Bibliography May 04

1. Erratum: Regulation of peripheral blood and synovial fluid lymphocyte apoptosis in juvenile idiopathic arthritis (Scandinavian Journal of Rheumatology (2004) 33 (7-12)). Scandinavian Journal of Rheumatology (Norway ) 33:3 198, 2004

2. ANDREAKOS E: Common and uncommon features of rheumatoid arthritis and chronic obstructive pulmonary disease: clues to a future therapy. Curr Drug Targets Immune Endocr Metabol Disord 4:2 85-92, 2004
   Organism: Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK evangelosandreakos@imperialacukFAU - Andreakos, E
   Abstract: Over the last decade it has become apparent that common pathogenic mechanisms are shared between many human chronic inflammatory diseases of unrelated pathology and manifestation. These mechanisms include common inflammatory networks that control tissue destructive and repair processes and their study is of major therapeutic potential as recently demonstrated for TNFalpha. Thus, early studies in rheumatoid arthritis defined TNFalpha as a major therapeutic target, the blockade of which was subsequently proved to be of great efficacy in the clinic. This paved the way for the successful blockade of TNFalpha in various other diseases including Crohn's disease, psoriasis, spondyloarthropathies and juvenile arthritis, although no similar networks with anti-TNFalpha at their apex had previously been demonstrated. In this article, we review the current knowledge of the pathogenic mechanisms involved in rheumatoid arthritis and chronic obstructive pulmonary disease with particular emphasis on the role of inflammatory cytokines, chemokines, and tissue degrading enzymes as revealed by studies in the laboratory and the clinic. Direct comparison of these mechanisms may provide clues for a future therapy for these painful and incurable diseases

3. CHEN YS, YANG YH, LIN YT, CHIANG BL: A patient diagnosed with pauciarticular juvenile rheumatoid arthritis after a mechanical prosthetic valve replacement due to aortic regurgitation. J Microbiol Immunol Infect 37:3 200-202, 2004
   Organism: Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan, ROCFAU - Chen, Yu Shu
   Abstract: Valvular heart disease is a rare complication of juvenile rheumatoid arthritis (JRA), with most cases associated with polyarticular JRA. The aortic valve is most commonly affected, and valvular involvement occurs months or years after the onset of JRA. Reported cases of valvular heart disease in patients with JRA in a pauciarticular pattern are rare. We report a case of severe aortic insufficiency in a 12-year-old boy who underwent aortic valve replacement before diagnosis of JRA with a pauciarticular pattern

4. CINEK O, VAVRINCOVA P, STRIZ I, DREVINEK P, SEDLAKOVA P, VAVRINEC J, SLAVCEV A: Association of single nucleotide polymorphisms within cytokine genes with juvenile idiopathic arthritis in the Czech population. Journal of Rheumatology (Canada ) 31:6 1206-1210, 2004
   Abstract: Objective. To examine the possible association of juvenile idiopathic arthritis (JIA) with polymorphisms within cytokine genes in the Czech population. Methods. In a case-control study, genotypes of 130 patients with JIA (63 male, 67 female; age at onset 7.6 +/- 4.4 yrs; 43 oligoarticular, 72 polyarticular, 15 systemic form) were compared to 102 healthy unrelated blood donors. Using the polymerase chain reaction technique with sequence-specific primers from the 13th IHWG workshop, we analyzed 19 single nucleotide polymorphisms within 12 different cytokine genes [interleukin (IL)-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12, transforming growth factor (TGF)-beta, interferon (IFN)-gamma], and related molecules (IL-1R, IL-1RA, IL-4Ralpha). Genotype frequencies were compared using chi-square analysis, and the significance level was corrected for the number of independent tests. Results. Significant positive association was found for the G allele of the IL-4-1098 T/G polymorphism, which was carried by 10% of cases and 25% of controls [odds ratio (OR) 0.32, 95% confidence interval (CI) 0.16-0.67, corrected p = 0.038). Also, a nonsignificant increase in the frequency of the IL-1beta +3962 C allele was detected in cases (96%) versus controls (84%) (OR 4.65, 95% CI 1.64-13.2, corrected p = 0.091). We did not replicate previously found associations with the IL-1alpha, IL-6, IL-10, and IL-1RA polymorphisms. Conclusion. Our study showed association with JIA for the IL-4 -1098 T/G polymorphism. It also underlines the genetic contribution of IL-1 polymorphisms to the pathogenesis of JIA, as another polymorphism within the IL-1beta may influence the risk of the disease

