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Background

This is a controversial disease entity. Some investigators believe that the childhood variant of this is juvenile rheumatoid arthritis, distinguishing it from the Adult-onset Still's disease. Others feel that Still's disease and juvenile rheumatoid arthritis are two separate and distinct disease entities, although both share overlapping signs and symptoms. Classically, patients present with fever, a skin rash, and joint pain. With time the disease may evolve to a chronic arthritis.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/
Other Diagnostic Testing
 
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

 

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS  
INCIDENCE/
PREVALENCE
 
Familial aggregation of juvenile idiopathic arthritis.

Prahalad S, O'brien E, Fraser AM, Kerber RA, Mineau GP, Pratt D, Donaldson D, Bamshad MJ, Bohnsack J.

University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Arthritis Rheum. 2004 Dec;50(12):4022-7. Abstract quote  

OBJECTIVE: To estimate the degree of familial aggregation of juvenile idiopathic arthritis (JIA), determine whether the aggregation of JIA and the aggregation of type 1 diabetes mellitus (type 1 DM) overlap, and identify multiplex JIA pedigrees.

METHODS: Records of individuals with JIA or type 1 DM were probabilistically linked with records in the Utah Population Database (UPDB), a large computerized family history database. For each case of JIA or type 1 DM, 10 matched controls or 5 matched controls, respectively, were selected. All familial relationships among cases of JIA or type 1 DM were established. A familial risk score was calculated for each subject. For various levels of familial exposure to JIA or type 1 DM, one's risk (odds ratio [OR]) of developing JIA or type 1 DM was established (cases compared with controls). Recurrence risks for JIA were computed for relatives of JIA cases compared with relatives of controls. Extended JIA families were identified from a list of common ancestors.

RESULTS: Records of a total of 443 patients were linked with the UPDB. Of these, 381 (86.0%) met criteria for JIA. An increased risk for JIA was observed among relatives of probands with JIA. The prevalence of type 1 DM among JIA cases was higher than the US prevalence of type 1 DM (P < 0.003). The recurrence risk for JIA was significantly elevated among first-degree relatives of cases with JIA (OR 30.4). The overall prevalence of JIA was 28/100,000. Four extended JIA pedigrees were identified.

CONCLUSION: There is familial aggregation of JIA in the Intermountain West region of the US. We have demonstrated that multiplex JIA pedigrees can be identified using a genealogic database.
AGE  
SEX  
GEOGRAPHY  
Prevalence of pediatric systemic lupus erythematosus and juvenile chronic arthritis in a Chinese population: a nation-wide prospective population-based study in Taiwan.

Huang JL, Yao TC, See LC.

Department of Pediatrics, College of Medicine, Chang Gung University, Chang Gung Children's Hospital, Taoyuan, Taiwan.
Clin Exp Rheumatol. 2004 Nov-Dec;22(6):776-80. Abstract quote  

OBJECTIVE: To estimate the national prevalence of systemic lupus erythematosus (SLE) and juvenile chronic arthritis (JCA) in Chinese children in Taiwan.

METHODS: A nationwide prospective population based epidemiologic study for the prevalence of pediatric SLE and JCA was undertaken in Taiwan (23 million inhabitants). The population at risk was identified as children under the age of 16 living in Taiwan (5.78 million). All citizens have been obligated to participate in Taiwan's National Health Insurance program since 1995. This gave us access to nationwide case data from the Major Illness/Injury registry and enabled us to calculate population prevalence. The population data were derived from the 1999 Taiwan census.

RESULTS: Three hundred sixty-five and 218 prevalent cases of pediatric SLE and JCA were identified, respectively. The prevalence of pediatric SLE was 6.3 per 100,000 (95% CI: 5.7-7.0). The prevalence in girls (11.2 per 100,000, 95% CI: 10.0-12.5) was 6.2 times higher than that in boys (1.8 per 100,000, 95% CI: 1.4-2.4). The prevalence of SLE substantially increased in children over the age of seven, especially in girls. The prevalence of JCA was 3.8 per 100,000 (95% CI: 3.3-4.3). The figures were similar for boys (3.5 per 100,000, 95% CI: 2.9-4.2) and girls (4.1 per 100,000, 95% CI: 3.3-4.9).

CONCLUSION: In this first population based epidemiologic survey of pediatric SLE and JCA in Taiwan, we provided a good starting point in our understanding of the epidemiology of these serious conditions in the Chinese population. The discrepancies between our prevalence figures and those reported from Western countries are possibly the results from true differences pertaining to ethnicity, geography or both. Future studies are necessary to elucidate the implications suggested by these data.

 

DISEASE ASSOCIATIONS CHARACTERIZATION
AUTOIMMUNE DISEASE  
Thyroid function, autoimmune thyroiditis and coeliac disease in juvenile idiopathic arthritis.

Stagi S, Giani T, Simonini G, Falcini F.

Department of Paediatrics, University of Florence, Italy.

Rheumatology (Oxford). 2005 Apr;44(4):517-20. Epub 2005 Feb 3. Abstract quote  

OBJECTIVES: Autoimmune diseases have been associated with some organ non-specific rheumatological disorders such as rheumatoid arthritis and systemic lupus erythematosus; however, few studies have been performed in an extensive cohort of children with juvenile idiopathic arthritis (JIA). Our objective was to evaluate the thyroid function and the prevalence of antithyroid antibodies, autoimmune thyroiditis and coeliac disease in children with JIA.

METHODS: One hundred and fifty-one children (120 female, 31 male, median age 8.3 yr, range 2.4-16.9 yr) with JIA were evaluated. All patients underwent thyroid function tests (u-TSH, free T(4) and free T(3)), antithyroglobulin (TgA) and antiperoxidase (TPOA) antibodies, antigliadin, anti-endomysium and antitransglutaminase antibodies. All patients with raised thyroid stimulating hormone levels, low thyroid hormone levels or positive TPOA and/or TgA values had a thyroid high-resolution sonography examination. Coeliac disease was confirmed by jejunal biopsy if the specific antibodies profile was positive. One hundred and fifty-eight age- and sex-matched Caucasian children from the same geographical area acted as controls.

