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    "textoCompleto" => "<p class="elsevierStylePara">In recent decades many advances in paediatric rheumatology have been achieved&#44; in particular in classification&#44; outcome measurements&#44; and therapeutic regimens&#46; In particular&#44; the collaborative effort of multicenter studies has helped to improve the recognition and treatment of less common rheumatic diseases in childhood&#46; Due to a close cooperation among researchers in Europe and United States&#44; new drugs and treatment strategies have been tried in a large number of children&#44; with a significant amelioration of the quality of life&#46; Nevertheless&#44; connective tissue diseases remain a challenge for paediatric rheumatologists over the world&#46; This review will briefly focus on some recent advances the field of pediatric rheumatology&#46; For space constraint&#44; we have chosen to cite those article that seemed to us more important&#44; either from a research or from a clinical point of view&#44; and we have concentrated our attention on juvenile idiopathic arthritis and the major connective tissue diseases &#40;systemic lupus&#44; dermatomyositis&#44; and Kawasaki disease&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Juvenile idiopathic arthritis</span></p><p class="elsevierStylePara">The International League of Associations for Rheumatology met in 2001 to delineate&#44; for research and clinical purposes&#44; relatively homogenous&#44; mutually exclusive categories of idiopathic arthritis in childhood&#44; based on predominant clinical and laboratory features <span class="elsevierStyleSup">1</span>&#46; Juvenile idiopathic arthritis &#40;JIA&#41; is now the preferred term&#44; and the classification was recently approved for use in trials by the US Food and Drug Administration&#46;</p><p class="elsevierStylePara">Amomg diagnostic techniques&#44; MRI was recently studied by Knight et al <span class="elsevierStyleSup">2</span>&#44; who examined MRI T2 relaxation times in the weight-bearing cartilage of the distal femur in healthy children and in children with JIA&#46; Differences in cartilage microstructure were seen&#59; this may allow for early detection of cartilage changes and provide an objective and quantitative method of monitoring disease progression&#44; with the long-term potential to guide therapy&#46;</p><p class="elsevierStylePara">The issue of low bone density on children with rheumatic disorders&#44; including JIA&#44; is becoming more and more important in the follow-up of our patients&#46; While dual-Xray absorptiometry &#40;DXA&#41; is still the gold standard to monitor bone density&#44; new promising approaches such as bone ultrasound are gaining interest <span class="elsevierStyleSup">3&#44;4</span>&#46; Peripheral quantitative Computer Tomography&#44; for the time being still a research tool&#44; has been used to evaluate bone density and geometric parameters in the forearm of 57 patients with polyarticular&#44; oligoarticular&#44; and systemic JIA <span class="elsevierStyleSup">5</span>&#46; Patients in all disease groups had significantly reduced muscle cross-sectional area&#44; which strongly correlated with muscle force and abnormalities in geometric parameters of bone&#44; including a significant reduction in cortical thickness&#46; Trabecular density was affected only in the polyarticular JIA group&#44; and cortical density was normal in all subgroups&#46; Thinned bony cortices might therefore predispose to fractures even though cortical bone density itself is normal&#46;</p><p class="elsevierStylePara">Treatment of JIA is still based on administration of nonsteroidal anti-inflammatory drugs&#44; with the addition of second-line drugs in case of insufficient response&#46; Among the numerous second-line drugs now available&#44; methotrexate &#40;MTX&#41; is still the first choice in patients with polyarticular disease because of its relative safety&#44; low-cost&#44; and long follow-up data&#46; It has been recently shown that patients who do not respond to 10 mg&#47;sq&#46; meter&#47;week might respond to higher dosages&#46; However&#44; the plateau of efficacy of MTX was reached with parenteral administration of 15 mg&#47;sq&#46; meter&#47;week&#44; and a further increase in dosage was not associated with any additional therapeutic benefit <span class="elsevierStyleSup">6</span>&#46;</p><p class="elsevierStylePara">The availability of biologic agents&#44; in particular the anti-TNFa drugs&#44; has greatly improved the prognosis in cases who are resistant to methotrexate treatment&#46; The efficacy of these drugs in JIA has been shown both in open &#40;for infliximab&#41; <span class="elsevierStyleSup">7</span> and controlled &#40;for etanercept&#41; <span class="elsevierStyleSup">8</span> studies&#46;</p><p class="elsevierStylePara">Recently&#44; Silverman and colleagues have compared the safety and efficacy of leflunomide with that of methotrexate in the treatment of polyarticular JIA in a randomized&#44; controlled trial <span class="elsevierStyleSup">9</span>&#46; The authors concluded that in patients with polyarticular JIA&#44; both methotrexate and leflunomide resulted in high rates of clinical improvement&#44; with a slightly greater rate for methotrexate&#46;</p><p class="elsevierStylePara">Once clinical remission is achieved&#44; it is always a problem to choose the