5. COLE P, RABASSEDA X: The soluble tumor necrosis factor receptor etanercept: A new strategy for the treatment of autoimmune rheumatic disease. Drugs of Today (Spain ) 40:4 281-324, 2004
   Abstract: Rheumatoid arthritis is a severe, debilitating condition for which existing therapies are of limited efficacy. In addition, the most common structure of treatment for patients with rheumatoid arthritis has recently been called into question, and many believe it should be reversed so that stronger treatments are administered earlier in the progression of the disease. Pivotal to the changes in rheumatoid arthritis treatment is the introduction of the pro-inflammatory tumor necrosis factor (TNF) antagonists. Overexpression of cytokines in inflamed joints plays an important role in joint inflammation and tissue damage, and the place of cytokines in the pathology of rheumatoid arthritis has offered hope that their antagonism will reduce symptoms and slow the advancement of the condition. With this in mind, etanercept, a fully human soluble TNF receptor fusion protein, was developed. The potency of this novel drug in blocking TNF activity has been shown in animal models and in clinical trials. The latter have demonstrated a positive safety profile and efficacy in reducing pain and the number of tender and swollen joints in rheumatoid arthritis patients. The effects of etanercept have also been observed soon after administration and have been sustained over several years. Etanercept has offered encouragement for those seeking new, more efficacious and less toxic methods of treating rheumatoid arthritis in children, adults and the elderly. In addition to the treatment of adult and juvenile rheumatoid arthritis, etanercept has also demonstrated utility in treating ankylosing Spondyltitis and psoriatic arthritis. (c) 2004 Prous Science. All rights reserved

6. EL GAMAL YM, HESHMAT NM, EL KERDANY TH, FAWZY AF: Serum thrombomodulin in systemic lupus erythematosus and juvenile idiopathic arthritis. Pediatr Allergy Immunol 15:3 270-277, 2004
   Organism: Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, EgyptFAU - El-Gamal, Yehia M
   Abstract: El-Gamal YM, Heshmat NM, El-Kerdany TH, Fawzy AF. Serum thrombomodulin in systemic lupus erythematosus and juvenile idiopathic arthritis. Pediatr Allergy Immunol 2004: 15: 270-277. Copyright 2004 Blackwell MunksgaardThrombomodulin is a thrombin receptor on the vascular endothelial cell surface which is likely released upon endothelial cell damage. Serum soluble thrombomodulin (sTM) was assessed and investigated as a parameter of disease activity in children and adolescents with systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA). Patients included in this study were regularly attending the Allergy and Immunology Clinic, Children's Hospital, Ain Shams University. They were 38 (76%) females and 12 (24%) males, their ages ranged between 5 and 18 years with a mean of 14.3 +/- 4.84 years and median of 13 years. They were divided into two groups: SLE group which included 20 patients and JIA group which included 30 patients; and the control group which included 30 healthy age and sex-matched individuals for comparison. Disease activity in SLE patients was evaluated by systemic lupus erythematosus disease activity index (SLEDAI) score, while in JIA patients disease activity was determined by number of joints with active arthritis, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Serum levels of sTM were determined by enzyme-linked immunosorbent (ELISA) assay. Serum levels of sTM were significantly higher in SLE and JIA patients in comparison with the control group; there was no significant difference between SLE and JIA patients. In SLE patients, a highly significant correlation was found between sTM and SLEDAI score (r = 0.99, p < 0.001). In JIA patients, a highly significant correlation was found between sTM and number of joints with active arthritis as well as ESR (r = 0.85, p < 0.001; r = 0.93, p < 0.001, respectively). Levels of sTM were significantly higher in CRP-positive than CRP-negative JIA patients. Serum sTM is a useful serologic marker of disease activity in SLE and JIA. It may prove to be a potential indicator for early and more aggressive treatment. Furthermore, sTM may prove to be an important marker for vasculitis in general

7. GATTORNO M, GREGORIO A, FERLITO F, GERLONI V, PARAFIORITI A, FELICI E, SALA E, GAMBINI C, PICCO P, MARTINI A: Synovial expression of osteopontin correlates with angiogenesis in juvenile idiopathic arthritis. Rheumatology (Oxford) .: 2004
   Organism: Second Division of Pediatrics, 'G Gaslini' Institute and Department of Pediatrics, University of Genoa, Genoa, Italy
   Abstract: OBJECTIVE: To evaluate the synovial expression of osteopontin (OPN) and its possible correlation with the degree of synovial angiogenesis in human chronic idiopathic arthritis. METHODS: Forty-five patients with active juvenile idiopathic arthritis (JIA) were studied. All patients underwent SF aspiration before steroid injection. A paired plasma sample was collected from 22 JIA patients. Plasma from 15 age-matched healthy subjects was used as control. Plasma and SF were tested by ELISA for OPN and vascular endothelial growth factor (VEGF). Synovial tissue was obtained at synovectomy from 10 JIA patients. Immunohistochemistry was performed according to a standard technique with anti-OPN, anti-CD68, anti-CD31 anti-VEGF and anti-alphavbeta3 antibodies. RESULTS: OPN levels were significantly higher in SF than in paired plasma samples (P<0.001). The same pattern was observed for VEGF (P<0.001). A positive correlation between OPN and VEGF concentrations was found in SF (r = 0.6, P = 0.001). In synovial tissue, OPN was expressed at the level of the lining and sublining layers with a distribution similar to that observed for VEGF. OPN expression in the lining layer correlated with the number of vessels present in the areas underlying the sublining layer. CONCLUSIONS: Synovial expression of OPN correlates with parameters of angiogenesis in JIA. These data support, in human disease, the possible role of OPN in the vascularization of inflamed synovial tissue, as previously shown in OPN-deficient animal models of arthritis

