Systemic Juvenile Idiopathic Arthritis

Epidemiology

sJIA accounts for 5% to 15% of children with JIA seen in North America and Europe. The exact prevalence of the disease is not known, but studies from Europe indicate an annual incidence for sJIA between 0.3 and 0.8 cases per 100,000 children under 16 years of age. In Europe, the incidence appears to be higher in most northern countries than in southern European countries. In Asia, sJIA may account for a greater proportion of all childhood arthritis. Of individuals with JIA, 25% of cases in India and 50% in Japan, respectively, appear to have sJIA. ^,

The onset of sJIA may occur at any time during childhood, with a broad peak of onset between 1 and 5 years of age. It occasionally manifests before 1 year of age, and it also occurs in adolescence. As stated earlier , AOSD is the term used for patients who develop the disease when they are over the age of 16 years. There is an equal sex ratio for both sJIA and AOSD. Although one study documented a marked seasonal variation, with no patients having disease onset in the winter months, subsequent studies failed to find clear evidence for seasonal variation in disease onset. ^,

Etiology and Pathogenesis

Although its onset resembles an infectious disease, sJIA has not been consistently associated with any pathogen. sJIA is rarely familial, which is consistent with the hypothesis that the genetic background of the disease is complex and related to multiple susceptibility alleles. In the past decade, genome-wide association studies on a large number of sJIA patients assembled from multiple large (national) cohorts have shed some light on the genetic background of this intriguing disease, providing important hints for future translational studies. The most consistently reported associations are polymorphisms in the regulatory sequences of genes coding for cytokines of the innate immune response, including macrophage inhibitory factor (MIF), tumor necrosis factor (TNF)-α, interleukin (IL)-6 genes, and the IL-1 and IL-1 receptor loci. Most of these polymorphisms are functionally relevant, affecting expression levels of the corresponding cytokines. However, a reexamination of these associations in the large non-Asian aggregate cohort mentioned earlier (minus the TNF association, which was found in Japanese patients) yielded significant association only with IL1RN (encodes IL-1 receptor antagonist). The polymorphism affected levels of expression, with an inverse correlation between sJIA risk and IL1RN levels. Homozygosity for high expression levels correlated with unresponsiveness to recombinant IL-1Ra (anakinra) therapy.

The absence of autoantibodies (at least until a late phase of disease) and of autoreactive T cells are findings that set sJIA apart from other JIA categories. Ombrello et al. did find a strong association of sJIA with HLA-DRB1∗11 and other major histocompatibility complex (MHC) class II loci, suggesting that the adaptive immune system does play an important role in this complex disease. Alternatively, human leukocyte antigen (HLA) class II molecules also contribute to innate immune pathways and proinflammatory cytokine production by antigen presenting cells, and these functions may underlie the sJIA-HLA association. Especially in the early phase of sJIA, innate immune cells, such as monocytes and neutrophils, are clearly increased in peripheral blood and seem to play a cardinal role in the evolving systemic inflammation. ^, Studies of gene expression profiles in blood cells provide substantial evidence of a dysregulated innate immune response with consequent increased production of inflammatory cytokines. Overexpression of genes of the IL-6 and Toll-like receptor (TLR)/IL-1R pathways has been demonstrated. Moreover, gene pathways related to natural killer (NK) cells or T cells are downregulated. The pathways involved appear to be different from those involved in polyarticular JIA, highlighting the unique disease mechanism of sJIA.

Prominent innate immune activation results in elevated levels of several inflammatory cytokines, including IL-1, IL-6, IL-8, IL-18, MIF, and TNF. Exaggerated production of these cytokines produced by monocytes/macrophages and neutrophils appears to explain many of the features of sJIA, although not exclusively. Measurement of up to 30 cytokines, and subsequent cluster analysis, showed that patients with sJIA cluster together and can be distinguished from patients with oligoarticular or polyarticular JIA. Similarly, pathway analysis of plasma proteins in sJIA flares showed a typical signature that distinguished sJIA flares from active polyarticular JIA or from febrile illness.

