JNK Pathway-Associated Phosphatase as a Serum Marker for Disease Activity and Treatment Outcome of Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is a heterogeneous autoimmune disease characterized by arthritis of unknown etiology. JNK pathway-associated phosphatase (JKAP) is reported to be a negative regulator of T-cell activation, but its clinical role in JIA is unknown. This study aimed to investigate the correlation of JKAP with disease activity and treatment response to a tumor necrosis factor (TNF) inhibitor, etanercept (ETN), in JIA patients. Totally, 104 JIA patients (6.9 ± 2.7 years old) and 100 age- and sex-matched healthy controls (HCs) (7.2 ± 2.4 years old) were enrolled, and their serum samples were collected for measuring JKAP by enzyme-linked immunoassay. In JIA patients, after 24-week ETN treatment, clinical response was assessed based on the American College of Rheumatology pediatric criteria (ACRpedi) 50 criteria. Results showed that JKAP levels were significantly lower in JIA patients compared with HCs, and of good value in differentiating JIA patients from HCs. Among JIA patients, higher JKAP levels were associated with lower disease activity indexes, including C-reactive protein, number of joints with active arthritis, physician's global assessment of disease activity, and the present history of disease-modifying antirheumatic drugs; higher baseline JKAP levels were correlated with worse ACRpedi 50 response to ETN at week 24, and was also an independent predictive factor for worse ACRpedi 50 response to ETN. Thus, it may be inappropriate to use ETN for JIA patients with higher JKAP levels. In conclusion, serum JKAP is a potential biomarker for JIA activity and treatment response to a TNF inhibitor.

The expression of DNMTs is dramatically decreased in peripheral blood mononuclear cells of male patients with juvenile idiopathic arthritis.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is an autoimmune rheumatic disease, which affects primarily the joints in children under 16 years old. The etiology of JIA is yet unknown but research has shown that JIA is a multifactorial disease implicating several genes and environmental factors. Environmental factors affect immune cells via epigenetic mechanisms. One of the most important epigenetic mechanisms is DNA methylation catalyzed by DNA methyltransferases (DNMTs) and usually associated with gene silencing. In this study, we analyzed the expression of three DNA methyltransferases namely DNMT1, DNMT3a and DNMT3b in peripheral blood mononuclear cells (PBMCs) of patients with JIA and compared it with the expression of these genes in healthy young individuals. MATERIALS AND METHODS: Peripheral blood mononuclear cells of 28 JIA patients and 28 healthy controls were isolated. Total RNA was extracted, cDNA was synthesized and the transcript levels of DNMTs were analyzed by quantitative PCR. RESULTS: Analysis of DNMT1, DNMT3a and DNMT3b relative gene expression in PBMCs of JIA patients and control individuals shows that the expression of DNMT1 and DNMT3a is reduced significantly by 7 folds and 5.5 folds, respectively, in JIA patients compared to healthy controls. Furthermore, the expression of all three DNMTs were significantly and drastically reduced in young affected males compared to healthy males. CONCLUSION: This study shows that the expression of DNMTs is reduced in JIA patients and this reduction is severe in male JIA patients.

Overexpression of the transmembrane carbonic anhydrase isoforms IX and XII in the inflamed synovium.

Juvenile idiopathic arthritis (JIA) is the most common form of chronic rheumatic disease affecting children worldwide, with some features similar to adult rheumatoid arthritis (RA). In the present study, we aim at investigating novel markers that will allow in the future for tailored, more personalized treatment strategies. Hence, taking notice of several reports proving the role of local acidosis as a causal link between inflammatory diseases and related pain, and the involvement of several carbonic anhydrases (CA, EC 4.2.1.1) isoforms in articular diseases, we evaluated in JIA patients the expression of these metalloenzymes. We identified that JIA patients show high levels of active CA IX and XII isoforms. Our results represent the first evidence of the identification of these enzymes as potential therapeutic targets and development of novel innovative therapies for arthritis, also considering that the two isoforms are validated antitumor targets.

Measurement and evaluation of isotypes of anti-citrullinated fibrinogen and anti-citrullinated alpha-enolase antibodies in juvenile idiopathic arthritis.