8. GENOVESE MC, KREMER JM: Treatment of rheumatoid arthritis with etanercept. Rheumatic Disease Clinics of North America (United States ) 30:2 311-328, 2004
   Abstract: Etanercept is effective in the treatment of RA when used as monotherapy, in early disease, and in combination with MTX. Radiographic progression of disease was significantly slowed when the drug was used for a 24-month period and was statistically significantly better than MTX. In addition to RA, etanercept is approved by the FDA for use in other rheumatologic conditions, including psoriatic arthritis, ankylosing spondylitis, and juvenile chronic arthritis. Reports of opportunistic infections, tuberculosis, and lymphoma have emerged with anti-TNF treatment, including etanercept. It seems from early reports that the incidence of certain opportunistic infections, such as tuberculosis, may be lower with etanercept than infliximab; however, patients should be informed that tuberculosis, other opportunistic infections, and lymphoma have been reported in individuals who were receiving etanercept. An individual's risk is probably greater with coadministration of corticosteroids and other immunosuppressive agents, such as MTX, although this has not been established. Patients deserve to know about these theoretical risks and have the baseline discussion documented in their medical chart. Precise quantitation of an individual's risk for development of any of these complications must be weighed against the risk of continued inflammation with its attendant cardiovascular, infectious, and oncogenic potential as well as the inevitable progression of disease itself. Informed decisions can be made between a caring, but honest, physician and a patient who may have a predisposition to view some of the new agents with unrealistic expectations of risk-free benefit

9. HAFNER R, TRUCKENBRODT H, MICHELS H: Rheumatic pain in childhood
   SCHMERZEN BEI RHEUMATISCHEN ERKRANKUNGEN IM KINDESALTER. Biologische Medizin (Germany ) 33:1 25-28, 2004
   Abstract: Rheumatic pain in childhood is to differentiate into acute, chronic and chronified pain. Acute pain occurs due to a highly inflammatory arthritis. The children show a direct pain reaction. Therapy requires immediate medical intervention to reduce pain. Children with insidious onset of chronic arthritis may not be able to utter their pain precisely but rather demonstrate nonverbal pain reactions like pain relieving joint positions, decreased mobilitiy, sleep disturbances, frequent crying or behavioural changes. The treatment of chronic arthritis includes medical, physiotherapeutic and psychosocial care. In chronified pain the pain sensation is separated from a pain stimulus due to a central sensitization with a general lowering of the pain threshold. Severe general or local musculoskeletal pain arises, which does not respond to medical therapy. Psychic crisis and chronic stress can trigger the pain syndrome. Therapy must consider to activate patients and guide them into a life concept of self-responsibility and self-defence

10. HANDA R: Spondylo-arthropathies. J Indian Med Assoc 101:9 514, 516, 518, 2003
    Organism: Rheumatology Service, Department of Medicine, All India Institute of Medical Sciences, New Delhi 110029FAU - Handa, R
    Abstract: Spondylo-arthropathies are a broad group of inflammatory diseases that primarily involve the axial skeleton and the sacro-iliac joints. The pattern of peripheral joint involvement in spondylo-arthropathies differs from rheumatoid arthritis. Spondylo-arthropathies are known to include several conditions like ankylosing spondylitis, reactive arthritis (including Reiter's syndrome), arthritis associated with psoriasis and inflammatory bowel disease, juvenile and also undifferentiated spondylo-arthropathies. The characteristic features of spondylo-arthropathies are absence of rheumatoid factor, inflammatory low backache, sacro-iliitis, peripheral arthritis, enthesopathy, tendency to familial aggregation and association with HLA-B27. ESR may be elevated and patients may exhibit anaemia of chronic inflammation. HLA-B27 is a useful adjunctive test. The radiologic interpretation is very important. Non-steroidal anti-inflammatory drugs and spinal exercises are the cornerstone of therapy. Intra-articular corticosteroids are helpful. Patients may be benefited from, sulfasalazine, methotrexate or azathioprine

11. HELLIWELL PS: Relationship of psoriatic arthritis with the other spondyloarthropathies. Curr Opin Rheumatol 16:4 344-349, 2004
    Organism: Rheumatology and Rehabilitation Research Unit, University of Leeds, Leeds, United KingdomFAU - Helliwell, Philip S
    Abstract: PURPOSE OF REVIEW: The seronegative spondyloarthropathies are a group of disorders sharing common clinical features, the hallmark of which is sacroiliitis. Despite the 40 years since psoriatic arthritis was recognized, controversy still exists about which patients to include within this disease group and the relation of psoriatic arthritis with the other spondyloarthropathies. RECENT FINDINGS: Early disease can present difficulties because it is inappropriate to use criteria developed on established cases in early arthritis, in which many cases may be initially undifferentiated. The taxonomy of juvenile spondyloarthropathy remains a contentious issue, and further modifications of the Durban criteria have been suggested. The predictive value of the European Spondyloarthropathy Study Group criteria for spondyloarthropathy varies with the prevalence of the disease in the population under consideration, as has been demonstrated in ambulatory practice in France and Spain. It appears that physicians differ in their interpretation of the individual features, particularly of such clinical items as asymmetry and predominantly lower limb involvement. The combination of dactylitis of a toe, heel pain, and oligoarthritis appears to be strongly suggestive of psoriatic arthritis. However, solitary heel pain can be problematic, and ultrasonographic entheseal erosion at the calcaneum has been shown equally in rheumatoid arthritis and psoriatic arthritis. MRI may be more sensitive and quantitatively discriminative in psoriatic arthritis. Spinal involvement in psoriatic arthritis can be asymptomatic, as in classical ankylosing spondylitis. Importantly, psoriatic spondylitis has been observed in the absence of sacroiliitis. SUMMARY: Clinicians generally agree that psoriatic arthritis constitutes a discreet subset within the spondyloarthropathy group, but the demarcation continues to be the subject of clinical research. The matter is confounded by the lack of agreed classification criteria for psoriatic arthritis; although in both adult and juvenile disease criteria for spondyloarthropathy exist, the place of psoriatic arthritis within this larger group requires further definition