right timing of drug discontinuation&#46; Foell et al <span class="elsevierStyleSup">10</span> investigated whether the duration of MTX treatment after the induction of remission influences the subsequent duration of remission in patients with JIA&#44; and the usefulness of a biologic marker &#40;S100A8&#47;S100A9&#41; as a predictor for the stability of remission&#46; The results suggested that the presence of residual subclinical synovial inflammation &#40;as measured by S100A8&#47;S100A9&#41;&#44; not duration of MTX treatment after the induction of remission&#44; influences the rate of relapse after discontinuation of MTX&#46; However&#44; the number of patients was small&#44; and a larger controlled study specifically designed for this purpose is currently underway&#46;</p><p class="elsevierStylePara">Systemic-onset JIA is one of the challenges of our clinics&#46; There are some cases who are totally steroid-dependent&#44; and in whom nothing seems to work&#46; Recently&#44; Pascual et al&#46; have demonstrated the role of interleukin-1 in the disease pathogenesis&#44; as well as the efficacy of a recombinant IL-1 receptor antagonist in an open study on nine patients who were refractory to other therapies <span class="elsevierStyleSup">11</span>&#46; Complete remission was obtained in seven patients&#44; and partial response in the other two&#46;</p><p class="elsevierStylePara">Since interleukin-6 is also known to be one of the key mediators in this disorder&#44; treatment with recombinant human anti-interleukin-6 receptor monoclonal antibody &#40;MRA&#41; has been tried in children with systemic-onset JIA refractory to high-dose&#44; long-term corticosteroids <span class="elsevierStyleSup">12</span>&#46; An individual escalating-dose trial was conducted in 11 children with active disease&#46; MRA abruptly reduced disease activity in 10 of these patients&#44; as assessed by the occurrence of febrile episodes&#44; active arthritis&#44; Childhood Health Assessment Questionnaire&#44; and acute-phase reactants&#46; The drug was well tolerated&#46; However&#44; larger controlled studies are needed before drawing any firm conclusions&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Systemic lupus erythematosus</span></p><p class="elsevierStylePara">SLE is not uncommon in children&#44; since in about 15 &#37; of all cases the disease begins in childhood&#46; It is associated with frequent organ system damage and influences the normal physical and psycho-social development of patients <span class="elsevierStyleSup">13</span>&#46;</p><p class="elsevierStylePara">With regard to etiopathogenesis&#44; an important role for interferon-&#945; &#40;IFN-&#945;&#41; has been recognized&#44; without substantial differences between children and adults with regard to leukocyte gene expression profiles&#46; Blanco et al&#46; hypothesized that the disease may be caused by alterations in the functions of dendritic cells&#46; Indeed&#44; monocytes from SLE patients&#39; blood were found to function as antigen-presenting cells <span class="elsevierStyleItalic">in vitro</span>&#44; and sera from SLE patients induced normal monocytes to differentiate into dendritic cells&#46; The capacity of SLE sera to induce DC differentiation correlated with disease activity and depended on the actions of IFN-&#945; <span class="elsevierStyleSup">14</span>&#46;</p><p class="elsevierStylePara">The survival of newly diagnosed SLE children has increased&#44; the major reason for death being now infections&#44; as opposed to renal failure as in the past&#46; While a survival of 80-85 &#37; during a follow-up of 5-10 years was considered satisfactory in the past&#59; the goal of new therapies is to obtain both a more prolonged survival and a reduced organ system damage&#46; Renal and cerebral involvement are the major concerns in SLE children&#44; and require an early aggressive therapeutic approach in order to reduce the degree of disease morbidity and mortality&#46; Males and females seem not to have a different outcome in this regard <span class="elsevierStyleSup">15</span>&#46;</p><p class="elsevierStylePara">Azathioprine has been used for at least 30 years as second-line agent&#44; but controlled trials are lacking in childhood&#46; Anedoctal reports suggest that cyclosporin may allow the tapering steroids and better control of disease activity&#59; however&#44; hypertension and increased serum creatinine limit its use in children with renal involvement&#46; Cytoxan pulses are now the first line treatment for severe lupus nephritis <span class="elsevierStyleSup">16</span>&#59; promising results have been reported in adults with Mycophenolate Mofetil &#40;MMF&#41;&#44; a novel immunosuppressive agent&#46; The experience in childhood is limited to small case series <span class="elsevierStyleSup">17</span>&#46; Even though long-term follow-up is not available&#44; MMF seems a promising drug for the treatment of severe juvenile SLE&#46; Wulfraat et al&#46; report autologous stem cell transplantation with sustained control of disease activity&#44; off any medication&#44; in two adolescents with intractable disease <span class="elsevierStyleSup">18</span>&#46; A long-term follow-up is however necessary&#44; as well as strict inclusion criteria that should also consider the high risk of the procedure itself&#46; Of the new biological therapies&#44; in pediatrics anti-CD20 &#40;Rituximab&#41; seem to be the more promising agent <span class="elsevierStyleSup">19</span>&#46; No controlled trials are yet available&#46;</p><p class="elsevierStylePara">Among short and long-term complications&#44; osteopenia and osteoporosis are certainly a major risk&#44; due to decreasd sun exposure&#44; inflammatory disease activity&#44; and corticosteroid use <span class="elsevierStyleSup">20</span>&#46; The use of bisphosphonates in patients with low bone density has significantly increased bone mass <span class="elsevierStyleSup">21</span>&#46; Accelerated atherosclerosis with carotid media-intima thickness <span class="elsevierStyleSup">22</span> and abnormalities in lipoprotein oxidation <span class="elsevierStyleSup">23</span> are another major concern&#46; Soep et al <span class="elsevierStyleSup">24</span> investigated atherosclerotic risk factors and endothelial function in pediatric SLE&#46; Lipoproteins&#44; oxidized state&#44; autoantibodies to oxidized low-density lipoprotein&#44; and endothelial function &#40;brachial artery reactivity&#41; were measured&#46; Patients had significantly decreased mean levels of high-density lipoprotein cholesterol and apolipoprotein A-I when compared to controls&#46; Due to the risk of atherosclerotic coronary artery disease&#44; the profile of plasma lipids should therefore be evaluated in all SLE children in order to prevent early myocardial infarction&#46; The best preventive strategies include no smoking&#44; low-fat diet and physical activity&#46; The role of antimalarials as lipid-lowering effect is known in adults&#44; but studies of their usefulness in children are lacking&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Juvenile dermatomyositis</span></p><p class="elsevierStylePara">Idiopathic inflammatory myopathies are rare in childhood and display a less heterogeneous pattern than in adults&#46; Juvenile dermatomyositis &#40;JDM&#41; with the characteristic skin and muscle abnormalities represents the most common form in childhood <span class="elsevierStyleSup">25</span>&#46; Recently&#44; Mendez et al evaluated the incidence of JDM in the United States&#59; the estimated annual incidence rates ranged from 2&#46;5 to 4&#46;1 cases per million children <span class="elsevierStyleSup">26</span>&#46; The results of the study provide evidence for sex&#44; and possibly racial differences in the risk of JDM in the U&#46;S&#46;&#44; with girls affected more than boys &#40;ratio 2&#46;3&#58;1&#41;&#44; and white non-Hispanic and African-American children more frequently affected than Hispanic&#46;</p><p class="elsevierStylePara">The etiology of JDM is still unknown&#58; despite serological evidence of coxsackie virus B infection&#44; the search of viral genomes in cells from JDM patients by polymerase chain reaction has not been fruitful&#46; On the contrary&#44; juvenile dermatomyositis has seen advances both in diagnostic procedures and in therapeutic approaches&#46;</p><p class="elsevierStylePara">A recent study demonstrated the usefulness of MRI as a quantitative measure of muscle inflammation&#44; and showed a good correlation with measures of disease activity&#46; The MRI T2 relaxation times in the thigh muscle were significantly increased in patients with active JDM compared with those with inactive JDM and healthy children&#44; indicating a detectable increase in inflammation within the muscles <span class="elsevierStyleSup"> 27</span>&#46; There were also good correlations between the MRI scores and measures of muscle strength and function&#44; but no correlation between the MRI and muscle enzymes&#46;</p><p class="elsevierStylePara">Light microscopic and immunohistochemical analysis of muscle biopsy specimens from 10 patients with early JDM was performed to assess expression of MHC Class I genes <span class="elsevierStyleSup">28</span>&#46; Class I gene overexpression was evident on muscle fibers in all samples&#44; even in a biopsy reported as normal by conventional histology&#46; MHC Class I gene overexpression is an early event in JDM and may occur in the absence of lymphocytic infiltration and muscle damage&#46;</p><p class="elsevierStylePara">The outcome of the disease has dramatically improved since the introduction of corticosteroids&#44; with a marked decrease in mortality&#46; Conventionally&#44; either oral prednisone &#40;2 g&#47;kg&#47;day in 2-4 divided doses&#41; and&#47;or methylprednisolone pulses &#40;30 mg&#47;kg&#44; max 1 g&#47;day&#41; are administered until a fall in the serum levels of muscle enzymes&#44; and then gradually tapered&#46; Since not all children respond to steroid treatment&#59; intravenous gammaglobulins &#40;IVIG&#41;&#44; methotrexate&#44; and cyclosporin A&#44; alone or in combination&#44; have all been used for refractory cases&#46; In a retrospective review study of 12 patients with severe refractory JDM&#44; after 6 months of treatment with intravenous cyclophosphamide &#40;0&#46;5-1 g&#47;m <span class="elsevierStyleSup">2</span>&#41; administered monthly&#44; 10 patients showed a significant improvement in muscle function as assessed by the Childhood Myositis Assessment Scale&#44; muscle strength&#44; global extramuscular disease score&#44; skin disease severity&#44; and LDH levels <span class="elsevierStyleSup">29</span>&#46; Clinical improvement was maintained after discontinuation of cyclophosphamide &#40;follow-up duration 0&#46;5-7 