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Systemic juvenile idiopathic arthritis (SJIA) is an inflammatory condition characterized by fever, lymphadenopathy, rash, arthritis, and serositis. Although the ultimate etiology of this disorder remains elusive, recent work defining cytokine effector mechanisms has led to a new treatment paradigm for this condition. In this review, we describe the recent immunological reclassification of SJIA as an autoinflammatory disorder as well as detail the dramatic changes in its treatment.
SJIA is an autoinflammatory disorder where defects of innate immune system pathways lead to significant inflammation. Recent studies of the pathophysiology, as well as successful treatment trials, have established interleukin-1β (IL-1β) and IL-6 as key cytokines in the pathogenesis of this condition. As a result, their inhibition has become the centerpiece of the current SJIA treatment paradigm.
There has been a major shift away from the traditional treatments of SJIA towards therapeutics that inhibit IL-1β and IL-6. In fact, the IL-1 blocker anakinra is now regarded as standard-of-care for SJIA patients with systemic symptoms while the IL-6 inhibitor tocilizumab shows great potential. Future research holds promise for the development of more efficient cytokine inhibition as well a more comprehensive knowledge of the innate cytokine networks in this disease.
Systemic juvenile idiopathic arthritis (SJIA) is inflammatory condition characterized by quotidian fever, lymphadenopathy, evanescent rash, arthritis, and serositis. Laboratory values include a marked leukocytosis with a strong left shift of neutrophils and significantly elevated high inflammatory markers, such as C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR). SJIA is frequently complicated by the macrophage activation syndrome (MAS), which imparts much of the morbidity and mortality seen in this disorder. MAS is characterized by pancytopenia, marked hyperferritinemia and/or hypertriglyceridemia, transaminitis, hepatosplenomegaly, and hemophagocytosis within the bone marrow, in addition to the typical SJIA symptomatology [1,2,3]. Interestingly, an intermediate phenotype referred to as subclinical or occult MAS occurs in patients with SJIA who have many features of MAS but do not fulfill all criteria. This has led to the idea that MAS may represent an extreme phenotype of the SJIA spectrum [4,5]. Here, we provide a brief overview of recent publications pertaining to the current understanding of the pathophysiology and a revised treatment approach to SJIA.
Over the last few years, there had been a shift in our understanding of the pathophysiology of SJIA, which may be better viewed as an autoinflammatory disease [6,7] rather than an autoimmunity disease. The development of classic autoimmunity is caused by abnormalities in the adaptive arm of the immune system. It is typically associated with the emergence of auto-reactive antigen-specific T cells and high-titer autoantibodies leading to destructive immune responses to self-antigens [8,9]. Classic autoimmune diseases typically are strongly associated with particular major histocompatibility complex (MHC) class II alleles, implicating MHC class II-restricted CD4 T cells in pathogenesis. Systemic lupus erythematosus and autoimmune thyroiditis are some examples of this group. In contrast, abnormalities in innate immunity pathways may lead to the development of a distinct group of pathologic conditions now known as autoinflammatory syndromes [8,9], with Familial Mediterranean Fever (FMF) a prototype disorder of this group. These conditions lack strong MHC associations, and high-titer autoantibodies or antigen-specific T cells are typically not seen in these patients. Predominance of monocytes and neutrophils, rather than T cells or B cells as effector cells is another important feature of these diseases.
Unlike classic autoimmune diseases, SJIA lacks strong MHC class II associations, with the possible exception in some populations of a weak association with HLA-DR4 in a subgroup of patients with erosive arthritis . In contrast, the most consistently reported inherited genetic risk factors in SJIA are polymorphisms within the promoter elements and genes encoding interleukin-6 (IL-6) [11,12], macrophage inhibitory factor (MIF)[13,14], IL-10 , and tumor necrosis factor-α (TNF-α) , and even these associations are comparatively weak. A more recent study showed an increased frequency of IL-10 promoter polymorphism (-1082G/A), which is associated with reduced IL-10 expression, and a protective effect of IL-10 promoter polymorphism (GCC haplotype), which is associated with increased IL-10 expression . Other recent reports describe associations with genetic variants in the IL-1 superfamily, specifically IL1A, IL1F10, IL1RN, IL1R2,  and with minor alleles of SLC26A2(solute carrier family 26 (sulfate transporter) member 2 . SLC26A2 mutations are known to cause a range of osteochondrodysplasias, but the role of SLC26A2 in the pathogenesis of SJIA remains unclear.