12. HO CL, WONG EYM, WALTON DS: Goniosurgery for glaucoma complicating chronic childhood uveitis. Archives of Ophthalmology (United States ) 122:6 838-844, 2004
    Abstract: Objectives: To describe the safety and efficacy of goniotomy in medically uncontrolled glaucoma complicating chronic uveitis and the factors affecting its outcome. Methods: All goniotomies performed by a single surgeon for refractory childhood uveitic glaucoma were retrospectively reviewed. Success was defined as final intraocular pressure (IOP) of no greater than 21 mm Hg without medications and qualified success as IOP of no greater than 21 mm Hg with medications. Unless otherwise indicated, data are expressed as mean +/- SD. Results: Fifty-four goniotomies were performed in 40 eyes of 31 patients. Juvenile rheumatoid arthritis-associated uveitis was the diagnosis in 30 eyes (75%). Eleven eyes (28%) were aphakic. Mean follow-up was 98.9 months (range, 2-324 months). Mean age at surgery was 10.3 +/- 4.7 years (range, 4-22 years). Mean preoperative IOP was 36.7 +/- 6.4 mm Hg while receiving a mean of 2.9 +/- 1.1 medications. Overall surgical success was achieved in 29 eyes (72%), including success in 22 (55%) and qualified success in 7 (18%) while receiving a mean of 1.6 +/- 1.1 medications. Mean postoperative IOP in the success and qualified-success groups were 14.3 +/- 2.8 and 15.7 +/- 3.1 mm Hg, respectively. Kaplan-Meier survival probabilities (95% confidence interval) at 1, 5, and 10 years were 0.92 (0.82-1.00), 0.81 (0.65-0.97), and 0.71 (0.49-0.92), respectively. Phakic eyes, eyes with fewer peripheral anterior synechiae, patients younger than 10 years, and eyes with no prior surgery had significantly better outcomes. Hyphema, typically mild and transient, occurred in 43 procedures (80%). Conclusions: Goniosurgery is low risk and effective for refractory glaucoma complicating chronic childhood uveitis. It should be considered the surgical procedure of choice for this condition. Surgical outcome is adversely affected by increased age, peripheral anterior synechiae, prior surgeries, and aphakia

13. HUANG CM, YANG YH, CHIANG BL: Different familial association patterns of autoimmune diseases between juvenile-onset systemic lupus erythematosus and juvenile rheumatoid arthritis. J Microbiol Immunol Infect 37:2 88-94, 2004
    Organism: Department of Pediatrics, National Taiwan University Hospital, No 7 Chung-Shan South Road, Taipei, Taiwan 100, ROCFAU - Huang, Chun-Mei
    Abstract: The aim of this study was to determine if the prevalence of autoimmune disorders in the relatives of patients with systemic lupus erythematosus (SLE) is greater than that of relatives of patients with juvenile rheumatoid arthritis (JRA). Interviews were used to obtain histories of the following autoimmune disorders among living or deceased first-, second-, and third-degree relatives of 91 SLE and 110 JRA families: ankylosing spondylitis, SLE, rheumatoid arthritis (RA), JRA, multiple sclerosis, juvenile dermatomyositis, Sjogren's syndrome, myasthenia gravis, psoriasis, and thyroid diseases. There were statistically significant differences between the SLE and JRA probands in mean age and gender ratio (19.1 +/- 4.8 vs 14.0 +/- 5.5 years; M (male)/F (female): 17/74 vs 62/48, p<0.005). The prevalence rate of autoimmune diseases in relatives of SLE families (20.9%) was greater than in JRA families (11.8%), but not statistically significantly so. The mean age (18.0 +/- 5.3 vs 14.0 +/- 4.3 years), mean age at diagnosis (13.4 +/- 4.3 vs 7.9 +/- 3.9 years) and gender ratio (F/M, 16/3 vs 5/8) of the patients with affected relatives between these 2 groups all had statistically significant differences. A higher prevalence of SLE in relatives was found in SLE families than in JRA cases. Furthermore, this study revealed a higher incidence of autoimmune disorders among second- and third-degree relatives of SLE or JRA probands versus first-degree ones, especially sisters (including 1 pair of twins) and the maternal aunt in SLE families. These data demonstrate that the prevalence of autoimmune disorders in the relatives of patients with SLE is greater than those of relatives of patients with JRA. This suggests that clinically different autoimmune phenotypes may share common susceptibility genes, which may act as risk factors for autoimmunity

