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.     

Disease course and outcome of juvenile rheumatoid arthritis in a multicenter cohort

OBJECTIVE: To determine the disease course and outcome in a multicenter cohort of patients with juvenile rheumatoid arthritis (JRA). METHODS: All patients with JRA seen at 3 pediatric rheumatology centers were identified from databases and/or clinic records. Inclusion criteria were a diagnosis of JRA (1977 American College of Rheumatology criteria), a followup period of at least 5 years since onset, and a minimum age of 8 years. Patients were examined and completed a Childhood Health Assessment Questionnaire (CHAQ). Kaplan-Meier curves were constructed to estimate rates of remission, relapse, and arthroplasty. Remission was defined as absence of active arthritis while off treatment for at least 2 years. Outcome measures were active disease duration, CHAQ scores, pain determined by visual analog scales, physician's global assessments, and Steinbrocker functional classifications. Years of education and employment status were ascertained. RESULTS: We studied 392 patients of 652 (60%) who met the selection criteria. The probabilities of remission at 10 years after onset were 37, 47, 23, and 6% for patients with systemic, pauciarticular, RF- polyarticular, and RF+ polyarticular JRA, respectively. The probability of relapse varied from 30 to 100% at 15 years. The probability of arthroplasty varied from 13 to 57% after 15 years of active disease. We found 2.5% of patients assessed were in Steinbrocker Classes III or IV and 6% were in the highest CHAQ score (> 1.5) group. Compared with national statistics, fewer female patients received post-secondary education and unemployment rates for patients 20 to 24 years of age were higher. CONCLUSION: Our results indicate that JRA is a disease that often extends into adulthood. Compared to previous decades, functional outcome has improved; however, the estimated rate of arthroplasty remains very high. Patients with JRA may have difficulty entering the workforce.     

Health status of patients with juvenile rheumatoid arthritis at 1 and 5 years after diagnosis

OBJECTIVE: To describe the health and functional status of children with juvenile rheumatoid arthritis (JRA) diagnosed in the early 1990s. METHODS: Patients were obtained from the Pediatric Rheumatology Disease Registry, a database of patients seen in pediatric rheumatology centers across the United States. Questionnaires designed to be filled out after retrospective chart review were sent to pediatric rheumatologists caring for children diagnosed with JRA between 1992 and 1997. RESULTS: We studied 703 patients -- 376 with pauciarticular onset (pauci), 232 with polyarticular onset (poly), and 95 with systemic onset JRA (systemic). At 1 year after diagnosis, half of the pauci and systemic patients no longer required medication, compared to 78% of the poly patients; 98% of the patients functioned in Steinbrocker classes I and II. Six percent of pauci, 27% of poly, and 11% of systemic patients had limitations in school function. Nearly 1/3 of poly patients already had joint space narrowing on radiograph. By 5 years after diagnosis, all pauci, 88% of poly, and 70% of systemic patients were in Steinbrocker classes I and II; but 6% of pauci, 28% of poly, and 44% of systemic patients had limitations in school function. Nearly 2/3 of poly and systemic patients had joint space narrowing. CONCLUSION: In these children treated prior to the era of biologic therapy, at 5 years after onset, > 25% of poly and nearly half of systemic patients had functional limitations that required modifications in their school schedule. Radiographically evident joint space damage was seen within a year of onset in poly patients, and by 5 years 2/3 of poly and systemic patients had damage.     

Prognostic factors in juvenile rheumatoid arthritis: a case-control study revealing early predictors and outcome after 14.9 years