RESULTS: Fourteen (9.3%) patients showed subclinical hypothyroidism, 17 (11.9%) patients showed autoimmune thyroiditis with nine patients also showing a non-homogeneous thyroid parenchyma at ultrasound evaluation. Coeliac disease was demonstrated in 10 (6.6%) patients. Compared with controls, JIA patients had higher prevalence of subclinical hypothyroidism (P < 0.01), autoimmune thyroiditis (P < 0.0001) and coeliac disease (P < 0.005).

CONCLUSIONS: JIA children have an increased prevalence of autoimmune thyroiditis, subclinical hypothyroidism and coeliac disease. These data seem to suggest careful monitoring of thyroid function, thyroid autoantibodies and coeliac disease in JIA children.

 

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

Oen K, Malleson PN, Cabral DA, Rosenberg AM, Petty RE, Nickerson P, Reed M.

Departments of Paediatrics, University of Manitoba, Winnipeg, Manitoba, Canada.

Rheumatology (Oxford). 2005 May 18; [Epub ahead of print] Abstract quote  

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.
TAPASIN GENE  
Tapasin gene polymorphism in systemic onset juvenile rheumatoid arthritis: a family-based case-control study.

Bukulmez H, Fife M, Tsoras M, Thompson SD, Twine NA, Woo P, Olson JM, Elston RC, Glass DN, Colbert RA.

William S, Rowe Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
Arthritis Res Ther. 2005;7(2):R285-90. Epub 2005 Jan 11. Abstract quote  

Juvenile rheumatoid arthritis (JRA) comprises a group of chronic systemic inflammatory disorders that primarily affect joints and can cause long-term disability. JRA is likely to be a complex genetic trait, or a series of such traits, with both genetic and environmental factors contributing to the risk for developing the disease and to its progression. The HLA region on the short arm of chromosome 6 has been intensively evaluated for genetic contributors to JRA, and multiple associations, and more recently linkage, has been detected. Other genes involved in innate and acquired immunity also map to near the HLA cluster on 6p, and it is possible that variation within these genes also confers risk for developing JRA.

We examined the TPSN gene, which encodes tapasin, an endoplasmic reticulum chaperone that is involved in antigen processing, to elucidate its involvement, if any, in JRA. We employed both a case-control approach and the transmission disequilibrium test, and found linkage and association between the TPSN allele (Arg260) and the systemic onset subtype of JRA. Two independent JRA cohorts were used, one recruited from the Rheumatology Clinic at Cincinnati Children's Hospital Medical Center (82 simplex families) and one collected by the British Paediatric Rheumatology Group in London, England (74 simplex families). The transmission disequilibrium test for these cohorts combined was statistically significant (chi2 = 4.2, one degree of freedom; P = 0.04). Linkage disequilibrium testing between the HLA alleles that are known to be associated with systemic onset JRA did not reveal linkage disequilibrium with the Arg260 allele, either in the Cincinnati systemic onset JRA cohort or in 113 Caucasian healthy individuals.

These results suggest that there is a weak association between systemic onset JRA and the TPSN polymorphism, possibly due to linkage disequilibrium with an as yet unknown susceptibility allele in the centromeric part of chromosome 6.

 

LABORATORY/
RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
RADIOLOGIC  
Radiographic progression in children with polyarticular juvenile rheumatoid arthritis: a pilot study.

Mason T, Reed AM, Nelson AM, Thomas KB.

Division of Rheumatology, Mayo Clinic, Rochester, MN 55905, USA.
Ann Rheum Dis. 2005 Mar;64(3):491-3. Abstract quote  

OBJECTIVE: To assess disease progression on hand/wrist x rays from children with polyarticular juvenile rheumatoid arthritis.

METHODS: Initial and subsequent films of 13 white children (10 girls) were read blind by a paediatric radiologist for the presence of joint space narrowing (JSN), erosions, and relative carpal length (RCL).

RESULTS: One child had subcutaneous nodules; one (of 11) was rheumatoid factor positive; six were ANA positive. Median age at diagnosis was 10.7 years (2.5 to 15.9). Median number of involved joints (swelling, pain, or decreased range of motion) at diagnosis was 16 (6 to 33). Four initial x rays had either erosions or JSN. Subsequent x rays were done at (median) 13.3 (8.3 to 24.9) months after initial x rays. One of 10 subsequent x rays had shortened RCL, and six of 13 were worse than the initial ones. Four of these developed new erosions, one had increased number of erosions, and one developed new JSN.

CONCLUSIONS: About half the children with polyarticular juvenile rheumatoid arthritis will have evidence of radiographic progression within two years after diagnosis. Thus newly diagnosed children are at high risk of substantial joint destruction and potential disability, emphasising the need for prompt treatment.
Frequency of abnormal hand and wrist radiographs at time of diagnosis of polyarticular juvenile rheumatoid arthritis.

Mason T, Reed AM, Nelson AM, Thomas KB, Patton A, Hoffman AD, Achenbach S, O'Fallon WM.

Department of Radiology, Mayo Clinic, Rochester, Minnesota 55905, USA.

J Rheumatol. 2002 Oct;29(10):2214-8. Abstract quote  

OBJECTIVE: To determine the frequency of radiographic abnormalities in hand/wrist radiographs of children with newly diagnosed polyarticular juvenile rheumatoid arthritis (polyJRA) because radiographs of small joints are an important tool in assessing outcomes in RA and there are clinical similarities between RA and polyJRA.