years&#41;&#44; and no severe side effects were seen&#46;</p><p class="elsevierStylePara">Calcinosis is one of the most severe complications of JDM&#44; and disabling calcifications still occur in about one third of patients&#46; Long-standing active disease&#44; a delay in the initial appropriate treatment&#44; and a short duration of steroid treatment are thought to be associated with the development of calcinosis&#44; while aggressive management may result in decreased incidence <span class="elsevierStyleSup">30</span>&#46; The pathogenesis of calcinosis is poorly understood&#44; but an association with inflammation is supported by the presence of cytokines &#40;IL-6&#44; IL-1&#44; and TNF-alpha&#41; in the milky fluid obtained from calcium deposits <span class="elsevierStyleSup">31</span>&#46; The approaches to treating this complication are still anedoctal&#59; moreover&#44; it has to be known that in about half of the cases it can reduce spontaneously&#44; and therefore any new possible success might just be due to natural history of the disease&#46; Only placebo-controlled trials would answer this question&#44; but to show a statistically significant superiority of any drug regimen&#44; very large numbers would be needed&#46;</p><p class="elsevierStylePara">The impact of corticosteroids on bone mineral density has been studied in 15 children with JDM&#44; and low BMD values were found by DXA in the majority of cases&#44; with persistent or worsening osteopenia in patients with ongoing active disease <span class="elsevierStyleSup">32</span>&#46; Bisphosphonates&#44; a group of antiresorptive agents that have been shown to be effective in osteogenesis imperfecta&#44; have proven to be efficacious in this group of patients as well <span class="elsevierStyleSup"> 21</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Kawasaki disease</span></p><p class="elsevierStylePara">Kawasaki disease &#40;KD&#41;&#44; the most common systemic vasculitis in childhood after Henoch-Sh&#246;nlein Purpura&#44; is the major cause of acquired heart disease in children in the United Kingdom and USA&#44; and may be a risk factor for adult ischemic heart disease&#46; Despite numerous efforts&#44; there is still no diagnostic test available for KD&#44; and the diagnosis is based on clinical criteria after the exclusion of other diseases presenting with high and persistent fever&#46; While from the clinical point of view there have been no recent advances&#44; novel findings in pathogenesis warrant some considerations&#46;</p><p class="elsevierStylePara">Despite numerous studies the cause of KD remains uncertain&#46; The role of an infectious trigger inducing the disease in a genetically susceptible host is strongly suggested by the epidemiology of the disease in Japanese and North American epidemics&#44; resembling the spread of viral or bacterial infections&#46; The peak incidence in early childhood and the virtual absence of KD in adulthood suggests that a possible causative agent could be a microbe&#44; with acquired immunity by adulthood&#46; The rarity of illness in infants in the first months of life suggests passive protection by maternal antibodies&#46; KD has some similarities to toxin-mediated diseases&#44; both from a clinical and from an immunological point of view&#46; The role of one or more superantigens capable of stimulating large numbers of T-cells produced by certain strains of Staphylococcus or Streptococcus has been discussed in the etiology of KD&#44; but no general consensus has been achieved&#46; After the first reports by Abe et al <span class="elsevierStyleSup">33&#44;34</span> describing selective expansion of Vb2 &#43; and Vb8&#46;1 &#43; T cells in patients with acute KD&#44; several other similar studies have been published&#44; both with positive and with negative evidence for a superantigen-driven process <span class="elsevierStyleSup"> 35-37</span>&#46; Pro-inflammatory cytokines have been thought to play a role in the disease pathogenesis&#44; and preliminary evidence for a genetic predisposition to elevated TNF-&#945; levels in KD patients has been demonstrated <span class="elsevierStyleSup">38</span>&#46; An interesting hypothesis refers to the role of IgA plasma cells that have been found in the vascular walls of KD patients&#59; an oligoclonal pattern has been demonstrated&#44; consistent with an antigen-driven immune response <span class="elsevierStyleSup">39&#44;40</span>&#46; The nature of this antigen is however still unknown&#46;</p><p class="elsevierStylePara">With regard to prognosis&#44; it is now recognized that subjets who suffered from KD in childhood might have long-term consequences&#44; such as vascular function abnormalities and premature atherosclerosis <span class="elsevierStyleSup"> 41-44</span>&#46; The only novel findings regarding treatment are represented by the anectodal reports or small series describing clnical response with corticosteroids&#44; and more recently with anti-TNF agents <span class="elsevierStyleSup">45</span> in patients who were refractory to IVIG&#46; Results of controlled trials currently in progress are not available at the present time&#46;</p>"
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Update in pediatric rheumatology
Actualización en reumatología pediátrica
R. Cimaza
a Clinica Pediatrica. Fondazione Policlinico Mangiagalli, Milano Italy. Universitè Lyon 1. Lyon. France.