OBJECTIVE: To describe the physical and psychosocial outcome in patients with juvenile rheumatoid arthritis (JRA), compared with subjects in the general population, and to determine patient characteristics, HLA alleles, and disease variables within the first 6 months of disease onset that predict persistent disease, joint erosions, and physical disability. METHODS: A cohort of 268 (85%) of 316 patients with JRA first admitted to the hospital between 1980 and 1985 were examined after a median of 14.9 years (range 11.7-25.1) of disease duration. Controls matched for age, sex, and geographic region were randomly selected from the general population. Patients' medical records were retrospectively reviewed. Clinical examinations and radiographs of the hips, ankles, and affected joints were obtained. HLA-DRB1 and DPB1 alleles were determined by genotyping and HLA-B27 by serologic testing. Physical and psychosocial health status was assessed using the Short-Form Health Survey (SF-36) and the Health Assessment Questionnaire (HAQ). RESULTS: At followup, 133 patients with JRA (50%) were in remission, 63 (24%) had developed joint erosions, and 93 (36%) had impaired physical functioning (HAQ > 0.0). Patients had greater disability, more bodily pain, and poorer general health than controls. Comparable levels of education, social function, and mental health were found, but the patients had higher rates of unemployment than controls (19% vs 7%; p < 0.001). Predictors of persistent disease and joint erosions were: young onset age and large numbers of affected joints, long duration of elevated erythrocyte sedimentation rate (ESR), and positive IgM rheumatoid factor (RF) within the first 6 months. Additionally, persistent disease was predicted by the presence of DRB1*08, and joint erosions were predicted by symmetric arthritis and DRB1*08 and HLA-B27 in combination. DRB1*01 was a predictor of joint erosions in the pauciarticular onset type (n = 163). Predictors of physical disability were: female sex, symmetric arthritis, hip joint involvement, long duration of elevated ESR and IgM RF. CONCLUSION: Compared with healthy controls, patients with JRA had impaired physical health and lower employment rates after more than 11 years of disease duration. Elevated ESR, extensive and symmetric arthritis, positive IgM RF, DRB1*08, DRB1*01, HLA-B27 and DRB1*08 in combination, early onset, and female sex were early risk factors for an unfavorable outcome.     

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.     

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.     

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.     

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).     

Radiographic progression in children with polyarticular juvenile rheumatoid arthritis: a pilot study

OBJECTIVE: To assess disease progression on hand/wrist x rays from children with polyarticular juvenile rheumatoid arthritis. METHODS: Initial and subsequent films of 13 white children (10 girls) were read blind by a paediatric radiologist for the presence of joint space narrowing (JSN), erosions, and relative carpal length (RCL). RESULTS: One child had subcutaneous nodules; one (of 11) was rheumatoid factor positive; six were ANA positive. Median age at diagnosis was 10.7 years (2.5 to 15.9). Median number of involved joints (swelling, pain, or decreased range of motion) at diagnosis was 16 (6 to 33). Four initial x rays had either erosions or JSN. Subsequent x rays were done at (median) 13.3 (8.3 to 24.9) months after initial x rays. One of 10 subsequent x rays had shortened RCL, and six of 13 were worse than the initial ones. Four of these developed new erosions, one had increased number of erosions, and one developed new JSN. CONCLUSIONS: About half the children with polyarticular juvenile rheumatoid arthritis will have evidence of radiographic progression within two years after diagnosis. Thus newly diagnosed children are at high risk of substantial joint destruction and potential disability, emphasising the need for prompt treatment.     

Antibodies against cyclic citrullinated peptide are associated with HLA–DR4 in simplex and multiplex polyarticular‐onset juvenile rheumatoid arthritis

Objective

Anti–cyclic citrullinated peptide (anti‐CCP) antibodies have been detected in patients with juvenile rheumatoid arthritis (JRA), particularly in those with polyarticular, rheumatoid factor (RF)‐positive JRA. Our objectives were to determine whether anti‐CCP antibodies are associated with HLA–DR4 in children with polyarticular JRA, whether anti‐CCP antibodies are associated with clinical features of disease, and whether affected sibling pairs (ASPs) with JRA are concordant for this antibody.

Methods

Stored serum samples obtained from 230 HLA‐typed patients with JRA (77 with polyarticular‐onset disease and 153 with pauciarticular‐ or systemic‐onset disease), 100 JRA ASPs, and 688 healthy children were tested for anti‐CCP antibodies and RF.

Results

Thirteen percent of the patients with polyarticular‐onset JRA and 2% of the other JRA patients exhibited anti‐CCP antibodies, compared with only 0.6% of the controls. Fifty‐seven percent of RF‐positive patients with polyarticular‐onset JRA had anti‐CCP antibodies. HLA–DR4–positive patients with polyarticular‐onset JRA were more likely to have anti‐CCP antibodies than were those without HLA–DR4 alleles (odds ratio [OR] 5.20, 95% confidence interval [95% CI] 1.30–20.9). Anti‐CCP antibodies were associated with polyarticular onset (OR 7.46, 95% CI 1.99–28.0), a polyarticular disease course (OR 9.78, 95% CI 1.25–76.7), and erosive disease (OR 14.3, 95% CI 3.01–67.9). Concordance rates for anti‐CCP antibodies among ASPs were statistically significant.