Recent microarray-based gene expression studies provide additional evidence that, as in other autoinflammatory syndromes, the adaptive immunity plays a limited role in SJIA compared to the other JIA subtypes, whereas the innate immune system contributes more prominently [20,21,22,23]. Based on these studies, SJIA can be distinguished from other subtypes of JIA by up-regulation of innate immune responses, including the IL-6, Toll-like receptor (TLR)/IL-1 receptor, and peroxisome proliferator-activated receptor (PPAR)-γ signaling pathways, and by down-regulation of gene networks involving natural killer (NK) cells, T cells, and MHC-related biological processes, including antigen presentation . Consistent with the idea of a limited role for the adaptive immunity, only rarely do SJIA patients have a positive tests for antinuclear antibody (ANA) or rheumatoid factor [1,7].
The relative importance of cytokines that contribute to the perpetuation of the inflammatory process in SJIA is also very different from other subtypes of juvenile idiopathic arthritis. A growing number of clinical and translational studies suggest critical roles for IL-1β, IL-6, and IL-18, whereas the role for TNF-α appears to be rather limited. Another feature that distinguishes SJIA from other subtypes of juvenile idiopathic arthritis is the relative absence of the interferon (IFN)-γ-induced chemokines IP-10, MIG, and I-TAC [20,21,23].
IL-18 is a member of the IL-1 superfamily that is produced by macrophages and has the ability to stimulate IFN-γ production and release by T cells . In one recent study, serum IL-18 was found to be significantly higher in patients with MAS and active SJIA than in patients with active Kawasaki disease or Ebstein-Barr virus-associated hemophagocytic lymphohistiocytosis. In addition, during active SJIA, IL-18 positively correlated with CRP, aspartate aminotransferase (AST), ferritin, lactate dehydrogenase (LDH), neopterin, and tumor necrosis factor-receptor II (TNF-RII) [25*]. This study was notable for the detection of neopterin, a protein produced mainly by activated macrophages exposed to IFN-γ , whereas an IFN-γ-induced genetic signature has not been detected within the peripheral blood mononuclear cells of active SJIA patients [20,21,22].
In contrast to gradual progress in the understanding of the pathophysiology of SJIA, there has been a recent dramatic shift in its treatment. In 2005, IL-1β was identified as a likely major mediator of disease in SJIA. Traditionally, standard-of-care treatments for SJIA mirrored what was effective for other subtypes of juvenile idiopathic arthritis, i.e., nonsteroidal anti-inflammatory drugs, methotrexate, and anti-TNF-α therapeutics (such as etanercept). However, their efficacy for SJIA was less than optimal [27,28,29,30,31,32*], and alternative therapies were actively sought.
Based on the observation that exposure of healthy peripheral blood mononuclear cells to serum from patients with active SJIA caused these cells to secrete excessive amounts of IL-1β, a small trial of an anti-IL-1 blocking agent (anakinra) was begun. Anakinra is a recombinant form of IL-1RA, an endogenously produced protein that binds to IL-1 receptors thereby antagonizing the effects of IL-1β and IL-1α. Strikingly, complete remission ensued after anakinra therapy in seven of the nine patients with partial response in the other two . In a larger French trial, five of 20 SJIA achieved at least a 50% improvement of their disease using a dose of 1-2 mg/kg/day, and nine of them were able to reduce their daily total corticosteroid use .
A more recent trial continued to show anakinra's promise, but also a possible weakness: Twenty-four subjects were randomized into two groups treated with either placebo or control in a double-blind manner. After one month, eight of 12 in the treatment group showed at least a 30% decrease in their disease severity, had resolution of systemic symptoms, and a reduction of both CRP and ESR by 50% from basal levels. Only one of 12 in the placebo group managed to achieve this amount of improvement. However, after a 12-month period of open-label administration, surprising shifts occurred within Anakinra group: Of the original responders, six became non-responders and two of the original non-responders became responders [34*]. In yet another trial, 10 of 22 patients showed a dramatic response to anakinra, while 11 of 22 either showed an incomplete response or no response at all. Here, it was found that patients with a lower total number of active joints and with an increased absolute neutrophil count were more likely to respond to anakinra . Thus, the long-term efficacy of anakinra has yet to be firmly established and it would be useful to have predictors of efficacy available at the onset of therapy. These observations also suggest that there might be different subsets within the disease , and studies aimed at the identification of biologic markers that would predict response are in progress.
