Review: Is There a Window of Opportunity for Treatment of Systemic

ARTHRITIS & RHEUMATOLOGY
Vol. 66, No. 6, June 2014, pp 1405–1413
DOI 10.1002/art.38615
© 2014, American College of Rheumatology
REVIEW
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Is There a Window of Opportunity for Treatment of
Systemic Juvenile Idiopathic Arthritis?
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Peter A. Nigrovic
Introduction
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Systemic JIA is a serious disease
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Systemic JIA represents ⬃5–15% of arthritis that
begins during childhood. Like some other forms of JIA,
the epidemiology of systemic JIA features an early
incidence peak between 1 and 5 years of age, although
the disease may arise at any time during childhood (1–3).
A similar disease occurs in adults (adult-onset Still’s
disease [AOSD]). Both sexes are affected with approximately equal frequency. The hallmark clinical feature is
fever, often but not invariably with a quotidian pattern
of sharp elevations in temperature once or twice daily to
104°F (40°C) or higher, separated by periods during
which body temperature dips below normal. In ⬎80% of
cases, fever is accompanied by an evanescent erythematous rash, often described as salmon pink in color (2,3).
Overt synovitis is present in 80–90% of patients at
presentation, but may sometimes appear only months
later (2). Inflammatory markers, including erythrocyte
sedimentation rate and C-reactive protein levels, are
markedly elevated, as are ferritin and, in many cases,
D-dimer levels. Depending on the definition used, 10–
50% of patients develop features of macrophage activation syndrome (MAS), a cytokine storm syndrome associated with disseminated intravascular coagulation,
hyperferritinemia, hepatitis, and sepsis physiology resulting in sometimes fatal end-organ dysfunction (4).
Long-term outcomes of systemic JIA are highly
variable. Between 40% and 50% of patients have a
self-limited course, either monocyclic (a single phase
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Among subcategories of juvenile idiopathic arthritis (JIA), one stands out as very different from the
others. Systemic JIA involves an abrupt onset of fever
and in most cases an evanescent erythematous rash,
sometimes preceding the appearance of overt synovitis
by weeks or months. While some patients continue this
so-called systemic phase for years, a more common
course is for fevers and rash to fade away, leaving behind
a chronic, destructive, and often therapy-resistant arthritis. Recent data have raised the possibility that early
cytokine blockage might abrogate this latter phase,
reflecting a potential “window of opportunity” in the
care of these challenging patients. The purpose of this
review is to evaluate the data in support of, and against,
this hypothesis, and more broadly to consider how
human and murine immunologic studies could help us
understand the transition from systemic phase to chronic
persistent arthritis in systemic JIA.
Dr. Nigrovic’s work was supported by grants from the Rheumatology Research Foundation (Disease Targeted Research Innovative Grant), the NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Institute of Allergy and
Infectious Diseases, and the Cogan Family Fund.
Peter A. Nigrovic, MD: Boston Children’s Hospital, Brigham
and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts.
Dr. Nigrovic has received consulting fees from Alkermes,
Genentech, and Momenta Pharmaceuticals (less than $10,000 each)
and from Novartis (more than $10,000) and has received research
support from the Baxter BioScience Foundation.
Address correspondence to Peter A. Nigrovic, MD, Boston
Children’s Hospital and Brigham and Women’s Hospital, One Jimmy
Fund Way, Smith 516B, Boston MA 02115. E-mail: pnigrovic@
partners.org.
Submitted for publication November 25, 2013; accepted in
revised form February 27, 2014.
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Traditionally, systemic JIA has been therapeutically difficult terrain, characterized by incomplete responses to disease-modifying drugs and therefore requiring high doses of steroids, especially for patients in
the systemic phase of disease. However, therapy with
IL-1 antagonists has proven promising (18,19). Pascual
and colleagues observed dramatic response of fevers and
a somewhat slower and less complete resolution of
synovitis in 9 patients treated with the IL-1 receptor
antagonist (IL-1Ra) anakinra (19). Yet IL-1 blockade is
not always effective. Excellent responses to anakinra are
restricted to approximately half of patients with established systemic JIA (20–22). In the only randomized
controlled trial (RCT), enrolling patients with a mean
disease duration of 3.7 years, Quartier and colleagues
observed adapted American College of Rheumatology
(ACR) Pediatric 30 (Pedi 30) (23) responses to anakinra
(2 mg/kg/day) in 8 of 12 patients; only 5 patients showed
an ACR Pedi 70 response, and none achieved inactive
disease (24). Rilonacept, a recombinant “trap” for IL-1,
yielded ACR Pedi 70 responses in 35–40% of patients
with chronic systemic JIA (25,26). Better, though still
partial, responses have been observed with the anti–
IL-1␤ antibody canakinumab (67% adapted ACR Pedi
50 responses and 30% inactive disease), though these
studies differed from the anakinra and rilonacept trials
in enrolling only patients with ongoing fever as well as
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Interleukin-1 (IL-1) blockade is exceptionally effective
in new-onset systemic JIA
arthritis (27,28). AOSD, the adult counterpart of systemic JIA, also responds to IL-1 antagonism (29).
