Shared T cell recognition sites on human histocompatibility leukocyte antigen class II molecules of patients with seropositive rheumatoid arthritis

Seropositive rheumatoid arthritis (RA) in adult and juvenile patients is associated with the serologic marker HLA-DR4. This association is incomplete; about one-third of the patients lack the disease-associated HLA-DR4 haplotype. The main biological function of class II molecules is to restrict the recognition of antigen by T lymphocytes. We therefore tested the hypothesis that patients with seropositive RA share T cell recognition sites for an unknown antigen and that such T cell "epitopes" are not identified by conventional serologic typing. We generated alloreactive human T cell clones by stimulating peripheral blood lymphocytes of normal donors against a lymphoblastoid cell line from a juvenile patient with seropositive RA. A panel of clones that recognized only HLA-Dw14 cells on a panel of homozygous typing cells was used to analyze class II molecules of adult patients with seropositive RA. By inhibition studies using monoclonal antibodies, the epitopes recognized by the different clones could be further characterized and assigned either to DR- or to DQ-encoded cell surface products. By using four different clones, it was possible to identify Dw14-associated T cell epitopes on all seropositive rheumatoid patients tested who typed HLA-DR4-positive and also on all eight DR4-negative patients tested. Approximately one-half of nonrheumatoid DR4-positive donors carried one or more determinants recognized by these clones; the expression of these allodeterminants in DR4-negative nonrheumatoid patients was rare (less than 10%). Thus, alloreactive human T cell clones are powerful tools to define T cell recognition sites on class II molecules that are not identified by conventional typing. Using T cell clones with specificities for determinants expressed on Dw14 homozygous typing lines, we were able to demonstrate shared epitopes on cells of all patients tested with seropositive RA irrespective of their HLA-D or HLA-DR type. These data suggest that major histocompatibility complex class II antigens of RA patients might be much more homogeneous than demonstrated by the incomplete HLA-DR4 association.     

Familial rheumatoid arthritis: linkage of HLA to disease susceptibility locus in four families where proband presented with juvenile rheumatoid arthritis.

The occurrence of a chronic seronegative polyarthritis has been studied in four families in which the proband presented with some form of juvenile rheumatoid arthritis. In these families, histocompatibility testing suggested that susceptibility to arthritis was controlled by a dominant allele with variable penetrance and expressivity at the rheumatoid-like arthritis, first locus (RLA-1). The combined lod scores for the four families (2.70) indicated that the odds in favor of genetic linkage between the major histocompatibility complex and the postulated disease susceptibility gene, RLA-1, were 500:1. In one family, a recombinant event permitted localization of RLA-1 centromeric to HLA-D. Of major interest was the fact that there was significant pleomorphism in the clinical manifestations of arthritis in affected individuals. In some, symptoms first occurred in childhood and in others, in adult life. Even among those with childhood-onset arthritis, different types of juvenile rheumatoid arthritis were observed within the same family.     

Chronic musculoskeletal pain in children: part II. Rheumatic causes

Primary care physicians should have a working knowledge of rheumatic diseases of childhood that manifest primarily as musculoskeletal pain. Children with juvenile rheumatoid arthritis can present with painless joint inflammation and may have normal results on rheumatologic tests. Significant morbidity may result from associated painless uveitis, and children with juvenile rheumatoid arthritis should be screened by an ophthalmologist. The spondyloarthropathies (including juvenile ankylosing spondylitis and reactive arthritis) often cause enthesitis, and patients typically have positive results on a human leukocyte antigen B27 test and negative results on an antinuclear antibody test. Patients with acute rheumatic fever present with migratory arthritis two to three weeks after having untreated group A beta-hemolytic streptococcal pharyngitis. Henoch-Schbnlein purpura may manifest as arthritis before the classic purpuric rash appears. Systemic lupus erythematosus is rare in childhood but may cause significant morbidity and mortality if not treated early. Nonsteroidal anti-inflammatory drugs and physical therapy may be useful early interventions if a rheumatic illness is suspected. Family physicians should refer children when the diagnosis is in question or subspecialty treatment is required. Part I of this series discusses an approach to diagnosis with judicious use of laboratory and radiologic testing.     

