The iridocyclitis of early onset pauciarticular juvenile rheumatoid arthritis: outcome in immunogenetically characterized patients.

In a cohort of 72 patients with iridocyclitis (iritis) and early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) the course of the eye disease was matched with ocular outcome. Chronicity of inflammation (greater than 6 months/episode) was correlated with complications of eye disease that caused impairment of vision. HLA antigens in these patients were compared with the HLA antigens in a cohort of 77 patients with EOPA-JRA in whom iridocyclitis had failed to develop over a followup of 5 years or longer. HLA-DR5 (11) was correlated with the presence of eye disease, and HLA-DR1 with its absence; HLA-DRw8, which strongly predisposes to EOPA-JRA, was neutral with respect to eye disease.     

Pregnancy and early onset pauciarticular juvenile chronic arthritis

OBJECTIVES: To study interaction of early onset pauciarticular juvenile chronic arthritis (EOP-JCA) and pregnancy in the Polish population, in particular to confirm the ameliorating effect of pregnancy on disease activity reported by others and to analyse the factors that govern the occurrence of postpartum flare, with emphasis on the potential role of breast feeding. METHODS: The reproductive outcome and disease status in 39 adult women with history of EOP- JCA was examined by means of a questionnaire and an interview. In all patients the disease onset occurred before the 6th birthday, 19 had persistent pauciarticular JCA (PeEOP-JCA) and 20 had extended pauciarticular JCA (ExEOP-JCA). RESULTS: 23 women had at least one successful pregnancy, seven had unsuccessful pregnancies but all of them had also one or more successful pregnancies. Among those who have never been pregnant (n=16) there was a higher frequency of eye disease and ExEOP-JCA compared with the rest of the group. In almost all cases pregnancy was associated with remission of disease activity, however a postpartum flare appeared after 22 pregnancies (52%). The flares were more frequent in women who had an active disease before pregnancy, had a flare after a previous pregnancy and/or were breast feeding. CONCLUSIONS: In EOP-JCA patients pregnancy generally has a good outcome and induces amelioration of disease activity. After delivery, however, a flare of disease often appears, especially in women who were breast feeding, had a postparum flare previously or had an active disease before pregnancy. The pattern of interaction between disease and pregnancy found in EOP-JCA makes EOP-JCA similar in this respect to RA, but different from systemic lupus erythematosus and ankylosing spondylitis.     

Stridor due to cricoarytenoid arthritis in pauciarticular onset juvenile rheumatoid arthritis

A 2-year-old girl developed severe inspiratory and expiratory stridor 2 months after onset of pauciarticular juvenile rheumatoid arthritis (JRA). Direct laryngoscopy demonstrated that both vocal cords were immobile and approximated to each other in the midline secondary to arthritis of the cricoarytenoid joints. High dose corticosteroid therapy resulted in clinical and laryngoscopic improvement and tracheostomy was avoided. Cricoarytenoid arthritis can be a life threatening complication in JRA. Early institution of corticosteroids appears to be the treatment of choice.     

Patterns of joint involvement at onset differentiate oligoarticular juvenile psoriatic arthritis from pauciarticular juvenile rheumatoid arthritis

OBJECTIVE: To compare the patterns of joint involvement of patients with oligoarticular onset juvenile psoriatic arthritis (Oligo-JPsA) and pauciarticular onset juvenile rheumatoid arthritis (Pauci-JRA) in order to estimate the predictive performance of specific patterns for the diagnosis of Oligo-JPsA. METHODS: Twenty-three children who fulfilled the diagnostic criteria for JPsA (Vancouver criteria) and who had fewer than 5 joints involved in the first 6 months of disease (Oligo-JPsA), and 64 children with Pauci-JRA (ACR criteria) were enrolled. Patients were also classified with respect to the ILAR criteria for juvenile idiopathic arthritis (JIA). Patient characteristics and clinical features at onset and during followup were determined. Patterns of joint involvement at onset of disease and their ability to differentiate between Oligo-JPsA and Pauci-JRA/Oligo-JIA were evaluated. RESULTS: Small joint disease (defined as involvement of any of the metatarsophalangeal or proximal or distal interphalangeal joints of the foot, or metacarpophalangeal or proximal or distal interphalangeal joints of the hand) was significantly more frequent in Oligo-JPsA than in Pauci-JRA at disease onset. The odds of patients with Oligo-JPsA having small joint disease or wrist disease within 6 months of disease onset were much higher than those with Pauci-JRA or Oligo-JIA (p < 0.05 or 0.001). CONCLUSION: Small joint disease and wrist disease are suggestive of Oligo-JPsA. The use of a criterion consisting of small joint disease and/or wrist disease and/or dactylitis instead of dactylitis alone may increase the ability to differentiate Oligo-JPsA from Pauci-JRA or Oligo-JIA.     