Conclusion

These data demonstrate increased anti‐CCP antibody formation in HLA–DR4–positive patients with polyarticular‐onset JRA. The overall prevalence of anti‐CCP antibodies in JRA is low, but a substantial proportion of RF‐positive patients with polyarticular‐onset JRA have these antibodies. Anti‐CCP antibodies in JRA are associated with polyarticular onset, a polyarticular course, and erosive disease.

     

Cross-cultural adaptation and validation of an argentine Spanish version of the Stanford childhood health assessment questionnaire

Objectives . To translate into Argentine Spanish and cross-culturally adapt the Childhood Health Assessment Questionnaire (CHAQ) and validate the adapted instrument in Argentine patients with juvenile rheumatoid arthritis (JRA). Methods . Five bilingual Argentine pediatric rheumatologists translated into Argentine Spanish and cross-culturally adapted the United States English CHAQ. Pretesting was done in a sample of 23 parents using a probe question technique. Parents of 70 patients with JRA and 21 healthy children (controls) participated in the validation phase. All were from Argentina. Results . The mean disability index (DI) scores for patients with systemic, polyarticular, or pauciarticular onset JRA were 0.64, 0.32, and 0.1, respectively. Healthy controls averaged 0.2. Intercomponent correlations were between 0.4 and 0.9, suggesting internal consistency, but also some redundancy. Test-retest reliability, studied at a 1-week interval, was moderate (mean DI 0.44 [in clinic] and 0.29 [one week later], Pearson's correlation = 0.82). We compared CHAQ scores from 15 parents with those of their children >10 years of age. Significantly higher DI scores were given by patients than their respective parents (P > 0.019), but the pairwise scores (parent–patient) were highly correlated (r = 0.986). Conclusions . Cross-cultural adaptation of the US CHAQ to Argentina required few changes. Although DI scores for all patient subgroups were higher than for controls subjects, the scores were low, particularly for those with pauciarticular disease. Prospective studies designed to examine the sensitivity to change and predictive validity will help to assess further the usefulness of the adapted CHAQ in the Argentine population.     

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     

Is measurement of IgM and IgA rheumatoid factors (RF) in juvenile rheumatoid arthritis clinically useful?

The prevalence and clinical relevance of IgM and IgA RF detected by ELISA were studied in 91 patients with juvenile rheumatoid arthritis (JRA) and 45 healthy children. IgM and IgA RF were detected, respectively, in 33 and 44% of the patients, compared to 6.7 and 15.6% of the healthy children (p = 0.001 and 0.0006, respectively). The frequency of IgM RF was significantly higher in patients with polyarticular (52%) as compared to systemic onset JRA (21%; p = 0.04). Five out of ninety-one patients and none of the control group were IgM RF positive by the latex test. High levels of IgM RF were detected more frequently in patients with active disease (p = 0.01) and positive latex agglutination test (p < 0.001) and had a marginally significant association with severe radiological deformities (p = 0.05). The presence of IgA RF was associated with active disease in polyarticular onset JRA children (p = 0.04). In conclusion, high levels of IgM RF and the detection of IgA RF can be useful in assessing clinical activity in a subset of patients with JRA.     

Differences in the profiles of circulating levels of soluble tumor necrosis factor receptors and interleukin 1 receptor antagonist reflect the heterogeneity of the subgroups of juvenile rheumatoid arthritis

OBJECTIVE: To determine whether levels of soluble tumor necrosis factor receptor 55 (sTNFR55), sTNFR75, and interleukin 1 receptor antagonist (IL-1Ra) can differentiate different subtypes of juvenile rheumatoid arthritis (JRA), and to determine if the levels of these proteins correlate with disease activity. METHODS: Serum sTNFR (55 and 75) and IL-1Ra levels were measured by ELISA in 34 patients with JRA and these values were correlated with disease subtype and activity. RESULTS: Serum sTNFR55 levels were significantly elevated in patients with systemic onset JRA (SoJRA) (mean +/- 2 SD, 2.9 +/- 1.8 ng/ml) (p < or = 0.05) compared to rheumatoid factor positive (RF+) polyarticular JRA (2.1 +/- 0.6), RF-polyarticular JRA (1.5 +/- 0.6), and pauciarticular JRA (1.4 +/- 0.4). There was a trend for elevation of sTNFR75 levels in patients with SoJRA compared to other subtypes (p = 0.08). More patients had elevated levels of sTNFR75 than sTNFR55 (15 vs 7). This was true for all subsets (SoJRA 7 vs 5; polyarticular JRA 4 vs 2; and pauciarticular JRA 4 vs 0). In contrast to sTNFR, IL-1Ra levels were significantly elevated in RF+ polyarticular JRA compared to the other subgroups (p < or = 0.001). We found statistically significant Pearson correlations between (1) sTNFR75 and hemoglobin concentration: and (2) IL-1Ra and number of active joints and number of joints with effusions. CONCLUSION: The increased serum level of sTNF receptors in SoJRA suggests that TNF is likely more important than IL-1 in systemic inflammation and in particular in SoJRA. Conversely, IL-1 is likely more important in the inflammatory arthritis of JRA and in particular in the pathogenesis of RF+ polyarticular JRA. Our results suggest that cytokines have differing roles in JRA subtypes and likely reflect JRA subtype heterogeneity.     