METHODS: A medical record review was performed to identify cases of polyJRA seen at Mayo Clinic from January 1, 1994, to December 31, 2001. Hand/wrist radiographs, obtained at the time of diagnosis, were reviewed by 3 radiologists with attention to periarticular osteopenia, joint space narrowing (JSN), or erosion. At least 2 radiologists had to independently identify abnormal findings on the same radiograph. The relative carpal length (RCL), judged by Poznanski's method, was also determined.

RESULTS: From the review of 159 medical records, 60 cases of newly diagnosed polyJRA were identified. Twenty-five of these had hand/wrist radiographs at diagnosis; 18 sets were available for this study. Of those, 2/3 were female, 6% (1/18) had subcutaneous nodules, 7% (1/14) had elevated levels of serum rheumatoid factor, and 44% (7/16) had elevated serum levels of antinuclear antibodies. Median age at diagnosis was 10.2 years, median duration of hand/wrist symptoms at diagnosis was 10 months, and median number of joints with either swelling, pain on range of motion (ROM), or limited ROM was 14.5. Sixty-one percent of radiographs taken at the time of diagnosis of polyJRA were abnormal. While 44% had periarticular osteopenia, 28% had either erosions or JSN. Six (33%) had RCL > 2 SD below the mean for age. Five (83%) of those with RCL, > 2 SD below the mean for age, had periarticular osteopenia, JSN, or erosion.

CONCLUSION: We conclude the frequency of abnormal hand/wrist radiographs is very high very early in the course of polyJRA. More studies are needed to determine to what extent these radiographic abnormalities correlate with clinical outcomes.
Radiologic features in juvenile idiopathic arthritis: a first step in the development of a standardized assessment method.

van Rossum MA, Zwinderman AH, Boers M, Dijkmans BA, van Soesbergen RM, Fiselier TJ, Franssen MJ, ten Cate R, van Suijlekom-Smit LW, Wulffraat NM, Kuis W, van Luijk WH, Oostveen JC, Dijkstra PF; Dutch Juvenile Idiopathic Arthritis Study Group.

Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
Arthritis Rheum. 2003 Feb;48(2):507-15. Abstract quote  

OBJECTIVE: To describe radiologic features of patients with juvenile idiopathic arthritis (JIA) in a standardized manner, to test the reliability and feasibility of this description, and to correlate these features with clinical signs as a first step in the development of a standardized assessment method.

METHODS: The placebo-controlled study of sulfasalazine in patients with oligoarticular, extended oligoarticular, and polyarticular JIA performed by the Dutch Juvenile Idiopathic Arthritis Study Group yielded the data for this study. All trial entry radiographs (clinically involved joints and contralateral joints) were scored (in consensus by a skeletal radiologist and pediatric rheumatologist) for the presence of swelling, osteopenia, joint space narrowing, growth abnormalities, subchondral bone cysts, erosions, and malalignment.

RESULTS: Data on 67 of 69 patients were analyzed. The mean age was 9.1 years (range 2.5-17.6 years), and the median disease duration was 24 months (range 5-176 months). Thirteen percent of the patients were IgM rheumatoid factor (IgM-RF) positive, and 16% were HLA-B27 positive. All 68 clinically evaluated joints were included in the maximum of 19 radiographed joints (or joint groups) per patient. The mean number of radiographed joints per patient was 7 (range 2-15); knees, hands, ankles, and feet were most frequently affected. Fifty-eight patients (87%) had radiologic abnormalities in at least one joint (soft-tissue swelling in 63% of patients, growth disturbances in 48%, joint space narrowing in 28%, and erosions in 15%). In total, half of the radiographs of the clinically involved joints showed radiologic abnormalities, including two-thirds of the radiographs of the clinically affected hands and knees. Univariate analysis revealed a good correlation between the overall articular (clinical) severity and the presence of radiologic abnormalities (odds ratio [OR] 1.38, P < 0.0001). Multivariate analysis showed increased ORs for the presence of radiologic abnormalities and IgM-RF positivity (OR 4.6, P = 0.005) or HLA-B27 positivity (OR 3.0, P = 0.004). In general, reproducibility of the radiologic scoring method was good (mean kappa coefficient of 0.74 [range 0.40-0.86]), although there were scoring discrepancies for swelling, osteopenia, and growth disturbances. The scoring took 10-20 minutes per patient.

CONCLUSION: Our model of describing and scoring radiologic abnormalities of radiographed joints in JIA was feasible, mostly reproducible, correlated well with the overall articular severity score, and added substantial new information not available on clinical examination.
LABORATORY MARKERS  
ANTI-CCP (CYCLIC CITRULLINATED PEPTIDE)  
Antibodies against cyclic citrullinated peptide are associated with HLA-DR4 in simplex and multiplex polyarticular-onset juvenile rheumatoid arthritis.

Ferucci ED, Majka DS, Parrish LA, Moroldo MB, Ryan M, Passo M, Thompson SD, Deane KD, Rewers M, Arend WP, Glass DN, Norris JM, Holers VM.

Division of Rheumatology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.


Arthritis Rheum. 2005 Jan;52(1):239-46. Abstract quote  

OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies have been detected in patients with juvenile rheumatoid arthritis (JRA), particularly in those with polyarticular, rheumatoid factor (RF)-positive JRA. Our objectives were to determine whether anti-CCP antibodies are associated with HLA-DR4 in children with polyarticular JRA, whether anti-CCP antibodies are associated with clinical features of disease, and whether affected sibling pairs (ASPs) with JRA are concordant for this antibody.

METHODS: Stored serum samples obtained from 230 HLA-typed patients with JRA (77 with polyarticular-onset disease and 153 with pauciarticular- or systemic-onset disease), 100 JRA ASPs, and 688 healthy children were tested for anti-CCP antibodies and RF.

