INTRODUCTION — Systemic juvenile idiopathic arthritis (formerly called Still's disease or systemic-onset juvenile rheumatoid arthritis [JRA]) is officially a subset of juvenile idiopathic arthritis (JIA), although the pathophysiology is most consistent with an autoinflammatory disorder [1]. Adult-onset Still's disease (AOSD) is probably the same disease when it begins in patients ≥16 years of age. (See "Classification of juvenile idiopathic arthritis", section on 'Systemic arthritis'.)
Children with systemic JIA require close supervision and careful monitoring. Systemic complications, including infections, macrophage activation syndrome (MAS), and pericarditis, are common in this subtype of JIA and are associated with increased morbidity and mortality [2]. Chronic lung disease and other forms of internal organ involvement are less common but are seen with increasing frequency [3-5].
The clinical course, prognosis, and complications of systemic JIA are discussed in this review. The clinical manifestations, diagnosis, and treatment of systemic JIA are discussed separately, as are oligoarticular and polyarticular JIA. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis" and "Systemic juvenile idiopathic arthritis: Treatment" and "Classification of juvenile idiopathic arthritis" and "Oligoarticular juvenile idiopathic arthritis" and "Polyarticular juvenile idiopathic arthritis: Clinical manifestations, diagnosis, and complications".)
COURSE — The course of systemic JIA is highly variable, which has prompted many observers to suspect that systemic JIA is not a single entity. The disease course in a typical child with systemic JIA starts with a several-month period of spiking fevers and rash, with varying degrees of arthralgia and arthritis. This may be followed by a relative quiescence of the systemic manifestations. However, there are some children who have persistently active systemic disease, which is associated with worse outcomes [3,6]. (See 'Prognosis' below.)
Generally speaking, there are three disease-course patterns: monophasic, polycyclic, and persistent [6-8]. The actual proportions of systemic JIA patients who follow these disease course patterns are unclear since all studies looking at disease course were single-center studies and the definitions of remission and inactive disease were variable.
●Monophasic course – These patients present with active systemic JIA. However, their disease becomes completely quiescent, usually after a period of four to six months, and does not recur.
●Polycyclic course – These patients have recurrences of active systemic JIA episodes but have long periods of disease inactivity in between. The inactive periods may range from a few months to years. In all series, this is the least common.
●Persistent course – These patients (usually the most common course) continue to have a chronic course that can take various forms:
•Systemic manifestations (ie, fever and rash and sometimes recurrent macrophage activation syndrome [MAS]), but little to no arthritis.
•Persistent systemic manifestations (sometimes with recurrent MAS) and progressive arthritis.
•Persistent arthritis despite resolution of systemic manifestations. Some of these children have relentless destructive arthritis that progresses despite any therapy and require joint replacements at an early age.
Arthritis resolves completely in approximately 40 to 50 percent of patients [9]. The child who appears well after six months has a substantial probability of remaining well, whereas the child who continues to have active disease six months after diagnosis typically has a more difficult and chronic course [6,10,11]. However, some children have recurrences even after years of appearing disease free. Thus, some patients who present with adult-onset Still's disease (AOSD) may, with careful questioning, give a history that suggests that the actual initial onset was in childhood.
PROGNOSIS — Children with systemic JIA who fail to respond adequately to therapy have a significantly poorer prognosis than do children who achieve disease control. In one large, Canadian cohort of children diagnosed with JIA from 2005 to 2010, 71 percent of patients with systemic JIA attained inactive disease within one year, and 47 percent achieved remission within five years [12]. Similar results were seen in a German cohort of patients diagnosed from 2000 to 2013, with 72 percent of patients reported to have inactive disease at three-year follow-up [13]. Retrospective and prospective studies have suggested that there is a "window of opportunity" in which early, effective treatment may greatly improve the chances of remission [14-16]. (See "Systemic juvenile idiopathic arthritis: Treatment".)
In one study that used a "treat to target" approach using anakinra in 42 patients with new-onset systemic JIA in a single Dutch center, the rate of inactive disease at one year was 76 percent, with 52 percent of these patients off medication. After five years of follow-up, 75 percent of the patients had inactive disease off medications, potentially supporting the concept of a window of opportunity [17].
