Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. RESULTS: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. CONCLUSIONS: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.

Uveitis associated with juvenile rheumatoid arthritis.

Chronic nongranulomatous uveitis associated with JRA, a distinctive clinical entity occurring almost exclusively in the pediatric age group, represents an important cause of visual impairment in children. Despite continuing clarification of the clinical manifestations of this disorder, the etiology of uveitis associated with JRA remains unknown and the pathophysiology is still poorly understood. Further study of uveitis-associated JRA, by the application of improved immunologic theories and techniques, should aid in developing more effective therapeutic and preventive strategies.

Antinuclear antibodies during pregnancy.

First, second, and third trimester serum samples from 100 healthy pregnant women, umbilical cord serum samples from each delivery, and, for comparison, sera from 76 nonpregnant control subjects were assayed by indirect immunofluorescence for the presence of antibody to human epithelioid cell nuclei at titers of greater than or equal to 1:80. At serum dilutions of 1:80, the numbers of samples positive in the first, second, third trimester, and cord sera were 18, 21, 21, and 15, respectively. At serum dilutions of 1:160, the numbers of sera positive for antinuclear antibodies in each trimester and in cord sera were 9, 12, 9, and 8, respectively. All but three women with positive tests for antinuclear antibodies remained positive throughout their pregnancies. The frequencies with which antinuclear antibodies were found during pregnancy were not significantly higher than the frequency of antinuclear antibodies in nonpregnant female control subjects. A review of pregnancy outcome indicated that maternal antinuclear antibodies are not, in general, associated with abnormalities of the pregnancy or of the offspring.

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.

Age and its effect on perceptions of psychopathology.

Fifty young (M age = 27.2 years) and 50 older (M age = 66.1 years) laywomen read descriptions of a healthy woman and women with four types of psychopathology. One half of each age group read descriptions of a younger woman, and one half read identical descriptions of an older woman. Participants rated both the severity of the problem and reasons for their judgments. No support was obtained for the hypothesis that psychopathological symptoms are viewed as part of the "normal" aging process.

Prevalence of antinuclear antibodies in a rural population.

Exposure to environmentally and occupationally encountered toxicants can be associated with the development of certain autoimmune diseases and with the induction of antinuclear antibodies (ANA). Some chemicals used in the agricultural industry are known to affect immune function but their roles in the induction of autoimmunity in general, and ANA in particular, have not been reported previously. This study was undertaken to establish the prevalence of ANA in a rural population and to determine environmental and occupational exposures with which they are associated. This cross-sectional study represented one component of an interdisciplinary project (Prairie Ecosystem Study [PECOS], Eco-Research Program, Tri-Council Secretariat of Canada) designed to explore, in a rural population, the roles of environmental exposures as determinants of human health status. Information regarding lifetime, current, and main occupational exposures in the rural-dwelling study population was derived from a self-administered questionnaire. Sera from consenting subjects, collected during the months of February and March 1996, were assayed for ANA by indirect immunofluorescence on HEp-2 cells. The study population comprised 322 adult subjects (mean age 49.3+/-14.7 yr; range 16-87 yr). Statistical analyses adjusted for age and sex revealed that the presence of ANA among the participants was associated with a current agricultural occupation that included oilseed production, hog production, or poultry production. There was a significant association between ANA positivity and a current main farming operation of crop production. There was also an association among individual participants between lifetime exposure to the insecticide class of pesticides and the presence of ANA. In this rural study population, ANA positivity was significantly associated with lifetime exposure specifically to carbamate, organochlorine (including aldrin, chlordane, dieldrin, endrin, heptachlor, and lindane, but excluding DDT and methoxychlor), and pyrethroid insecticides and to phenoxyacetic acid herbicides, including 2,4-D. After adjustment for age, sex, and other insecticide exposures, multivariate analyses indicated that ANA positivity was associated with current oilseed production and with lifetime exposure to pyrethroid insecticides. In a rural population, ANA were associated with production of certain crops and certain animals and exposure to specific pesticides. The data indicate that some occupational exposures related to the agricultural industry are associated with the presence of ANA, a serologic expression of autoimmunity.

Cytokine genotypes correlate with pain and radiologically defined joint damage in patients with juvenile rheumatoid arthritis.

