Systemic JIA: new developments in the understanding of the pathophysiology and therapy. Best Pract Res Clin Rheumatol

Department of Pediatric Immunology Wilhelmina Children s Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA, Utrecht, the Netherlands.
Best practice & research. Clinical rheumatology (Impact Factor: 2.6). 10/2009; 23(5):655-64. DOI: 10.1016/j.berh.2009.08.003
Source: PubMed


Systemic juvenile idiopathic arthritis (sJIA) is a rare, systemic inflammatory disease classified as a subtype of JIA. Besides arthritis, it is characterised by systemic features such as spiking fever, skin rash, hepatosplenomegaly or serositis. It is becoming clear now that abnormalities in the innate immunity (cytokines such as interleukin (IL)-1, IL-6 and IL-18, and neutrophils and monocytes/macrophages rather than lymphocytes) play a major role in the pathogenesis of sJIA, distinguishing it from other JIA subtypes. Another distinctive feature of sJIA is its strong association with macrophage activation syndrome (MAS). Based on this, consensus is emerging that sJIA should be viewed as an autoinflammatory syndrome rather than a classic auto-immune disease. As a consequence of the progression in understanding the underlying mechanisms of sJIA, major changes in the management are evolving. So far, treatment has been based on glucocorticosteroids in combination with disease-modifying drugs such as methotrexate. Recently, remarkable improvement has been observed with IL-1 and IL-6 targeted therapies. These therapies might also change the long-term outcome of this disease. However, controlled trials set up in international collaboration are needed to determine the optimal treatment strategies for all sJIA patients.

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Available from: Sebastiaan J Vastert
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    • "Control of the underlying disease is of key importance in the overall treatment concept. For rheumatological disease this in particular involves the use of IL-1 receptor antagonists and IL-6 antibodies in Still's disease and anti-TNF in some other rheumatological diseases [74,75]. Whether these agents may also trigger MAS is a matter of debate. "
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    ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages secreting high amounts of inflammatory cytokines. It is a frequent manifestation in patients with predisposing genetic defects, but can occur secondary to various infectious, malignant, and autoimmune triggers in patients without a known genetic predisposition. Clinical hallmarks are prolonged fever, cytopenias, hepatosplenomegaly, and neurological symptoms, but atypical variants presenting with signs of chronic immunodeficiency are increasingly recognized. Impaired secretion of perforin is a key feature in several genetic forms of the disease, but not required for disease pathogenesis. Despite progress in diagnostics and therapy, mortality of patients with severe HLH is still above 40%. Reference treatment is an etoposide-based protocol, but new approaches are currently explored. Key for a favorable prognosis is the rapid identification of an underlying genetic cause, which has been facilitated by recent immunological and genetic advances. In patients with predisposing genetic disease, hematopoietic stem cell transplantation is performed increasingly with reduced intensity conditioning regimes. Current research aims at a better understanding of disease pathogenesis and evaluation of more targeted approaches to therapy, including anti-cytokine antibodies and gene therapy.
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    • "Several lines of evidence suggest that the role of the adaptive immune system in SJIA is limited compared with the other JIA subtypes, while the contribution of the innate immunity is more prominent [Barnes et al. 2009; Frosch and Roth, 2008; Fall et al. 2007; Ogilvie et al. 2007; Pascual et al. 2005; Ramanan and Grom, 2005]. Many of the clinical features of SJIA are similarly seen in the auto-inflammatory syndromes including: fever, multisystem involvement, a polycyclic course in some patients, and the laboratory markers of inflammation [Vastert et al. 2009]. New data supports neutrophils and monocytes as the effector cells as opposed to lymphocytes. "
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    ABSTRACT: THE GOALS OF TREATMENT FOR JUVENILE IDIOPATHIC ARTHRITIS (JIA) INCLUDE: suppression of inflammation, achievement of remission, relief of pain, maintenance of function and doing so with minimal toxicity. Important discoveries over the past 10-15 years have led to more targeted treatments for children with JIA. The International League of Associations for Rheumatology (ILAR) classification system for childhood arthritides, better assessment tools for clinical response, improved definitions of remission, new imaging techniques and evidence in gene expression profiling have all contributed to the development of more targeted treatments. Nonsteroidal anti-inflammatory agents still have a role in mild disease and intra-articular steroid injections continue to be used most commonly in patients with oligoarticular JIA. Disease-modifying agents such as methotrexate have demonstrated efficacy and safety; however, in many patients, the disease remains active despite this treatment. These children now receive more targeted treatment including the tumor necrosis factor alpha (TNFα) inhibitors, interleukin-1 blockade, interleukin-6 blockade, selective costimulation modulators and selective B-cell blockade. The biologic targeted therapies have changed the strategy in which we treat our children with JIA; however, there remains much to be learned about the long-term effects and safety of these medicines.
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    • "Innate immune abnormalities in sJIA make it likely to be grouped with the autoinflammatory diseases [34], and indeed, according to the fourth international congress on the systemic autoinflammatory diseases, sJIA is a complex multifactorial autoinflammatory disease [35]. The lack of strong major histocompatibility complex association can be seen both in sJIA and autoinflammatory diseases [34]. Pyrin (also known as marenostrin) is a 781 amino acid protein encoded by the familial Mediterranean fever gene (MEFV) found on chromosome 16p [36] [37]. "
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