In the past, more than one in three children with systemic JIA developed permanent joint damage [18], with a propensity to affect the hip joint, and more than one-half required substantial prolonged systemic glucocorticoid therapy (often for years) [19]. Patients with active disease (eg, fevers, arthritis, elevated platelet count, continued requirement for glucocorticoid therapy) after the first six months of disease onset have a worse prognosis for continued disease and destructive arthritis [6,10,11]. In addition, one study suggested that children who develop systemic JIA at a very early age, before 18 months of age, may have worse outcomes (arthritis, disability, growth) [20].
However, significant advances in the treatment of systemic JIA, particularly the use of biologic response modifiers, such as tocilizumab (anti-interleukin [IL] 6 receptor monoclonal antibody), canakinumab (anti-IL-1-beta monoclonal antibody), and anakinra (IL-1 receptor antagonist), are felt to have dramatically improved the prognosis in children with systemic JIA. A study of 372 patients with systemic JIA in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry showed that the overwhelming majority of children with systemic JIA are doing well from a disease activity and disability point of view, but there are children who continue to have significant arthritis despite the use of these biologic agents [21].
An unusual form of chronic lung disease associated with a poor prognosis is increasingly reported in systemic JIA [3-5]. (See 'Lung disease' below.)
Mortality — The overall mortality rate is low in children with systemic JIA, although higher rates are seen in children with more severe disease and in adults with a history of systemic JIA.
One study examined mortality outcomes in 49,023 pediatric patients diagnosed with a rheumatic disease [22]. The subset of patients with systemic JIA did not have a significantly increased mortality rate, but this study may have missed hospitalized patients at highest risk of mortality. In two clinical trials of systemic JIA patients, there were 3 deaths in 117 patients (2 of which occurred after the trial period) and 4 deaths in 190 patients (2 of which were after the trial period) in the trials of tocilizumab (IL-6 inhibitor) and canakinumab (IL-1 inhibitor), respectively. These patients mostly had severe, refractory systemic JIA [23,24].
A high rate of mortality (40 to 60 percent) is also seen in patients with systemic JIA and pulmonary disease [3-5]. One series of 61 patients in 2019 reported a five-year survival rate of 43 percent [4].
Issues in adulthood — Adults whose disease began during childhood may have residual problems, including musculoskeletal problems and severe disability. The rates of long-term morbidities are expected to decrease with improvements in therapy, especially if treatment is started early in the disease course [14,16]. (See "Systemic juvenile idiopathic arthritis: Treatment".)
In one study of adults with a history of JIA published in 2002, the mean duration of disease among the 52 patients with systemic JIA was approximately 29 years. The following disease-related features were noted in this cohort of patients whose disease began on average in the 1960s and 1970s, prior to the availability of biologic response modifiers [25]:
●Leg-length discrepancies of more than 2 cm were found in 31 percent, possibly related to hip replacement surgery.
●Restricted jaw opening was present in 54 percent.
●Severe disability, as indicated by Health Assessment Questionnaire (HAQ) scores of 1.5 to 3.0 or by modified Steinbrocker classes of III or IV, was present in 62 and 65 percent, respectively.
●Amyloidosis was present in nearly 20 percent.
These results illustrate the importance of effective therapy and the inadequacy of the therapeutic modalities used when these adults were children and developed systemic JIA. These complications are most likely far less frequent with the availability of biologic response modifiers.
COMPLICATIONS — Macrophage activation syndrome (MAS), severe growth retardation, and osteoporosis are the most common complications of systemic JIA and/or its treatment. With more common and earlier usage of biologic response modifiers such as interleukin (IL) 1 and IL-6 inhibitors, complications such as growth retardation and osteoporosis are less likely to occur, but long-term outcomes in the era of biologic treatment still need to be studied. As an example, the actual incidence of lung disease is unknown and should be studied systematically, such as in the context of a large disease registry.
Macrophage activation syndrome — MAS is a severe complication of systemic JIA that should be treated as a life-threatening emergency [26,27]. The clinical and histopathologic characteristics of MAS are similar to those of hereditary lymphohistiocytic hemophagocytosis (HLH), but the diagnostic criteria for HLH are often not useful to diagnose MAS in systemic JIA. Evidence suggests that there is a shared genetic component in that some patients with systemic JIA and MAS also have protein-altering variants in HLH-associated genes [28]. The specifics of MAS as they relate to systemic JIA are briefly discussed here. This syndrome and its treatment are reviewed in greater detail separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Rheumatologic disorders/MAS' and "Treatment and prognosis of hemophagocytic lymphohistiocytosis", section on 'MAS/Rheumatologic conditions'.)