TNF-α levels, as well as levels of the two soluble TNF receptors, are increased in sJIA, ^{, ,} but TNF-α levels do not correlate with fever peaks. ^, The clinical response to TNF blockade of patients with sJIA is limited compared with that in other JIA forms, suggesting that TNF does not play a major role in sJIA. A substantial body of evidence supports a major role of increased IL-6 production in mediating signs and symptoms of sJIA. IL-6 is markedly elevated in the blood and synovial fluid. ^{, ,} IL-6 levels increase just before fever spikes and correlate with the systemic features of the disease, arthritis, and increase in acute phase reactants. ^{, ,} In vitro studies have documented increased production of IL-6 by peripheral blood mononuclear cells from patients with sJIA. In addition to the involvement of IL-6 in animal models of arthritis, studies support a role for prominent IL-6 production in the limitation of growth, systemic osteoporosis, thrombocytosis, and microcytic anemia seen in sJIA. ^, Studies on serum and synovial fluid expression (both proteins and messenger RNA [mRNA] levels) of IL-1β in sJIA have been difficult to interpret, mainly because of technical difficulties in reliably measuring IL-1β protein levels in plasma or serum. Sera from patients with active sJIA induce expression of IL-1β in peripheral blood mononuclear cells from healthy controls, ^, as well as expression of IL-1β inducible genes. The mechanism leading to abnormal production of IL-1β remains to be elucidated. An in vitro study of classical inflammasome stimulation, and subsequent caspase 1 activation and IL-1β secretion, failed to find abnormalities. Other proteases in other cell types (e.g., neutrophils) might be involved in processing IL-1. Moreover, the myeloid-related protein 8 (MRP-8) and MRP-14, secreted by neutrophils and monocytes/macrophages, are markedly elevated in the serum of active sJIA patients. ^, The MRP-8/MRP-14 complex acts as an endogenous ligand for TLR4 and induces inflammatory cytokines. ^, Neutralization of MRP-8/MRP-14 inhibits the stimulatory effect of sJIA sera on IL-1β production, suggesting that MRP-8/MRP-14 may be at least one of the factors involved in inducing IL-1β production. Serum amyloid A, an acute phase reactant that is elevated in association with sJIA flares, also induces IL-1 production by monocytes.

Another prominent cytokine in the biological signature of sJIA is IL-18. IL-18 is a strong activating molecule for NK cell function in human physiology. However, notwithstanding the increased levels of IL-18 in active sJIA, most sJIA patients display deficits in NK cell lytic function, as well as in numbers, This is interesting given the fact that low NK cell function can be linked to the increased risk for development of sJIA-associated macrophage activation syndrome (MAS), a form of secondary hemophagocytic lymphohistiocytosis (HLH). ^, One possibility is IL-18 increases in an effort to overcome low NK function and then has pathological consequences. These observations seem to have translational potential into clinical practice, as recombinant IL-18 binding protein (rIL-18BP) is currently being tested for use in AOSD and primary forms of HLH.

Although polymorphisms in cytokine promoters may contribute to excessive cytokine expression, research data from 2002, 2007, and 2010 also point to defective inhibition of immune responses. Although classical antiinflammatory mechanisms appear to be stimulated in sJIA, they may not be upregulated to a level sufficient to effectively inhibit responses. These include production of the antiinflammatory cytokine IL-10, ^{, ,} expression of suppressor of cytokine signaling 3 (SOCS3), which inhibits IL-1 and IL-6 intracellular signaling, activity of the alternatively activated macrophages and number, and suppressor activity of regulatory T lymphocytes.

In summary, the available evidence points to a dysregulation of the innate response with a prominent role of cells and cytokines of the innate response. The efficacy of treatment with IL-1 or IL-6 inhibitors provides additional compelling evidence supporting this hypothesis. These observations, together with the absence of autoantibodies and autoreactive T cells, suggest that sJIA should be considered an acquired autoinflammatory disease, with a subset of patients experiencing a later phase of chronic polyarthritis, possibly driven by aberrant adaptive immunity.