14. LOVELL D: Biologic agents for the treatment of juvenile rheumatoid arthritis : current status. Paediatr Drugs 6:3 137-146, 2004
    Organism: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USAFAU - Lovell, Daniel
    Abstract: Biologic therapies, primarily anticytokine therapies, are being increasingly used in patients with juvenile rheumatoid arthritis (JRA). Levels of a variety of proinflammatory cytokines have been shown to be elevated in the peripheral blood and synovial fluid and tissue in children with JRA.In a blinded, randomized, controlled trial in children with severe, long-standing, polyarticular-course JRA not responsive to standard therapies, etanercept showed a statistically significantly greater response rate than placebo. Approximately 75% of these children responded to etanercept. Etanercept has been efficacious in 50-60% of children with active systemic JRA in open clinical trials with acceptable tolerance. Adverse events seen in children treated with etanercept have been similar in type and frequency to those reported in adults.Infliximab has been studied in several open clinical trials in both polyarticular and systemic JRA and found to, overall, have demonstrated efficacy in approximately 60% of patients. Approximately 3-5% of patients have demonstrated infusion reactions or frank allergic reactions and 9% developed new autoantibodies.Anakinra has been studied in children with polyarticular JRA. Approximately 65% of patients developed injection-site reactions and 68% demonstrated a response to the medication. Anakinra may have increased efficacy in systemic JRA.Interleukin (IL)-6 is highly related to the systemic disease manifestations in systemic JRA and two patients treated with a monoclonal antibody to the IL-6 receptor have demonstrated significant improvement with prolonged clinical control with continued treatment.A particular pediatric concern is the effect of immunosuppressive biologics in children who are exposed to or develop varicella. These children should be treated, both in terms of prophylaxis and aggressive antivaricella treatment, as for other immunosuppressed children.Anticytokine biologics have demonstrated great promise in the treatment of JRA and a variety of other pediatric rheumatic diseases, although at this time the randomized, placebo-controlled data are limited only to etanercept in children with polyarticular JRA. Randomized trials are ongoing to better define both the efficacy and safety of these novel treatments for children with JRA and other rheumatic diseases

15. LYBACK CO, BELT EA, SAVOLAINEN HA, LEHTINEN JT, LYBACK CC, LEHTO MU: Previous synovectomy or epiphyseal stapling and the influence on knee replacement in juvenile chronic arthritis. Int Orthop 28:3 134-137, 2004
    Organism: Porvoo District Hospital, Porvoo, FinlandFAU - Lyback, C O
    Abstract: Seventy-seven anatomically graduated components (AGC) total knee arthroplasties (TKA) were performed on 52 patients with juvenile chronic arthritis. According to the nature of previous surgery on the knee, the patients were subdivided into three groups. The mean age at onset of disease in 23 patients with previous synovectomy of the knee was 11 (1.5-16) years, the mean age at the time of synovectomy was 20 (4-42) and the mean age when arthroplasty was performed was 31 (18-45) years. In nine patients with previous epiphyseal stapling, the mean age at disease onset was 4 (1.5-8) years, at stapling 8 (4-16) years, and at arthroplasty 23 (18-30) years. In patients with no previous surgery, the mean age at disease onset in this group was 7 (1.5-16) years and the mean age at arthroplasty 34 (16-64) years. Patients with need for epiphyseal arrest had an early disease onset and knee replacement in early adulthood. The mean age at knee replacements was highest in the group with no prior surgery

16. MAENO N, TAKEI S, IMANAKA H, YAMAMOTO K, KURIWAKI K, KAWANO Y, ODA H: Increased interleukin-18 expression in bone marrow of a patient with systemic juvenile idiopathic arthritis and unrecognized macrophage-activation syndrome. Arthritis and Rheumatism (United States ) 50:6 1935-1938, 2004
    Abstract: The aberrant induction of proinflammatory cytokines is considered to be crucial in the pathogenesis of systemic juvenile idiopathic arthritis and adult-onset Still's disease. Interleukin-18 (IL-18) in particular has been reported to be a candidate for the key cytokine in both diseases; however, the origin of IL-18 is unclear. To clarify the origin, we investigated specimens from various organs obtained during autopsy of a child with systemic JIA and macrophage activation syndrome, using immunohistochemical staining. Our results showed a high number of cells expressing IL-18 in the bone marrow but not in the other organs. This finding suggests that bone marrow is the origin of increased serum IL-18 and raises the possibility that other proinflammatory cytokines are also induced by IL-18 in bone marrow in this disease. Bone marrow may be an essential organ in the pathogenesis of systemic JIA