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    "textoCompleto" => "<p class="elsevierStylePara">In recent decades many advances in paediatric rheumatology have been achieved&#44; in particular in classification&#44; outcome measurements&#44; and therapeutic regimens&#46; In particular&#44; the collaborative effort of multicenter studies has helped to improve the recognition and treatment of less common rheumatic diseases in childhood&#46; Due to a close cooperation among researchers in Europe and United States&#44; new drugs and treatment strategies have been tried in a large number of children&#44; with a significant amelioration of the quality of life&#46; Nevertheless&#44; connective tissue diseases remain a challenge for paediatric rheumatologists over the world&#46; This review will briefly focus on some recent advances the field of pediatric rheumatology&#46; For space constraint&#44; we have chosen to cite those article that seemed to us more important&#44; either from a research or from a clinical point of view&#44; and we have concentrated our attention on juvenile idiopathic arthritis and the major connective tissue diseases &#40;systemic lupus&#44; dermatomyositis&#44; and Kawasaki disease&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Juvenile idiopathic arthritis</span></p><p class="elsevierStylePara">The International League of Associations for Rheumatology met in 2001 to delineate&#44; for research and clinical purposes&#44; relatively homogenous&#44; mutually exclusive categories of idiopathic arthritis in childhood&#44; based on predominant clinical and laboratory features <span class="elsevierStyleSup">1</span>&#46; Juvenile idiopathic arthritis &#40;JIA&#41; is now the preferred term&#44; and the classification was recently approved for use in trials by the US Food and Drug Administration&#46;</p><p class="elsevierStylePara">Amomg diagnostic techniques&#44; MRI was recently studied by Knight et al <span class="elsevierStyleSup">2</span>&#44; who examined MRI T2 relaxation times in the weight-bearing cartilage of the distal femur in healthy children and in children with JIA&#46; Differences in cartilage microstructure were seen&#59; this may allow for early detection of cartilage changes and provide an objective and quantitative method of monitoring disease progression&#44; with the long-term potential to guide therapy&#46;</p><p class="elsevierStylePara">The issue of low bone density on children with rheumatic disorders&#44; including JIA&#44; is becoming more and more important in the follow-up of our patients&#46; While dual-Xray absorptiometry &#40;DXA&#41; is still the gold standard to monitor bone density&#44; new promising approaches such as bone ultrasound are gaining interest <span class="elsevierStyleSup">3&#44;4</span>&#46; Peripheral quantitative Computer Tomography&#44; for the time being still a research tool&#44; has been used to evaluate bone density and geometric parameters in the forearm of 57 patients with polyarticular&#44; oligoarticular&#44; and systemic JIA <span class="elsevierStyleSup">5</span>&#46; Patients in all disease groups had significantly reduced muscle cross-sectional area&#44; which strongly correlated with muscle force and abnormalities in geometric parameters of bone&#44; including a significant reduction in cortical thickness&#46; Trabecular density was affected only in the polyarticular JIA group&#44; and cortical density was normal in all subgroups&#46; Thinned bony cortices might therefore predispose to fractures even though cortical bone density itself is normal&#46;</p><p class="elsevierStylePara">Treatment of JIA is still based on administration of nonsteroidal anti-inflammatory drugs&#44; with the addition of second-line drugs in case of insufficient response&#46; Among the numerous second-line drugs now available&#44; methotrexate &#40;MTX&#41; is still the first choice in patients with polyarticular disease because of its relative safety&#44; low-cost&#44; and long follow-up data&#46; It has been recently shown that patients who do not respond to 10 mg&#47;sq&#46; meter&#47;week might respond to higher dosages&#46; However&#44; the plateau of efficacy of MTX was reached with parenteral administration of 15 mg&#47;sq&#46; meter&#47;week&#44; and a further increase in dosage was not associated with any additional therapeutic benefit <span class="elsevierStyleSup">6</span>&#46;</p><p class="elsevierStylePara">The availability of biologic agents&#44; in particular the anti-TNFa drugs&#44; has greatly improved the prognosis in cases who are resistant to methotrexate treatment&#46; The efficacy of these drugs in JIA has been shown both in open &#40;for infliximab&#41; <span class="elsevierStyleSup">7</span> and controlled &#40;for etanercept&#41; <span class="elsevierStyleSup">8</span> studies&#46;</p><p class="elsevierStylePara">Recently&#44; Silverman and colleagues have compared the safety and efficacy of leflunomide with that of methotrexate in the treatment of polyarticular JIA in a randomized&#44; controlled trial <span class="elsevierStyleSup">9</span>&#46; The authors concluded that in patients with polyarticular JIA&#44; both methotrexate and leflunomide resulted in high rates of clinical improvement&#44; with a slightly greater rate for methotrexate&#46;</p><p class="elsevierStylePara">Once clinical remission is achieved&#44; it is always a problem to choose the right