RESULTS: Thirteen percent of the patients with polyarticular-onset JRA and 2% of the other JRA patients exhibited anti-CCP antibodies, compared with only 0.6% of the controls. Fifty-seven percent of RF-positive patients with polyarticular-onset JRA had anti-CCP antibodies. HLA-DR4-positive patients with polyarticular-onset JRA were more likely to have anti-CCP antibodies than were those without HLA-DR4 alleles (odds ratio [OR] 5.20, 95% confidence interval [95% CI] 1.30-20.9). Anti-CCP antibodies were associated with polyarticular onset (OR 7.46, 95% CI 1.99-28.0), a polyarticular disease course (OR 9.78, 95% CI 1.25-76.7), and erosive disease (OR 14.3, 95% CI 3.01-67.9). Concordance rates for anti-CCP antibodies among ASPs were statistically significant.

CONCLUSION: These data demonstrate increased anti-CCP antibody formation in HLA-DR4-positive patients with polyarticular-onset JRA. The overall prevalence of anti-CCP antibodies in JRA is low, but a substantial proportion of RF-positive patients with polyarticular-onset JRA have these antibodies. Anti-CCP antibodies in JRA are associated with polyarticular onset, a polyarticular course, and erosive disease.
ICAM  
Association of intercellular adhesion molecule-1 with clinical manifestations and interleukin-18 in patients with active, untreated adult-onset Still's disease.

Chen DY, Lan JL, Lin FJ, Hsieh TY.

National Yang-Ming University, Taipei, and Taichung Veterans General Hospital, Taichung, Taiwan.
Arthritis Rheum. 2005 Jun 2;53(3):320-327 [Epub ahead of print] Abstract quote  

OBJECTIVE: To investigate the association of intercellular adhesion molecule 1 (ICAM-1) with clinical manifestations and interleukin-18 (IL-18) levels in patients with active untreated adult-onset Still's disease (AOSD).

METHODS: We determined serum soluble ICAM-1 (sICAM-1) levels by enzyme-linked immunosorbent assay in 50 patients with active untreated AOSD, 20 patients with active rheumatoid arthritis (RA), and 20 healthy controls. The levels of ICAM-1 messenger RNA expression in IL-18-stimulated peripheral blood mononuclear cells (PBMCs) and in biopsy specimens obtained from AOSD patients with Still's rash or synovitis were investigated using real-time quantitative polymerase chain reaction.

RESULTS: Significantly higher serum levels of sICAM-1 were observed in patients with active untreated AOSD compared with those with active RA and healthy controls. Serum sICAM-1 levels were significantly correlated with the clinical activity score (r = 0.565, P < 0.001), ferritin values (r = 0.462, P < 0.005), and IL-18 levels (r = 0.462, P < 0.005) in patients with AOSD. The serum sICAM-1 level was identified as a predictor of hepatic dysfunction (odds ratio [OR] 1.016, P = 0.011) and disseminated intravascular coagulation (DIC) (OR 1.013, P = 0.023). Up-regulation of ICAM-1 gene expression was demonstrated in IL-18-stimulated PBMCs from patients with AOSD. Increased levels of ICAM-1 transcripts were observed in the biopsy specimens obtained from AOSD patients with Still's rash or synovitis compared with healthy skin and patients with osteoarthritis.

CONCLUSION: The serum sICAM-1 level may be used as a clinical marker to assess disease activity and may predict the occurrence of hepatic dysfunction and DIC in AOSD. IL-18-up-regulated gene expression of ICAM-1 may contribute to the inflammatory response in AOSD.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
Does systemic-onset juvenile idiopathic arthritis belong under juvenile idiopathic arthritis?

Ramanan AV, Grom AA.

Department of Paediatric Rheumatology, North Bristol NHS Trust & Royal National Hospital for Rheumatic Diseases, Bath, UK.
Rheumatology (Oxford). 2005 Jun 14; [Epub ahead of print] Abstract quote  

'Science is the systematic classification of experience' George Henry Lewes (1817-78), English philosopher, critic, dramatist, scientist. Juvenile idiopathic arthritis (JIA) is prevalent in about 1 in 1000 children. The earliest formal description of this disease was by Sir George Frederick Still in 1897 [1].

This work was done when he was a registrar at the Hospital for Sick Children, Great Ormond Street, London [2]. In this initial description of 19 patients he identified three patterns of arthritis, one of which came to be known later as Still's disease [now known as systemic-onset juvenile idiopathic arthritis (SoJIA)]. Over the next few decades it came to be appreciated that one form of arthritis in children is very different and dominated by the presence of systemic manifestations.

Over the last two decades several paediatric rheumatologists have come together to classify juvenile arthritis for purposes of better disease identification and research. All along, the systemic form of juvenile arthritis was always recognized as belonging to a distinct group; in fact for several decades (and even now in some countries) the systemic form of juvenile arthritis was referred to as Still's disease.

In this article we will attempt to highlight the reasons why we feel that SoJIA is perhaps not best retained in the company of JIA.
VARIANTS  
ANA POSITIVE  
Patients with antinuclear antibody-positive juvenile idiopathic arthritis constitute a homogeneous subgroup irrespective of the course of joint disease.

Ravelli A, Felici E, Magni-Manzoni S, Pistorio A, Novarini C, Bozzola E, Viola S, Martini A.

IRCCS G. Gaslini, Genoa, Italy.
Arthritis Rheum. 2005 Mar;52(3):826-32. Abstract quote  

OBJECTIVE: We recently hypothesized that in the International League of Associations for Rheumatology (ILAR) classification of juvenile idiopathic arthritis (JIA), the presumably homogeneous patient group characterized by early onset of disease, a female predilection, the presence of antinuclear antibodies (ANA), asymmetric arthritis, and the risk for iridocyclitis is classified into different categories. We sought to investigate whether ANA-positive patients belonging to the ILAR categories of oligoarthritis and rheumatoid factor (RF)-negative polyarthritis share homogeneous features and to compare these features with those of ANA-negative patients with JIA in the same categories.

