Systemic juvenile idiopathic arthritis is a subtype of juvenile idiopathic arthritis, according to the recent International League of Associations for Rheumatology diagnostic criteria.1 In North America and Europe, systemic juvenile idiopathic arthritis accounts for 5% to 15% of children diagnosed with juvenile idiopathic arthritis, although the disease is seen worldwide.2 This review will summarize the clinical manifestations, pathogenesis, treatment, and prognosis of systemic juvenile idiopathic arthritis. It will also review one of the most interesting and feared complications of the disease, macrophage activation syndrome.
Systemic juvenile idiopathic arthritis (sJIA) is often easily differentiated from other forms of JIA due to the presence of specific systemic features. These include fever, rash, lymphadenopathy, hepatosplenomegaly, serositis, and abnormal hematologic parameters such as anemia, leukocytosis, and thrombocytosis. The systemic features can predominate early in the disease course when arthritis is not present, making the diagnosis difficult.3 Children often appear quite ill at the time of diagnosis.
In order to satisfy the International League of Associations for Rheumatology (ILAR) classification criteria for sJIA there must be arthritis present in one or more joints with or preceded by fever of at least 2 weeks duration and is documented as daily for at least 3 days. Additionally, one or more of the following findings must be present: 1) nonfixed (evanescent) erythematous rash; 2) generalized lymphadenopathy; 3) hepatomegaly or splenomegaly; or 4) serositis.4
The diagnosis of sJIA is clinical and is usually a diagnosis of exclusion (see Figure 1). The differential diagnosis at presentation is quite wide and includes: malignancy, infection, inflammatory bowel disease (IBD), other connective tissue disorders, and auto-inflammatory syndromes. Biopsies of bone marrow or lymph nodes are sometimes necessary to rule out malignancy when the diagnosis of sJIA is suspected but uncertain.
Figure 1. 2011 American College of Rheumatology (ACR) recommendations for treatment escalation of systemic juvenile idiopathic arthritis with active systemic features. Poor prognostic features include active systemic disease for more than 6 months (fever, elevated erythrocyte sedimentation rate, C-reactive protein, or need for systemic glucocorticoids). MD Global = physician global assessment of overall disease activity (range 0–10); NSAID = nonsteroidal anti-inflammatory drug.Image courtesy of Beukelman et al.1 Reprinted with permission from 2011 ACR recommendations.
The fever pattern on sJIA is typically a high daily (quotidian) or twice daily spiking fever (double quotidian), usually rising to 39 degrees or higher. Although the fever spikes may occur at any time of day, they are often seen in the late afternoon or evening.2 This pattern is suggestive of the diagnosis, but may not be seen early in the disease, and it may be impossible to distinguish from fever caused by infection. Usually, the fever is accompanied by the classic rash of sJIA, which consists of discrete erythematous or “salmon colored” macules approximately 2 mm to 5 mm in size.5 (see Figure 2).
Figure 2. Typical appearance of the evanescent rash seen in systemic juvenile idiopathic arthritis.Image courtesy of Arielle D. Hay, MD. Reprinted with permission.
It is usually migratory or evanescent, appearing with fever and then disappearing within hours, leaving no residual markings.2 The Koebner phenomenon may be elicited by scratching the normal-looking skin, by hot baths, or stress and is characterized by the isomorphic skin rash, with individual lesions resembling the original sJIA rash.
The arthritis of sJIA most often involves the knees, ankles, and wrists, but can affect any number of joints throughout the disease course. As with other forms of arthritis, symptoms include joint swelling or effusions, limitation of motion, pain, and warmth. Joint stiffness that is worse after periods of rest and improved with use is also characteristic of arthritis. The joint disease can be severe, damaging, and in some children, quite resistant to treatment.6 The arthritis may be minimal at disease onset but usually increases in severity with time.