timing of drug discontinuation&#46; Foell et al <span class="elsevierStyleSup">10</span> investigated whether the duration of MTX treatment after the induction of remission influences the subsequent duration of remission in patients with JIA&#44; and the usefulness of a biologic marker &#40;S100A8&#47;S100A9&#41; as a predictor for the stability of remission&#46; The results suggested that the presence of residual subclinical synovial inflammation &#40;as measured by S100A8&#47;S100A9&#41;&#44; not duration of MTX treatment after the induction of remission&#44; influences the rate of relapse after discontinuation of MTX&#46; However&#44; the number of patients was small&#44; and a larger controlled study specifically designed for this purpose is currently underway&#46;</p><p class="elsevierStylePara">Systemic-onset JIA is one of the challenges of our clinics&#46; There are some cases who are totally steroid-dependent&#44; and in whom nothing seems to work&#46; Recently&#44; Pascual et al&#46; have demonstrated the role of interleukin-1 in the disease pathogenesis&#44; as well as the efficacy of a recombinant IL-1 receptor antagonist in an open study on nine patients who were refractory to other therapies <span class="elsevierStyleSup">11</span>&#46; Complete remission was obtained in seven patients&#44; and partial response in the other two&#46;</p><p class="elsevierStylePara">Since interleukin-6 is also known to be one of the key mediators in this disorder&#44; treatment with recombinant human anti-interleukin-6 receptor monoclonal antibody &#40;MRA&#41; has been tried in children with systemic-onset JIA refractory to high-dose&#44; long-term corticosteroids <span class="elsevierStyleSup">12</span>&#46; An individual escalating-dose trial was conducted in 11 children with active disease&#46; MRA abruptly reduced disease activity in 10 of these patients&#44; as assessed by the occurrence of febrile episodes&#44; active arthritis&#44; Childhood Health Assessment Questionnaire&#44; and acute-phase reactants&#46; The drug was well tolerated&#46; However&#44; larger controlled studies are needed before drawing any firm conclusions&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Systemic lupus erythematosus</span></p><p class="elsevierStylePara">SLE is not uncommon in children&#44; since in about 15 &#37; of all cases the disease begins in childhood&#46; It is associated with frequent organ system damage and influences the normal physical and psycho-social development of patients <span class="elsevierStyleSup">13</span>&#46;</p><p class="elsevierStylePara">With regard to etiopathogenesis&#44; an important role for interferon-&#945; &#40;IFN-&#945;&#41; has been recognized&#44; without substantial differences between children and adults with regard to leukocyte gene expression profiles&#46; Blanco et al&#46; hypothesized that the disease may be caused by alterations in the functions of dendritic cells&#46; Indeed&#44; monocytes from SLE patients&#39; blood were found to function as antigen-presenting cells <span class="elsevierStyleItalic">in vitro</span>&#44; and sera from SLE patients induced normal monocytes to differentiate into dendritic cells&#46; The capacity of SLE sera to induce DC differentiation correlated with disease activity and depended on the actions of IFN-&#945; <span class="elsevierStyleSup">14</span>&#46;</p><p class="elsevierStylePara">The survival of newly diagnosed SLE children has increased&#44; the major reason for death being now infections&#44; as opposed to renal failure as in the past&#46; While a survival of 80-85 &#37; during a follow-up of 5-10 years was considered satisfactory in the past&#59; the goal of new therapies is to obtain both a more prolonged survival and a reduced organ system damage&#46; Renal and cerebral involvement are the major concerns in SLE children&#44; and require an early aggressive therapeutic approach in order to reduce the degree of disease morbidity and mortality&#46; Males and females seem not to have a different outcome in this regard <span class="elsevierStyleSup">15</span>&#46;</p><p class="elsevierStylePara">Azathioprine has been used for at least 30 years as second-line agent&#44; but controlled trials are lacking in childhood&#46; Anedoctal reports suggest that cyclosporin may allow the tapering steroids and better control of disease activity&#59; however&#44; hypertension and increased serum creatinine limit its use in children with renal involvement&#46; Cytoxan pulses are now the first line treatment for severe lupus nephritis <span class="elsevierStyleSup">16</span>&#59; promising results have been reported in adults with Mycophenolate Mofetil &#40;MMF&#41;&#44; a novel immunosuppressive agent&#46; The experience in childhood is limited to small case series <span class="elsevierStyleSup">17</span>&#46; Even though long-term follow-up is not available&#44; MMF seems a promising drug for the treatment of severe juvenile SLE&#46; Wulfraat et al&#46; report autologous stem cell transplantation with sustained control of disease activity&#44; off any medication&#44; in two adolescents with intractable disease <span class="elsevierStyleSup">18</span>&#46; A long-term follow-up is however necessary&#44; as well as strict inclusion criteria that should also consider the high risk of the procedure itself&#46; Of the new biological therapies&#44; in pediatrics anti-CD20 &#40;Rituximab&#41; seem