Pauciarticular-onset Juvenile Rheumatoid Arthritis Research Articles

Do children with lupus have fewer male siblings?

It is widely acknowledged that genetic factors play a significant role in the pathogenesis of systemic lupus erythematosus (SLE). However, the female preponderance remains unexplained. We hypothesized that the female preponderance in childhood SLE results from selection early in the course of conception against male fetuses bearing genetic material predisposing to SLE. If this hypothesis is accurate, there should be a decreased number of male children in families with a child with SLE. Alternatively, children with SLE would have fewer male siblings. Further, this hypothesis may apply to other diseases with a female predominance such as pauciarticular onset juvenile rheumatoid arthritis (PaJRA), and not apply to diseases without female preponderance such as systemic onset juvenile rheumatoid arthritis (SoJRA). Chart review of patients with childhood onset SLE and PaJRA revealed a greater number of female children in these families compared with families of patients with SoJRA. Large-scale epidemiologic studies with precise counting of miscarriages and abortions could help to confirm these findings. Detailed studies of genetic and maternal intrauterine factors are required to conclusively prove this hypothesis.

Ocular manifestations of juvenile rheumatoid arthritis in Olmsted County, Minnesota: a population-based study.

Juvenile rheumatoid arthritis (JRA) is the most common systemic cause of uveitis in Europe and North America. The cumulative incidence of uveitis in JRA has been reported at between 8.5% and 25% in series from referral centers in the USA. There have been no population-based studies of the cumulative incidence of uveitis in JRA in the USA. We performed a population-based, retrospective cohort study of patients residing in Olmsted County, Minnesota between 1 January 1960 and 31 December 2000 who met American College of Rheumatology diagnostic criteria for JRA. The patients were identified using the Rochester Epidemiology Project (REP), a surveillance and medical records-linkage system which provides access to medical records of residents of Olmsted County. Patient histories were reviewed and information regarding rheumatic and ocular disease was extracted and analyzed. The main outcome measures were: cumulative incidence of uveitis, of complications of uveitis, of keratoconjunctivitis sicca (KCS) and of adverse visual outcome. Of the 88 patients identified, three patients developed uncomplicated uveitis [3.4%; 95% confidence intervals [CI] 0.7-9.6%), all with pauciarticular onset JRA. Two patients developed KCS (2.3%; 95% CI 0.3-8.0%). The visual acuity of these five patients at last follow-up (mean length of follow-up 22.6 years, range 8-36 years) was 20/20. There were no patients with visual loss attributable to JRA. In a population-based study of JRA in the United States, uveitis occurred at a lower frequency than expected. In the limited number of cases in this cohort with JRA-associated ophthalmologic complications there was no resulting loss of visual acuity.

Juvenile rheumatoid arthritis affected sibpairs: extent of clinical phenotype concordance.

To investigate the clinical phenotypes and demographic characteristics of 183 affected sibling pairs (ASPs) with juvenile rheumatoid arthritis (JRA) and to determine whether there are differences between the clinical phenotypes of the ASP cohort compared with patients with sporadic disease and whether there is greater sharing of specific clinical features within versus between sibpairs. Details of the JRA Affected Sibpair Registry operations have been described previously. The frequencies of phenotypes in the 2 cohorts were tabulated, summary statistics were determined, and comparisons were made by chi-square test or t-test. Sibling risk, sibling risk ratios (lambda(s)), and odds ratios were calculated to assess familial aggregation of several different clinical manifestations. The most common onset type among the 164 nontwin ASPs was pauciarticular (65% overall). Fifty-three percent of the ASPs were concordant for pauciarticular-onset JRA; 19% were concordant for a polyarticular disease onset. Among subjects with polyarticular-onset disease, significantly more joints were involved at onset in simplex patients than in ASPs (P = 0.008). The difference in age at JRA onset within sibpairs (sibling 1 versus sibling 2) was not significantly different. ASPs developed disease at a mean real-time difference of 5.1 years apart. Familial aggregation was found for tenosynovitis (lambda(s) 29.5), leukocytosis (lambda(s) 25), rheumatoid factor (lambda(s) 11.0), anemia (lambda(s) 1.7), and antinuclear antibodies (lambda(s) 1.3). This study confirms the findings of earlier studies showing that a high proportion of ASPs overall show concordance of disease-onset type, except for the subset of patients with systemic disease, and that nontwin ASPs do not develop disease at the same point in real time. We conclude that JRA and its clinical manifestations do not differ substantially between ASPs and the simplex population. The exception is the number of affected joints at JRA onset among patients with polyarticular-onset disease. Familial aggregation of clinical features among ASPs adds strong evidence for a genetic background in this disease.