Clinical presentation — MAS typically occurs within the first few days or weeks of the onset of systemic JIA, although it can occur at any point over the course of the disease. Overt MAS occurs in 10 percent of children with systemic JIA but can occur subclinically in another 30 to 40 percent [29]. Some patients have recurrent episodes of MAS. Triggers may include viral or bacterial infections or new medications, but often no inciting event is identified.
Children may present with spontaneous bleeding, bruising, hepatic dysfunction, lethargy, seizures, coma, or shock. Unremitting fever and rash (unlike the intermittent daily fever and evanescent rash typical of simple active systemic JIA), lymphadenopathy, and hepatosplenomegaly are also common findings. The white blood cell count, hemoglobin, platelet count, and serum fibrinogen typically drop precipitously; liver function tests, triglycerides, and lactate dehydrogenase (LDH) rapidly become elevated; and the ferritin level can climb to well over 1000 ng/mL (often much higher). There is also a paradoxical drop in the erythrocyte sedimentation rate (ESR) due to fibrinogen consumption, which is an important clue [30]. On bone marrow examination, numerous benign macrophages typically exhibit hemophagocytosis, but not all bone marrow specimens from patients with MAS demonstrate this finding and can be normal in appearance.
Diagnosis — Early MAS can be difficult to diagnose in the setting of systemic JIA because a systemic disease flare has similar clinical features. In addition, a review of the literature showed that patients who are treated with biologics may have less typical clinical features of MAS that may make it even more challenging to recognize, such as no or lower fever and significantly lower C-reactive protein and ferritin levels in tocilizumab-treated patients [31]. The HLH diagnostic criteria often cannot be applied to MAS in patients with systemic JIA even though the clinical syndromes are similar, because the HLH criteria are too stringent to be able to identify systemic JIA patients in early MAS, when they are most responsive to treatment [32]. Part of the problem lies in the fact that patients with systemic JIA "normally" have highly elevated white blood and platelet counts as well as acute-phase reactants such as the ESR and fibrinogen, so that the initial "normal" levels of these blood tests can be misleading as they are due to declining levels and are actually a signal of impending MAS. As such, there have been many attempts to try to develop clinically useful diagnostic criteria and scoring tools for MAS in systemic JIA patients [26,32,33].
The differences between the various diagnostic and classification criteria available are shown in the table (table 1). According to the adapted HLH 2004 guidelines, meeting three of five diagnostic criteria has a sensitivity of 79 percent and specificity of 75 percent to diagnose HLH [32]. The preliminary 2004 MAS in systemic JIA guidelines require that at least two of the laboratory criteria, or three or more of a combination of clinical and/or laboratory criteria, are met. The sensitivity and specificity of these criteria to distinguish between systemic JIA with MAS versus systemic JIA without MAS were both 86 percent [32]. In an attempt to identify more useful criteria, the 2016 classification criteria for MAS in systemic JIA were developed through a combination of expert consensus methods and analysis of real patient data [33]. These require an elevated ferritin and any two of the other criteria.
A diagnostic scoring tool to differentiate MAS in systemic JIA from active systemic JIA without MAS, called the MAS/sJIA (MS) score, was developed and validated in 2019 [34] using multinational patient data collected for the creation of MAS classification criteria in 2016 (table 2) [33]. Fever is a mandatory criterion for the diagnosis and is not included in the score, although, as stated above, fever may not be present in patients with systemic JIA treated with tocilizumab even when MAS is present. This score still requires validation in clinical practice and may need revisions that take into account the use of biologic agents.
A diagnostic scoring tool to help distinguish HLH from MAS in systemic JIA based upon a few clinical parameters, called the MH (MAS-HLH) score, is also available (table 3) [35]. This score was validated using data from a large, multinational, retrospectively collected cohort of patients with systemic JIA and MAS compared with data from clinical trials of genetically confirmed patients with HLH. This tool was able to distinguish these two illnesses with high specificity and sensitivity. The MH score assigns points for age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. Having an age less than or equal to 1.6 years at onset and a neutrophil count less than or equal to 1.4 x 109/L were the most important factors in favor of a diagnosis of HLH rather than MAS complicating systemic JIA.