to be the more promising agent <span class="elsevierStyleSup">19</span>&#46; No controlled trials are yet available&#46;</p><p class="elsevierStylePara">Among short and long-term complications&#44; osteopenia and osteoporosis are certainly a major risk&#44; due to decreasd sun exposure&#44; inflammatory disease activity&#44; and corticosteroid use <span class="elsevierStyleSup">20</span>&#46; The use of bisphosphonates in patients with low bone density has significantly increased bone mass <span class="elsevierStyleSup">21</span>&#46; Accelerated atherosclerosis with carotid media-intima thickness <span class="elsevierStyleSup">22</span> and abnormalities in lipoprotein oxidation <span class="elsevierStyleSup">23</span> are another major concern&#46; Soep et al <span class="elsevierStyleSup">24</span> investigated atherosclerotic risk factors and endothelial function in pediatric SLE&#46; Lipoproteins&#44; oxidized state&#44; autoantibodies to oxidized low-density lipoprotein&#44; and endothelial function &#40;brachial artery reactivity&#41; were measured&#46; Patients had significantly decreased mean levels of high-density lipoprotein cholesterol and apolipoprotein A-I when compared to controls&#46; Due to the risk of atherosclerotic coronary artery disease&#44; the profile of plasma lipids should therefore be evaluated in all SLE children in order to prevent early myocardial infarction&#46; The best preventive strategies include no smoking&#44; low-fat diet and physical activity&#46; The role of antimalarials as lipid-lowering effect is known in adults&#44; but studies of their usefulness in children are lacking&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Juvenile dermatomyositis</span></p><p class="elsevierStylePara">Idiopathic inflammatory myopathies are rare in childhood and display a less heterogeneous pattern than in adults&#46; Juvenile dermatomyositis &#40;JDM&#41; with the characteristic skin and muscle abnormalities represents the most common form in childhood <span class="elsevierStyleSup">25</span>&#46; Recently&#44; Mendez et al evaluated the incidence of JDM in the United States&#59; the estimated annual incidence rates ranged from 2&#46;5 to 4&#46;1 cases per million children <span class="elsevierStyleSup">26</span>&#46; The results of the study provide evidence for sex&#44; and possibly racial differences in the risk of JDM in the U&#46;S&#46;&#44; with girls affected more than boys &#40;ratio 2&#46;3&#58;1&#41;&#44; and white non-Hispanic and African-American children more frequently affected than Hispanic&#46;</p><p class="elsevierStylePara">The etiology of JDM is still unknown&#58; despite serological evidence of coxsackie virus B infection&#44; the search of viral genomes in cells from JDM patients by polymerase chain reaction has not been fruitful&#46; On the contrary&#44; juvenile dermatomyositis has seen advances both in diagnostic procedures and in therapeutic approaches&#46;</p><p class="elsevierStylePara">A recent study demonstrated the usefulness of MRI as a quantitative measure of muscle inflammation&#44; and showed a good correlation with measures of disease activity&#46; The MRI T2 relaxation times in the thigh muscle were significantly increased in patients with active JDM compared with those with inactive JDM and healthy children&#44; indicating a detectable increase in inflammation within the muscles <span class="elsevierStyleSup"> 27</span>&#46; There were also good correlations between the MRI scores and measures of muscle strength and function&#44; but no correlation between the MRI and muscle enzymes&#46;</p><p class="elsevierStylePara">Light microscopic and immunohistochemical analysis of muscle biopsy specimens from 10 patients with early JDM was performed to assess expression of MHC Class I genes <span class="elsevierStyleSup">28</span>&#46; Class I gene overexpression was evident on muscle fibers in all samples&#44; even in a biopsy reported as normal by conventional histology&#46; MHC Class I gene overexpression is an early event in JDM and may occur in the absence of lymphocytic infiltration and muscle damage&#46;</p><p class="elsevierStylePara">The outcome of the disease has dramatically improved since the introduction of corticosteroids&#44; with a marked decrease in mortality&#46; Conventionally&#44; either oral prednisone &#40;2 g&#47;kg&#47;day in 2-4 divided doses&#41; and&#47;or methylprednisolone pulses &#40;30 mg&#47;kg&#44; max 1 g&#47;day&#41; are administered until a fall in the serum levels of muscle enzymes&#44; and then gradually tapered&#46; Since not all children respond to steroid treatment&#59; intravenous gammaglobulins &#40;IVIG&#41;&#44; methotrexate&#44; and cyclosporin A&#44; alone or in combination&#44; have all been used for refractory cases&#46; In a retrospective review study of 12 patients with severe refractory JDM&#44; after 6 months of treatment with intravenous cyclophosphamide &#40;0&#46;5-1 g&#47;m <span class="elsevierStyleSup">2</span>&#41; administered monthly&#44; 10 patients showed a significant improvement in muscle function as assessed by the Childhood Myositis Assessment Scale&#44; muscle strength&#44; global extramuscular disease score&#44; skin disease severity&#44; and LDH levels <span class="elsevierStyleSup">29</span>&#46; Clinical improvement was maintained after discontinuation of cyclophosphamide &#40;follow-up duration 0&#46;5-7 years&#41;&#44; and