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.     

HLA-DP antigens in patients with pauciarticular juvenile rheumatoid arthritis

The distribution of the recently described HLA-DP antigens was examined in a population of patients with pauciarticular juvenile rheumatoid arthritis and iridocyclitis, in an attempt to further characterize the immunogenetically determined susceptibility to this disease. There was a significantly increased frequency of the HLA-DPw2 antigen in the patients compared with the controls (67% versus 34%; odds ratio 3.9, P = 0.003 by Fisher's exact test). Population studies and family studies showed that this association with HLA-DPw2 was not secondary to linkage disequilibrium with the previously defined HLA-D region markers of disease (HLA-DR5 and HLA-DRw8) in these patients. These data raise the possibility that susceptibility to this form of juvenile rheumatoid arthritis may be regulated by more than one HLA-linked gene.     

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.     

DNA analysis of HLA-DR, DQ and DP genes in pauciarticular juvenile rheumatoid arthritis.

HLA-DR, DQ, and DP alleles were determined by restriction fragment length polymorphism (RFLP) and oligonucleotide hybridization analysis in 50 Caucasian children with pauciarticular juvenile rheumatoid arthritis (PaJRA) and 82 controls. There was an increased frequency of DR5, DRw8, and DQw4, as well as individual DQ alpha and beta chains, DQA*0401 and DQB1*0402, respectively, in this group of patients. There was an absolute association between DRw8, DQw4, DQA1*0401, and DQB1*0402 in the patient population. HLA-DPw2.1 was also increased in frequency. There was little evidence of linkage disequilibrium found between DPw2.1 and DR5, DRw8, or DQw4. These MHC Class II associations were more characteristic of those patients with young age of onset (less than 5 years), rather than those with onset greater than or equal to 5 years of age. Our data confirmed the previous associations of HLA-DR5, DRw8, and DPw2.1 with PaJRA and suggested a new association for DQ alpha and beta genes in the clinical expression of this disease.     

HLA antigens in juvenile arthritis

Serologic HLA typing was performed in 77 patients with juvenile arthritis (JA). The frequency of the DR4 antigen was significantly increased in the seropositive but decreased in the seronegative patients—53% and 17%, respectively (P < 0.025)—compared with 27% in healthy Norwegians. An increased frequency of the HLA-DR4 antigens was also found in polyarticular onset JA (50% compared with 27%, P < 0.05). The frequency of both the HLA-B27 (21%) and the DR5 antigen (21%) was increased in the whole patient group compared with controls (10% and 9%, respectively, P < 0.01). The DR5 antigen was also increased in the systemic onset patients (40%, P < 0.05). Both the DR5 and the DR8 antigens were increased in the pauciarticular onset group (P < 0.05 and P < 0.01, respectively). The results support the view that seropositive and seronegative JA are different disease entities and also that seropositive JA may be an early form of seropositive rheumatoid arthritis. The association between the DR4 antigen and IgM rheumatoid factor suggests that the HLA-DR4 gene or a closely linked gene may regulate autoimmune responses to self IgG.     

HLA antigens in juvenile arthritis. Genetic basis for the different subtypes

Serologic HLA typing was performed in 77 patients with juvenile arthritis (JA). The frequency of the DR4 antigen was significantly increased in the seropositive but decreased in the seronegative patients--53% and 17%, respectively (P less than 0.025)--compared with 27% in healthy Norwegians. An increased frequency of the HLA-DR4 antigens was also found in polyarticular onset JA (50% compared with 27%, P less than 0.05). The frequency of both the HLA-B27 (21%) and the DR5 antigen (21%) was increased in the whole patient group compared with controls (10% and 9%, respectively, P less than 0.01). The DR5 antigen was also increased in the systemic onset patients (40%, P less than 0.05). Both the DR5 and the DR8 antigens were increased in the pauciarticular onset group (P less than 0.05 and P less than 0.01, respectively). The results support the view that seropositive and seronegative JA are different disease entities and also that seropositive JA may be an early form of seropositive rheumatoid arthritis. The association between the DR4 antigen and IgM rheumatoid factor suggests that the HLA-DR4 gene or a closely linked gene may regulate autoimmune responses to self IgG.     