METHODS: We identified patients who were followed up during a 15-year period. All patients had JIA according to the ILAR criteria, with oligoarticular or polyarticular onset. ANA positivity was defined as 2 or more positive results at a titer of >or=1:160. Demographic and clinical features, including the number of joints involved over time and measures of JIA severity at the last followup visit, were recorded retrospectively.

RESULTS: A total of 256 patients were included: 190 were ANA positive (109 had persistent oligoarthritis, 48 had extended oligoarthritis, and 33 had RF-negative polyarthritis), and 66 were ANA negative (35 had RF-negative polyarthritis, and 31 had oligoarthritis). All patients who were positive for ANA were similar in terms of age at disease presentation, female-to-male ratio, and frequency of symmetric arthritis and iridocyclitis. Compared with ANA-positive patients with polyarticular disease, ANA-negative patients with polyarticular arthritis were older at disease presentation and had a lower frequency of iridocyclitis, a higher frequency of symmetric arthritis, a greater cumulative number of joints affected over time, and a different pattern of joint disease, with a greater frequency of shoulder and hip involvement. The strong relationship between the presence of ANA and younger age at disease presentation, asymmetric arthritis, and development of iridocyclitis was confirmed by multivariate regression analysis.

CONCLUSION: Our results support the hypothesis that patients with similar characteristics are currently classified into different JIA categories. The value of ANA positivity as a possible modifier of the current classification system deserves consideration.
MACROPHAGE ACTIVATION SYNDROME  
Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.

Ravelli A, Magni-Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N, Viola S, Martini A.

Department of Pediatrics, Division of Pediatrics II, University of Genoa, Istituto G. Gaslini, Largo G. Gaslini 5, 16147 Genoa, Italy.
J Pediatr. 2005 May;146(5):598-604. Abstract quote  

OBJECTIVE: To develop diagnostic guidelines for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (S-JIA).

STUDY DESIGN: We followed the classification criteria approach that is based on the comparison of patients with the index disease with patients with a "confusable" disease. The former group included 74 patients with S-JIA-associated MAS reported in the literature or seen by the authors; the latter group included 37 patients with S-JIA who had 51 instances of "high disease activity" seen by the authors. The relative power of clinical, laboratory, and histopathologic variables in discriminating patients with MAS from patients with high disease activity was evaluated by calculating the sensitivity rate, specificity rate, area under the receiver operating characteristic curve, and diagnostic odds ratio (DOR). The combinations of variables that led to best separation between patients and control subjects were identified through "the number of criteria present" method.

RESULTS: The strongest clinical discriminators were hemorrhages (DOR = 67) and central nervous system dysfunction (DOR = 63); the strongest laboratory discriminators were decreased platelet count (DOR = 1092), increased aspartate aminotransferase (DOR = 247), leukopenia (DOR = 70), and hypofibrinogenemia (DOR = 165). The best separation between patients and control subjects occurred when any 2 or more laboratory criteria (DOR = 1309) were simultaneously present; the second best performance was provided by the presence of any 2, 3, or more clinical and/or laboratory criteria (DOR = 765 and 743, respectively).

CONCLUSION: We identified preliminary diagnostic guidelines for MAS complicating S-JIA. These guidelines deserve prospective validation.
UVEITIS  
Visual outcome of juvenile rheumatoid arthritis-associated uveitis in adults.

Ozdal PC, Vianna RN, Deschenes J.

McGill University, Department of Ophthalmology, Uveitis Service Montreal Canada.
Ocul Immunol Inflamm. 2005 Feb;13(1):33-8. Abstract quote  

PURPOSE: Juvenile rheumatoid arthritis (JRA) is the systemic disease most frequently associated in childhood uveitis. The disease may cause several ocular complications, visual impairment, and blindness. Recent studies revealed a more favorable ocular prognosis. Our purpose was to analyze the long-term visual outcome of JRA-associated uveitis.

METHODS: Ocular complications and visual outcome in adult patients with JRA-associated uveitis were evaluated. Among 18 patients included in the study, uveitis was bilateral in 12 (66.7%) and unilateral in six (33.3%), for a total of 30 eyes with ocular involvement.

RESULTS: The mean durations of JRA and its associated uveitis were 24.9 and 20.5 years, respectively. All eyes (100%) had at least one ocular complication. The most frequently observed ocular complications were cataract (83.3%), band keratopathy (60%), posterior synechia (46.7%), glaucoma (33.3%), hypotony (16.7%), and macular pathology (13.3%). Final visual acuity was impaired in 40% of the eyes, poor in 20%, and totally lost in 10%. Therefore, 70% of the eyes were either visually handicapped or totally blind. Most eyes underwent at least one surgical procedure. Inflammation was active at last examination in 63.3% of eyes. All patients were still treated topically and with systemic NSAID. Sixty-one percent of the patients were using an immunosuppressive agent.

CONCLUSION: JRA-associated uveitis still has a severe course and blinding potential. Patients suffer from uveitis and its complications even during the adulthood period. However, because our series represents a more severe subset of the disease, the outcome may be poorer than that of some other outcome studies.

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL  
SKIN  
Histopathology of persistent papules and plaques in adult-onset Still's disease.

Lee JY, Yang CC, Hsu MM.

Department of Dermatology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
J Am Acad Dermatol. 2005 Jun;52(6):1003-8. Abstract quote  

BACKGROUND: Persistent plaques and linear pigmentation have been reported as specific skin lesions in some patients with adult-onset Still's disease (AOSD).

OBJECTIVE: We sought to characterize the histologic findings of AOSD-associated persistent rash in 11 cases and correlate the histologic findings with the clinical features.

