A 6-year-old girl was referred to our pediatric rheumatology clinic for evaluation of intermittent fevers for the past 3 weeks associated with joint pain and decreased energy level. She had been evaluated in her local emergency department 15 days earlier, and was given a course of antibiotics for a suspected throat infection. Her symptoms did not improve on the antibiotics. She continued to have daily spiking fevers that started in the late afternoon, persisting for several hours, and peaking at 39.5°C. Her joint pain increased during the fevers, accompanied by swelling of her finger and knee joints. Her parents noted a transient pink-appearing rash on her trunk, arms, and legs in the evenings that was not present in the morning. Except for mild morning stiffness lasting approximately 15 minutes, she felt fairly well during the day and was able to attend school and participate in gym class. In the evenings and night when her fevers were present, her parents treated her with ibuprofen, which ameliorated her fever and joint symptoms but did not resolve them entirely. Prior to the development of fever, rash, and joint pain 3 weeks ago, she had been a healthy child with no medical issues.
sJIA was first described by George Frederic Still1 in the 1890s, and for decades this entity was known as Still’s disease. It was referred to as systemic-onset juvenile rheumatoid arthritis (JRA) in the last quarter of the 20th century, and was 1 of the 3 subtypes of JRA (pauciarticular and polyarticular JRA being the others). In 1998, a new nomenclature of chronic arthritis in children was developed, changing the terminology from JRA to juvenile idiopathic arthritis (JIA) and including eight (instead of three) subtypes of childhood arthritis: (1) systemic, (2) persistent oligoarthritis, (3) extended oligoarthritis, (4) rheumatoid factor negative polyarthritis, (5) rheumatoid factor positive polyarthritis, (6) psoriatic, (7) enthesitis-related, and (8) undifferentiated arthritis.2 sJIA, which represents approximately 10% of the JIA population, is unique among the JIA subtypes because of its distinctive clinical presentation, laboratory findings, pathophysiology, complications, and treatment approaches. Each of these aspects of sJIA is discussed in the following text.
Active sJIA is characterized by the presence of fevers, rash, and other systemic features, as well as arthritis. The fever has a specific pattern with one, or rarely two, daily spikes to temperatures usually ≥39°C with a fairly rapid return after a few hours to ≤37°C or below. This daily spiking fever pattern is known as quotidian. When the fever is present, the child usually experiences more malaise, joint symptoms, and skin rash.
The classic systemic rash is migratory and evanescent, often resolving within hours and leaving no residua. It consists of discrete, salmon-colored macules that may be more difficult to see on darker-skinned children. The lesions are 2 to 5 mm in size, occasionally with central clearing, and present primarily on the trunk, arms, and legs and less commonly on the face, palms, and soles (Figure 1). It is pruritic in a minority of patients. The rash is frequently missed by the clinician as it tends to be most prominent during the evening fevers when the child is at home. A Koebner phenomenon, in which a central wheal with surrounding erythema develops with mild scratching of the skin, frequently is present in these children.
Systemic rash located on the trunk and arms of the patient.
Joint involvement in sJIA is variable. Arthritis may be prominent, minimal, or even absent at fever presentation, often increasing in severity with passing weeks and months. It is usually polyarticular, potentially affecting all large and small joints, including cervical spine and temporomandibular joints. Injury to involved joints may occur quite rapidly, with progressive loss of joint space, range of motion, and function over a few years. More than one-third of patients with sJIA had severe joint destruction within 5 years of diagnosis in the era before biologic medications.
Systemic features of sJIA include splenomegaly, hepatomegaly, lymphadenopathy, serositis (pericardial, pleural, peritoneal), pneumonitis, and anemia of chronic disease. Criteria for diagnosis of sJIA are arthritis and a history of ≥2 weeks of fever (including ≥3 days of a quotidian fever pattern), with at least one of the following: evanescent rash, generalized lymphadenopathy, enlarged liver or spleen, or serositis.2 Unlike patients with other subtypes of JIA, children with active sJIA have abnormal laboratory studies that reflect systemic inflammation, including elevated white blood cell count, platelets, ESR, CRP, and ferritin. Hemoglobin is depressed (often 7–10 g/dL). Transaminases are mildly to moderately increased in up to 25% of patients at presentation. Rheumatoid factor and antinuclear antibodies are negative.
Differential diagnosis in children with suspected sJIA is broad, especially early in the presentation when the fever is prominent and the arthritis may be absent. Included in the differential diagnosis are infections, other rheumatologic diseases (especially vasculitides such as Kawasaki disease or polyarteritis nodosa), inflammatory bowel disease, malignancy, and autoinflammatory diseases (especially the cryopyrin-related entities).
When the classic quotidian fever, evanescent rash, and arthritis are present, the diagnosis of sJIA may be clear. However, if the clinical presentation is incomplete or the laboratory profile is atypical, such as the presence of a low platelet count in the setting of systemic inflammation, then further testing is indicated, particularly to rule out a malignancy. If any doubt regarding the diagnosis exists, performance of a bone marrow biopsy to rule out leukemia is essential, especially prior to starting corticosteroid treatment. A lymph node biopsy is sometimes indicated in those patients with significant lymphadenopathy and an ambiguous clinical and/or laboratory profile.