OBJECTIVES: Single nucleotide polymorphisms (SNPs) in cytokine genes have been associated with risk of a number of autoimmune diseases. Moreover, some SNPs are associated with variations in rates of in vitro gene expression, and it is therefore possible that these functional polymorphisms may differentially affect inflammatory processes and disease outcome. This project's objective was to determine whether cytokine genotypes correlate with disease outcomes in patients with juvenile rheumatoid arthritis (JRA). METHODS: Genotypes of SNPs of pro-inflammatory cytokines, tumour necrosis factor-alpha -308G -->A, interleukin-6 (IL-6) -174G -->C and interferon-gamma +874G -->A, and anti-inflammatory, immunosuppressive cytokines, interleukin-10 -1082G -->A, -819C -->T and -592A -->C and transforming growth factor-beta1 (TGF-beta1) codon 10T -->C and codon 25G -->C, were determined for patients with JRA who previously participated in a long-term outcome study. Cytokine genotypes and clinical variables showing significant correlations with clinical outcomes at the alpha = 0.100 level in univariate analyses were entered in multivariate tests. RESULTS: In multivariate tests, the IL-6 genotype -174G/G was positively correlated with pain [regression coefficient B = 0.899, 95% confidence intervals (CI) 0.185, 1.612, P = 0.014]. The homozygous TGF-beta1 codon 25G/G genotype showed a protective effect against joint space narrowing on radiographs taken within 2 yr of disease onset, but confidence intervals were wide [odds ratio (OR) 0.176, 95% CI 0.037, 0.837 P = 0.029]. CONCLUSIONS: The correlation of IL-6 genotype with pain and the possible association of the TGF-beta1 codon 25 genotype with short-term radiographic damage (G/C with greater risk and G/G with decreased risk) suggests that both these polymorphisms may be useful early prognostic indicators. Further studies of the relation between cytokine genotypes and outcomes in patients with all forms of juvenile idiopathic arthritis (JIA) are warranted.

Advanced drug therapy for juvenile rheumatoid arthritis.

Childhood rheumatic diseases are frequently chronic, painful, and potentially debilitating. They may adversely affect growth and development, compromise future quality of life, and contribute added stress to the patient and family. Awareness of these consequences provides a stimulus to develop more effective therapeutic regimens. There is optimism that new therapeutic strategies will result in the more widespread and earlier use of drugs, including those discussed, that may substantially impede or arrest the underlying disease.

The clinical associations of antinuclear antibodies in juvenile rheumatoid arthritis.

To clarify further the clinical correlates of antinuclear antibodies (ANA) in children with juvenile rheumatoid arthritis (JRA) this study compared the features of 60 ANA positive and 25 ANA negative children with JRA. ANA was more likely to be present in those with pauciarticular JRA than polyarticular JRA particularly if the ANA was of high titer. ANA positive subjects were more likely to have extraarticular manifestations, especially iridocyclitis. No significant differences were observed in onset ages, sex distribution, season of disease onset, family histories, or prognosis. There was no correlation between ANA titer and disease activity. Thus, while certain clinical features do correlate with ANA positivity in JRA, most clinical manifestations do not occur with distinctively different frequencies in the ANA negative and ANA positive groups.

Analysis of a pediatric rheumatology clinic population.

This analysis evaluates the role of a pediatric rheumatology clinic in assessing children with suspected rheumatic diseases and establishes relative disease frequencies in a clinic population. The study population comprised 875 children referred to a pediatric rheumatology clinic serving a population of 290,000 children. The mean annual referral rate was 113 patients. A diagnosis was established in 580 (66%) of whom 337 (58%) had a rheumatic disease. Of those with a rheumatic disease 156 (46%) had juvenile rheumatoid arthritis, 104 (31%) a spondyloarthropathy, 62 (18%) a connective tissue/collagen vascular disorder and 15 (5%) a variety of other conditions. Of the 243 diagnosed as having a nonrheumatic disease 79 (33%) had a mechanical or traumatic cause for musculoskeletal symptoms, 33 (14%) had an infection, 15 (6%) a neoplastic disorder and 71 (29%) a variety of other disorders. In addition, 45 children (19%) were evaluated because of family histories of rheumatic diseases or questionably abnormal symptoms or signs; after evaluation all these children were considered to be normal. The remaining group comprised 295 subjects (34%) for whom a definite diagnosis has not been made. In addition to diagnosing and caring for children with rheumatic disorders a pediatric rheumatology clinic serves to identify nonrheumatic conditions and provides information concerning relative frequencies and epidemiologic characteristics of childhood rheumatic diseases.

Advances in pediatric rheumatology.

Rheumatic diseases among children are being recognized with increasing frequency. The emergence of rheumatology as a pediatric subspecialty has been associated with a more comprehensive and co-ordinated approach to patient assessment and care. More clearly focused pediatric rheumatology research has contributed to improved disease classification, to the development of more sophisticated diagnostic tests, and to more judicious use of pharmacologic therapy. A heightened awareness among physicians of rheumatic diseases in children has been an important factor contributing to earlier diagnosis and improved care.

Treatment of juvenile rheumatoid arthritis: approach to patients who fail standard therapy.

Approaches to the initial management of juvenile rheumatoid arthritis and comprehensive therapeutic strategies for the management of children who fail to respond to first line treatment are reviewed. Guidelines for introducing advanced antirheumatic drugs, combination therapy, experimental agents, and alternative forms of therapy are considered.

Evaluation of associations between breast feeding and subsequent development of juvenile rheumatoid arthritis.