METHODS: From 1988 to 2004, 17 cases fulfilling Yamaguchi's criteria for AOSD in our hospital were reviewed and 11 (65%) manifested persistent papules and plaques. The pathology of 13 biopsy specimens of persistent eruption from 9 patients was reviewed.

RESULTS: The 11 patients consisted of 3 men and 8 women with age of onset ranging from 19 to 67 years (average 34.7 years). Evanescent Still's rash was recorded in 9 patients. The persistent rash manifested as pruritic, red, violaceous, or brownish scaly or crusted lichenoid papules and plaques usually widely distributed over the trunk, neck, face, and extensor sides of the extremities. Lesions arranged in a bizarre linear pattern resulting from scratching were noted in some patients. Three patients died of severe disease, systemic complications, or both. The histology of persistent papules and plaques was characterized by: (1) multiple individual necrotic keratinocytes, singly or in aggregates, mainly located in the upper epidermis, including the normal or parakeratotic horny layer; and (2) infiltration of lymphocytes and neutrophils in the papillary and middermis. Other less common findings included basal vacuolar alteration, nuclear dust, and subcorneal or intracorneal pustules.

CONCLUSIONS: A clinically and pathologically distinct form of persistent lichenoid eruption was commonly observed in our patients with AOSD. The combination of multiple individual necrotic keratinocytes in the upper epidermis and a dermal infiltrate of neutrophils allow for histologic differentiation of this persistent eruption from most other lichenoid and interface dermatitides and may facilitate an earlier diagnosis of AOSD.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
SPECIAL STAINS  
IMMUNOPEROXIDASE  
ELECTRON MICROSCOPY  

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

 

PROGNOSIS CHARACTERIZATION
GENERAL  
Outcome following onset of juvenile idiopathic inflammatory arthritis: I. Frequency of different outcomes.

Adib N, Silman A, Thomson W.

Arthritis Research Campaign Epidemiology Unit, School of Epidemiology and Health Sciences, University of Manchester Medical School, Manchester M13 9PT, UK.
Rheumatology (Oxford). 2005 Apr 12; [Epub ahead of print] Abstract quote  

Objective. To determine the outcome, following the onset of juvenile idiopathic inflammatory arthritis, in terms of remission of disease activity, loss of function and structural damage based on a review of the available published data.

Methods. Electronic databases were searched for major studies publishing outcome data in the past 10 yr in juvenile idiopathic arthritis, juvenile rheumatoid arthritis and juvenile chronic arthritis, and 21 studies were selected. The proportions of children in the different categories of the outcomes of interest are described. Data were stratified where possible by disease subtype.

Results. There were major differences between the studies reviewed in terms of study design, case selection and the results obtained. In general, children with systemic- or polyarticular-onset disease were much less likely to go into remission than those with oligoarticular onset, although the remission rates in the latter group ranged from 36 to 84%. Several different approaches were used to assess functional outcome but the pattern of results between the different subgroups was the same as with remission. Similarly, children with polyarticular disease in all the cohorts reviewed were substantially more likely to have erosive radiological damage on follow-up. The rates of individual outcomes, even within a subgroup, varied considerably between studies and this does not appear to be explained solely by differences in methodology.

Conclusions. There remains a considerable lack of clarity in the prognosis following onset of juvenile idiopathic arthritis for the major outcomes considered, although those with oligoarthritis at presentation have the best outcome. The ability to offer accurate prognosis is particularly important to both reassure parents and guide treatment at disease onset. To achieve this, large definitive prospective studies will be required.

 

TREATMENT CHARACTERIZATION
GENERAL  
ANTI-INTERLEUKIN 6  
Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis.

Yokota S, Miyamae T, Imagawa T, Iwata N, Katakura S, Mori M, Woo P, Nishimoto N, Yoshizaki K, Kishimoto T.

Yokohama City University School of Medicine, Kanagawa, Japan.
Arthritis Rheum. 2005 Mar;52(3):818-25. Abstract quote  

OBJECTIVE: To investigate the safety and efficacy of a recombinant human anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody (MRA) that indirectly inhibits the effects of IL-6 in children with systemic-onset juvenile idiopathic arthritis (JIA) refractory to high-dose, long-term corticosteroids.

METHODS: An individual escalating-dose trial was conducted in 11 children with active systemic-onset JIA who met the inclusion criteria. All were first administered an intravenous dose of 2 mg/kg MRA. Each child without active inflammation was given a second identical dose 2 weeks later and a third identical dose 2 weeks after the second dose. Children with disease flares according to laboratory marker values received a 4-mg/kg dose. Those without disease flares at this dose received a second 4-mg/kg dose 2 weeks later and a third 4-mg/kg dose 2 weeks after the second dose, while those with active inflammation received an additional 3 doses of 8 mg/kg MRA. Efficacy was evaluated every 2 weeks according to responses on the JIA core set of improvement criteria and the results of laboratory tests.

RESULTS: MRA abruptly reduced disease activity in 10 of the 11 children, as assessed by the occurrence of febrile episodes, active arthritis, scores on the Childhood Health Assessment Questionnaire, and levels of acute-phase reactants. However, levels of inflammatory reactants fluctuated until the proper MRA dose for each child was reached. Two weeks after the third fixed dose of MRA, 90.9% of all patients had a 30% improvement response, 90.9% had a 50% improvement response, and 63.6% had a 70% improvement response.

CONCLUSION: MRA treatment of children with active systemic disease results in clinical improvement and in normalized levels of acute-phase reactants. MRA was safe and well tolerated and provided greater clinical benefit than conventional corticosteroids, considering the ill effects of IL-6 and adverse events.
AUTOLOGOUS STEM CELL TRANSPLANTATION  
Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical effects, mortality, and transplant related morbidity.