Effective IL-1β antagonism by anakinra may be limited by the large number of IL-1β receptors expressed on many different cell types, and the rapid excretion of IL-1RA by the healthy kidney. Two other IL-1β-blocking therapeutics that have the potential for more effective IL-1β antagonism than Anakinra are rilonacept and canakinumab. Rilonacept, a fusion protein composed of the IL-1 receptor and the Fc-portion of IgG1, has a much longer half-life than anakinra, thus allowing for much less frequent dosing . Although it binds to IL-1β with a much higher affinity, it also has the capacity to also bind to IL-1RA, which might offset physiological IL-1β blockade mediated by endogenously produced IL-1RA, and to IL-1α, which could reduce its availability for IL-1β binding. Nevertheless, despite these potential limitations, rilonacept has been shown to be effective in the IL-1β-mediated cryopyrin-associated periodic syndromes (CAPS) [37,38], and a Phase III trial of this agent in SJIA is currently in progress. Canakinumab is a fully humanized monoclonal antibody (mAb) that is highly specific for IL-1β (it does not bind IL-1RA or IL-1α) and will perhaps allow even less frequent administration. Canakinumab has also been shown to cause a sustained improvement in patients with CAPS  and is also being actively studied for the treatment of SJIA.
The role of IL-6 in SJIA came under intense scrutiny when it was found that IL-6 serum levels not only correlated with the number and severity of inflamed joints, but also tended to peak during times of fever . Additionally, synovial levels of IL-6 were also demonstrated to be significantly higher in active SJIA patients than in oligoarticular juvenile idiopathic arthritis or rheumatoid arthritis patients . An initial open-labeled, dose-response study of 18 Caucasians with SJIA patients then showed that a single-dose of an anti-IL-6 receptor (tocilizumab) was sufficient to produce some degree of improvement. This provided proof-of-principle that IL-6 was a key regulator in the in vivo pathogenesis of SJIA . From these preliminary studies, a small human anti-IL-6 receptor mAb clinical trial commenced: Disease activity was promptly decreased in ten of eleven children who experienced at least 30% improvement of their SJIA . A much larger study subsequently confirmed anti-IL-6 receptor mAb as a potent therapeutic: After a six-week open-label phase, 51 of 56 (91%) of SJIA patients experienced a 30% improvement, 48 of 56 (86%) experienced a 50% improvement, and 38 of 56 (68%) experienced a 70% improvement of their disease severity. Of the 43 of these responders who continued in the double-blind phase of the trial, four of the 23 (17%) who received a placebo and 16 of the 20 (80%) within the treatment group maintained at least a 30% improvement in their SJIA disease severity. Common adverse effects during this trial were mild gastrointestinal and upper respiratory infections . Interestingly and perhaps most importantly, a radiographic improvement in large joints as well as in osteoporosis was observed in SJIA patients on 8 mg/kg of tocilizumab administered every two weeks after a mean follow-up period of 56 months [45*].