Epidemiologic study on the distribution of HLA antigens in rheumatoid arthritis

Serologic HLA typing was carried out on 71 seropositive and 40 seronegative patients with rheumatoid arthritis and compared with values in 134 normal controls. A significant increase of HLA DR4 antigen, compared with control values, was found only in seropositive rheumatoid arthritis; HLA A1 and B35 antigens were significantly increased in seronegative rheumatoid arthritis patients (p less than 0.05), when compared with control values, but only HLA A1 antigen remained significantly higher when the p-correct test was performed.     

Chemotaxis of polymorphonuclear leukocytes from patients with rheumatoid arthritis

Using a new in vitro method of measuring the chemotaxis of polymorphonuclear leukocytes from peripheral blood, a chemotactic index has been calculated. The mean chemotactic index of 320 in 24 patients with definite rheumatoid arthritis, was significantly less (P < 0.0005) than the mean of 555 in 24 normal controls matched for age and sex.The mean chemotactic index of 435 in eight patients with juvenile rheumatoid arthritis was also significantly less (P < 0.01) than that of 553 in similarly matched controls.The chemotactic index could not be correlated with age, sex, disease activity, drugs used in treatment, latex titer, immunoglobulin levels, or protein coating on the cells. However, there was a correlation between the chemotactic index and the serum complement B(1e)/B(1a) value (P < 0.01) in 17 patients with adult onset rheumatoid arthritis. Although the serum complement B(1e)/B(1a) values were within the normal range, the lowest chemotactic indices were associated with the lowest complement values.The chemotactic indices in three patients with severe connective tissue disease (seropositive rheumatoid arthritis, systemic lupus erythematosus, and polymyositis) returned to normal after 5 days' treatment with 60 mg of prednisolone per day. Incubation of the cells from patients with rheumatoid arthritis with hydrocortisone in vitro failed to alter the chemotactic indices.Prior incubation of normal cells with purified rheumatoid factor complexes, rheumatoid serum, or macromolecules of iron dextran impaired their chemotaxis. It is suggested that phagocytosis of complexes in vivo is a possible mechanism by which the chemotaxis of the polymorphonuclear leukocytes of patients with rheumatoid arthritis is impaired.This impairment in chemotaxis may explain the increased incidence of bacterial infection, both during life and as a cause of death in these patients.     

Juvenile rheumatoid arthritis.

Juvenile rheumatoid arthritis is a diverse group of diseases that includes systemic-onset, polyarticular, and pauciarticular types. Appreciation of the different types and their hallmarks is particularly important to accurate diagnosis, which is determined by exclusion of other known disease entities in children with chronic arthritis (more than three months' duration). Therapy should be directed at the arthritis per se (synovitis), at the extra-articular manifestations, and at the whole child. Salicylates provide the most satisfactory control of the arthritis per se and of the systemic manifestations in most cases. Iridocyclitis should be managed in consultation with an ophthalmologist. Patients should not be regarded as invalids or restricted needlessly. The prognosis for children with juvenile rheumatoid arthritis is good. In most patients, the disease remits without causing permanent joint damage.     

Specific HLA-DR4-associated histocompatibility molecules characterize patients with seropositive juvenile rheumatoid arthritis

The structural and functional heterogeneity of HLA-DR4-associated specificities was investigated in patients with seropositive juvenile rheumatoid arthritis, a DR4-associated disease. Using a combination of HLA-D analysis by mixed lymphocyte culture and electrophoretic analysis of immunoprecipitated Ia molecules by two-dimensional polyacrylamide gels, we observed a surprisingly homogeneous pattern of HLA-D antigen expression. All patients expressed common structural products of the DR and DS loci, and 7/12 homozygous DR4 patients expressed a rare and subtle HLA-D heterozygous phenotype.     

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.     