Juvenile rheumatoid arthritis, juvenile chronic arthritis, and juvenile spondyloarthropathies.

Immunogenetics are supporting the marked heterogeneity of chronic arthritis in children. Thus DRw13-DRw18 and DQw6-DQw18 were associated with persistent pauciarticular disease in children with an early onset of disease. Several studies have shown DPw2 as an additional susceptibility factor in this subgroup. Standardization of diagnostic criteria for juvenile onset spondyloarthropathy and psoriatic arthritis is necessary; various studies are in progress, and although HLA-B27 provides the common marker, this may only apply to a small group of juvenile psoriatics who have spondyloarthropathy. In the management of juvenile rheumatoid arthritis, methotrexate in moderate doses has been shown to be superior to lower doses of methotrexate and placebo in controlling polyarthritis. Methotrexate may be of particular value in treating the polyarthritis that follows a pauciarticular onset. The possible value of sulfasalazine in a B27 group with persistent polyarthritis has been suggested. Highlights of corticosteroid therapy were intra-articular injections, particularly in pauciarticular disease, the suggestion that deflazacort has a calcium sparing effect, and the possible role of intravenous methylprednisone in the management of severe 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.     

Spontaneous secretion of a proteoglycan releasing factor by mononuclear cells in juvenile arthritis

Patients with juvenile arthritis (JA) spontaneously produced a substance which accelerated proteoglycan loss from cultured articular cartilage. Peripheral blood mononuclear cells (PBMC) from 15 patients with JA were cultured for varying days, and cell-free PBMC conditioned media were added to articular cartilage cultures. Release of proteoglycan and collagen from cartilage was quantified by analysis of chondroitin sulfate and hydroxyproline content, respectively, after 4 days of culture. Conditioned media from PBMC of patients with systemic onset JA (3/3) and 5/7 patients with polyarticular JA increased release of proteoglycan when added to cartilage cultures. Mitogen stimulation of the PBMC was unnecessary for activity and addition of mitogen did not alter proteoglycan release. The PBMC conditioned media from the other patients (2/7) with polyarticular JA, from patients (3/3) with systemic onset JA which had progressed to polyarticular JA, and from patients with pauciarticular JA, did not enhance proteoglycan release without mitogen stimulation. PBMC of normal children produced media which enhanced proteoglycan release after mitogen stimulation. No conditioned medium accelerated proteoglycan release if cartilage was freeze killed before culture and none tested reduced cartilage collagen content.     

Autoantibody profiles in juvenile arthritis

Serologic and correlational testing was performed in a series of 65 patients diagnosed as having juvenile arthritis (JA) and in 21 age matched controls to detect the presence of antinuclear antibodies (ANA), antibodies to ssDNA, IgM and IgG rheumatoid factor (RF), immune complexes (IC) and antibodies to bovine type I and human type II collagen. ANA were found in 51% of the JA patients; the highest incidence (75%) was noted in the pauciarticular onset disease group. Low levels of anti-ssDNA antibodies were detected in 22% of the patients, all of whom had active disease. IgM RF was detected in 35% of the JA patients but only 6% of patients had IgG RF. Similarly, about one fourth of the JA patients had IC detected by the Clq assay. Antibodies to bovine type I and human type II collagen were noted in about 12% of the JA patients.     

Collagen antibodies in juvenile arthritis and adult rheumatoid arthritis: differences in levels and type-specificity

Antibodies to both native and denatured type II collagen were measured in the serum of 63 patients with juvenile onset arthritis (JA) and in 67 patients with adult onset rheumatoid arthritis (RA). Levels of antibodies in the 2 groups were compared with antibody levels in 30 healthy adult controls, and in 20 children with nonrheumatic diseases. Antibodies to denatured and native collagen were increased in RA but not in JA. There was no apparent difference between the collagen antibody levels in any of the 3 subgroups of JA, pauciarticular, polyarticular or systemic onset disease. Antibodies to denatured collagen were not type specific, and reacted similarly with type I and type II collagens, but antibodies to native collagen were much more specific, and most reacted more strongly on type II collagen than on type I collagen. Our results, unlike those in previous reports, imply that antibodies to collagen are infrequent in JA and hence cannot be implicated in the pathogenesis of that disease, which is in contrast to adult onset RA.     