no severe side effects were seen&#46;</p><p class="elsevierStylePara">Calcinosis is one of the most severe complications of JDM&#44; and disabling calcifications still occur in about one third of patients&#46; Long-standing active disease&#44; a delay in the initial appropriate treatment&#44; and a short duration of steroid treatment are thought to be associated with the development of calcinosis&#44; while aggressive management may result in decreased incidence <span class="elsevierStyleSup">30</span>&#46; The pathogenesis of calcinosis is poorly understood&#44; but an association with inflammation is supported by the presence of cytokines &#40;IL-6&#44; IL-1&#44; and TNF-alpha&#41; in the milky fluid obtained from calcium deposits <span class="elsevierStyleSup">31</span>&#46; The approaches to treating this complication are still anedoctal&#59; moreover&#44; it has to be known that in about half of the cases it can reduce spontaneously&#44; and therefore any new possible success might just be due to natural history of the disease&#46; Only placebo-controlled trials would answer this question&#44; but to show a statistically significant superiority of any drug regimen&#44; very large numbers would be needed&#46;</p><p class="elsevierStylePara">The impact of corticosteroids on bone mineral density has been studied in 15 children with JDM&#44; and low BMD values were found by DXA in the majority of cases&#44; with persistent or worsening osteopenia in patients with ongoing active disease <span class="elsevierStyleSup">32</span>&#46; Bisphosphonates&#44; a group of antiresorptive agents that have been shown to be effective in osteogenesis imperfecta&#44; have proven to be efficacious in this group of patients as well <span class="elsevierStyleSup"> 21</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Kawasaki disease</span></p><p class="elsevierStylePara">Kawasaki disease &#40;KD&#41;&#44; the most common systemic vasculitis in childhood after Henoch-Sh&#246;nlein Purpura&#44; is the major cause of acquired heart disease in children in the United Kingdom and USA&#44; and may be a risk factor for adult ischemic heart disease&#46; Despite numerous efforts&#44; there is still no diagnostic test available for KD&#44; and the diagnosis is based on clinical criteria after the exclusion of other diseases presenting with high and persistent fever&#46; While from the clinical point of view there have been no recent advances&#44; novel findings in pathogenesis warrant some considerations&#46;</p><p class="elsevierStylePara">Despite numerous studies the cause of KD remains uncertain&#46; The role of an infectious trigger inducing the disease in a genetically susceptible host is strongly suggested by the epidemiology of the disease in Japanese and North American epidemics&#44; resembling the spread of viral or bacterial infections&#46; The peak incidence in early childhood and the virtual absence of KD in adulthood suggests that a possible causative agent could be a microbe&#44; with acquired immunity by adulthood&#46; The rarity of illness in infants in the first months of life suggests passive protection by maternal antibodies&#46; KD has some similarities to toxin-mediated diseases&#44; both from a clinical and from an immunological point of view&#46; The role of one or more superantigens capable of stimulating large numbers of T-cells produced by certain strains of Staphylococcus or Streptococcus has been discussed in the etiology of KD&#44; but no general consensus has been achieved&#46; After the first reports by Abe et al <span class="elsevierStyleSup">33&#44;34</span> describing selective expansion of Vb2 &#43; and Vb8&#46;1 &#43; T cells in patients with acute KD&#44; several other similar studies have been published&#44; both with positive and with negative evidence for a superantigen-driven process <span class="elsevierStyleSup"> 35-37</span>&#46; Pro-inflammatory cytokines have been thought to play a role in the disease pathogenesis&#44; and preliminary evidence for a genetic predisposition to elevated TNF-&#945; levels in KD patients has been demonstrated <span class="elsevierStyleSup">38</span>&#46; An interesting hypothesis refers to the role of IgA plasma cells that have been found in the vascular walls of KD patients&#59; an oligoclonal pattern has been demonstrated&#44; consistent with an antigen-driven immune response <span class="elsevierStyleSup">39&#44;40</span>&#46; The nature of this antigen is however still unknown&#46;</p><p class="elsevierStylePara">With regard to prognosis&#44; it is now recognized that subjets who suffered from KD in childhood might have long-term consequences&#44; such as vascular function abnormalities and premature atherosclerosis <span class="elsevierStyleSup"> 41-44</span>&#46; The only novel findings regarding treatment are represented by the anectodal reports or small series describing clnical response with corticosteroids&#44; and more recently with anti-TNF agents <span class="elsevierStyleSup">45</span> in patients who were refractory to IVIG&#46; Results of controlled trials currently in progress are not available at the present time&#46;</p>"
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Article information
ISSN: 16954033
Original language: English
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Idiomas
Anales de Pediatría (English Edition)
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