OBJECTIVES: Our objective was to evaluate sera from juvenile idiopathic arthritis (JIA) patients to investigate the presence of isotypes (IgA, IgG, IgM) of anti-citrullinated fibrinogen and anti-α-enolase antibodies and their association with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody isotypes. METHODS: Sera were obtained from 89 JIA patients and were measured for isotypes (IgA, IgM) of anti-citrullinated and native fibrinogen and anti-α-enolase antibodies by enzyme-linked immunosorbent assay. Results were compared to anti-CCP antibody isotypes and RF isotypes, in addition to previously measured IgG anti-citrullinated fibrinogen and α-enolase antibodies. RESULTS: IgA anti-citrullinated fibrinogen antibodies were positive in 20 JIA patients and IgM in 11 JIA patients. Two IgM RF-positive polyarthritis patients were positive for all 3 isotypes of anti-citrullinated fibrinogen antibodies. IgA anti-citrullinated α-enolase antibodies were positive in 7 JIA patients and IgM in 9 JIA patients. IgA and IgG anti-citrullinated fibrinogen antibodies were commonly found in JIA patients positive for IgG anti-CCP antibodies and IgM RF. IgG anti-CCP antibodies and IgM RF levels were significantly higher in JIA patients with 3 or more anti-citrullinated autoantibody isotypes present. CONCLUSIONS: We have shown that isotypes of anti-citrullinated fibrinogen and α-enolase can be found in the serum of children with JIA of all onset types. Citrullinated autoantibody isotype diversity may indicate a more severe disease course in JIA patients.

[Indices of matrix metalloproteinases (MMP-2, MMP-9, TIMP-1) with juvenile arthritis in children].

UNLABELLED: One of the perspectives of modern rheumatology is the study of matrix metalloproteinases (MMP) in juvenile arthritis--enzymes that play a key role in the process of joint destruction. AIM: To analyse the content of matrix MMP-2 and MMP-9 and their tissue inhibitor (TIMP-1) in blood serum and synovial fluid in various embodiments of juvenile arthritis in children. PATIENTS AND METHODS: The study involved 82 children with juvenile arthritis, and 20 healthy children. The level of MMP-2, MMP-9 and TIMP-1 were determined in serum and synovial fluid by ELISA. RESULTS: It was found out that with any form of arthritis serum concentrations of MMP-2, MMP-9 and TIMP-1 was significantly higher than control values, but the level of MMP-2 in a subset of enthesitis-related arthritis, didn't differ from the control. Studied parameters in the synovial fluid were much higher than the serum level. With the development of uveitis TIMP-1 in blood serum was lower than in the absence of eye damage. On treatment of patients significant changes in the studied enzymes weren't established. On a good response to therapy the level of MMP-9 in serum decreased, on the lack of effectiveness - increased. CONCLUSIONS: The analysis results confirm the involvement of MMP-2, MMP-9 and TIMP-1 in the processes of inflammatory changes of the joints in juvenile idiopathic arthritis (JIA) and reactive arthritis, regardless the patients' sex or age.

HMOX1 promoter (GT)n polymorphim is associated with childhood-onset systemic lupus erythematosus but not with juvenile rheumatoid arthritis in a Mexican population.

OBJECTIVES: The heme oxigenase 1 (HO-1), a rate-limiting enzyme for heme degradation, is an important cytoprotective protein. Transcriptional activity of HO-1 coding gene (HMOX1) can be regulated by the presence of a dinucleotide repeat polymorphism (GT)n at its promoter region. Accordingly, length of (GT)n repeat has been associated with susceptibility to several diseases. We investigated whether the HMOX1 (GT)n polymorphism was associated with childhood-onset systemic lupus erythematosus (SLE) and juvenile rheumatoid arthritis (JRA) susceptibility. METHODS: We studied 207 and 333 unrelated Mexican patients with JRA and childhood-onset SLE, respectively. The control population consisted of 653 individuals ethnically matched with cases. The HMOX1 (GT)n polymorphism was genotype by PCR and fluorescence technology. RESULTS: We found 27 different alleles, with the 22 and 29 repeats as the most common alleles. Distribution of short allele (n<25) and SS genotype was not statistically associated with JRA subjects. Interestingly, the frequency of both short allele and SS genotype was significantly associated with SLE susceptibility (OR=1.47, 95%CI [1.14-1.89], p=0.002; and OR=2.79, 95%CI [1.24-6.24], p=0.01, respectively). CONCLUSIONS: The distribution pattern of HMOX1 (GT) alleles was different in the Mexican population than those reported elsewhere. Our results suggest that HMOX1 (GT)n polymorphism was associated with susceptibility to childhood-onset SLE but not with JRA in Mexican individuals.