De Kleer IM, Brinkman DM, Ferster A, Abinun M, Quartier P, Van Der Net J, Ten Cate R, Wedderburn LR, Horneff G, Oppermann J, Zintl F, Foster HE, Prieur AM, Fasth A, Van Rossum MA, Kuis W, Wulffraat NM.

Paediatric BMT unit, Suite KC 03.063, University Medical Centre Utrecht, PO box 85090, 3508 AB Utrecht, Netherlands.

Ann Rheum Dis. 2004 Oct;63(10):1318-26. Abstract quote  

OBJECTIVE: To evaluate the safety and efficacy of autologous stem cell transplantation (ASCT) for refractory juvenile idiopathic arthritis (JIA).

DESIGN: Retrospective analysis of follow up data on 34 children with JIA who were treated with ASCT in nine different European transplant centres. Rheumatological evaluation employed a modified set of core criteria. Immunological reconstitution and infectious complications were monitored at three month intervals after transplantation.

RESULTS: Clinical follow up ranged from 12 to 60 months. Eighteen of the 34 patients (53%) with a follow up of 12 to 60 months achieved complete drug-free remission. Seven of these patients had previously failed treatment with anti-TNF. Six of the 34 patients (18%) showed a partial response (ranging from 30% to 70% improvement) and seven (21%) were resistant to ASCT. Infectious complications were common. There were three cases of transplant related mortality (9%) and two of disease related mortality (6%).

CONCLUSIONS: ASCT in severely ill patients with JIA induces a drug-free remission of the disease and a profound increase in general wellbeing in a substantial proportion of patients, but the procedure carries a significant mortality risk. The following adjustments are proposed for future protocols: (1) elimination of total body irradiation from the conditioning regimen; (2) prophylactic administration of antiviral drugs and intravenous immunoglobulins until there is a normal CD4+ T cell count.
CALCIUM, DIETARY  
Prevention of Osteoporosis: A Randomized Clinical Trial to Increase Calcium Intake in Children with Juvenile Rheumatoid Arthritis.

Stark LJ, Janicke DM, McGrath AM, Mackner LM, Hommel KA, Lovell D.

Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Division of Psychology, SEC-4, Cincinnati, Ohio 45229.
J Pediatr Psychol. 2005 Jul;30(5):377-386. Epub 2005 Feb 23. Abstract quote  


OBJECTIVE:To test the efficacy of a behavioral intervention (BI) compared to an enhanced standard of care (ESC) dietary counseling on increasing dietary calcium (Ca) intake in children with juvenile rheumatoid arthritis (JRA).

METHODS:Three-day food diaries collected at baseline and posttreatment were analyzed for Ca intake in 49 children with JRA randomly assigned to either BI or an ESC treatment.

RESULTS:Children in the BI (N = 25) demonstrated a significantly greater increase in average dietary Ca intake (M = 839) than children in the ESC (N = 24; M = 420) (F = 14.39; p < .001). Post hoc analysis revealed that children in both groups demonstrated significant gains in dietary Ca intake baseline to posttreatment. A significantly greater percentage of children in the BI (92%) attained the goal of 1500 mg/Ca at posttreatment compared to the ESC (17%), X(2) = 28.09; p < .001.

CONCLUSIONS:Behavioral intervention can have a positive impact on increasing dietary Ca intake. Future research will need to evaluate the maintenance of gains in dietary Ca intake following treatment cessation and the impact of increased Ca intake on bone mineral density.
ENTANERCEPT  
Etanercept treatment in patients with refractory systemic onset juvenile rheumatoid arthritis.

Kimura Y, Pinho P, Walco G, Higgins G, Hummell D, Szer I, Henrickson M, Watcher S, Reiff A.

Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center, Hackensack, New Jersey 07601, USA.
J Rheumatol. 2005 May;32(5):935-42. Abstract quote

OBJECTIVE:. To assess the efficacy and safety of etanercept in a large cohort of children with refractory systemic onset juvenile rheumatoid arthritis (SOJRA).

METHODS: Standardized questionnaires were sent to US pediatric rheumatologists about patients with SOJRA treated with etanercept. Data were collected at baseline and at the last visit on etanercept. Response to treatment was assessed and compared to baseline as the mean percentage reduction in the following: acute phase reactants, prednisone dose, active joint count, and physician global assessment of disease activity. Response was defined as poor if the mean reduction was < 30%, fair if 30% to < 50%, good if 50% to < 70%, and excellent if > 70%.

RESULTS: We analyzed data obtained by survey of 82 SOJRA patients treated with etanercept for a mean of 25 months. Poor response to treatment was observed in 45% of the children, fair response in 9%, good in 13%, and excellent in 33%. Baseline steroid therapy could be discontinued in 27/59 (46%) patients. One or more disease flares occurred in 45% of all patients. Twenty-nine patients (35%) discontinued therapy, mostly due to lack of response or flare. There were 32 adverse event reports, most not considered serious, except for 2 cases of macrophage activation syndrome.

CONCLUSION: In this cohort of children with SOJRA, 46% had a good or excellent response, and most were able to reduce concomitant corticosteroid doses. The response to etanercept was fair or poor in more than half our study population, and disease flares were common. Due to the unique cytokine profile of SOJRA, tumor necrosis factor blockade may not be the optimal therapeutic approach for children with treatment-resistant SOJRA.
LEFLUNOMIDE  
Leflunomide and azathioprine combination in refractory adult-onset Still's disease.

Cefle A.

Chief of Rheumatology, Medical Faculty, Department of Internal Medicine, Division of Rheumatology, Kocaeli University, Kocaeli, Turkey.
Ann Pharmacother. 2005 Apr;39(4):764-7. Epub 2005 Mar 1.Abstract quote  

OBJECTIVE: To present a case of Adult-onset Still's disease (ASD) in a patient who was successfully treated with leflunomide and azathioprine.