Current Medication Choices in Juvenile Rheumatoid Arthritis II –Update of a Survey Performed in 1993

The documentation of treatments used for Juvenile Rheumatoid Arthritis (JRA) is important to allow for the evaluation of practice patterns for future outcome studies. A survey of nine pediatric rheumatologists was performed between September 1999 and February 2000. Each of the physicians prospectively recorded demographic and treatment information on consecutively sampled JRA patients (n=395). Pauciarticular onset JRA was present in 46%, polyarticular onset JRA in 35%, and systemic onset JRA in 19% of the children. Naproxen was the most frequently prescribed medication (55% of the patients), followed by methotrexate (MTX), which was used in 39% of the patients. Folic acid supplementation (1 mg/day) was provided to 69% of the patients treated with MTX. Etanercept was used in 11% of the children. Eleven percent of the patients received corticosteroids, and 13% of children on corticosteroids took calcium supplements. Uveitis was present in 8% and had a chronic course in 79% of those cases. Although systemic medications were used in 50% of the children with uveitis to control eye inflammation, severe damage to the eyes developed in 30% of them. Fourteen percent of the patients required gastroprotective medications. Compared with findings of a similar survey performed in 1993, there was no significant change in the frequency of use of naproxen, but nabumetone is now more often prescribed, and COX-2 inhibitors have been introduced in the therapy of JRA. Changes among second-line agents used for JRA have also occurred, although there was no change in the frequency of use of MTX or corticosteroids. JRA continues to be a treatment challenge for the practicing pediatric rheumatologist. Patients often show incomplete response to the currently available medications. Therefore, new therapeutic agents need to be evaluated for their use in JRA, and the treatment of JRA associated uveitis especially needs to be improved.

Myeloid-related proteins 8 and 14 are specifically secreted during interaction of phagocytes and activated endothelium and are useful markers for monitoring disease activity in pauciarticular-onset juvenile rheumatoid arthritis.

To analyze which physiologic stimuli induce secretion of myeloid-related protein 8 (MRP8) and MRP14, two S100 proteins expressed in neutrophils and monocytes, and to determine whether serum concentrations of these proteins are reliable parameters for monitoring inflammatory activity in pauciarticular juvenile rheumatoid arthritis (JRA). Secretion of MRP8 and MRP14 was analyzed using a coculture system of endothelial cells and monocytes. Concentrations of MRP8/MRP14 in the serum and synovial fluid of JRA patients or culture medium were determined by enzyme-linked immunosorbent assay. The expression of MRP8 and MRP14 by leukocytes in synovial tissue or fluid was investigated using immunohistochemistry. MRP8 and MRP14 were specifically released during interaction of activated monocytes with tumor necrosis factor-stimulated endothelial cells. Secretion was mediated via an increase in intracellular calcium levels in monocytes. In contrast, contact with resting endothelium inhibited protein kinase C-induced secretion of the proteins by monocytes. In JRA patients, MRP8 and MRP14 were strongly expressed in infiltrating neutrophils and monocytes within the inflamed joints and could be found in significantly higher concentrations in synovial fluid (mean 42,800 ng/ml) compared with serum (2,060 ng/ml). Concentrations of MRP8/MRP14 in serum correlated well with those in synovial fluid (r = 0.78) and showed a strong correlation with disease activity (r = 0.62). After intraarticular triamcinolone therapy, the serum concentrations of MRP8/MRP14 decreased significantly in therapy responders, whereas no differences were found in patients who showed no clinical benefit. MRP8 and MRP14 are specifically released during the interaction of monocytes with inflammatory activated endothelium, probably at sites of local inflammation. Their serum concentrations represent a useful marker for monitoring local inflammation in JRA.

Immunopathogenesis of juvenile rheumatoid arthritis.

The immunopathogenic mechanisms of juvenile rheumatoid arthritis (JRA) have been debated. A possible cellular-mediated hypothesis versus a possible B cell hyperreactivity have been entertained. This review will focus on some recent cellular work in JRA and also further evaluation of cytokine levels and their role in inflammation in JRA. Recent studies have evaluated the interrelationship of Th1/Th2 immune responses in the immunopathogenesis of JRA, and their effect on cytokine release. Studies have indicated a pro-inflammatory response in systemic-onset JRA manifested by increased secretion of interleukin-6, whereas an anti-inflammatory response has been noted by increases of IL-4 mRNA and IL-10 mRNA in pauciarticular-onset JRA. The continued finding of elevated levels of tumor necrosis factor-alpha (TNF-alpha) and its receptors in association with inflammatory activity has been seen. The recent use of a TNF fusion protein to block TNF-alpha activity in JRA has further contributed to this finding. Further studies on specific cytokines will be helpful in the future in trying to determine the different roles cytokines play in JRA subtypes and would contribute to the development of better therapeutic regimens.