Serositis is one of the diagnostic criteria for sJIA and most often manifests as pericarditis with pericardial effusions, but pleuritis and sterile peritonitis also occur. Pericardial involvement in sJIA is estimated to occur in 3% to 9% of patients.7 Pericardial involvement may occur as asymptomatic effusions, or be accompanied by shortness of breath, chest pain that is worsened by lying flat, tachycardia, diminished heart sounds and pericardial friction rub. This may occur at any time during the disease, but often accompanies flares of disease. Cardiac tamponade is a rare, but serious complication requiring urgent intervention and drainage. Pericarditis is not considered a poor prognostic factor.7
Lymphadenopathy and hepatosplenomegaly may occur, and along with other symptoms, such as daily fever, can be suggestive of malignancy such a lymphoma. The enlarged lymph nodes are nontender, mobile, and symmetric. Symmetric cervical, axillary, or inguinal adenopathy is common. Splenomegaly is more common than hepatomegaly and can be extreme, but is rarely associated with functional abnormalities.2 See Sidebar 1 for the ILAR criteria for diagnosis of sJIA.
ILAR Criteria for Diagnosis of sJIA
Arthritis in one or more joints with or preceded by fever of at least 2 weeks’ duration that is documented to be daily (“quotidian”) for at least 3 days, and accompanied by one or more of the following:
Evanescent erythematous rash
Generalized lymph node enlargement
Hepatomegaly and/or splenomegaly
Psoriasis or a history of psoriasis in the patient or first-degree relative.
Arthritis in an HLA-B27–positive male beginning after the 6th birthday.
Ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome or acute anterior uveitis, or a history of one these disorders in a first-degree relative.
The presence of immunoglobulin M rheumatoid factor on at least two occasions at least 3 months apart.
ILAR = International League of Associations for Rheumatology; sJIA = systemic juvenile idiopathic arthritis.
Research into the pathogenesis of sJIA points toward dysregulation of the innate immune system. An imbalance between pro-inflammatory and anti-inflammatory cytokines and their receptors is thought to mediate the findings seen in sJIA.8 Consequently, sJIA is starting to be viewed more as an autoinflammatory disease rather than an autoimmune disease. Classic autoimmune conditions usually have strong MHC associations, involvement of autoreactive T-lymphocytes and high titer autoantibodies. These are not seen in sJIA. The main effector cells of sJIA are monocytes and neutrophils, not lymphocytes.9 Proinflammatory cytokines such as IL-1, IL-6, and IL-2 have been shown in multiple studies to have a role in the pathogenesis of sJIA.8,10 Elevated levels of IL-6 have been found in the blood and synovial fluid of sJIA patients. Additionally, correlation between elevated IL-6 levels and disease activity has been demonstrated.11
When healthy peripheral blood mononuclear cells are incubated with serum from sJIA patients, upregulation of genes involved in innate immunity, including IL-1 and its receptors occurs.10 The significant role of IL-1 in sJIA pathogenesis is supported by the marked clinical improvement, which can be seen in some sJIA patients treated with IL-1 inhibition. Furthermore, while levels of TNF-a have been shown to be increased in sJIA patients, the clinical response to TNF inhibition is poor.2 This is a major distinction between sJIA and the other JIA subtypes in which TNF inhibition is a mainstay of treatment. Despite the recent advances in the knowledge of sJIA pathogenesis, there is much left to be discovered.
Once the diagnosis of sJIA is established, treatment is started to control both the joint manifestations and systemic inflammation. Children are often hospitalized at the time of diagnosis since they appear acutely ill, and the diagnosis may not be obvious. In many cases, initiation of nonsteroidal anti-inflammatory drugs (NSAIDs) is the appropriate first step in treatment. Although NSAIDs can be helpful, when used alone they are rarely successful in fully treating the systemic symptoms.2 Early on, glucocorticoids are indicated as additional therapy. Prednisone at 1 mg/kg/day to 2 mg/kg/day may be necessary to control active disease.
Due to the many unwanted side effects of glucocorticoids, tapering the prednisone to a very low dose over time, and even withdrawing steroids completely, is an important goal of treatment. This is often difficult in some patients, as their disease will flare once prednisone doses are decreased to a certain level. In 2011, The American College of Rheumatology published recommendations for the treatment and monitoring of JIA.
