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Summary Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and comprises of multiple subtypes. The most relevant disease subtypes, grouped upon current insight in disease mechanisms, are nonsystemic (oligo- and polyarticular) JIA and systemic JIA (sJIA). In this review, we summarize some of the main proposed mechanisms of disease in both nonsystemic and sJIA and discuss how current therapeutic modalities target some of the pathogenic immune pathways. Chronic inflammation in nonsystemic JIA is the result of a complex interplay between effector and regulatory immune cell subsets, with adaptive immune cells, specifically T-cell subsets and antigen-presenting cells, in a central role. There is, however, also innate immune cell contribution. SJIA is nowadays recognized as an acquired chronic inflammatory disorder with striking autoinflammatory features in the first phase of the disease. Some sJIA patients develop a refractory disease course, with indications for involvement of adaptive immune pathways as well. Currently, therapeutic strategies are directed at suppressing effector mechanisms in both non-systemic and sJIA. These strategies are often not yet optimally tuned nor timed to the known active mechanisms of disease in individual patients in both non-systemic and sJIA. We discuss current treatment strategies in JIA, specifically the ‘Step-up’ and ‘Treat to Target approach’ and explore how increased insight into the biology of disease may translate into future more targeted strategies for this chronic inflammatory disease at relevant time points: preclinical disease, active disease, and clinically inactive disease.

Juveniele idiopathische artritis (jia) is een systemische auto-immuunziekte die vooral de gewrichten treft. De gevolgen van de ziekte zijn veelzijdig en liggen op het gebied van de groei en psychosociale en motorische ontwikkeling. In dit reviewartikel worden de nieuwe ontwikkelingen op het gebied van classificatie, etiologie, pathofysiologie, prognose en behandeling van jia besproken.

Objective. To study the relationships of muscle strength and maximal oxygen consumption (VO2peak) with Childhood Health Assessment Questionnaire (CHAQ) score, Childhood Myositis Assessment Score (CMAS) and Child Health Questionnaire wphysical summary (CHQ-PhS) and psychosocial summary (CHQ-PsS)x scores in juvenile dermatomyositis. Method. Fifteen patients (age 5–14 yr) participated. CMAS, CHAQ, CHQ, muscle strength and VO2peak were measured. Results. Correlations revealed significant relationships between CHAQ and (i) muscle strength (r=20.72) and (ii) absolute VO2peak (r=20.68); between CMAS and relative VO2peak (r=0.73); and between CHQ-PhS and (i) muscle strength (r=0.57) and (ii) relative VO2peak (r=0.58). Backward regression analysis showed that muscle strength was the best indicator of variation in CHAQ. Age and relative VO2peak were the best indicators for CMAS. Body mass and age were the best indicators for CHQ-PsS. Body mass and muscle strength were the best indicators for CHQ-PhS. Conclusion. CMAS, CHAQ and CHQ correlate with muscle strength and VO2peak. CMAS, CHAQ and CHQ depend on different physical and physiological variables.

The impact of systemic onset JCA on functional outcome was studied in a multidimensional construct. Twenty-one patients were subjected to auxologic evaluation, a laboratory check, pulmonary and cardiac function tests, radiographic evaluation, joint count on tenderness, swelling and function, ADL, health assessment (CHAQ), and psychosocial evaluation. Six of 21 patients had active systemic disease. Restrictive pulmonary function was found in 8/17 patients, 1/21 had pericarditis. Joint impairment was moderate. Functional limitations were mild. Self-esteem was positive. Parental report on functional limitation correlated significantly with joint impairment. Performance of daily activities correlated strongly with perceived competence. Active inflammatory disease did not correlate with joint impairment and functional limitation. Patients with systemic onset JCA develop mild functional limitations, which partially correlate with the more serious impairments. Pulmonary function disorders are a common impairment. Active inflammatory disease might influence functional outcome, but there is no evidence that it influences joint impairment outcome.

Juvenile dermatomyositis (DM) is a systemic autoimmune disorder of unknown immunopathogenesis in which the immune system targets the microvasculature of skeletal muscles, skin, and other organs. The current mainstay of therapy is a steroid regimen in combination with other immunosuppressive treatments. To date, no validated markers for monitoring disease activity have been identified, which hampers personalized treatment. This study was undertaken to identify a panel of proteins specifically related to active disease in juvenile DM.We performed a multiplex immunoassay for plasma levels of 45 proteins related to inflammation in 25 patients with juvenile DM in 4 clinically well-defined groups, as determined by clinical activity and treatment. We compared them to 14 age-matched healthy children and 8 age-matched children with nonautoimmune muscle disease.Cluster analysis of circulating proteins showed distinct profiles for juvenile DM patients and controls based on a group of 10 proteins. In addition to CXCL10, tumor necrosis factor receptor type II (TNFRII) and galectin 9 were significantly increased in active juvenile DM. The levels of these 3 proteins were tightly linked to active disease and correlated with clinical scores (as measured by the Childhood Myositis Assessment Scale and physician's global assessment of disease activity on a visual analog scale).Our findings indicate that CXCL10, TNFRII, and galectin 9 correspond to disease status in juvenile DM and thus could be helpful in monitoring disease activity and guiding treatment. Furthermore, they might provide new knowledge about the pathogenesis of this autoimmune disease.