High expression of the ectonucleotidase CD39 on T cells from the inflamed site identifies two distinct populations, one regulatory and one memory T cell population.

The ectonucleotidase CD39 has recently been described as being highly expressed on regulatory Foxp3(+) CD4 T cells. Through hydrolysis of proinflammatory extracellular ATP, CD39 activity represents a newly described mechanism of regulatory T cell action. We report a novel population of human CD4 T cells that express CD39 yet are Foxp3 negative. These cells produce the proinflammatory cytokines IFN-gamma and IL-17 and fail to suppress proliferation; however, they still have high ATP hydrolysis activity. In the inflammatory site in human juvenile idiopathic arthritis, the CD39(+)Foxp3(-) population is greatly increased compared with peripheral blood of patients or healthy controls. We also show that cells expressing the AMPase CD73 are less frequent in the joint than in blood. To our knowledge, this is the first study to describe and characterize CD39 function on CD4 T cells from the target site in a human autoinflammatory condition. Our data suggest that in human CD4(+) T cells from the inflamed site, CD39 can be highly expressed on two populations, one regulatory and the other of a memory phenotype.

Salivary antioxidants and metalloproteinases in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common autoimmune inflammatory disease in children; joint inflammation is the hallmark of the disease. Thirty-five children with JIA were studied, of whom 26 had active disease and 14 were receiving anti-TNF therapy (5 with Infliximab, 9 with Etanercept). Sixteen healthy controls also were studied. Saliva samples were obtained for analysis of anti-oxidant status, metalloproteinases (MMPs) and sialochemistry. The total antioxidant status was significantly higher in the saliva of all JIA patients, whether treated (P = 0.014) or not treated (P = 0.038) with anti-TNF agents. The increase in antioxidant status (TAS) in the saliva of the active patients was nearly two times higher than that of non-active patients (P = 0.01). MMP levels were significantly lower in JIA patients than in controls. MMP-9, MMP-3 and MMP-2 were lower in JIA patients without anti-TNF treatment by 36.7% (P = 0.01), 30.0% (P = 0.0001) and 10.7% (P = 0.0001), respectively. A greater reduction in MMP levels was observed in the group of patients treated with anti-TNF drugs: MMP-9, MMP-3 and MMP-2 were lower than in controls by 51.1% (P = 0.0001), 61.5% (P = 0.0001) and 55.4% (P = 0.0001), respectively. Children with JIA exhibited a significantly higher salivary antioxidant activity and significantly lower MMP levels. Anti-TNF treatment was associated with a further decrease in MMP levels in the saliva of JIA patients while an active state of JIA was associated with a further increase in the salivary antioxidant activity. Anti-TNF treatment may modulate the degradation process during the course of arthritis by inhibition of the activity of MMP.

Induction of metalloproteinases expression by TLR ligands in human fibroblast like synoviocytes from juvenile idiopathic arthritis patients.