The recommendations for escalation of therapy in sJIA are broken down into two categories: patients with active systemic inflammation, but without arthritis and those with active arthritis, but without active systemic features. The algorithm of treatment is shown in Figures 1 and 3.1 As with other forms of JIA, the era of biologic therapy has had a major impact on treatment of sJIA. Anti-TNF, anti–IL-1 and anti–IL-6 agents have been studied to varying degrees for treatment of sJIA.
Figure 3. 2011 American College of Rheumatology recommendations for treatment of systemic juvenile idiopathic arthritis with active arthritis but without active systemic features. Poor prognostic factors include hip arthritis and/or radiographic damage of joints. MD Global = physician global assessment of overall disease activity (range 0–10); NSAID = nonsteroidal anti-inflammatory drug; TNF = tumor necrosis factor. *Switching from anakinra to a TNF-alpha inhibitor may be appropriate for some patients with moderate or high disease activity.Image courtesy of Beukelman et al.1 Reprinted with permission from 2011 ACR recommendations.
While anti-TNF agents have used successfully in other forms of JIA, they are less useful for treating sJIA. A recent survey of US pediatric rheumatologists showed that more than half of sJIA patients treated with anti-TNF therapy had only fair or poor response and flares of disease were common.12
Anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist has been successfully used to treat sJIA and is usually given in doses of 1 mg/kg/day to 2 mg/kg/day requiring daily injections. While there have been no controlled trials studying the effects of anakinra, several studies have demonstrated its effectiveness.10 As shown in Figure 1, it is part of the treatment algorithm recommended by the ACR.1 Rilonacept is a longer-acting IL-1 antagonist that is a fusion protein of the IL-1 receptor and the Fc portion of human IgG. It is used to treat certain periodic fever syndromes, but is currently being studied in a multicenter clinical trial as a potential treatment for sJIA. One of the major advantages of this drug is weekly administration rather than daily administration needed for anakinra.
Tocilizumab is a monoclonal antibody against the IL-6 receptor and is the only available anti–IL-6 treatment. (Tocilizumab was FDA approved for use in sJIA in April 2011 after the Genentec phase 3 TENDER trial.) Another promising biologic agent undergoing clinical trials for the treatment of sJIA is canakinumab, a fully humanized anti–IL-1beta antibody. Results of a phase 2 trial were published in early 2012.
There has been a recent trend toward using biologic therapy such as anakinra or tocilizumab as first-line therapy for sJIA, although controlled studies are needed before these can become universal recommendations.
Macrophage Activation Syndrome
Macrophage activation syndrome (MAS) is one of the most feared and potentially devastating complications of sJIA. It is characterized by over-activation and expansion of T cells and macrophages, which leads to an overwhelming inflammatory response.13 Hemophagocytic lymphohistiocytosis (HLH), a term for a related histiocyte disorder, resembles MAS.
HLH is subdivided into primary or familial HLH and secondary or reactive HLH. The former subtype is most often inherited as an autosomal disorder with specific gene defects, while the latter subtype can occur after certain infections such as EBV or CMV or in association with certain malignancies. Reactive HLH is synonymous with MAS, in our opinion.
While MAS has been reported in association with almost all of the rheumatic diseases, including systemic lupus erythematosus and Kawasaki disease, it most often occurs in patients with systemic JIA. MAS can occur at any time during the disease course, but is most often associated with active disease.
Clinical features of MAS include persistent fever; hepatosplenomegaly and liver dysfuntion; mental status changes; lymphadenopathy; cytopenias; mucosal bleeding; and purpura.13 In severe cases, multiorgan disease with renal and respiratory failure, hypotension, and shock can occur. Typical laboratory findings include anemia and thrombocytopenia, elevated liver enzymes, LDH, triglycerides, D-dimer and ferritin. Extreme hyperferritinemia with values greater than 10,000 and associated hypofinbrinogenemia is common.
Additionally, prothrombin and partial thromboplastin times are prolonged with a decrease in levels of vitamin K−dependent clotting factors. A sharp decline in the erythrocyte sedimentation rate (ESR) is seen while the C-reactive protein level (CRP) remains elevated. The drop in ESR is considered paradoxical because sJIA is an inflammatory condition, and normally with active inflammation the ESR would be elevated.
