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.     

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.     

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.     

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).     

Serum IgG and IgM Rheumatoid Factors by Solid Phase Radioimmunoassay

In this report, solid phase radioimmunoassays that specifically measure IgG rheumatoid factor (RF) and IgM RF in absolute concentrations are described. Polyclonal RF preparations were utilized as standards, and as little as 40 ng/ml of IgG RF and 1 ng/ml of IgM RF were detected. The IgG RF concentration of 26 seropositive rheumatoid sera was 439 ± 755 μg/ml (mean ± 1 SD), a level 107 times that of normal controls (P < 0.001). In contrast, levels for 49 children with juvenile rheumatoid arthritis (JRA) were 6.1 ± 3.7 μg/ ml for those with a polyarticular onset (JRA-Po), 27.3 ± 113 μg/ml for the pauciarticular group (JRA-Pa), and 12.6 ± 20.7 μg/ml for the group with a systemic onset (JRA-S). None of these values differed significantly from the value of 6.0 ± 3.9 μg/ml measured in a juvenile control group. The IgM RF level in adult rheumatoid arthritis (RA) of 175 ± 221 μg/ml was also significantly elevated compared to controls (P < 0.001). In JRA, however, mean levels of 1.4 ± 2.0 μg/ml (JRA-Po), 2.8 ± 8.3 μg/ml (JRA-Pa), and 1.1 ± 0.7 μg/ml (JRA-S) were not elevated significantly above the value of 1.2 μ 1.2 μg/ml measured in the juvenile control group. Hidden IgM RF was not found in 9 JRA sera tested. These marked differences in RF levels provide another indication that adult RA and JRA are distinct diseases.     

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.     

Complement-fixing hidden rheumatoid factor in juvenile rheumatoid arthritis

Fifteen to twenty percent of patients with juvenile rheumatoid arthritis (JRA) have positive latex fixation tests (LFT), whereas approximately 46% have previously been demonstrated to have hidden rheumatoid factors (RF), i.e., 19S IgM RF which can be detected by the LFT after acid separation of the IgM-containing fraction from serum. In this study, hidden RF were found in 59% of patients with seronegative JRA by use of a complement-dependent hemolytic assay. The median titer of JRA patients was 1:42, and in healthy and disease controls it was 1:7. The difference was significant at P < 0.001. When data from patients with active disease were analyzed separately, the median titer for polyarticular JRA was 1:97 and for pauciarticular JRA, 1:91. The differences due to active disease were significant at P < 0.001 and P < 0.005, respectively. The results demonstrate that the hemolytic assay is more sensitive than the LFT in determining the presence of hidden RF, and activity of disease correlates well with high hemolytic RF titers.     

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.     

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.     

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.     

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.     

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.     

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.     

Prevalence of IgM, IgA and IgG rheumatoid factors in juvenile rheumatoid arthritis

Using an enzyme immunoassay, sera from 50 children with juvenile rheumatoid arthritis (JRA) and 39 controls were tested for IgM, IgA and IgG rheumatoid factors (RF). RF of the IgM and IgA isotypes were present in 11 (22%) patients, but in only one control (p = 0.008). IgG RF was present in the sera of 2 (4%) patients and in none of the controls (p = 0.21). Of the 22 patients with IgM RF or IgA RF, only 3 sera (14%) contained RF of both isotypes. IgM RF was more common in patients with polyarticular disease, while IgA RF was more common in patients with pauciarticular disease. These results indicate that IgM and IgA RF are present in a significant minority of JRA patients and suggest that there is independent expression of the respective RF isotypes.     

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.

     

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.     

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.     

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.     

Safety and efficacy of high dose etanercept in treatment of juvenile rheumatoid arthritis

OBJECTIVE: To evaluate safety and efficacy of high dose etanercept (> 0.8 mg/kg, maximum 25 mg subcutaneously twice weekly) (Enbrel) in children with juvenile rheumatoid arthritis (JRA) and inadequate prior response to standard dose etanercept. METHODS: Retrospective chart review of 8 children (6 girls, 2 boys, mean age 8.4 yrs, range 5-16 yrs). Five children had systemic onset, polyarticular course JRA; 2 had polyarticular onset; and one had pauciarticular onset, polyarticular course JRA. All children had failed at least 3 mo (mean 9 mo) treatment with standard dose etanercept (0.4 mg/kg SC twice a week). All 8 children had increase in the etanercept dose to at least 0.8 mg/kg (mean 1.1 mg/kg, maximum 25 mg SC twice weekly) for a mean of 7 mo (range 3-10 mo). Efficacy of high dose etanercept was evaluated by changes in joint count, laboratory data, and ability to decrease concomitant medication. RESULTS: Improvements in the joint count and laboratory findings (erythrocyte sedimentation rate, hemoglobin and platelet count) were observed in 2 of 8 (25%) children. In these 2, concomitant prednisone was reduced or discontinued. In contrast, no changes in disease activity or laboratory findings were observed in the other 6 children. Overall, high dose etanercept was well tolerated. No laboratory abnormalities were detected and no child withdrew because of adverse events. CONCLUSION: High dose etanercept is safe and well tolerated in children, but efficacy seems limited. In children with unsatisfactory response to standard dose etanercept, an increased dose or treatment prolongation may not offer any additional benefit.     

Sexual maturation in Egyptian boys and girls with juvenile rheumatoid arthritis

Children with juvenile rheumatoid arthritis (JRA) exhibit a compromised growth status while information concerning the pattern of their sexual maturity is scant. The aim of the current work was to study sexual maturity in boys and girls with JRA. The study included eighty JRA patients they were 45 male and 35 female and eighty age- and sex-matched normal children served as controls. Development of genitalia was evaluated as per sexual maturity rating criteria given by Tanner score. Development of hair (pubic, axillary and facial) and age of monarch to JRA females were noted The mean (±SD) age of appearance of genitalia stage G-2 in boys with systemic onset JRA (12.0 ± 0.3 years) was earlier when compared with pauciarticular (12.60 ± 0.93 years) and polyarticular (13.39 ± 0.93 years) JRA but delayed for all types of JRA when compared with controls (10.06 ± 0.63 years). In comparison with female groups, the mean (±SD) age of appearance of genitalia stage G-2 with systemic onset JRA (12.0 ± 0.4 years) was also earlier when compared with pauciarticular (12.68 ± 1.09 years) and polyarticular (13.72 ± 0.39 years). Age of menarche delayed in all JRA female patients. None of the study group reach stage G-5 of genitalia development. The timing of initiation of sexual maturity in boys and girls with JRA delayed and this delay variable according to disease subtype.