17. MAENO N, TAKEI S, FUJIKAWA S, YAMADA Y, IMANAKA H, HOKONOHARA M, KAWANO Y, ODA H: Antiagalactosyl IgG antibodies in juvenile idiopathic arthritis, juvenile onset Sjogren's syndrome, and healthy children. Journal of Rheumatology (Canada ) 31:6 1211-1217, 2004
    Abstract: Objective. To determine the normal range of antiagalactosyl IgG antibodies in healthy children, and to investigate the utility of determination of antiagalactosyl IgG antibodies in patients with juvenile idiopathic arthritis (JIA) and juvenile onset Sjogren's syndrome (SS). Methods. Serum concentrations of antiagalactosyl IgG antibodies were measured in 225 healthy children, 68 patients with JIA (systemic arthritis in 21, polyarthritis in 29, oligoarthritis in 18), and 15 patients with juvenile onset SS, using a lectin-enzyme immunoassay employing prepared human agalactosyl IgG as antigen. A comparison was made between the prevalence and utility of antiagalactosyl IgG antibodies in patients and those of conventional rheumatoid factors (RF) determined by laser nephelometry. Results. The average serum concentration of antiagalactosyl IgG antibodies for healthy controls was 2.41 +/- 0.93 arbitrary units (AU)/ml, and the cutoff value of the normal range was set at 4. 3 AU/ml (mean + 2 SD). As a result, antiagalactosyl IgG antibodies were positive in 25 (37%) of 68 patients with JIA, and 14 (93%) of 15 patients with juvenile onset SS, in whom values were much higher than the frequencies of RF positivity. The serum concentrations of antiagalactosyl IgG antibodies in patients were closely correlated with those of RF. Thirteen patients with JIA and 6 patients with juvenile onset SS were positive for antiagalactosyl IgG antibodies despite being negative for RF. With regard to prognosis during followup periods of at least 5 years, JIA patients positive for antiagalactosyl IgG antibodies, even if negative for RF, were resistant to treatment. However, positivity for antiagalactosyl IgG antibodies had no relation to joint destruction. Conclusion. Our data suggest that antiagalactosyl IgG antibodies, compared with RF, show higher sensitivity to detect immunological disorders in JIA and juvenile onset SS

18. MINDEN K, NIEWERTH M, LISTING J, BIEDERMANN T, SCHONTUBE M, ZINK A: Burden and cost of illness in patients with juvenile idiopathic arthritis. Ann Rheum Dis 63:7 836-842, 2004
    Organism: Deutsches Rheuma-Forschungszentrum Berlin, Schumannstr 21/22, 10117 Berlin, Germany minden@drfzdeFAU - Minden, K
    Abstract: OBJECTIVE: To estimate the cost of illness in an incidence based cohort of patients with juvenile idiopathic arthritis. METHODS: Direct costs (healthcare and non-healthcare costs) and indirect costs (productivity loss due to sick leave and work disability) were measured in 215 JIA patients, assessed on an average of 17 years after disease onset. Assessment included a clinical evaluation, a structured interview, and two self completion questionnaires. Annual direct costs were estimated based on the reported use of healthcare services and resources, using average unit prices. Indirect costs were estimated from the number of work days missed-that is, using the human capital approach. RESULTS: The mean total cost of late JIA was estimated to be 3500 per patient and year, of which the direct cost contributed more than half. Patients with still active disease (55%) incurred the major share (90%) of the cost. They had a mean total cost of 5700 per patient year, with those under rheumatological care incurring a cost of 9300. Having a certain JIA subgroup, functional disability, or receipt of specialised care independently contributed to the total cost in active JIA. Highest mean total costs were found in active seropositive polyarthritis (17 000) and extended oligoarthritis (11 000), while the lowest were found in active enthesitis related arthritis (1500) and persistent oligoarthritis (2700). CONCLUSIONS: Estimated 12 month costs in late JIA are considerable, differing among the various JIA subgroups. Treatment strategies in JIA should be analysed for their cost effectiveness in the long term

19. MOROLDO MB, CHAUDHARI M, SHEAR E, THOMPSON SD, GLASS DN, GIANNINI EH: Juvenile rheumatoid arthritis affected sibpairs: Extent of clinical phenotype concordance. Arthritis and Rheumatism (United States ) 50:6 1928-1934, 2004
    Abstract: Objective. To investigate the clinical phenotypes and demographic characteristics of 183 affected sibling pairs (ASPs) with juvenile rheumatoid arthritis (JRA) and to determine whether there are differences between the clinical phenotypes of the ASP cohort compared with patients with sporadic disease and whether there is greater sharing of specific clinical features within versus between sibpairs. Methods. Details of the JRA Affected Sibpair Registry operations have been described previously. The frequencies of phenotypes in the 2 cohorts were tabulated, summary statistics were determined, and comparisons were made by chi-square test or t-test. Sibling risk, sibling risk ratios (lambdaSUBs), and odds ratios were calculated to assess familial aggregation of several different clinical manifestations. Results. The most common onset type among the 164 nontwin ASPs was pauciarticular (65% overall). Fifty-three percent of the ASPs were concordant for pauciarticular-onset JRA; 19% were concordant for a polyarticular disease onset. Among subjects with polyarticular-onset disease, significantly more joints were involved at onset in simplex patients than in ASPs (P = 0.008). The difference in age at JRA onset within sibpairs (sibling 1 versus sibling 2) was not significantly different. ASPs developed disease at a mean real-time difference of 5.1 years apart. Familial aggregation was found for tenosynovitis (lambdaSUBs 29.5), leukocytosis (lambdaSUBs 25), rheumatoid factor (lambdaSUBs 11.0), anemia (lambdaSUBs 1.7), and antinuclear antibodies (lambdaSUBs 1.3). Conclusion. This study confirms the findings of earlier studies showing that a high proportion of ASPs overall show concordance of disease-onset type, except for the subset of patients with systemic disease, and that nontwin ASPs do not develop disease at the same point in real time. We conclude that JRA and its clinical manifestations do not differ substantially between ASPs and the simplex population. The exception is the number of affected joints at JRA onset among patients with polyarticular-onset disease. Familial aggregation of clinical features among ASPs adds strong evidence for a genetic background in this disease