Over the last 5 years, there has been a major shift in the current standard-of-care of SJIA, with a recent trend of using anakinra or tocilizumab as first-line therapies. A recent retrospective study identified 46 patients with SJIA, via an online survey, who had received anakinra as part of their initial therapy. Of these 46, 10 (22%) received anakinra monotherapy, with 67% also receiving a corticosteroid and 33% also receiving an additional disease-modifying anti-rheumatic drug . Of the 10 who received anakinra monotherapy, eight experienced a control of both their arthritis and systemic symptoms. Critics of this study point to the heterogeneity of the study subjects as a weakness; 14 of the 46 patients had arthritis for less than the recommended criteria of six weeks duration, and it is important to note that some patients with SJIA follow a self-limiting course. It is possible the patients who received anakinra only were deemed less severe, thus permitting a more limited therapeutic approach. Others argue that a randomized, placebo-controlled, double-blinded study would have been a more appropriate study design to draw any conclusions. Nevertheless, this study underscores the current treatment approach of trialing anakinra earlier in the disease course in an attempt to prevent the evolution of SJIA into a more chronic arthritis. In fact, the authors noted that only 11% of anakinra-treated patients remained with active arthritis after a median of twelve months of follow-up. Additionally, they found that the younger the patient at disease onset, the less likely they would have a complete response to standard-dose anakinra, suggesting that higher dose therapy might be important in this age group. Lastly and perhaps most importantly, patients on anakinra were able to significantly taper their total corticosteroid dose over time [46*].
The 2011 American College of Rheumatology (ACR) recommendations for treatment of new-onset juvenile idiopathic arthritis [47**] divide SJIA into two categories; those with systemic features and those without. Unfortunately, the use of tocilizumab as an initiating therapy was not considered since it was not widely available commercially at the time of their study. These recommendations were not meant to be applied to SJIA patients with MAS, and deviation from them was warranted under life-threatening scenarios, such as cardiac tamponade.
Due to a lack of published evidence, the use of specific systemic corticosteroids or specific routes was not considered, but in general corticosteroids were recommended as an initial therapy in patients with a fever of greater than two weeks duration. Figure 1 is the current ACR recommendations treatment decision tree for SJIA with systemic features [47**]. Briefly, for patients with fever for less than six months duration irrespective of the levels of inflammatory markers, a trial of corticosteroids is recommended. For patients with six months or more of active systemic disease – i.e., fever, elevated inflammatory markers, or progression of disease while on a corticosteroid - treatment with anakinra is recommended. The use of methotrexate in patients with systemic features, but without active arthritis, is deemed inappropriate.
Like SJIA with systemic features, this group was further subdivided into those with “poor prognosis”, i.e., arthritis of the hip and/or radiographic evidence of joint damage and those without these findings. Figure 2 is the current ACR recommendations treatment decision tree for SJIA with active arthritis (but without systemic features) [47**]. After a one-month trial period of an NSAID and corticosteroid joint injection(s) as needed, irrespective of disease activity or prognosis, all SJIA patients with active arthritis (but without systemic features) should be on methotrexate. For patients who still have moderate or high disease activity, as defined in the recommendations, after three months of methotrexate treatment, a TNF-α inhibitor should be initiated. Anakinra, in lieu of a TNF-α inhibitor, may also be tried at this point in patients with relatively recent onset of disease or for those who have failed to respond to TNF-α blocking therapy. Supporting NSAID therapy and/or corticosteroid joint injections may still be used throughout the therapies involving these other agents. Interestingly, the consensus was that treatment with anakinra might be less appropriate later in the arthritic disease course as compared to earlier in the disease course. For patients whose disease severity remains moderately or highly active despite a four-month trial of a TNF-α inhibitor, regardless of prognosis, a change to abatacept, which acts by blocking T-cell co-stimulation, is warranted.
SJIA is an autoinflammatory disorder where significant defects of the innate immune system lead to an inflammatory condition characterized by fever, lymphadenopathy, rash, arthritis, and serositis. While both IL-1β and IL-6 have been heavily implicated in the pathogenesis of this disease, the exact defect(s) leading to this disease remain a mystery. Questions that remain unanswered include what exact role IFN-γ plays in the activation of pathogenic macrophages within active SJIA and what further defects are sufficient in leading to the development of fulminant MAS. Clinically, the apparent shortfall of anakinra in some SJIA patients needs to be understood. Perhaps this problem may be ameliorated with higher than traditional doses of Anakinra or, alternatively by more potent IL-1β-blocking therapeutics, i.e., canakinumab and rilonacept, which are currently being evaluated in clinical trials.
This work was supported in part by NIH grants AR047784 and AR048929 (both A.G.). A.G. also serves as a consultant for Novartis.
Disclosures: Supported in part by NIH grants P60 AR047784 and R01 AR059049 (both to A.G.). A.G. also serves as a consultant for Novartis.
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