Autoantibodies to transcriptional regulation proteins DEK and ALY in a patient with systemic lupus erythematosus

A human cDNA expression library that was used to investigate the nature of autoantigens recognized by the serum from a patient with systemic lupus erythematosus revealed the presence of antibodies directed against two transcriptional regulation protein: DEK, a site-specific 45 kD DNA binding protein, likely involved in signal transduction and transcriptional regulation, and a novel 28 kD protein that showed a 94% homology with murine ALY, a nuclear protein that plays a role in regulating the activity of TCRα enhancer complex. Whereas autoantibodies directed to epitopes on DEK are commonly found in patients with pauciarticular onset juvenile rheumatoid arthritis, autoantibodies against ALY have not been described and their occurrence has led to the cloning of the cDNA sequence of the first member of the human ALY family.

Transmission disequilibrium as a test of linkage and association between HLA alleles and pauciarticular-onset juvenile rheumatoid arthritis.

To determine if HLA class I and II alleles previously found to be associated with (or protective against) pauciarticular-onset juvenile rheumatoid arthritis (pauci-onset JRA) in population-association studies are transmitted from heterozygous parents to an extent different from the expected 50%. One hundred one Caucasian North American families that had a child with pauci-onset JRA and at least 1 parent who was heterozygous for the allele of interest were available for analysis. Both biologic parents and all children (affected and unaffected) were typed for HLA class I and II alleles. The transmission disequilibrium test (TDT) was used to determine if affected offspring received the disease-associated (or protective) allele more (or less) frequently than its alternate allele. In families in which an unaffected sibling was available, the unmatched chi-square test was used to determine if a meiotic segregation distortion bias existed. HLA class I alleles A2, B27, and B35 showed a significantly higher than expected frequency of transmission to affected offspring, as did class II alleles DR5 and DR8. HLA-DR4 was found to be transmitted significantly less frequently than expected to affected, but not unaffected, offspring. All alleles that showed an excess transmission to affected offspring were transmitted to unaffected offspring at expected rates. When the data were stratified by age and sex, the likelihood of transmission of some of the alleles was strongly influenced by these variables. For example, excess transmission of HLA-DR5 was found exclusively in female patients who were younger at the time of disease onset. Results from these family-based studies rule out the possibility that HLA disease associations found in earlier studies were a result of population stratification and establish linkage and association between the major histocompatibility complex and pauci-onset JRA.

Antibodies against a peptide sequence located in the linker region of the HMG-1/2 box domains in sera from patients with juvenile rheumatoid arthritis.

To extend our work on the mapping of B cell epitopes on nucleosomal high mobility group (HMG) proteins in the sera of patients with juvenile rheumatoid arthritis (JRA). Seventy-seven pauciarticular-onset JRA serum samples from antinuclear antibody (ANA)-positive patients and 42 polyarticular-onset JRA patient sera found to react with HMG-2 by immunoblotting were used in this study. To identify B cell epitopes on HMG-2, recombinant HMG-2 protein fragments were used in enzyme-linked immunosorbent assay (ELISA) and in competition ELISA experiments with a set of overlapping synthetic peptides. Fine epitope mapping was achieved by oligopeptide synthesis, followed by immunoblotting. Pauciarticular, but not polyarticular, JRA patient sera were found to recognize a lysine-rich major epitope (KKGKKKDP), which is located in the linker region of the HMG box domains of the HMG-2 nonhistone chromosomal protein. No significant immunoreactions were observed in sera from ANA-negative JRA patients and in sera from children with nonrheumatic diseases, indicating that this epitope seems to be specific for pauciarticular-onset JRA. In addition to our previous finding that JRA sera will react with a defined epitope on HMG-17, pauciarticular JRA patient sera were also found to recognize a defined epitope on the HMG-2 protein, thus suggesting the importance of this epitope in the etiology of JRA.

DEK, an autoantigen involved in a chromosomal translocation in acute myelogenous leukemia, binds to the HIV-2 enhancer.

