subset of JRA patients with systemic onset disease, higher serum concentrations of the RCRI.     

Sex ratio and sibship size in juvenile rheumatoid arthritis kindreds

In a study of sibship size and sex ratio in juvenile rheumatoid arthritis, the anticipated sex ratios, including a marked female predominance in early onset pauciarticular disease and in polyarticular disease, were found. The size of the sibship showed a progressive increase with increasing age of the proband at onset of disease. In addition, the sex ratios of the sibs deviated from expected, among families where the proband's disease was characterized as either early onset pauciarticular or polyarticular in its presentation.     

Soluble interleukin-2 receptors in children with juvenile chronic arthritis.

Concentrations of interleukin-2 receptors were studied in sera of 81 patients with pauciarticular-, polyarticular-, and systemic-onset juvenile chronic arthritis using a double antibody "sandwich" enzyme-linked immunosorbent technique. Serum concentrations were significantly increased in all subgroups when compared with the healthy controls. Higher concentrations were found in systemic onset disease than in pauci- or polyarticular onset disease. Serum levels were found to be increased in both inactive and active disease, showing maximal values in patients with systemic features. A correlation to C-reactive protein, alpha 1-acid glycoprotein, and erythrocyte sedimentation was observed. Increased sIL-2R values suggest disease activity despite the absence of clinical symptoms.     

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.     

Hla antigens in juvenile Arthritis

Using DNA techniques, we investigated the role of HLA—DR, DQ, and DP alleles in susceptibility to juvenile arthritis (JA). We studied 2 groups of patients with JA having a different disease prognosis and course. The pauciarticular form is usually benign, while the polyarticular disease frequently leads to joint destruction and disability. Persistent pauciarticular disease developed preferentially in patients having HLA—DRw13-Dw18 and DQw6-Dw18, but these antigens did not confer susceptibility in patients whose disease converted to the polyarticular form. HLA—DPw2.1 was an additional susceptibility factor for patients with JA of pauciarticular onset. In the polyarticular form of JA, HLA—DPw3 was the major factor for susceptibility, giving a relative risk of 10.3 (P < 0.0001). In addition, we found that DRw8.1 and DQw4 were increased, and HLA—DR4 was markedly decreased, in patients with pauciarticular and polyarticular disease. These results indicate that in addition to some shared factors, distinct HLA class II alleles are important in pauciarticular or polyarticular JA. We conclude that typing with oligonucleotide probes may be useful in predicting the outcome in some children with arthritis.     

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.     

Serum interleukin 12 concentration in juvenile chronic arthritis

OBJECTIVES—The aim of this study was to evaluate serum interleukin (IL) 12 concentration in patients with juvenile chronic arthritis (JCA), according to disease subtype, activity, and duration. IL12 has been demonstrated to prime the selective expansion of T helper (Th) cells with a Th1-type pattern of cytokine production.
METHODS—Sixty eight serum samples from 50 JCA patients (12 systemic, 12 polyarticular, 26 pauciarticular), 20 serum samples from age matched healthy controls were tested with two different immunoassays specific for total IL12 (p40 and p70 heterodimer) and for IL12 (p70) heterodimer, respectively. The following disease activity parameters were evaluated: (a) presence of arthritis at least in one joint, (b) physician global estimate of disease activity, (c) disability index according to the Childhood Health Assessment Questionnaire (CHAQ), (d) C reactive protein (CRP).
RESULTS—Total IL12 (p40 and p70 heterodimer) was significantly higher in JCA active patients than in those on clinical remission and in healthy controls (p < 0.001). Conversely, detectable concentrations of IL12 (p70) heterodimer were found in three active JCA patients only. Moreover, total IL12 (p40 and p70 heterodimer) showed a significant negative correlation both with time from disease diagnosis (r = −0.29, p = 0.04) and, for the pauciarticular subgroup, with disease activity duration (r = − 0.71, p < 0.001).
CONCLUSIONS—This study shows that the p40 moiety of IL12 is increased in serum samples from active JCA patients, especially in the earliest phases of the disease, whereas biological active IL12 (p70) heterodimer is virtually undetectable.

Keywords: juvenile chronic arthritis; interluekin 12; cytokines; T helper cells     

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.