Increased frequency of TAP2B in early onset pauciarticular juvenile chronic arthritis.

OBJECTIVES--To determine whether polymorphisms of the TAP genes, which lie within the major histocompatibility complex (MHC), are associated with juvenile chronic arthritis (JCA). METHODS--Eighty five JCA patients and 166 white controls were typed for the TAP gene alleles using ARMS-PCR. The same populations were analysed for DRB1 and DPB1 alleles using PCR-SSO typing. RESULTS--TAP2B was increased in early onset pauciarticular JCA (EOPA-JCA) compared with controls (62% v 44% Odds ratio (OR) 2.1, 95% CI 0.9-4.7). After allowing for the known linkage disequilibrium between TAP2B and DR1 the association of TAP2B and EOPA-JCA was maintained (OR 3.5, 95% CI 1.3-9.7). HLA-DRB1*04 and TAP2D were found to be in linkage disequilibrium in both the control (delta 0.018 p < 0.05) and JCA patient groups (delta 0.021 p < 0.05). No linkage disequilibrium was found between the TAP and DPB1 alleles. CONCLUSIONS--The association between TAP2B and EOPA-JCA is a further indication of the heterogeneity which exists in this clinically defined subgroup of patients.     

Antibody to ribonucleoprotein in pauciarticular juvenile rheumatoid arthritis

Sera from 8 children with pauciarticular juvenile rheumatoid arthritis (JRA) were studied to determine the nuclear antigen to which antinuclear antibody (ANA) is directed. No patient had antibody to native DNA, nuclear histones, or saline soluble nuclear antigens. Trypsin treatment of the nuclear substrate abrogated ANA staining for all sera tested, while RNase treatment abrogated ANA activity for 6 of 8 sera. These results indicate that ANA in most patients with pauciarticular JRA is directed to a ribonucleoprotein that requires both RNA and protein moieties for antigenic integrity.     

Positive association of the HLA DMB1*0101-0101 genotype with rheumatoid arthritis.

OBJECTIVE: HLA DM is a non-classical major histocompatibility complex (MHC) class II molecule that has been shown to facilitate peptide loading with classical class II molecules. METHODS: In this study, we analysed the polymorphism in exon 3 of HLA DMA and DMB genes by a polymerase chain reaction-sequence-specific oligonucleotide probe method in 163 rheumatoid arthritis (RA) patients and 146 ethnically matched controls. The HLA-DRB1 genotype was also analysed by a reverse-dot blot method. RESULTS: Our results show in RA patients a significant increase in the HLA DMB*0101 allele frequency (83% vs 72.3% of the controls, P < 1.6 x 10(-3), significance at P < 0.0125) and in the HLA DMB*0101-0101 homozygote genotype frequency [70.8% vs 50% of the controls, P < 4.2 x 10(-4), significance at P < 0.00625, odds ratio (OR) = 2.4, 95% confidence interval (CI): 1.43-4]. The increase in DMB*0101 allele and homozygote genotype frequencies was independent of a linkage disequilibrium between DMB and DRB1 alleles. The analysis of non-random associations between the HLA-DM and DRB1 alleles only revealed a significant association in controls between DMB*0104 and DRB1*07 alleles (delta = 0.01, P < 7 x 10(-4), significance at P < 9.6 x 10(-4)). On the other hand, the DMB*0101-0102 genotype frequency was increased in DRB1*0401-negative RA patients as compared to controls (11% vs 2%, P < 0.011, significance at P < 0.015, OR = 6.2, 95% CI: 1.2-30). CONCLUSION: Our data suggest that HLA-DM alleles could play a role in the genetic susceptibility to RA.     

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.     

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.     

HLA-DR and MT associations with the clinical and serologic manifestations of pauciarticular onset juvenile rheumatoid arthritis

Significant HLA-DR and MT associations were observed with certain clinical and serologic manifestations of pauciarticular onset juvenile rheumatoid arthritis (PO-JRA). An increase in the MTI frequency was found in 56 children with PO-JRA in comparison to 95 normal controls. This association was limited to children with a younger age of onset (less than 6 years) and a persistent pauciarticular course. An increase in HLA-DRW8 and a decrease in DR4 were associated with a younger age of onset and antinuclear antibody (ANA) seropositivity. In addition, an increased frequency of DR5 was seen in ANA positive children. All of these HLA-DR and MT associations were independent of coassociating Ia specificities.     