Fibrinogen is one of the acute phase reactants most responsible for elevations in the ESR during active inflammation. The drop in the ESR seen in MAS is due to the consumption of fibrinogen because of coagulopathy and disseminated intravascular coagulation.
The diagnosis of MAS can be very difficult because there are no established diagnostic criteria. It is suspected when a patient with a chronic rheumatic disease presents with a drop in the ESR, thrombocytopenia, elevated CRP, D-dimer, and ferritin. The diagnosis can be confirmed with bone marrow biopsy demonstrating macrophages phagocytosing hematopoetic cells (See Figure 4). While this finding can confirm the diagnosis, it may not always been seen due to sampling error or hemophagocytosis occurring in tissues other than bone marrow.
Figure 4. Bone marrow aspirate revealing an activated macrophage engulfing a neutrophilic band form.Image courtesy of Arielle D. Hay, MD. Reprinted with permission.
Often when trying the make the diagnosis of MAS, the well-established and validated HLH diagnostic criteria are considered. This can be quite problematic because many of the clinical features used for HLH diagnosis occur in active sJIA without MAS. Therefore, the diagnosis of MAS remains one based on high level of suspicion.
Early recognition of MAS and prompt treatment is necessary because it is a life-threatening condition. Initial treatment usually consists of high-dose methylprednisolone therapy (30 mg/kg/day for 3 days) followed by 2 mg/kg/day to 3 mg/kg/day divided into four doses.13 As the clinical and laboratory manifestations improve, the steroids can be carefully tapered. In patients who are resistant to corticosteroids, cyclosporine A can be highly effective.14 If there is no response with the use of steroids and cyclosporine A, the use of etoposide can be considered.
Steroids, cyclosporine A and etoposide are the main components of the HLH-2004 protocol, which were developed by the International Histiocyte Society.14 The reported mortality rates of MAS reach 20%.13 Successful treatment depends upon early recognition of the disease and prompt management with appropriate therapy. Since the condition can recur, patients who experience MAS must be closely monitored for future episodes. There have been reports of IL-1 and IL-6 inhibition both triggering MAS but also as treatments for MAS.
Course and Prognosis
The course of sJIA can be quite variable. Approximately 40% of patients experience a monocyclic course with complete recovery.2 Other children will experience a polycyclic course with multiple episodes of active disease followed by periods of remission. A persistent disease course can be seen in about one half of patients.15 Long-term treatment with glucocorticoids in patients who follow a protracted disease course can lead to significant morbidity.
Some studies report achievement of remission in only one third of patients.16,17 Overall prognosis is more dependent on joint involvement than persistent systemic symptoms, since the arthritis can be destructive. Early predictors of destructive arthritis include polyarthritis, thrombocytosis, persistent fever, and the need for systemic glucocorticoids in the first 6 months after disease onset.18,19 Additionally, early hip arthritis confers a worse prognosis (see Sidebar 2).20 Disease-associated death from sJIA is less than 0.5% in North America, often involving infections in patients treated with glucocorticoids.2
Features of Poor Prognosis
Active systemic symptoms (fever, elevated erythrocyte sedimentation rate/C-reactive protein requiring systemic glucocorticoids)
Arthritis of the hip
Systemic arthritis with active systemic feature, without arthritis.
Systemic arthritis with active arthritis, but without active systemic features.
Systemic JIA is a rare disease characterized by fever, arthritis, lymphadenopathy, rash, and serositis. Overall systemic inflammation is a hallmark feature. Diagnosis can be difficult due to clinical overlap with many other processes. Treatment is aimed at controlling both the systemic features and joint inflammation with the goal of preserving joint function and preventing joint damage.
Macrophage activation syndrome is a life-threatening complication associated with sJIA, and clinicians must be on the lookout for early signs and symptoms. Newer treatments, which block the action of specific inflammatory cytokines, have made a major impact in the treatment of this disease.
Continued research into the pathophysiology of the disease and development of new targeted treatments of the disease and its complications will help improve the prognosis of this potentially devastating illness.