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.     

Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis

OBJECTIVE: To examine the role of NRAMP1 in susceptibility to juvenile rheumatoid arthritis (JRA). METHODS: DNA from 119 JRA patients (72 pauciarticular, 47 polyarticular) and 111 healthy controls from Latvia was genotyped for a functional repeat polymorphism in the promoter of NRAMP1 and a linked (<150 kb) microsatellite D2S1471. The findings were compared with those from HLA-DQ alleles typed previously. Chi-square analyses were performed using the Mantel-Haenszel test and stratification according to pure Latvian or pure Russian descent. Haplotype analysis was performed using the Associate program to implement the expectation-maximization algorithm based on the gene-counting technique. RESULTS: Allele 3 at NRAMP1 conferred increased risk (odds ratios [ORs] 2.26, 2.31, and 2.19; P = 0.0006, 0.003, and 0.019) of disease in the JRA, pauciarticular, and polyarticular patient groups, respectively. Allele 2 conferred protection (OR 0.44, 0.43, and 0.46). Alleles at D2S1471 that conferred susceptibility (6 and 12) or protection (11) did so only when on a haplotype with alleles 3 or 2, respectively, at NRAMP1. Allele 3 at NRAMP1 was additive with HLA-DQ7 for susceptibility (OR 3.71, 3.71, and 4.02), and allele 2 at NRAMP1 was additive with HLA-DQ5 for protection (OR 0.19, 0.08, and 0.12). CONCLUSION: The NRAMP1 allele conferring susceptibility to JRA drives high levels of NRAMP1 expression, while the allele associated with protection drives low levels. These 2 alleles are inversely associated with susceptibility to infectious disease, consistent with their maintenance in populations through balancing selection.     

Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles.

OBJECTIVE: To define the onset and duration of effect of the HLA alleles that are associated with disease susceptibility and protection in juvenile rheumatoid arthritis (JRA) and 2 of its subtypes. METHODS: We typed 680 patients with JRA and 254 ethnically matched unrelated controls for HLA class I and II genes. The frequency of each allele was calculated for each of the age-at-onset, onset type, and sex categories and plotted against the allele frequency in the control population. Survival analysis (with onset of disease as the terminating event) was used to calculate the age by which 50% (St0.5) and 80% (St0.2) of the children with particular alleles and combinations of alleles develop disease. This allele-specific survival analysis also allowed for the comparison of the overall survival functions for the various JRA subtype and sex categories. RESULTS: Certain alleles are strongly associated with early susceptibility to pauciarticular JRA, including HLA-A2, DR8, DR5, and DPB1*0201. Fifty percent of the children carrying at least 1 of these alleles had disease onset prior to their third birthday. Among children who carried HLA-A2 and any 2 HLA-DR alleles (DR3, DR5, DR6, or DR8), the median age at the onset of pauciarticular disease was 2.7 years. Combinations of A2 and DPB1*0201 and one DR allele narrowed the window further to a median age at onset of 2.4 years. B27 and DR4 were associated with protection early in life but with increased risk later in childhood, with St0.5 values of 7.3 and 6.6 years, respectively, for pauciarticular JRA and St0.5 values of 10.2 and 10.7 years, respectively, for polyarticular JRA. Sex strongly influenced the age at which many of the alleles have their effect. CONCLUSION: These data define at what age and for how long various HLA alleles influence susceptibility and protection (window-of-effect) in patients with JRA. In addition, these data establish more clearly the boundaries of ages-at-onset for 2 of the subtypes of the disease.     

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.     