Clinical pictures of juvenile rheumatoid arthritis]

Juvenile rheumatoid arthritis is a clinical syndrome of primary chronic arthritis in childhood. JRA is subdivided into three subtypes according to the clinical picture within six months of the onset of the disease. The clinical picture of systemic onset type usually starts with a characteristic spiking fever. Children with this onset type, sometimes have pleursy, percarditis, myocarditis, generalyzed lymphnode swelling, hepatosplenomegaly and rheumatoid rash, but arthritis may not appear within the first few months. Children with polyarticular onset type, joint manifestations are similar to that of the rheumatoid arthritis of the adult. In patients with the pauciarticular onset type, the prognosis of arthritis is relatively fair compared with the other two types, but the doctor must always be aware of the complication of chronic and recurrent uveitis which sometimes develop to glaucoma, without subjective signs.     

Inherited deficiency of the second component of complement. Rheumatic disease associations.

The prevalence of homozygous and heterozygous deficiency of the second component of complement (C2) was determined in patients with rheumatic disease including 137 with systemic lupus erythematosus (SLE), 274 with juvenile rheumatoid arthritis, and 134 with rheumatoid arthritis. 1 C2 homozygous deficient and 19 possible heterozygous deficient individuals were identified by using both immunochemical and functional assays to determine C2 levels. Of the 20, 8 had SLE (5.9%), 10 had juvenile rheumatoid arthritis (3.7%), and 2 had rheumatoid arthritis (1.4%), the homozygous deficient individual having SLE. The prevalence of C2 deficiency in the SLE and juvenile rheumatoid arthritis patients was significantly increased (P = 0.0009 and P = 0.02, respectively) when compared with controls, 6 (1.2%) of 509 blood donors having C2 levels consistent with heterozygous deficiency. 15 of the 20 C2 deficient patients were HLA typed and found to have antigens A10(Aw25), B18, or both. The patients with C2 deficiency and SLE had earlier age of onset of disease and less antinuclear antibody when compared with the C2 normal SLE patients. 11 families of the propositi were studied and found to have one or more C2 heterozygous deficient individuals. The family members had an equal distribution of rheumatic disease and antinuclear antibody in the C2 deficient and C2 normal groups. C2 deficient individuals were found to have significantly lower levels of properdin Factor B (242 mug/ml+/-54) when compared with the non-C2 deficient family members (282 mug/ml+/-73). These data support the concept that inherited deficiency of C2 is significantly associated with both SLE and juvenile rheumatoid arthritis.     

Use of the faces pain scale to evaluate pain of a pediatric patient with pauciarticular juvenile rheumatoid arthritis

The Faces Pain Scale developed by Wong and Baker is a common assessment tool that uses cartoon-like faces to assess self reported pain in children. The purpose of this case report is to explore the appropriateness of the Faces Pain Scale as an outcome measure for a young child with pauciarticular juvenile rheumatoid arthritis. The patient was a four-year-old boy who had undergone a synovectomy on his right knee secondary to pauciarticular JRA. Each session the patient was asked to rate his pain using the Faces Pain Scale. The patient gainedfull knee range of motion and his functional mobility improved compared to initial visit. His subjective pain rating remained constant at "no hurt" throughout three weeks of visits. His functional mobility did not match his subjective rating of pain via the Faces Pain Scale. Further research is needed to determine the relationship of pain, stiffness, and function in children with rheumatic diseases.     

Increased levels of lactoferrin in synovial fluid but not in serum from patients with rheumatoid arthritis