The product of the dek oncogene is the 43-kDa DEK nuclear protein. DEK was first identified in a fusion with the CAN nucleoporin protein in a specific subtype of acute myelogenous leukemia. DEK has also been shown to be an autoantigen in patients with pauciarticular onset juvenile rheumatoid arthritis. Further, the last 65 amino acids of DEK can partially reverse the mutation-prone phenotype of cells from patients with ataxia-telangiectasia. However, in spite of these significant disease associations, the function of DEK has remained unclear. The HIV-2 peri-ets (pets) site is a TG-rich element found between the two Elf-1 binding sites in the HIV-2 enhancer. The pets element mediates transcriptional activation whether the enhancer is stimulated by phorbol 12-myristate 13-acetate (PMA) alone, phytohemagluttinin (PHA) alone, PMA plus PHA, soluble antibodies to the T cell receptor, immobilized antibodies to the T cell receptor, or by antigen. Previously, we purified and characterized the pets factor, demonstrating that it is a 43-kDa nuclear protein. We now describe the identification of DEK as this 43-kDa pets factor. Using a modified Southwestern screening procedure, we find that DEK can recognize the pets element. We demonstrate the ability of recombinant DEK to bind specifically to the pets site using the electrophoretic mobility shift assay (EMSA) and DNase I footprinting. "Supershift" EMSA further confirms that DEK is the dominant protein binding to the pets site in T cell extracts. Our findings show that DEK is a site-specific DNA binding protein that is likely involved in transcriptional regulation and signal transduction. This has implications for multiple pathogenic processes, including hematologic malignancies, arthritis, ataxia-telangiectasia, and AIDS caused by HIV-2.

Association of HLA-B39 with HLA-B27-negative ankylosing spondylitis and pauciarticular juvenile rheumatoid arthritis in Japanese patients. Evidence for a role of the peptide-anchoring B pocket.

To investigate the characteristics of HLA-B27 that render susceptibility to seronegative spondylarthropathies. Serologic HLA class I typing of Japanese patients with ankylosing spondylitis (AS), juvenile rheumatoid arthritis (JRA), and healthy controls, was performed. HLA-B39 subtypes were determined by polymerase chain reaction-sequence-specific oligohybridization. HLA-B27 was present in 40 of 48 patients with AS (83%), and in only 1 of 210 healthy controls (0.5%). Three of 8 patients (37.5%) who were negative for HLA-B27 were positive for HLA-B39, which was significantly higher compared with the HLA-B27-negative controls (6.2%; P = 0.01). Significant association with HLA-B39 was also noted in the JRA patients (16.7%; P < 0.01), especially in those patients with pauciarticular-onset disease (33.3%; P < 0.01). Ten of 13 HLA-B39-positive patients had subtype B*3901 and 3 had B*3902. Because HLA-B27 and HLA-B39 share Glu at position 45 and Cys at position 67, both of which constitute components of the peptide-anchoring B pocket, and because they possess similar peptide-ligand motifs, our results may support either the role of the peptides presented by class I antigens or the importance of Cys at position 67, in the development of spondylarthropathies and pauciarticular-onset JRA.

Use of a polymorphic dinucleotide repeat DNA marker in a T-cell receptor V beta gene to identify a distinct subset of pauciarticular-onset juvenile rheumatoid arthritis patients.

Use of a polymorphic dinucleotide repeat DNA marker in a T-cell receptor V beta gene to identify a distinct subset of pauciarticular-onset juvenile rheumatoid arthritis patients.

HLA and T cell receptor β‐chain DNA polymorphisms identify a distinct subset of patients with pauciarticular‐onset juvenile rheumatoid arthritis

To evaluate and extend upon a reported association of a T cell receptor (TCR) V beta coding region polymorphism with pauciarticular-onset juvenile rheumatoid arthritis (JRA). TCR V beta 6.1 genotypes and haplotypes in JRA and control groups were determined by DNA amplification. Haplotypes of the V beta 6.1 gene which encode a nonfunctional form of V beta 6.1 were significantly associated with pauciarticular JRA in patients possessing the HLA-DQA1*0101 allele (P = 0.0073). A TCR V beta gene segment in the vicinity of V beta 6.1, possibly V beta 6.1, is apparently involved in the pathogenesis of pauciarticular-onset JRA in DQA1*0101-positive individuals.

Autoantibodies to the chromosomal protein HMG-17 in juvenile rheumatoid arthritis.