To assess the impact of disease on the functional outcome of patients with polyarticular juvenile chronic arthritis (JCA), the relationship between impairments and functional limitations was studied. Therefore, variables from the impairment domain were correlated with variables of the functional limitation domain and outcome variables were analysed for differences as a result of inflammatory disease, rheumatoid factor (RF), disease duration and age at onset. Twenty-three patients with polyarticular JCA were subjected to auxologic evaluation, a laboratory check, radiographic evaluation, joint count on tenderness and swelling, joint mobility/deformity examination, functional assessment of skills, health assessment and psychosocial evaluation. Inflammatory disease parameters, like CRP, ESR, thrombocytosis and leucocytosis, were increased in 6/23 patients. The parameters of the impairment domain, like joint tenderness and swelling, showed mild outcome, while parameters of the functional limitation domain showed more severe outcome. Generally, perceived competence was found to be normal. A clinically relevant number of patients (10/13) showed low scores on the activity factor of the Child Behaviour Check List (CBCL). A significant relationship was found between inflammatory disease variables and functional limitation outcome. RF seropositivity was not a good outcome predictor. Disease duration and age of onset showed no significant difference in the outcome of the domains. Significant correlation was found between the parental report of the Childhood Health Assessment Questionnaire (CHAQ) and all impairment parameters. Joint swelling showed a significant relationship with CHAQ and Juvenile Arthritis Functional Assessment Report (JAFAR). Disability outcome did not correlate with functional limitation. In general, children with polyarticular JCA function rather well when using a multidomain evaluation approach. Compensatory and adaptational mechanisms might contribute to the poor correlation between impairment and functional limitation parameters. Laboratory evaluation of inflammatory disease, a joint count of swollen joints and parent's report of the child's health status related best in our study.

To document the psychological side effects of methotrexate (MTX) treatment in children with juvenile idiopathic arthritis (JIA) and to explore the usefulness of psychological therapy to ameliorate these side effects.The patients included in this study consisted of 29 patients with JIA using MTX. Of these, ten were referred to a pediatric psychologist because of MTX side effects, and had behavioural therapy to cope with these side effects with a strong behavioural component (anticipatory nausea, anxiety). The behavioural therapy was adapted to age and used systemic desensitization (distraction in a positive atmosphere) or cognitive behavioural therapy (relaxation and overruling negative thoughts by positive ones). The parents of the 29 children were interviewed about MTX treatment and the side effects their child had developed. Parents of children referred to the psychologist were also interviewed for their impression of the results of the behavioural therapy.Prior to the behavioural therapy, nine out of 10 children reported MTX related nausea. Six of these ten were nauseous even before the administration and developed anticipatory nausea. Nine out of ten patients also showed some sign of distress in anticipation of MTX treatment, either orally of via injections. The behavioural therapy they had fully abolished side effects in five children and decreased the severity of nausea and distress in two children. Of the remaining nineteen children, not referred to the pediatric psychologist, 11 reported nausea after MTX treatment and four of these developed anticipatory nausea. In addition, eight of these 18 developed behavioural distress in anticipation of the treatment.This study showed that children with JIA who receive MTX treatment frequently develop psychological side effects, such as anticipatory nausea and behavioural distress in anticipation of treatment. This is true for patients selected for reported MTX side effects, as well as for randomly chosen JIA patients using MTX. As MTX is still the first choice in the treatment of severe JIA, more attention should be given to the treatment and prevention of side effects. Psychological intervention can be of help, but further studies are needed on the nature of the side effects, as well as on the prerequisites and efficacy of behavioural therapy.

In 2002, all children in the Netherlands from four to 18 years of age, including the Juvenile Idiopathic Arthritis (JIA) population, were vaccinated with the group-C meningococci conjugate vaccine. The aim of this study is to determine whether the vaccine increases JIA disease activity by monitoring the core set criteria of JIA patients as well as investigates the efficacy of this vaccine in those receiving DMARDs. The core set criteria included Childhood Health Assessment Questionnaire (CHAQ) disability, CHAQ pain, CHAQ well being, number of inflamed joints, range of motion, ESR, CRP, and semi-quantitative physicians global assessment. These were monitored for six months prior to as well as after vaccination for any changes in 86 JIA patients. Blood samples were taken from patients to measure antibody production using ELISA as well as T cell proliferation through intracellular fluorescent dye CFSE. In summary, no significant differences (P>0.05) were found when comparing the core set criteria six months before as well as six months after vaccination. However, there were significant increases of CD4+ T cell proliferation both against the carrier protein of the vaccine (P=0.034) as well as the whole vaccine (P=0.035). Furthermore, anti-Men C IgG antibody production increased significantly (>18µg/ml) irrespective of DMARD therapy. In conclusion, our data suggests that the group-C meningococci conjugated vaccine does not increase JIA disease activity. Moreover, B as well as T lymphocyte activity against group-C meningococci are not significantly diminished in patients undergoing immune suppressive treatments.