Lactoferrin is a multifunctional immunoregulatory protein, stored in specific granules of neutrophil granulocytes, from which it is released following cell activation. As activated neutrophils play a crucial role in the destruction of synovial joints in rheumatoid arthritis, we evaluated lactoferrin concentration in synovial fluid and sera from 21 patients with rheumatoid arthritis and 11 patients with osteoarthritis. We also measured lactoferrin levels in sera from 12 healthy controls. Lactoferrin was measured by a solid-phase inhibition immunoassay. Median lactoferrin levels were significantly higher in synovial fluid from rheumatoid arthritis than from osteoarthritis patients (P = 0.0002). In contrast, no significant difference was found between serum lactoferrin from patients with rheumatoid arthritis or osteoarthritis compared with normal controls. In patients with rheumatoid arthritis, lactoferrin concentrations were higher in synovial fluid than in sera (P = 0.036). In both rheumatoid arthritis and osteoarthritis no correlation was found between serum and synovial fluid lactoferrin (P = 0.51 and P = 0.5, respectively). In synovial fluid from patients with rheumatoid arthritis, lactoferrin concentrations correlated with neutrophil granulocyte count (P < 0.0001), but neither serum nor synovial lactoferrin levels correlated with disease activity (P = 0.32 and P = 0.25, respectively). In conclusion, lactoferrin is a reliable marker of neutrophil activation at sites of inflammation in rheumatoid synovitis, but does not represent a marker of disease activity.     

Salicylic acid disposition in children with rheumatoid arthritis

The plasma level profile of SA and SUA after a single oral dose of ASA was studied in 8 children with juvenile rheumatoid arthritis, aged 3.5-15.0 years. Pharmacokinetic parameters were on average similar to those reported in the literature for adult subjects, although a somewhat larger intersubject variability was found.     

Increased excretion of two sialic acid-containing trisaccharides in the urine of patients with rheumatoid arthritis

The urinary excretion of sialic acid-containing trisaccharides in patients with active rheumatoid arthritis was studied. Sialyl-lactose and sialyl-N-acetyllactosamine were identified and their excretion patterns studied by thin layer and gas chromatography. The urinary output of sialyl-lactose was greater in patients with active rheumatoid arthritis (48.2 +/- 6.1 mg/24 h, SEM, n = 6) than in healthy subjects (19.8 +/- 3.7 mg/24 h, SEM, n = 5; P less than 0.01). The excretion of sialyl-N-acetyllactosamine was also higher in the rheumatoid group (18.5 +/- 2.1 mg/24 h, SEM, n = 6) than in the controls (11.1 +/- 1.2 mg/24 h, SEM, n = 5; P less than 0.05). The qualitative excretion patterns of the sialyl-oligosaccharide fraction were similar for the two groups as judged from the thin layer chromatograms. Correlating the results with the clinical state of the patients with rheumatoid arthritis suggests that the urinary level of the sialyl-oligosaccharides reflects the activity of the disease. A proposed mechanism for the increased excretion of sialic acid-containing trisaccharides in rheumatoid arthritis is presented.     

Haptoglobulin and 2 -macroglobulin levels in children with rheumatoid arthritis

Haptoglobulin was raised and α₂-macroglobulin was low in 25 children with clinical findings compatible with juvenile rheumatoid arthritis compared with 25 healthy children of comparable age.Patients and normal children showed considerable individual variations in serum α₂-macroglobulins but the mean value of juvenile rheumatoid arthritis group was lower than that of normal, the difference being statistically highly significant. Haptoglobulins on the other hand were considerably higher with a mean value three times higher than normal. The elevation of serum haptoglobulins may prove to be helpful in establishing the diagnosis of not conclusive cases especially those of septicaemic type in which haptoglobulins were invariably highly increased.     

葡萄糖6-磷酸异构酶与类风湿关节炎患者临床表现的关系

目的探讨葡萄糖6磷酸异构酶(G6PI)抗原在类风湿关节炎(RA)的发生发展中的作用。方法用酶联免疫吸附试验(ELISA)检测140例RA患者、75例其他风湿性疾病患者和50名健康对照者血清中G6PI抗原的浓度,同时检测RA患者C反应蛋白(CRP)、类风湿因子(RF)、血沉(ESR),关节疼痛和肿胀数以及X线分级等。结果 RA组血清G6PI抗原浓度为(3.13±2.62)μg/mL,明显高于其他风湿性疾病组(0.148±0.045)μg/mL和健康对照组(0.107±0.065)μg/mL。RA组G6PI抗原阳性率明显高于其他风湿性疾病组和健康对照组(P<0.01)。RA活动组G6PI抗原浓度及阳性率高于RA非活动组(P<0.05)。G6PI抗原浓度和RA患者疼痛和肿胀关节数及CRP呈正相关。结论 G6PI抗原在RA的发病及关节损伤中有一定的作用,有可能成为诊断RA、判断其疾病活动性及疗效监测的一个辅助指标。     