- Beukelman T, Patkar NM, Saag KG, et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken). 2011;63(4):465–482. doi:10.1002/acr.20460 [CrossRef]
- de Benedetti F, Schneider R. Textbook of pediatric rheumatology. In: Cassidy JT, ed. Textbook of Pediatric Rheumatology. 6th ed. Philadelphia, PA: Saunders; 2010.
- Behrens EM, Beukelman T, Gallo L, et al. Evaluation of the presentation of systemic onset juvenile rheumatoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Arthritis Registry (PASOJAR). J Rheumatol. 2008;35(2):343–348.
- Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390–392.
- Bywaters EG, Isdale IC. The rash of rheumatoid arthritis and Still’s disease. Q J Med. 1956;25(99):377–387.
- Schneider R, Lang BA, Reilly BJ, et al. Prognostic indicators of joint destruction in systemic-onset juvenile rheumatoid arthritis. J Pediatr. 1992;120(2 Pt 1):200–205. doi:10.1016/S0022-3476(05)80427-5 [CrossRef]
- Goldenberg J, Ferraz MB, Pessoa AP, et al. Symptomatic cardiac involvement in juvenile rheumatoid arthritis. Int J Cardiol. 1992;34(1):57–62. doi:10.1016/0167-5273(92)90082-E [CrossRef]
- Ilowite NT. Systemic Juvenile Idiopathic Arthritis – a 2006 update. Available at: www.medscape.org/viewprogram/5690. Accessed Oct. 2, 2012.
- Vastert SJ, Kuis W, Grom AA. Systemic JIA: new developments in the understanding of the pathophysiology and therapy. Best Pract Res Clin Rheumatol. 2009;23(5):655–664. doi:10.1016/j.berh.2009.08.003 [CrossRef]
- Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med. 2005;201(9):1479–1486. doi:10.1084/jem.20050473 [CrossRef]
- de Benedetti F, Martini A. Targeting the interleukin-6 receptor: a new treatment for systemic juvenile idiopathic arthritis?Arthritis Rheum. 2005;52(3):687–693. doi:10.1002/art.20946 [CrossRef]
- Kimura Y, Pinho P, Walco G, et al. Etanercept treatment in patients with refractory systemic onset juvenile rheumatoid arthritis. J Rheumatol. 2005;32(5):935–942.
- Grom AA. Macrophage activation syndrome. In: Cassidy JT, ed. Textbook of Pediatric Rheumatology. Philadelphia, PA: Saunders; 2010.
- Mouy R, Stephan JL, Pillet P, Haddad E, Hubert P, Prieur AM. Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases. J Pediatr. 1996;129(5):750–754. doi:10.1016/S0022-3476(96)70160-9 [CrossRef]
- Fantini F, Gerloni V, Gattinara M, Cimaz R, Arnoldi C, Lupi E. Remission in juvenile chronic arthritis: a cohort study of 683 consecutive cases with a mean 10 year followup. J Rheumatol. 2003;30(3):579–584.
- Minden K, Kiessling U, Listing J, et al. Prognosis of patients with juvenile chronic arthritis and juvenile spondyloarthropathy. J Rheumatol. 2000;27(9):2256–2263.
- Wallace CA, Huang B, Bandeira M, Ravelli A, Giannini EH. Patterns of clinical remission in select categories of juvenile idiopathic arthritis. Arthritis Rheum. 2005;52(11):3554–3562. doi:10.1002/art.21389 [CrossRef]
- Modesto C, Woo P, Garcia-Consuegra J, et al. Systemic onset juvenile chronic arthritis, polyarticular pattern and hip involvement as markers for a bad prognosis. Clin Exp Rheumatol. 2001;19(2):211–217.
- Sandborg C, Holmes TH, Lee T, et al. Candidate early predictors for progression to joint damage in systemic juvenile idiopathic arthritis. J Rheumatol. 2006;33(11):2322–2329.
- Bloom BJ, Alario AJ, Miller LC. Persistent elevation of fibrin D-dimer predicts longterm outcome in systemic juvenile idiopathic arthritis. J Rheumatol. 2009;36(2):422–426.