Although the etiology of sJIA is unknown, understanding of the pathophysiology of sJIA has increased greatly over the past few decades. Autoimmunity, autoreactive T cells, and specific human leukocyte antigen (HLA) alleles, which are notable in many rheumatologic diseases including other JIA subtypes, are not features of sJIA. Instead, the innate, and not the adaptive, immune system plays the major role in the expression of this disease, with neutrophils, monocytes/macrophages, and cytokines involved in its pathogenesis, suggesting that sJIA should be considered an autoinflammatory disease.3 Dysregulation of the innate immune response in sJIA leads to increased levels of several proinflammatory cytokines. Prominent among these is interleukin 6 (IL-6). An elevated IL-6 blood level is present just prior to a rise in fever and is associated with an increase in systemic features.4 Another proinflammatory cytokine implicated in the pathogenesis of sJIA is interleukin-1beta (IL-1beta). The significant and precipitous decrease in systemic features in sJIA patients treated with the IL-1 receptor antagonist, anakinra supports the role of IL-1beta in this disease.5
Prior to the development and availability of biologic medications that decrease inflammatory cytokine activity, children with sJIA were often treated with a combination of two or more medications, including NSAIDs, corticosteroids, methotrexate, IV gamma globulin, CsA, and rarely thalidomide.6 Many patients entered remission, but up to 50% had progressive disease over the ensuing years, with arthritis more prominent than systemic features.
Treatment of sJIA has undergone a significant transformation with the advent of biologic medications that target proinflammatory cytokines, often resulting in a rapid improvement of both the systemic and articular features. sJIA appears to have two phases of disease: the earlier phase has prominent systemic features, and the later one has persistent and progressive arthritis. Aggressive and successful treatment of the earlier phase of the disease may decrease the risk of progression to chronic arthritis. Anakinra is a recombinant human IL-1 receptor antagonist that interferes with binding of IL-1beta cytokine to receptor cells. Studies have demonstrated that treatment with anakinra shortly after diagnosis of sJIA can lead to rapid defervesence, improvement of systemic features and laboratory studies, and often remission.7 Treatment with anakinra later in the course of sJIA, when arthritis is the major component, is not very effective. Canakinumab is a fully human anti–IL-1beta monoclonal antibody recently approved for children with sJIA. Advantages of canakinumab over anakinra are its longer half-life (it is given subcutaneously every 28 days instead of daily) and increased efficacy in treating arthritis. However, compared to anakinra, it may be associated with increased risk of infection and is more expensive. Patients may have localized injection reactions with either of these anti–IL-1 medications.
Tocilizumab is a humanized IL-6 receptor antibody approved for sJIA that has been shown to be effective in treating both systemic and articular features of this disease.8 It is given intravenously every 2 weeks. It generally is considered a second-line biologic treatment for those who fail anti–IL-1 medications. Complications of tocilizumab treatment may include infusion reactions, cytopenia, transaminitis, hypercholesterolemia, and increased risk of infection. Anti-tumor necrosis factor medications, such as etanercept and adalimumab, which are used as first-line biologics in most subtypes of JIA, are not efficacious in the majority of patients with sJIA, especially those with primarily systemic features rather than arthritis.
All biologic medications alter the body’s normal immune response. Therefore, concern exists that malignancy may be a potential long-term complication of these drugs, although there is no convincing evidence that this is the case in children with JIA. As this class of medications suppresses immune defense, live vaccines should be avoided in children receiving biologics. Baseline hepatitis B and C, and tuberculosis (by blood or skin testing) studies should be performed prior to starting biologic treatment.
MAS is a serious and potentially fatal complication occurring in at least 7% of children with sJIA.9 The incidence is likely higher, as many patients appear to have an incomplete presentation with milder clinical and laboratory features consistent with this syndrome.10 MAS most often occurs in patients with active sJIA, and only rarely in those who are in a disease remission. In MAS, there is deficient natural killer cell and cytotoxic T-cell function associated with excessive T cell and macrophage activation, which leads to prolonged and increased production of proinflammatory cytokines. The pathophysiology and clinical complications of MAS closely resemble those that occur in primary (familial) hemophagocytic lymphohistiocytosis, an entity associated with genetic mutations principally affecting perforin production or function.
The diagnosis of MAS should be considered in patients with sJIA who have rapid development of unremitting fevers, lymphadenopathy, hepatosplenomegaly, liver failure, hemorrhages, seizures, and disorientation. Multiple laboratory abnormalities are seen in MAS. A precipitous fall in platelet count and sedimenatation rate, along with increased CRP and markedly elevated ferritin levels, frequently >10,000 ng/mL, are laboratory hallmarks of MAS. Transaminitis, leukopenia, anemia, elevated triglycerides, and coagulopathy (prolonged PT and PTT, hypofibrinogenemia, elevated d-dimer) are also prominent. Specific markers of lymphocyte activation (soluble IL-2 receptor) and of macrophage activation (soluble CD163) are usually highly elevated. Bone marrow aspiration shows evidence of macrophage hemophagocytosis in approximately 60% of the patients who have this procedure performed.11 The clinical, laboratory, and pathologic features of MAS are summarized in Table 1.
Clinical, Laboratory, and Pathologic Features of Macrophage Activation Syndrome
Prompt diagnosis and treatment of MAS are essential to decrease morbidity and mortality. Treatment with high-dose parenteral corticosteroids should be initiated as soon as the diagnosis is highly suspected. CsA has been shown to be efficacious, and perhaps may also serve as a steroid-sparing medication. IL-1 blockade with anakinra has been reported to result in a rapid improvement of MAS symptoms and laboratory abnormalities.12 This biologic medicine is being used with increasing frequency in sJIA complicated by MAS, as it appears to be efficacious for MAS as well as for the underlying sJIA. The mortality of MAS was historically reported to be approximately 8%. However, IL-1 blockade combined with corticosteroid and CsA treatment is likely superior to previous treatments. Mortality will hopefully decrease with more prompt diagnosis and effective treatment of this complication.