To test the hypothesis that T cell reactivity to self heat-shock protein 60 (Hsp60) in patients with remitting juvenile idiopathic arthritis (JIA) is part of an antiinflammatory, regulatory mechanism.Using peripheral blood-derived mononuclear cells (PBMCs) and synovial fluid-derived mononuclear cells (SFMCs) obtained from patients with JIA, we analyzed the expression of CD30 and the induction of regulatory cytokines in response to human and mycobacterial Hsp60.In oligoarticular JIA patients, in vitro activation of PBMCs and SFMCs with Hsp60 induced a high expression of CD30 on CD4+, activated (HLA-DR-positive), memory (CD45RO+) T cells. The expression of CD30 induced by human Hsp60 was much higher than that induced by mycobacterial Hsp60. In oligoarticular JIA patients with active disease, the expression of CD30 in response to human Hsp60 was paralleled by a high interleukin-10 (IL-10):interferon-gamma (IFNgamma) ratio. In addition, restimulated human Hsp60-specific T cell lines from oligoarticular JIA patients showed a high production of IL-10 and a low production of IFNgamma. In contrast, PBMCs and SFMCs from polyarticular JIA patients responded to human Hsp60 with virtually no expression of CD30 and a low IL-10:IFNgamma ratio.The results show that T cells responding to human Hsp60 in oligoarticular JIA patients express CD30, and during active phases of the disease, these T cells have a cytokine profile with a high IL-10:IFNgamma ratio. These findings suggest that in oligoarticular JIA patients, human Hsp60-specific CD4+ cells have a regulatory function and contribute to disease remission.

We report herein the results of the cross-cultural adaptation and validation into the Dutch language of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. The Dutch CHAQ was fully validated with 3 forward and 3 backward translations while the CHQ was already published and therefore it was revalidated. A total of 180 subjects were enrolled: 100 patients with JIA (17% systemic onset, 31% polyarticular onset, 18% extended oligoarticular subtype, and 34% persistent oligoarticular subtype) and 80 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Dutch version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

Objective. To determine whether T lymphocyte reactivity to endogenous human hsp60 plays a regulatory role in the course of oligoarticular juvenile rheumatoid arthritis (JRA). Methods. A prospective, longitudinal study of T cell reactivity to HSP in 15 patients with newly diagnosed HLA-B27 negative oligoarticular JRA was performed. Results were compared with those in a group of 20 patients with newly diagnosed polyarticular or systemic JRA or with acute arthritis caused by other systemic diseases or viral infections, as well as with those in a group of 9 healthy control subjects. Results. In 86% of the patients with oligoarticular JRA (13 of 15), significant T lymphocyte proliferative responses to hsp60 were found in peripheral blood mononuclear cells and/or synovial fluid mononuclear cells within 3 months after the onset of arthritis. Only 5% of the patients in the rheumatologic disease control group (1 of 20) showed such positivity. All patients with oligoarticular JRA and positive responses to human hsp60 developed a remission of their disease within 12 weeks. During this period of remission, blood samples were taken from 8 patients and showed significantly lower and even negative responses to hsp60, compared with active disease, when all 8 patients had good responses. Conclusion. The results show that significant proliferative responses to human hsp60 can be found early in the course of oligoarticular JRA. Furthermore, these responses correlate with disease activity in such a manner that T cell reactivity to human hsp60 seems to be associated with disease remission.

Of all the microorganisms, bacteria, especially, seem to exert continuous pressure on the immune system. The epithelial surfaces of the skin and the intestinal tract are colonized by a wide variety of bacterial species, forcing the immune system into a situation where it has to scan continuously an immense repertoire of foreign antigenic determinants. It may be self-evident that as much as the healthy immune system does not develop an aggressive response directed against self antigens, or autoantigens, the same immune system is not tuned to mount continuous and aggressive responses to antigens present in the resident bacterial flora. Nonetheless, the capacity to respond must be there. Within every healthy immune system, cells specific for autoantigens are present, and their potential for causing disease has been demonstrated in a variety of experimental autoimmune disease models. The mechanisms by which the immune

Heat-shock proteins are a category of proteins that are synthesized under stressful conditions (such as increased temperatures) both by prokaryotic and eukaryotic cells. Heat-shock proteins are a major target of the immune response and thus can be considered dominant antigens. Under physiological circumstances the response to heat-shock proteins is considered to play a role in the overall defence against bacterial infections. An aberrant immune response against heat-shock proteins may lead to autoimmunity, as illustrated by adjuvant arthritis in Lewis rats. Current evidence also points towards a role of T cell immunity against heat-shock proteins in the development of human autoimmune diseases such as juvenile chronic arthritis.