OBJECTIVE: To determine if previously breast fed children are more or less likely to have developed juvenile rheumatoid arthritis (JRA). Reports suggest that non-breast fed children are more likely to develop certain diseases for which an autoimmune pathogenesis is suspected. METHODS: Data from a longitudinal, case controlled population survey of childhood rheumatic diseases in Saskatchewan, Canada, included information pertaining to breast feeding history. These data were analyzed in the context of a retrospective, case controlled study to confirm results of an earlier report in which JRA was found to occur less frequently in previously breast fed children. For this analysis a child who had been breast fed for any length of time was categorized as having been a breast fed subject. RESULTS: A population of 88 children with pauciarticular JRA were more likely than an unmatched control population of 331 healthy children (p = 0.01) or those with polyarticular JRA (p = 0.006) to have been breast fed. However, when corrected for the number of comparisons made, statistical significance was not achieved 49 children with polyarticular JRA did not have a breast feeding history significantly different from the unmatched control population. In a retrospective, case control analysis of 54 children with pauciarticular JRA and 23 children with polyarticular JRA, no significant differences were noted when the JRA populations were compared to the parent selected, matched control populations (odds ratio for pauciarticular JRA 2.17: confidence interval 0.87-5.44; p = 0.06 and for polyarticular JRA 1.17: CI 0.33-4.20: p = 0.78). CONCLUSION: These results do not indicate a strong relationship between antecedent breast feeding and the subsequent onset of JRA and fail to confirm the results of earlier analyses in which JRA was found to occur more frequently in children who had not been breast fed.

Juvenile onset spondyloarthropathies.

Refinement of criteria for classifying childhood rheumatic diseases has contributed to earlier, more complete, and more precise diagnosis of children with spondyloarthropathies. Recent additions to the literature have contributed new international perspectives relating to the prevalence of juvenile spondyloarthropathies. Aspects of extra-articular features of juvenile spondyloarthropathies, including ocular, cardiac, and pulmonary disease have been considered in recent publications. The value of magnetic resonance imaging in identifying sacroiliitis in children and adolescents has been proposed. A study of cytokine profiles in chronic childhood arthritides could have both pathogenic and potential therapeutic implications. Factors influencing the course and prognosis of juvenile spondyloarthropathies have been presented in recent literature contributions.

Reiter's disease in children.

Three Canadian Indian boys, aged 2, 14, and 15 years, with features of Reiter's disease (RD) had arthritis occur that was characterized by noticeable tenderness and large effusions. The two youngest also had conjunctivitis and urethritis and thus conformed to the classical triad of RD. The eldest had dysuria and a history suggesting keratoderma blennorrhagica. All had HLA-B27 antigen. Inclusions indicative of chlamydial infection were seen in assays from the two youngest boys. Previously documented cases of childhood RD have been reviewed. More flexible diagnostic criteria may be useful in identifying this class of seronegative arthritis in children.

A syndrome of seronegative enthesopathy and arthropathy in children.

Thirty-nine children with a syndrome of seronegative enthesopathy and arthropathy were evaluated. The group included 25 patients with no apparent underlying primary disease and 13 with either ankylosing spondylitis, inflammatory bowel disease, reactive arthritis, or Reiter's syndrome. Significant distinguishing characteristics of the group included male predominance, late age at onset, positive family histories of arthritis, oligoarthropathy, axial skeleton involvement, and the presence of the B27 histocompatibility antigen. This syndrome is distinguishable from other childhood rheumatic disorders, including juvenile rheumatoid arthritis. Its recognition may reliably identify children with the prodromal manifestations of seronegative spondylarthropathies.

Antinuclear antibodies in arthritic and nonarthritic children with uveitis.

We determined whether a positive test for antinuclear antibodies correlated with uveitis only in children with juvenile rheumatoid arthritis (JRA) or whether they also represented a serologic marker for isolated idiopathic chronic uveitis in children. We conclude that the immunopathogenesis of uveitis associated with JRA is different from that of idiopathic chronic uveitis.

The relationship between ocular and articular disease activity in children with juvenile rheumatoid arthritis and associated uveitis.

The onset patterns and disease courses of children with juvenile rheumatoid arthritis and uveitis were reviewed to establish correlations. Results indicated that although the disease activity of arthritis and uveitis may at times run a parallel course, it is more common for the activities to be independent.

The binding of dsDNA and ssDNA to human types I, II and IV collagens.

Our study was undertaken to determine if dsDNA and ssDNA, which are known to bind to bovine collagen and to glomerular basement membrane, also bind to purified human types I, II and IV collagens. Four human sera with antibodies to dsDNA and 4 human sera with antibodies to ssDNA, when employed in an enzyme linked immunosorbent assay, detected DNA binding to the solid phase only when the solid phase had been precoated with collagen. Mean optical densities (OD) of .978, 1.062 and 1.033 for dsDNA binding to types I, II and IV collagens, respectively, were substantially higher than the mean OD value of .177 obtained when dsDNA was applied to the noncollagen coated solid phase. Similarly, mean OD values of .664, .526 and .902 for ssDNA binding to types I, II and IV collagens, respectively, were higher than the mean OD value of .147 obtained when ssDNA was applied to the noncollagen coated solid phase. The affinity of DNA for collagen could be an important factor contributing to the localization of DNA-anti-DNA complexes in target tissues.