Immunogenetics of juvenile chronic arthritis in Israel

Typing for HLA-A,B,C and DR antigens was performed in 61 Israeli patients with juvenile chronic arthritis (JCA) and in 120 unrelated controls. No significant associations were apparent in the overall patient group. DR5 was significantly increased in the non-Ashkenazi patients with pauciarticular onset of disease. The only three DRw8 positive patients in the study had pauciarticular onset. DR5 and DRw8 were found in 9 of 10 patients with age of onset less than 3 years. Increased frequencies of Bw50 and Cw6 were observed in patients with systemic onset. Typing for properdin factor (Bf) and glyoxylase (GLO) was carried out in 45 and 50 of the patients, respectively. No associations with alleles of the complement Bf system or the HLA linked GLO system were evident. The confirmation in the ethnically distinct Israeli population of the previously described association of DR5 with pauciarticular JCA suggests that this gene may be closely related to the disease susceptibility gene.     

Juvenile rheumatoid arthritis: linkage to HLA demonstrated by allele sharing in affected sibpairs

OBJECTIVE: To test for linkage between the HLA region and juvenile rheumatoid arthritis (JRA), with stratification by onset and course types, in a cohort of affected sibling pairs (ASPs). METHODS: Eighty pairs of siblings with JRA who were registered with the Research Registry for JRA ASPs (sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases) were typed for HLA-DR. The observed ratio of sharing of none, one, or both parental DR alleles was compared against the expected ratio of 1:2:1 by goodness-of-fit chi-square tests. A group of 265 unrelated control subjects served as a comparison population for HLA-DR allele frequencies among patients, by Fisher's exact test. RESULTS: Overall, there was excess sharing of 2 DR alleles among ASPs with JRA. The observed ratio of sharing 0, 1, or 2 DR alleles was 8:40:32, instead of the expected ratio of 20:40:20 (P < 0.001). When stratified by JRA onset type, excess allele sharing was demonstrated among ASPs who were concordant for onset type (P = 0.002). This was true for both pauciarticular and polyarticular onset. When stratified by disease course, excess allele sharing was also demonstrated among ASPs who were concordant for disease course (P < 0.001). This was true for both the pauciarticular and the polyarticular course. Among the 32 ASPs who shared two DR alleles, 5 pairs had both DR8 and DR11, which was significantly more frequent (P < 0.0001) than the incidence in the control group (n = 0). CONCLUSION: This study of an independent cohort of multiplex families confirms the previously reported linkage between pauciarticular JRA and the HLA-DR region that was identified using a different analytic method in a cohort of simplex families. Additionally, this study establishes evidence for linkage between polyarticular JRA and the HLA-DR region.     

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.     

Sulfasalazine for the management of juvenile rheumatoid arthritis

OBJECTIVE: Sulfasalazine (SSZ) has regulatory approval for treatment of inflammatory bowel disease in children and adults, and for use as a slow acting agent in adult rheumatoid arthritis (RA). This report surveys the literature for experience with SSZ in juvenile RA. METHODS: Medline, Excerpta Medica, and Derwent were searched under the terms juvenile, rheumatoid, arthritis, and sulfasalazine. RESULTS: The search found reports of experience in 550 patients, of whom about half had pauciarticular and nearly one-third polyarticular disease. The studies generally reported at least some drug associated benefit in all subtypes. Some identified late onset pauciarticular disease as most responsive, but others reported poly- and pauciarticular response rates about the same. Systemic onset disease responded poorly and showed a substantial incidence of intolerance in the form of serum sickness. Most studies showed useful disease control in spondylitis. Overall, the patterns of toxicity and intolerance were close to those seen in adult SSZ recipients, with the possible exception of the serum sickness-like response. CONCLUSION: SSZ has demonstrated useful antirheumatic activity and can contribute to the care of selected patients.     

Uveitis in juvenile chronic arthritis

About 20% of patients with juvenile chronic arthritis develop uveitis which is frequently bilateral. Risk factors for uveitis are: female gender, pauciarticular onset of arthritis, presence of circulating antinuclear antibodies, and the antigens HLA-DW5 and HLA-DPw2. The visual prognosis in patients with uveitis is good in 25% and fair in 50%. The remaining 25% develop cataract and/or glaucoma. The management of glaucoma is unsatisfactory, but the results of cataract surgery by lensectomy are good.