Treatment — Once MAS is diagnosed or suspected, treatment of MAS should be emergently initiated with high-dose glucocorticoids (most often "pulse" methylprednisolone at 30 mg/kg, maximum dose 1 gram, intravenously daily) [30]. There are case reports of successful treatment with cyclosporine, cyclophosphamide, etoposide, or anakinra, an IL-1 receptor antagonist [3,27,36,37]. Treatment for refractory MAS in patients with systemic JIA is the same as treatment regimens for HLH, which are discussed separately. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)
Lung disease — An unusual form of incompletely defined and characterized chronic lung disease with a high fatality rate is increasingly seen [3-5]. The reasons for the increased frequency of lung disease are unclear, although there is a temporal association coincident with the more common usage of biologic response modifiers in systemic JIA. Typically, these patients have severe systemic disease that is difficult to control, many with features of MAS (acute and chronic). Acute erythematous clubbing is an early physical sign in many patients, and it is associated with anaphylactic reactions to tocilizumab, younger age at onset, and trisomy 21 [4]. The pathology of lung disease in systemic JIA is also unusual, with pulmonary alveolar proteinosis (PAP) and/or endogenous lipoid pneumonia (ELP) predominant. Septal thickening of peripheral lobes with ground glass opacities are the most common lung computed tomography (CT) findings. Higher levels of IL-18 were seen in the serum of these patients as well as in the bronchoalveolar lavage (BAL) fluid, which also contained high levels of the interferon gamma-induced chemokine (C-X-C motif) ligands (CXCL) 9 and 10 [5].
Growth retardation — Profound growth abnormalities with obesity and short stature were common complications of disease when glucocorticoids were one of the primary treatments of systemic JIA. They resulted both from glucocorticoid side effects of the therapy and from incomplete suppression of systemic inflammation. These complications are less frequent due to the availability of safer and more effective therapies that allow more judicious use of glucocorticoids [38]. Short stature and failure to thrive may still be seen, however, in those with chronic unremitting disease, even in those who do not receive glucocorticoids [39-41].
Osteoporosis — Osteoporosis in children with systemic JIA was also more common prior to advances in treatment. Measures used in adults to treat osteoporosis are frequently ineffective or are poorly tolerated in children with systemic JIA. The optimal way to minimize this complication is to attain disease control with a minimum of glucocorticoid exposure, which was not often possible in the pre-biologic era. Minimizing glucocorticoid administration is the best way to avoid both growth retardation and osteoporosis. (See "Major adverse effects of systemic glucocorticoids", section on 'Bone and muscle effects'.)
Bisphosphonates may be an option for treating children with JIA and severe osteoporosis and may be necessary to prevent recurrent insufficiency fractures in severely affected patients, but the safety of bisphosphonate use by children remains uncertain. Excessive amounts can lead to osteopetrosis. The decision to use bisphosphonates must be made on a case-by-case basis since these medications may be teratogenic and have a long half-life, stored in and slowly released from the bone for years [42].
Other complications — A few cases of atypical renal, cardiac, hepatic, endocrine, or other complications have been reported in every large series, but the extent to which these represent incidental findings or complications of systemic JIA is uncertain [2].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Juvenile idiopathic arthritis".)
SUMMARY
●Clinical course – The course of systemic juvenile idiopathic arthritis (JIA) is highly variable, although there are three typical patterns: monophasic, polycyclic, and persistent (chronic). (See 'Course' above.)
●Patterns of chronic disease activity – Three patterns of chronic disease activity occur in those patients with persistent systemic JIA (see 'Course' above):
•Systemic manifestations (ie, fever and rash and sometimes recurrent macrophage activation syndrome [MAS]), but little to no arthritis
•Persistent systemic manifestations and progressive arthritis
•Progressive destructive arthritis despite resolution of systemic manifestations
●Prognosis – Morbidity and mortality from systemic JIA have decreased with improvements in therapy, but mortality is still high in patients with severe disease, especially those with recurrent or unrecognized MAS and severe pulmonary or vascular complications. (See 'Prognosis' above.)
●Complications – MAS is the most common complication of systemic JIA. Complications such as severe growth retardation and osteoporosis are now less frequent. There is a rising incidence of rare but severe pulmonary complications. (See 'Complications' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas JA Lehman, MD, who contributed to an earlier version of this topic review.
Do you want to add Medilib to your home screen?