20. NIEHUES T, HORNEFF G, MICHELS H, SAILER HM, SCHUCHMANN L: Evidence-based use of Methotrexate in children with rheumatic disorders
    EVIDENZBASIERTER EINSATZ VON METHOTREXAT BEI KINDERN MIT RHEUMATISCHEN ERKRANKUNGEN. Zeitschrift fur Rheumatologie (Germany ) 63:2 147-159, 2004
    Abstract: Juvenile idiopathic arthritis (JIA) is the most common diagnosis in children and adolescents with rheumatic disorders. In many children and adolescents, JIA is successfully treated with non-steroidal antiinflammatory drugs (NSAR) and physiotherapy. Still, in a significant number of cases the disease is resistant to this therapy and treatment with "second line" disease modifying antirheumatic drugs (DMARDs) is required. Methotrexate (MTX) is frequently referred to as "first choice second line agent" for the treatment of JIA. However, there are considerable differences among pediatric rheumatologists on how and when to use MTX. To increase drug safety, the Working Group for Children and Adolescents with Rheumatic Diseases in Germany (AGKJR) and the Working Group Pediatric Rheumatology Austria have initiated the formulation of evidence-based recommendations. Evidence is based on consensus expert meetings, a MEDLINE search with the key words "Methotrexate" and "juvenile arthritis" limited to age 0-18 years, standard textbooks and review articles, data from the central registry of the German Research Center for Rheumatic Diseases (Deutsches Rheumaforschungszentrum Berlin), experience with MTX in adults with rheumatoid arthritis (RA) and recommendations of the German Society of Rheumatology (DGRh). Based on these data, evidence and recommendations are graded and evidence-based recommendations for the use of MTX in children and adolescents with rheumatic disease are presented

21. PETERSON CC, PALERMO TM: Parental reinforcement of recurrent pain: the moderating impact of child depression and anxiety on functional disability. J Pediatr Psychol 29:5 331-341, 2004
    Organism: Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of MedicineFAU - Peterson, Catherine Cant
    Abstract: OBJECTIVE:To examine whether children's distress moderates the relationship between parental responses to children's pain behaviors and functional disability. METHODS:Participants were 215 children (ages 8 to 16 years) diagnosed with either headaches, juvenile idiopathic arthritis, or sickle cell disease. Children and parents completed questionnaires assessing sociodemographics, pain, depression, anxiety, parental solicitous responses to pain behaviors, and functional disability. RESULTS:Hierarchical linear regressions computed for parental responses to children's pain significantly predicted child functional disability, controlling for children's pain intensity. Significant interactions between parental solicitous behaviors and child depressive symptoms (beta =.74, p <.01) and between solicitous behaviors and child anxiety symptoms (beta =.91, p <.01) indicated that for children with more psychological distress, parental solicitous behaviors were associated with greater child functional disability. CONCLUSIONS:Child psychological distress may exacerbate the impact of parental solicitous responses to pain on functioning, suggesting the potential role of family intervention to enhance optimal functioning in children with recurrent pain

22. REVENGA MM, CEBALLOS LE, HORTAL AR, GAMIR GAMIR ML: Current treatment of juvenile idiopathic arthritis
    TRATAMIENTO ACTUAL DE LA ARTRITIS IDIOPATICA JUVENIL. Seminarios de la Fundacion Espanola de Reumatologia (Spain ) 4:4 171-189, 2003
    Abstract: Juvenile idiopathic arthritis (JIA) is the most common chilhood chronic inflamatory rheumatic disease. The variability in disease course with total recovery may explain the false thinking of a benign disease, but many children experience lifelong symptoms and significant disability with great disminution in their current and future quality of life. The goals of therapy are to get a total remission of disease, supress the inflammatory process, preserve joint and muscle function, control of pain, prevent deformities and achieve a normal growth and development. Timely diagnosis and early beginnig of more aggressive therapy of patiens with poor prognostic features, improve quality of life and outcome. Only one third of JIA patients responds to NSAIDs, intraarticular injections, physical therapy and occupational therapy. The most patients require the classical disease-modifyig antirheumatic drugs (DMARDs) as methotrexate. However, one third of these do not respond to methotrexate adequately. For these patientes there are new biologic therapies such as a TNF soluble receptor (etanercept), monoclonal antibodies (infliximab, adalimumab), interleukin-1 receptor antagonist (IL-1RA or anakinra) and much more in developement, that need more well-designed multicentric international long-term clinical trials to asure indications, dosing, safety, and efficacy. The therapeutic strategy should be planned individually according to age, subtype and disease activity and carried out as a multidisciplinary teamwork guided for a Pediatric Rheumatologist with several specialties. Finally, despite the advances with the new encouraging therapies that show a great promising future, there is still much work to be done, in the JIA therapy

23. ROTH J: Bone mass in adolescents with early-onset juvenile idiopathic arthritis: Comment on the article by Lien et al [2]. Arthritis and Rheumatism (United States ) 50:6 2036, 2004