Hla class ii alleles and heterogeneity of juvenile rheumatoid arthritis. drb1*0101 may define a novel subset of the disease

Objective. To examine the distribution of HLA class II alleles in clinically distinct juvenile rheumatoid arthritis (JRA) subsets. Methods. We typed 298 patients and 181 controls for HLA–DRB1, DQA1, DQB1, and DPB1 alleles using polymerase chain reaction and oligonucleotide probe techniques. Results. Each JRA subset was characterized by a distinct distribution of HLA class II alleles. For the persistently pauciarticular and rheumatoid factornegative polyarticular JRA subsets, certain combinations of DRB1 and DPB1 alleles were characteristic. In patients without antinuclear antibodies and chronic iridocyclitis, there was an increase of DRB1*0101/02 and DQA1*0101. Conclusion. Findings of HLA typing support clinical subdivisions of the disease and suggest the existence of a novel DRB1*0101/02 and DQA1*0101 associated disease subset.     

The early pattern of joint involvement predicts disease progression in children with oligoarticular (pauciarticular) juvenile rheumatoid arthritis

OBJECTIVE: To evaluate features during the first 6 months of disease that may be associated with a poor outcome as measured principally by extension to a polyarticular disease course in patients with oligoarticular-onset juvenile rheumatoid arthritis (oligo-JRA). METHODS: This study was a retrospective review of patients who fulfilled the American College of Rheumatology criteria for oligo-JRA, were followed up for at least 5 years, and did not have juvenile psoriatic arthritis, spondylarthropathy-like disease, or rheumatoid factor positivity. Data from the first 6 months of disease were collected. Continuous variables were dichotomized and then screened by univariate analysis for association with poor outcome at the last followup visit, as measured by extension of involvement (>4 accumulated involved joints) and by "clinically meaningful" extension (> or =10 accumulated joints). Variables significantly associated with this latter outcome, with the addition of disease duration as a confounding independent variable, were included in a multiple logistic regression analysis. The same variables were then examined in separate multiple logistic regression models to look at other measures of outcome, including use of disease-modifying antirheumatic drugs (DMARDs) at any time, erosive disease on radiographs, any remission of disease ever occurring, physician's global assessment of disease activity at the last visit, and disability as measured by the Childhood Health Assessment Questionnaire (C-HAQ)/HAQ. RESULTS: Of the 205 patients (160 of whom were female) studied for a median of 10.8 years (range 5-26.6 years), 39.5% developed extension to >4 joints and 17.6% developed arthritis in > or =10 joints. Using the logistic regression model, symmetric disease was predictive of all measures of poor outcome: extension to > or =10 joints (odds ratio [OR] 19.2), the need to use DMARDs (OR 11.5), radiographic demonstration of erosive disease (OR 4.73), inflammatory activity at last followup visit (OR 3.23), no remission of disease (OR 4.73), and disability as measured by a C-HAQ score >0.12 (OR 2.95). Ankle and/or wrist disease was predictive of extension (OR 6.61) and erosions (OR 3.59). Wrist disease alone was predictive of the need to use DMARDs (OR 5.87) and of inflammatory disease activity at the last followup visit (OR 4.01). An elevated erythrocyte sedimentation rate (ESR) was predictive of extension (OR 3.76), the need to use DMARDs (OR 6.47), and no remission of disease (OR 2.30). Disease duration was a confounding variable for extension (OR 1.18) and erosive disease (OR 1.19). CONCLUSION: The early presence of ankle and/or wrist disease, symmetric joint involvement, and an elevated ESR in a child with oligo-JRA indicates the likelihood of disease progression.     

Pregnancy outcome in women with rheumatoid arthritis before disease onset.

Pregnancy outcome before disease onset was evaluated for women with rheumatoid arthritis (RA) and control women as part of a prospective case-control study of newly diagnosed RA. An analysis of women who were ever gravid revealed no statistically significant difference in any adverse pregnancy outcome between RA cases (n = 144) and controls (n = 605) including spontaneous abortions and stillbirths. Thus, in contrast to reports both of an increase of adverse pregnancy outcomes and a decrease in women who subsequently develop RA, we found no evidence for any difference in pregnancy outcome in the RA group.     