Sleep quality in children with juvenile rheumatoid arthritis

Children with juvenile rheumatoid arthritis (JRA) report poor sleep quality, daytime sleepiness, fatigue, anxiety, and altered mood. Sleep disturbances in school-aged children are an issue of serious concern. Children are at an age when sleep is of primary importance to physical and intellectual growth, and sleep disturbances that begin in childhood may persist into adulthood. In this article we will review what is currently known about sleep in children with JRA, the influence of medications on sleep quality, the potential impact of poor sleep quality on daily life issues, and complementary/alternative modalities that may be effective in reducing sleep disturbances.     

Chronic musculoskeletal pain and functional status in juvenile rheumatoid arthritis: an empirical model

An empirical model is proposed and tested on variables hypothesized to influence functional status in 23 children with juvenile rheumatoid arthritis experiencing chronic musculoskeletal pain. Child psychological adjustment, family psychosocial environment, chronic musculoskeletal pain, and disease activity were entered into multiple regression analyses to statistically predict 4 functional status criterion variables: activities of daily living (ADL), activities involvement, school functioning, and social functioning. Predictor variable relationships were found for all 4 functional status criterion variables, suggesting initial support for this empirical model of functional status in children with juvenile rheumatoid arthritis experiencing chronic musculoskeletal pain.     

类风湿关节炎患儿外周血CD4+和CD8+T细胞CD25表达及意义

目的:分析小儿类风湿关节炎患者的外周血CD4 和CD8 T细胞CD25表达水平,并探讨它们在小儿关节炎症发生过程中的免疫病理作用。方法:收集24例类风湿关节炎患儿和16例健康儿童外周血标本,利用流式细胞仪检测CD4 、CD8 T细胞CD25表达,分析它们在疾病发展过程中的作用。结果:类风湿关节炎患儿外周血CD4 、CD8 T细胞CD25表达明显升高,与健康者比较差异有统计学意义(P<0.05),所有患儿均接受了有效的药物治疗,待症状控制后,分析发现患者的CD4 、CD8 T细胞表达CD25水平显著下降(P<0.05)。结论:类风湿关节炎患儿外周血T细胞表达CD25水平明显升高,提示T细胞在关节炎症病变过程中激活、增殖,参与关节滑膜组织及全身免疫应答。     

Exercise response in children with and without juvenile rheumatoid arthritis: a case-comparison study.

The primary purpose of the study was to compare the response to bicycle ergometer exercise in children with and without juvenile rheumatoid arthritis (JRA). Heart rate, exercise duration, highest work load completed, and peak oxygen consumption (peak VO2) were compared. A secondary purpose of the study was to determine the relationship between peak VO2 and articular disease severity. Thirty children with JRA and 30 controls matched for age, sex, and body surface area (BSA) were the subjects. Peak VO2 was determined by an open-circuit computerized gas analysis system. Peak VO2, highest work load completed, exercise duration, and peak heart rate were significantly lower among the children with JRA than their respective controls. Submaximal heart rate was significantly higher for the children with JRA. There was no difference in resting heart rate between the two groups. There was no relationship between peak VO2 and articular disease severity among the children with JRA. The results suggest that aerobic conditioning programs may be indicated soon after diagnosis for patients with JRA, regardless of the severity of their articular disease. One subject with JRA and 2 control subjects reported light-headedness and dizziness, and 1 subject with JRA complained of increased knee swelling. We recommend that physical therapists monitor patients for signs of exercise intolerance and joint symptoms during exercise training sessions. [Jasso Giannini M, Protas EJ. Exercise response in children with and without juvenile rheumatoid arthritis: a case-comparison study.