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.     

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.     

Antibodies against cyclic citrullinated peptide are associated with HLA-DR4 in simplex and multiplex polyarticular-onset juvenile rheumatoid arthritis

OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies have been detected in patients with juvenile rheumatoid arthritis (JRA), particularly in those with polyarticular, rheumatoid factor (RF)-positive JRA. Our objectives were to determine whether anti-CCP antibodies are associated with HLA-DR4 in children with polyarticular JRA, whether anti-CCP antibodies are associated with clinical features of disease, and whether affected sibling pairs (ASPs) with JRA are concordant for this antibody. METHODS: Stored serum samples obtained from 230 HLA-typed patients with JRA (77 with polyarticular-onset disease and 153 with pauciarticular- or systemic-onset disease), 100 JRA ASPs, and 688 healthy children were tested for anti-CCP antibodies and RF. RESULTS: Thirteen percent of the patients with polyarticular-onset JRA and 2% of the other JRA patients exhibited anti-CCP antibodies, compared with only 0.6% of the controls. Fifty-seven percent of RF-positive patients with polyarticular-onset JRA had anti-CCP antibodies. HLA-DR4-positive patients with polyarticular-onset JRA were more likely to have anti-CCP antibodies than were those without HLA-DR4 alleles (odds ratio [OR] 5.20, 95% confidence interval [95% CI] 1.30-20.9). Anti-CCP antibodies were associated with polyarticular onset (OR 7.46, 95% CI 1.99-28.0), a polyarticular disease course (OR 9.78, 95% CI 1.25-76.7), and erosive disease (OR 14.3, 95% CI 3.01-67.9). Concordance rates for anti-CCP antibodies among ASPs were statistically significant. CONCLUSION: These data demonstrate increased anti-CCP antibody formation in HLA-DR4-positive patients with polyarticular-onset JRA. The overall prevalence of anti-CCP antibodies in JRA is low, but a substantial proportion of RF-positive patients with polyarticular-onset JRA have these antibodies. Anti-CCP antibodies in JRA are associated with polyarticular onset, a polyarticular course, and erosive disease.     

Antiperinuclear factor in juvenile rheumatoid arthritis.

The serological diagnosis of juvenile rheumatoid arthritis (JRA) is difficult, with only 7-10% of patients 19S IgM rheumatoid factor positive. About 60-70% of patients are positive for hidden 19S IgM rheumatoid factor, but this test requires serum separation and is not available in most laboratories. Antiperinuclear factor has been described in both seropositive and seronegative adult patients with rheumatoid arthritis, but has not been thoroughly evaluated in children with JRA. This study determined the diagnostic sensitivity and specificity of antiperinuclear factor in patients with JRA. Serum samples from 64 children with JRA, 24 with systemic lupus erythematosus (SLE), and 24 control subjects were tested for the presence of antiperinuclear factor. A total of 10 (83%) of seropositive, polyarticular onset and six (37%) of seronegative, polyarticular onset patients with JRA were positive for antiperinuclear factor. The occurrence of antiperinuclear factor in five (19%) with pauciarticular onset and one (10%) with systemic onset (JRA) as well as in four (17%) with SLE was not increased compared with the control subjects (1/24 (4%)). These data show an overall diagnostic sensitivity and specificity of 34 and 90% respectively in this group of patients. Although less sensitive than the hidden rheumatoid factor assay, the antiperinuclear factor assay is easier to perform and may contribute to the serological diagnosis of JRA.     

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.     

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.