BACKGROUND & OBJECTIVE: Juvenile idiopathic arthritis (JIA) is characterized by chronic synovitis, cartilage damage and bone erosion. Both genetic and environmental factors and microbes probably play a role in pathogenesis. Microbes are recognized by Toll like receptors (TLRs) and activate innate immune response. We studied the ability of bacterial and viral products to produce matrix metalloproteinases (MMPs) and cytokines by fibroblast like synoviocytes (FLS) from patients with JIA. METHODS: FLS were cultured from synovial fluid (SF) of patients with JIA and subsequently stimulated for 48 h by different TLR ligands [peptidoglycan (PG) for TLR2, poly(I-C) for TLR3, lipopolysaccharide (LPS) for TLR4, flagellin for TLR5, imiquimod for TLR7 and CpG DNA for TLR9]. Later the production of IL6, IL8, MMP-1, MMP-3, tissue inhibitors of metalloproteinase (TIMP1) was measured in the culture supernatants by ELISA. Expression of TLR2, TLR4, TLR7 and TLR9 was studied in FLS derived from JIA patients by RT-PCR. RESULTS: IL6, IL8, MMP3 and MMP1 production was induced on stimulation of FLS with TLR2 ligand, TLR3 ligand, TLR4 ligand, TLR5 ligand but not with TLR7 ligand and TLR9 ligand. There was no effect of these ligands on the production of TIMP thus the balance was tilted in favour of MMPs after TLR ligation. TLR2, TLR4 and low expression of TLR9 was found but, no expression of TLR7 was found in FLS from JIA patients. INTERPRETATION & CONCLUSION: TLR pathway stimulation by microbial products or endogenous ligands could be involved in the production of MMPs in JIA and may contribute to disease pathology. Thus it may be beneficial to inhibit TLR pathway to reduce cartilage destruction.

The protease systems and their pathogenic role in juvenile idiopathic arthritis.

Numerous proteases produced by synovial cells of arthritic joints, chondrocytes, macrophages and polymorphonuclear cells have been identified as responsible for the joint damage in rheumatoid arthritis. There are few scientific contributions aimed to identify similar mechanisms in the joints of patients with juvenile idiopathic arthritis. Recently, some mechanisms emerged, triggered by the TH17 and TH1/TH17 lymphocytes, which could shed new light on unexpected pathogenic pathways of joint damage in the JIA, mainly regarding the RANK-RANKL pathway. Other novelties are linked to the mechanisms of acidification of the synovial fluid, which create a microenvironment suitable for the extracellular activity of lysosomal enzymes. Some biological drugs currently used in the therapy of JIA can interfere with these mechanisms.

Profile of exoglycosidases in synovial cell cultures derived from human synovial membrane.

OBJECTIVE: Determining the activity of lysosomal exoglycosidases in tissue cultures of synoviocytes derived from the knee joints of patients with injured anterior cruciate ligaments (ACL), juvenile idiopathic arthritis (JIA), and rheumatoid arthritis (RA). METHODS: The following exoglycosidases in cultured synoviocytes were analyzed with p-nitrophenyl derivatives of appropriate sugars as substrates: hexosaminidase (HEX) and its isoenzyme A (HEX-A), beta-glucuronidase (GluA), beta-galactosidase (GAL), alpha-mannosidase (MAN), and alpha-fucosidase (FUC). RESULTS: In our cell cultures, fibroblast-like synovial cells (FLS) dominated. In the group of patients with ACL-injuries, and in the groups of patients with JIA and RA, the activity of the investigated exoglycosidases was significantly higher in the intra- rather than in the extracellular compartment. Hexosaminidase was the predominant exoglycosidase. Stimulation of synoviocytes by IL-1beta in cell cultures significantly increased the activity of HEX, HEX-A, and GluA in both compartments, as well as of GAL, MAN, and FUC in the intracellular compartment. Stimulation by IL-1beta rheumatoidal synoviocytes increased by 128-201% the activity of HEX and HEX A in intracellular compartments and 33-72% in extracellular compartment. CONCLUSIONS: The profile of lysosomal exoglycosidases in a cell culture of human synoviocytes is similar, but not identical, to those in the knee joint. Hexosaminidase is the dominant glycosidase in cultured unstimulated and IL-1beta-stimulated human synoviocytes. The HEX inhibitors may be new drugs for the treatment of inflamed knee joints.

Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation.