Antibodies to peptidoglycan in juvenile onset ankylosing spondylitis and pauciarticular onset juvenile arthritis associated with chronic iridocyclitis

Using an indirect enzyme linked immunosorbent assay, antibodies of the IgG class to Streptococcus pyogenes group A peptidoglycan-polysaccharide polymers (PG-GSP) were measured in the sera of 37 patients with juvenile onset ankylosing spondylitis (JAS), 22 with pauciarticular onset juvenile arthritis associated with chronic iridocyclitis and 20 healthy children. Mean antibody activity, measured in arbitrary units, was of 184 U in JAS and 250 U in chronic iridocyclitis (p = NS). The results in both groups differed significantly from those found in healthy children (p less than 0.001 and p less than 0.01, respectively). This suggests either a possible role of bacterial cell wall products in the pathogenesis of these disorders or a state of immune reactivity to PG-GSP in these children.     

Comorbidity in rheumatoid arthritis of early onset. Effects on outcome parameters

Three-year follow-up data of 1,032 patients with recent onset rheumatoid arthritis (RA) were analyzed regarding the frequency of 21 common comorbid chronic conditions and their impact on health outcome (i.e., pain, functional capacity, disease activity, and radiographic joint damage). Multivariate logistic regression analyses were used to calculate age- and gender-adjusted odds ratios for each chronic condition on severe functional capacity (<60% of full function). Comorbidity was already common at the onset of RA, with 72% of the patients having at least one comorbid condition and almost 50% having at least two. Common comorbidities were associated with significantly worse baseline measures in at least three of seven investigated outcome parameters. The more of these conditions patients had, the worse their 3-year outcome. Functional capacity was most sensitive to comorbid conditions. In logistic regression, obesity, hypercholesterolemia, type II diabetes, and osteoporosis resulted in a twofold risk of severe functional limitation (<60% of full function), independent of each other and of age and gender. The impact of comorbidity on measures of disease severity should be considered when used to compare outcome parameters of different RA samples.     

Late onset pauciarticular juvenile chronic arthritis: relation to gut inflammation

Ileocolonoscopy with biopsy of the ileum, ileocecal valve and cecum was performed on 32 patients (22 males, 10 females) with juvenile chronic arthritis (JCA) with pauciarticular onset. Mean age at onset of disease was 12 years. Ankylosing spondylitis (AS) was diagnosed in 13 patients; the other 19 cases were classified as reactive arthritis with recurrent or persistent pauciarticular synovitis. Twenty-two patients (68%) were HLA-B27 positive; 8 patients (25%) carried the HLA-Bw62 antigen. Ileocolonoscopy was performed 6 months to 32 years after the initial manifestation of the disease (mean : 9 years). Fourteen patients had macroscopic lesions of the ileum and ileocecal valve although only 8 of these had a history of intestinal complaints. Twenty-six patients (81%) presented histological signs of gut inflammation. Most of the gut abnormalities were classified as active chronic or Crohn-like lesions (19/26). Only 7 patients had acute or bacterial enteritis-like lesions. Acute lesions were seen in only one patient with AS. All but 2 patients with sacroiliitis, in whom signs of gut inflammation were found, had active chronic lesions. All the 8 HLA-Bw62 positive patients had histological evidence of gut inflammation. Only chronic or Crohn-like lesions were found. In the majority of patients with JCA with pauciarticular onset, gut inflammation was found on ileum biopsy. Some of their lesions are related to Crohn's disease, and the presence of the HLA-Bw62 antigen could predispose to the arthritis seen in these cases.     

A specific HLA-DP beta allele is associated with pauciarticular juvenile rheumatoid arthritis but not adult rheumatoid arthritis.

Nonradioactive sequence-specific oligonucleotide probes specific for the HLA-DP beta locus have been used in a simple dot-blot format to type samples amplified by the polymerase chain reaction from 44 patients with pauciarticular juvenile rheumatoid arthritis, 32 patients with adult rheumatoid arthritis, and 50 random controls. The sequences of four new DP beta alleles derived from these patients and controls are reported, bringing the total number of alleles identified thus far to 19. The DPB2.1 allele is significantly increased in juvenile rheumatoid arthritis patients over controls; this allele is not increased in patients with adult rheumatoid arthritis. The association of juvenile rheumatoid arthritis with the DPB2.1 allele is independent of linkage with previously defined HLA-D region markers of disease. Analysis of the DPB2.1 sequence shows that it differs from the nonsusceptible DPB4.2 allele by only 1 amino acid at position 69 in the beta 1 domain.