CASE SUMMARY: A 24-year-old woman with ASD was initially treated with indomethacin, corticosteroids, and hydroxychloroquine; there was no clinical improvement. Methotrexate was added to the regimen, followed by azathioprine. The patient still experienced disease flares with this treatment, and cyclophosphamide was started. However, because of persisting disease activity, leflunomide combined with azathioprine was given. Only on this regimen was complete disease control achieved, with a normal erythrocyte sedimentation rate as well as normal C-reactive protein and ferritin levels. No recurrences or adverse effects attributable to leflunomide or azathioprine were observed at the one-year follow-up.

DISCUSSION: Clinical experience concerning leflunomide and azathioprine combination in ASD is limited. This combination may be modifying the clinical expression of ASD through its effects on T lymphocyte clonal expansion and production of proinflammatory cytokines.

CONCLUSIONS: Leflunomide combined with azathioprine appears to be an effective and safe treatment of ASD.
MELOXICAM  
A randomized, double-blind clinical trial of two doses of meloxicam compared with naproxen in children with juvenile idiopathic arthritis: short- and long-term efficacy and safety results.

Ruperto N, Nikishina I, Pachanov ED, Shachbazian Y, Prieur AM, Mouy R, Joos R, Zulian F, Schwarz R, Artamonova V, Emminger W, Bandeira M, Buoncompagni A, Foeldvari I, Falcini F, Baildam E, Kone-Paut I, Alessio M, Gerloni V, Lenhardt A, Martini A, Hanft G, Sigmund R, Simianer S; Pediatric Rheumatology International Trials Organization.

IRCCS G. Gaslini, Pediatria II, Reumatologia, Genoa, Italy.
Arthritis Rheum. 2005 Feb;52(2):563-72. Abstract quote  

OBJECTIVE: In an international, multicenter, double-blind, randomized clinical trial we evaluated the short-term (3 months) and long-term (12 months) efficacy and safety of 2 different doses of meloxicam oral suspension compared with the efficacy and safety of naproxen oral suspension in children with oligoarticular-course (oligo-course) or polyarticular-course (poly-course) juvenile idiopathic arthritis (JIA).

METHODS: Children ages 2-16 years who had active oligo-course or poly-course JIA and who required therapy with a nonsteroidal antiinflammatory drug were eligible for this trial. Patients were randomly allocated to receive therapy with meloxicam oral suspension, 0.125 mg/kg body weight in a single daily dose; meloxicam oral suspension, 0.25 mg/kg body weight in a single daily dose; or naproxen, 10 mg/kg body weight in 2 daily doses. The trial drugs were administered in a double-blind, double-dummy design for up to 12 months. Response rates were determined according to the American College of Rheumatology pediatric 30% improvement criteria (ACR pediatric 30). Safety parameters were assessed by evaluating the frequency of adverse events in the 3 groups.

RESULTS: Of 232 patients enrolled, 225 received treatment, 6 were not eligible for randomization, and 1 randomized patient was not treated. One hundred eighty-two patients (81%) completed the 12-month treatment period. Response rates according to the ACR pediatric 30 criteria improved from month 3 to month 12, as follows: from 63% to 77% in the meloxicam 0.125 mg/kg group, from 58% to 76% in the meloxicam 0.25 mg/kg group, and from 64% to 74% in the naproxen group. No statistically significant differences in response rates were observed between the groups. There were no differences in the frequency of adverse events or abnormal laboratory values between the 3 groups.

CONCLUSION: The short- and long-term safety and efficacy of meloxicam oral suspension appear to be comparable with the safety and efficacy of naproxen oral suspension in the treatment of oligo-course and poly-course JIA. The once-daily administration of meloxicam oral suspension might represent an improvement in the treatment of JIA.
METHOTREXATE  
Leflunomide or methotrexate for juvenile rheumatoid arthritis.

Silverman E, Mouy R, Spiegel L, Jung LK, Saurenmann RK, Lahdenne P, Horneff G, Calvo I, Szer IS, Simpson K, Stewart JA, Strand V; Leflunomide in Juvenile Rheumatoid Arthritis (JRA) Investigator Group.

Department of Pediatrics, University of Toronto, Toronto.
N Engl J Med. 2005 Apr 21;352(16):1655-66. Abstract quote  

BACKGROUND: We compared the safety and efficacy of leflunomide with that of methotrexate in the treatment of polyarticular juvenile rheumatoid arthritis in a multinational, randomized, controlled trial.

METHODS: Patients 3 to 17 years of age received leflunomide or methotrexate for 16 weeks in a double-dummy, blinded fashion, followed by a 32-week blinded extension. The rates of American College of Rheumatology Pediatric 30 percent responses (ACR Pedi 30) and the Percent Improvement Index were assessed at baseline and every 4 weeks for 16 weeks and every 8 weeks during the 32-week extension study.

RESULTS: Of 94 patients randomized, 86 completed 16 weeks of treatment, 70 of whom entered the extension study. At week 16, more patients in the methotrexate group than in the leflunomide group had an ACR Pedi 30 response (89 percent vs. 68 percent, P=0.02), whereas the values for the Percent Improvement Index did not differ significantly (-52.87 percent vs. -44.41 percent, P=0.18). In both groups, the improvements achieved at week 16 were maintained at week 48. The most common adverse events in both groups included gastrointestinal symptoms, headache, and nasopharyngeal symptoms. Aminotransferase elevations were more frequent with methotrexate than with leflunomide during the initial study and the extension study.

CONCLUSIONS: In patients with polyarticular juvenile rheumatoid arthritis, methotrexate and leflunomide both resulted in high rates of clinical improvement, but the rate was slightly greater for methotrexate. At the doses used in this study, methotrexate was more effective than leflunomide.

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