Stunted growth is a major complication of chronic inflammation and recurrent infections in children. Systemic juvenile rheumatoid arthritis is a chronic inflammatory disorder characterized by markedly elevated circulating levels of IL-6 and stunted growth. In this study we found that NSE/hIL-6 transgenic mouse lines expressing high levels of circulating IL-6 since early after birth presented a reduced growth rate that led to mice 50-70% the size of nontransgenic littermates. Administration of a monoclonal antibody to the murine IL-6 receptor partially reverted the growth defect. In NSE/hIL-6 transgenic mice, circulating IGF-I levels were significantly lower than those of nontransgenic littermates; on the contrary, the distribution of growth hormone pituitary cells, as well as circulating growth hormone levels, were normal. Treatment of nontransgenic mice of the same strain with IL-6 resulted in a significant decrease in IGF-I levels. Moreover, in patients with systemic juvenile rheumatoid arthritis, circulating IL-6 levels were negatively correlated with IGF-I levels. Our findings suggest that IL-6-mediated decrease in IGF-I production represents a major mechanism by which chronic inflammation affects growth.

SIAE Rare Variants in Juvenile Idiopathic Arthritis and Primary Antibody Deficiencies.

Sialic acid acetylesterase (SIAE) deficiency was suggested to lower the levels of ligands for sialic acid-binding immunoglobulin-like receptors, decreasing the threshold for B-cell activation. In humans, studies of rare heterozygous loss-of-function mutations in SIAE gene in common autoimmune diseases, including juvenile idiopathic arthritis (JIA), yielded inconsistent results. Considering the distinct pathogenesis of the two main subtypes of JIA, autoinflammatory systemic (sJIA) and autoimmune oligo/polyarticular (aJIA), and a predisposition to autoimmunity displayed by patients and families with primary antibody deficiencies (PADs), the aim of our study was to analyze whether SIAE rare variants are associated with both the phenotype of JIA and the autoimmunity risk in families with PADs. A cohort of 69 patients with JIA, 117 healthy children, 54 patients, and family members with PADs were enrolled in the study. Three novel SIAE variants (p.Q343P, p.Y495X, and c.1320+33T>C) were found only in patients with aJIA but interestingly also in their healthy relatives without autoimmunity, while none of PAD patients or their relatives carried SIAE defects. Our results show that SIAE rare variants are not causative of autoimmunity as single defects.

Activity of N-acetyl-beta-hexosaminidase and its isoenzymes in serum and synovial fluid from patients with different arthropathies.

OBJECTIVE: To evaluate the activity of N-acetyl-Beta-hexosaminidase (HEX) and its isoenzymes in the serum and synovial fluid of healthy volunteers and patients with an injury to the anterior cruciate ligament and/or meniscus (ACL) osteoarthritis (OA), juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA). METHODS: The activity of HEX and its isoenzymes was determined according to Zwierz et al. method. Protein content was determined by the biuret method. RESULTS: The specific activity of HEX and its isoenzymes in the serum of patients with JIA showed a tendency to increase in comparison to the reference group. The specific activity of total HEX in the serum of RA patients was significantly increased in comparison to control. Our results show, that specific activity of HEX in synovial fluid, in the reference group 4.2 +/- 0.21 microkat/kg protein (0.25 unit/mg protein), is similar to activity in normal temporomandibular joint fluid (0.3 unit/mg protein). Therefore, we included this group in our research. In patients with OA and ACL injuries, HEX and its isoenzymes showed a tendency to increase in the specific activity in synovial fluid. The specific activity of HEX and its isoenzymes in the synovial fluid of patients with RA and JIA was significantly elevated in comparison to the control and the remaining groups. CONCLUSION: In the synovial fluid of patients with JIA and RA, the specific activity of HEX and its isoenzymes significantly increased in comparison to control and patients with diseases of a non-inflammatory etiology (OA and ACL). In the synovial fluid of control and diseased groups, HEX constituted a higher percent of total proteins than in serum.

Nicotinamide Phosphoribosyltransferase Attenuates Methotrexate Response in Juvenile Idiopathic Arthritis and In Vitro.