To determine the antibody profiles in sera from patients with juvenile rheumatoid arthritis (JRA). Immunoblotting using nuclear extracts and recombinant high-mobility group (HMG) nonhistone chromosomal proteins. Antibodies directed against HMG-17 were found in 47% of antinuclear antibody (ANA)-positive patients with pauciarticular-onset JRA and in 16% of ANA-positive patients with polyarticular-onset JRA. HMG-17 values of 6% and 8%, respectively, were detected in ANA-negative patients with JRA and in those with nonrheumatic diseases. There is evidence for a high prevalence of anti-HMG-17 antibodies in sera of patients with pauciarticular-onset JRA.

SHOULDER LIMITATION IN JUVENILE RHEUMATOID ARTHRITIS

One hundred consecutive children with juvenile rheumatoid arthritis (JRA) were evaluated for shoulder dysfunction. Shoulder arthritis was virtually absent in all 45 children with pauciarticular onset JRA. Twenty of 40 children (50%) with polyarticular JRA and 12 of 15 (80%) with systemic onset JRA had shoulder involvement characterized by pain or restricted passive range of motion (PROM). Ninety-five percent of those with shoulder arthritis had bilateral involvement. Children with systemic onset were likely to have shoulder disease within 2.5 years of onset and to have more severely limited PROM. Children with polyarticular onset developed shoulder arthritis any time during the course of their disease. With either type of onset, internal rotation was the most commonly and severely limited motion, followed by abduction. Clinicians treating children with JRA should carefully monitor pain and examine both rotational and planar components of shoulder motion.

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 and T Cell Receptor Polymorphisms in Pauciarticular‐Onset Juvenile Rheumatoid Arthritis

The immunogenetic basis of pauciarticular-onset juvenile rheumatoid arthritis is unclear. We therefore analyzed the HLA and T cell receptor genes present in a clinically well-defined group of patients. We found that the DR8 haplotype contributes most of the HLA-associated risk, although alleles at other loci contribute independently. A candidate disease-associated T cell receptor polymorphism, in contrast, was not identified in this population. Mechanistic implications of these findings are discussed.

Shoulder limitation in juvenile rheumatoid arthritis.

One hundred consecutive children with juvenile rheumatoid arthritis (JRA) were evaluated for shoulder dysfunction. Shoulder arthritis was virtually absent in all 45 children with pauciarticular onset JRA. Twenty of 40 children (50%) with polyarticular JRA and 12 of 15 (80%) with systemic onset JRA had shoulder involvement characterized by pain or restricted passive range of motion (PROM). Ninety-five percent of those with shoulder arthritis had bilateral involvement. Children with systemic onset were likely to have shoulder disease within 2.5 years of onset and to have more severely limited PROM. Children with polyarticular onset developed shoulder arthritis any time during the course of their disease. With either type of onset, internal rotation was the most commonly and severely limited motion, followed by abduction. Clinicians treating children with JRA should carefully monitor pain and examine both rotational and planar components of shoulder motion.

Ocular Complications of Rheumatic Diseases of Childhood

The association between inflammatory ocular and articular disease is a strong one, although the pathogenesis of this relationship is obscure. For the physician or surgeon caring for children with chronic arthritis, awareness of the risk of chronic asymptomatic anterior uveitis is essential if early diagnosis, treatment, and prevention of visual impairment are to be accomplished. This is particularly true for children with pauciarticular-onset juvenile rheumatoid arthritis or psoriatic arthritis. Acute symptomatic anterior uveitis is characteristic of disorders such as ankylosing spondylitis. Whereas this disease is initially more unpleasant for the child, it has a good long-term prognosis.

Autoantibodies to nonhistone chromosomal proteins HMG‐1 and HMG‐2 in sera of patients with juvenile rheumatoid arthritis

IgG antibodies against the high mobility group (HMG) nonhistone chromosomal proteins HMG-1 and/or HMG-2 were detected in the sera of 49 (39%) of 126 antinuclear antibody (ANA)-positive patients with juvenile rheumatoid arthritis (JRA), by immunoblotting. Clinical diagnosis classified these patients in 2 major groups, 105 with pauciarticular-onset JRA and 21 with polyarticular-onset JRA. Anti-HMG-1 and/or anti-HMG-2 antibodies were found in 8 (25%) of 32 pauciarticular-onset JRA patients with uveitis and in 34 (47%) of 73 patients without uveitis, whereas anti-HMG-1 and/or anti-HMG-2 antibodies were found in 4 (24%) of 17 children with polyarticular-onset JRA without uveitis. Among 53 sera from ANA-negative JRA patients, 3 (6%) were positive for anti-HMG-1 and/or anti-HMG-2 antibodies, whereas no reactivity to HMG-1 or HMG-2 proteins was observed in 48 sera from age-matched children with nonrheumatic diseases.