Clinical Manifestations

Children with sJIA are usually very ill at the time the diagnosis is made. They are fatigued and febrile, they are in pain with myalgia and arthralgia (sometimes with chest pain and abdominal pain), and frequently they have lost weight. These features predominate early in the course of the disease and may overshadow the arthritis, which may not develop until weeks or months later. In a multicenter study of 136 children with sJIA the most common initial clinical features were fever (98%), arthritis (88%), and rash (81%). Only 39% had lymphadenopathy, 10% had pericarditis, and fewer had hepatosplenomegaly. It is noteworthy that many patients did not fulfill the ILAR classification criteria for sJIA, predominantly because they did not meet the strict definition of the quotidian fever, or because they did not have arthritis (some had none or did not have it for long enough). In fact, with the increased understanding of the underlying immunopathology in sJIA over the past decade, the requirement of arthritis as obligatory disease manifestation is under debate. The interval between the onset of systemic signs and the appearance of arthritis may be as long as 10 years. It is noteworthy that the Yamaguchi criteria for AOSD, a disease entity with many similarities with sJIA, do not require the presence of arthritis. Moreover, arthralgia that lasts for at least 2 weeks is only one of the four possible major criteria for AOSD. The strict application of the requirement for the presence of documented arthritis for the diagnosis of sJIA early in the disease course may result in unnecessary delays in initiating appropriate treatment. It is rare for fever to first manifest after the development of arthritis. Because of the necessity of treating these often very ill patients quickly, some patients are treated prior to fulfillment of the ILAR criteria, making the definite diagnosis of sJIA problematic in such cases. In the development of consensus treatment plans (CTPs) for sJIA, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) used a formal consensus process to develop modified diagnostic criteria that can be used at the point of care ( Box 17.2 ). ^,

Fever

The typical pattern of fever in sJIA is that the temperature rises to 39° C or higher on a daily or twice-daily basis, with a rapid return to baseline or below baseline ( Fig. 17.1 ). This quotidian pattern is highly suggestive of the diagnosis of sJIA, although very early in the course of the disease the classic quotidian fever may not be apparent, and the pattern may be indistinguishable from that of sepsis. In these children, a more typical fever pattern may be seen after treatment with nonsteroidal antiinflammatory drugs (NSAIDs) is initiated. The fever may occur at any time of the day but is characteristically present in the late afternoon to evening in conjunction with the appearance of, or worsening of, the rash. The temperature may be subnormal in the morning. Chills are frequent at the time of the fever, but rigors are rare. These children are often quite ill while febrile but may appear surprisingly well during the rest of the day. The fever usually lasts for several months, may recur with flares of disease, and occasionally persists for years if not treated appropriately.

Rash

The intermittent fever is almost always accompanied by a classic rash that consists of discrete, erythematous, slightly raised round or oval macules 2 to 5 mm in size that may appear in linear streaks ( Fig. 17.2 ). This rash is usually described as salmon pink, but very early in the disease it may be more erythematous, although never purpuric. It most commonly occurs on the trunk and proximal extremities but may develop on the face, palms, or soles. The macules are often surrounded by a zone of pallor and larger lesions develop central clearing. The rash tends to be migratory and is strikingly evanescent in any one area. Individual lesions disappear within a few hours and leave no residua. In darker skinned individuals, the rash may be difficult to detect. The rash may be much more persistent in children who are systemically very ill, and it may reappear with each systemic exacerbation. Individual lesions may be elicited by rubbing or scratching the skin (the Koebner phenomenon or isomorphic response ), by a hot bath, or by psychological stress. The rash is sometimes pruritic, particularly in older patients, where it can resemble urticaria. Cutaneous vasculitis is mentioned in reviews as being rare, but is not otherwise documented and has been associated with the use of TNF inhibitors. Persistent pruritic papules and plaques that are violaceous or brownish in color may be seen on the trunk, neck, face, and extensor surfaces of the extremities in AOSD and rarely in sJIA. ^,

Lymphadenopathy and Splenomegaly

Enlargements of lymph nodes and spleen may occur alone or together and are characteristic of sJIA. Marked symmetrical lymphadenopathy is particularly common in the anterior cervical, axillary, and inguinal areas and may suggest the diagnosis of lymphoma. The enlarged lymph nodes are typically nontender, firm, and mobile. Tender lymphadenopathy may reflect necrotizing lymphadenitis associated with Kikuchi disease. Splenomegaly is seen less often, is usually most prominent within the first years after onset, and may be extreme ( Fig. 17.3 ).