Variability in response to methotrexate (MTX) in the treatment of juvenile idiopathic arthritis (JIA) remains unpredictable and poorly understood. Based on previous studies implicating an interaction between nicotinamide phosphoribosyltransferase (NAMPT) expression and MTX therapy in inflammatory arthritis, we hypothesized that increased NAMPT expression would be associated with reduced therapeutic response to MTX in patients with JIA. A significant association was found between increased plasma concentrations of NAMPT and reduced therapeutic response in patients with JIA treated with MTX. Inhibition of NAMPT in cell culture by either siRNA-based gene silencing or pharmacological inhibition with FK-866 was found to result in a fourfold increase in the pharmacological activity of MTX. Collectively, these findings provide evidence that NAMPT inhibits the pharmacological activity of MTX and may represent a predictive biomarker of response, as well as a therapeutic target, in the treatment of JIA with MTX.

Increased carotid artery intima-media thickness and myeloperoxidase level in children with newly diagnosed juvenile idiopathic arthritis.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a frequent childhood rheumatic disease characterized by chronic inflammation. The latter has been related to impairment of arterial functional-structural properties, atherogenesis and later cardiovascular events. The objective of this study was to examine intima-media thickness (IMT) and the parameters of arterial stiffness in children with JIA at diagnosis and their correlation with JIA subtype and markers of inflammation and atherosclerosis. METHODS: Thirty-nine newly diagnosed patients with JIA (26 girls; mean age, 13.2 ± 2.6 years) and 27 healthy controls (9 girls; mean age, 13.6 ± 3.4 years) were included in the study. Twelve patients had oligoarthritis, fifteen had extended oligoarthritis and twelve had rheumatoid factor-negative polyarthritis. IMT of the common carotid artery was determined by ultrasonography, carotid-femoral pulse wave velocity (cfPWV) and augmentation index adjusted to a heart rate of 75 beats/min (AIx@75) were determined by applanation tonometry. The serum levels of atherosclerosis-related biomarkers, such as asymmetric dimethylarginine (ADMA), myeloperoxidase (MPO) and adiponectin, were measured by enzyme-linked immunosorbent assay. RESULTS: Mean IMT (0.46 ± 0.04 vs. 0.42 ± 0.04 mm; p = 0.0003) and MPO concentration (115.2 [95% confidence interval {95% CI}, 97.4-136.3] vs. 57.6 [95% CI, 47.1-70.3] ng/ml; p < 0.0001) were higher in the patients with JIA than in the control subjects. The cfPWV, AIx@75 and serum ADMA and adiponectin levels did not significantly differ between the groups and JIA subtypes. Serum adiponectin level correlated negatively with AIx@75 in patients with JIA (r = -0.38; p < 0.05). CONCLUSIONS: Patients with JIA have increased mean IMT and elevated MPO levels at early stages of the disease. AIx@75 was inversely independently associated with adiponectin level in the patients, suggesting that lower adiponectin levels might influence arterial subclinical stiffening in patients with newly diagnosed JIA.

STAT4 rs7574865 G/T and PTPN22 rs2488457 G/C polymorphisms influence the risk of developing juvenile idiopathic arthritis in Han Chinese patients.

Juvenile idiopathic arthritis (JIA) is a common autoimmune disease characterized by environmental influences along with several predisposing genes in the pathogenesis. The protein tyrosine phosphatase nonreceptor 22 (PTPN22) and signal transducer and activator of transcription factor 4 (STAT4) have been recognized as susceptibility genes for numerous autoimmune diseases. Associations of STAT4 rs7574865 G/T and PTPN22 (rs2488457 G/C and rs2476601 C/T) polymorphisms with JIA have repeatedly been replicated in several Caucasian populations. The aim of this study was to investigate the influence of three polymorphisms mentioned above on the risk of developing JIA in Han Chinese patients. Genotyping was performed on a total of 137 Chinese patients with JIA (JIA group) and 150 sex and age frequency-matched healthy volunteers (Control group). The single-nucleotide polymorphisms (SNP) were determined by using direct sequencing of PCR-amplified products. There were significant differences of PTPN22 rs2488457 G/C and STAT4 rs7574865 G/T polymorphisms between both groups. However, no significant difference was observed in distribution frequencies of PTPN22 rs2476601 polymorphism. The association with the PTPN22 rs2488457 G/C polymorphism remained significant in the stratifications by age at onset, ANA status, splenomegaly, lymphadenectasis and involvement joints. As with the STAT4 rs7574865 G/T polymorphisms, the enthesitis-related arthritis and presence of hepatomegaly had strong effect on the association. Our data strengthen STAT4 rs7574865 G/T and PTPN22 rs2488457 G/C polymorphisms as susceptibility factors for JIA.