24. STROBER BE, CLARKE S: Etanercept for the treatment of psoriasis: combination therapy with other modalities. J Drugs Dermatol 3:3 270-272, 2004
    Organism: Ronald O Perelman Department of Dermatology, New York University School of Medicine, USA b_strober@hotmailcomFAU - Strober, Bruce E
    Abstract: Etanercept is a self-administered medication that has FDA approval for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Etanercept is a human fusion protein of the tumor necrosis factor receptor (TNFR) and the Fc region of IgG1 that binds to and presumably inhibits the pro-inflammatory and pro-proliferative activity of the tumor necrosis factor (TNF). A recent multisite, randomized, double-blind, placebo-controlled study conclusively demonstrates that etanercept as monotherapy effectively treats patients with moderate-to-severe plaque psoriasis. This effect is dose-responsive, with the etanercept 50 mg twice-weekly dose significantly more effective than the 25 mg twice-weekly dose in reducing the Psoriasis Area and Severity Index (PASI) score over both 12 and 24 weeks of continuous therapy. Nevertheless, clinical trials do not instruct the dermatologist on how to practically integrate etanercept into a patient's pre-existing treatment regimen. Many psoriasis patients are already on other systemic therapies or have a medical history that necessitates a tailored approach to their therapy. Further, in some patients, etanercept at 25 mg twice weekly is ineffective in maximally clearing a patient of psoriasis. Below are cases that demonstrate how etanercept can be combined with other medications in order to both maximize clinical efficacy and minimize potential risk

25. TEN CATE R, NIBBERING PH, BREDIUS RG: Therapy-refractory systemic juvenile idiopathic arthritis successfully treated with statins. Rheumatology (Oxford) 43:7 934-935, 2004
    Organism: Department of Paediatrics, Leiden University Medical Centre, Mailbox 9600, 2300 RC Leiden, The Netherlands rgmbredius@lumcnlFAU - Ten Cate, R

26. VOLZ T, SCHWARZ G, FLECKENSTEIN B, SCHEPP CP, HAUG M, ROTH J, WIESMULLER KH, DANNECKER GE: Determination of the peptide binding motif and high-affinity ligands for HLA-DQ4 using synthetic peptide libraries. Hum Immunol 65:6 594-601, 2004
    Organism: University Children's Hospital, Tuebingen, GermanyFAU - Volz, Thomas
    Abstract: Juvenile idiopathic arthritis (JIA) is considered to be an autoimmune disease. Various human leukocyte antigen (HLA) associations for different subgroups of this heterogeneous disease have been found. For early-onset pauciarticular arthritis (now oligoarthritic JIA), a strong association with the HLA class II haplotype DQA1*0401/DQB1*0402 (DQ4) has been described. We determined the peptide-binding specificities of this HLA-DQ molecule by screening a synthetic acetylated nonapeptide amide library with one defined and eight random sequence positions. A characteristic binding motif could be deduced. By use of these data, we designed defined specific nonapeptides and identified high-affinity ligands binding to HLA-DQ4. The peptide binding motif of HLA-DQ4 is very similar to the motif of HLA-DQ7, also associated with oligoarthritic JIA. It is, however, different from binding motifs of neutral or protective HLA-DQ molecules. Our results further support the idea of differential peptide presentation in the pathogenesis of oligoarthritic JIA

27. ZEGGINI E, REGINATO AM, PRAIS A, THOMSON W, MCLEAN W, DONN R: Linkage and association studies of discoidin domain receptor 1 (DDR1) single nucleotide polymorphisms (SNPs) in juvenile oligoarthritis. Rheumatology (Oxford) .: 2004
    Organism: CIGMR, University of Manchester, Manchester, UK
    Abstract: OBJECTIVES: Multiple independent juvenile oligoarthritis susceptibility loci have been identified within the major histocompatibility complex (MHC), including HLA-A, HLA-DRB1 and an as yet unlocalized effect in the centromeric class I region. The discoidin domain receptor 1 (DDR1) gene resides within this region and codes for a receptor tyrosine kinase that plays an important role in regulating cell attachment to collagen, chemotaxis, proliferation and matrix metalloproteinase (MMP) production. DDR1 expression in chondrocytes has not been investigated. The objectives of this study were to investigate expression of DDR1 in healthy chondrocytes and to identify linkage and association of this candidate gene with juvenile oligoarthritis. METHODS: A set of 135 simplex juvenile idiopathic arthritis families consisting of one affected child and healthy parent(s) and 199 healthy unrelated individuals were genotyped for six single nucleotide polymorphisms (SNPs) within the DDR1 gene using the primer extension SNaPshot(TM) method. Single-point and multipoint transmission disequilibrium tests were carried out with the ETDT and TDTPHASE packages. Allele frequency comparisons between cases and controls were carried out with the chi(2) test. DDR1 expression was investigated in normal articular cartilage by RT-PCR and immunofluorescence methods. RESULTS: No linkage and association with any of the six SNPs or their haplotypic combinations were observed in the families studied. No significant differences were observed in allele frequencies between patients and controls. DDR1 expression was found in normal articular cartilage by RT-PCR and by immunofluorescence. CONCLUSIONS: The DDR1 SNPs examined are not involved in susceptibility to juvenile oligoarthritis