Serum enzyme abnormalities in juvenile rheumatoid arthritis.

Elevated serum transaminases, particularly SGOT, as a result of acetylsalicylic acid (ASA) therapy have been reported in patients with juvenile rheumatoid arthritis (JRA). In order to evaluate the possibilities that these elevated transaminases may result from JRA itself or from concomitant muscle injury, we correlated liver function tests and a specific test for muscle damage, creatine phosphokinase (CPK), with ASA therapy in 37 patients. These JRA patients were evaluated serially; 20 took ASA continuously, 6 took it intermittently, and 11 were on no therapy. Thirty-five healthy children were also studied to establish normal control values for the serum enzyme tests. Mean SGOT and SGPT in the 11 untreated subjects were significantly (P less than.001) higher than normal controls while CPK and alkaline phosphatase (AP) were not elevated. Mean SGOT and SGPT were also significantly (P less than .001) elevated in 20 children receiving ASA continuously; CPK was normal and AP less (P less than .05) than normal. CPK was elevated in 13 patients. Elevation of enzymes was sporadic and there was no correlation with serum salicylate, sex, age, disease duration, type, or activity. We conclude that mild abnormalities of SGOT and SGPT in JRA patients are common, but that they occur sporadically and elevated values appear to be unrelated to ASA therapy.

Expression of cathepsin B, D and L protein in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common childhood autoimmune rheumatic disease and like rheumatoid arthritis (RA), it is characterized by inflammation and the progressive destruction of joints. In RA, cathepsins as proteinases play a major role in destroying synovial tissue and cartilage matrix. So far no data on cathepsin expression in pannus tissue of HA patients exist. The aim of this study was to characterize the expression levels of cathepsins B, D, H, and L in HA and to compare them with those in RA. Synovectomy tissue from 16 HA and 12 RA patients was investigated for cathepsin expression levels by Western blot analysis. Expression of cathepsins B, D and L was on comparable levels in the synovectomy tissue of HA and RA patients. The following graduation of expression was determined: cathepsin D > cathepsin L > cathepsin B. Cathepsin H was neither found to be expressed in HA nor in RA patients. The expression levels of cathepsins in pannus tissue showed no clear difference between patients with systemic JIA and patients with monoarticular JIA. In summary, the comparable expression of cathepsins B, D and L in RA and JIA synovectomy tissue suggests that they may play a similarly important role in destroying synovial tissue and cartilage matrix in the course of HA and RA.

The discriminating value of serum lactate dehydrogenase levels in children with malignant neoplasms presenting as joint pain.

OBJECTIVES: To determine if serum lactate dehydrogenase levels distinguish patients with malignant neoplasm presenting with musculoskeletal complaints from patients with juvenile rheumatoid arthritis who reported similar symptoms. DESIGN: Retrospective case-comparison study. SETTING: Tertiary care, outpatient clinics. PATIENTS: Twelve patients with malignant neoplasms who presented with arthritis or arthralgias and normal complete blood cell counts and blood smears in whom rheumatologic diagnosis was initially made were compared with 24 children with a final diagnosis of juvenile rheumatoid arthritis. The patients with malignant neoplasms all had normal blood counts and elevated sedimentation rates at symptom onset. INTERVENTIONS: None. RESULTS: Serum lactate dehydrogenase levels were significantly higher in the cancer patients at 2.2 times the normal values vs 0.8 times high normal for patients with juvenile rheumatoid arthritis (P =.004, Mann-Whitney U test) No significant differences were observed in white blood cell counts, hemoglobin levels, platelet counts, erythrocyte sedimentation rate, or uric acid or aspartate aminotransferase levels at initial evaluation. CONCLUSIONS: Serum lactate dehydrogenase values may distinguish patients with malignant neoplasms from those with rheumatic disease early in the course of illness when symptoms and other laboratory values are not helpful.