More encouraging responses have been reported
when IL-1 blockade is used as first-line therapy. Several
observational series yielding such results have been
published (12,30,31). The largest of these, a retrospective series of 46 patients in whom anakinra was administered as part of initial disease-modifying therapy, documented inactive disease in almost 60% of patients,
with chronic synovitis in only 11%. Among 10 patients
treated with anakinra monotherapy, complete remission
was achieved in 8 (12). Comparable data have recently
been reported from a prospective series of 21 patients
from Utrecht, The Netherlands. Children with newonset systemic JIA who did not respond to initial
nonsteroidal antiinflammatory drug (NSAID) therapy
(20 of 21 patients) were treated with 2 mg/kg/day of
anakinra, escalated to 4 mg/kg/day if the response was
incomplete. Following this regimen, inactive disease was
attained in 13 of 20 patients, without exposure to
corticosteroids or other disease-modifying drugs (31). Of
the remaining 7 patients, most responded well, if partially, and systemic symptoms were abolished in all but 2.
Comparison of clinical responses in early and late
disease suggests, but falls far short of confirming, that
early systemic JIA might be different from chronic
systemic JIA. Not only were the anakinra studies not
controlled trials, but also the patients studied were
different from those in the RCTs. Most patients enrolled
in an RCT had already had years of disease and therefore were not destined for a monophasic course (11–
40% of patients with systemic JIA) (3,5,8). Disease in
most patients enrolled in an RCT had proven refractory
to alternate therapies. Thus, patient selection likely
skewed responses in favor of the first-line anakinra
series. Indeed, data from recent trials of canakinumab,
presented to date only in abstract form, appear to
indicate that patients with ⬍6 months of disease showed
very similar responses to those with ⬎4 years of (persistently febrile) systemic JIA (32). The apparent difference in efficacy of IL-1 blockade between early and
established systemic JIA could therefore simply reflect
the fact that the latter patients represent a subset of
systemic JIA that is harder to treat.
Further complicating interpretation of these
data, it turns out that fully antagonizing IL-1 is difficult.
A particularly illustrative example comes from the field
of autoinflammatory diseases. Neonatal-onset multisystem inflammatory disease (NOMID) is a genetic disease
mediated by mutations affecting cryopyrin, a component
of the IL-1␤–processing inflammasome. Patients with
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lasting up to 24 months) or polycyclic (several disease
flares separated by months or years of inactive disease)
(5–9). By contrast, approximately half of patients have
chronic persistent arthritis requiring extended antiinflammatory therapy, sometimes into adulthood (9). In
these patients, growth failure, radiographically evident
joint injury, and long-term disability have historically
been very common (10–12). In a recent Canadian inception cohort disease was still clinically active in ⬎40% of
patients with systemic JIA 6–9 months after diagnosis,
while almost 70% continued to receive daily corticosteroids (13). Despite multiple attempts, no markers have
been identified that distinguish, at disease onset, which
patients will have a prolonged and difficult course
(7,8,14–17). Taken together, the aggressive systemic
features, requirement for intensive immunosuppression,
and propensity to develop destructive chronic synovitis
render systemic JIA potentially the most dangerous
form of childhood arthritis.
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What does clinical efficacy of cytokine antagonism tell
us about disease biology?
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As noted, available data do not as yet allow us to
conclude that early and established systemic JIA respond differentially to cytokine antagonists. Nevertheless, it is clear that systemic JIA often evolves over the
course of the disease, from a febrile inflammatory phase
to a generally afebrile phase of chronic arthritis. Is it
possible that early cytokine blockade might interfere
fundamentally with this evolution to prevent the establishment of chronic synovitis in systemic JIA? We will
focus here on IL-1, but a similar case might be made for
IL-6.
IL-1 is strikingly pleiotropic (46,47). Two distinct
cytokines, IL-1␣ and IL-1␤, engage the main IL-1 receptor IL-1R, type I IL1R1. A second IL-1 receptor, IL1R2,
serves as a nonsignaling decoy. IL-1␣ and IL-1␤ are both
counterbalanced by the soluble IL-1Ra (of which anakinra is a recombinant copy), which competes for binding to IL1R1. The precise roles of IL-1␣ and IL-1␤ in
human biology remain incompletely understood. Generalizing very broadly, IL-1␣ is produced constitutively
and expressed and/or released upon activation or membrane compromise, helping cells such as keratinocytes,
macrophages, and platelets report injury or danger. In
contrast, IL-1␤ is synthesized de novo in response to
proinflammatory signals by immune cells such as neutrophils, macrophages, and dendritic cells, and its proteolytic activation is carefully regulated to orchestrate
the responses of leukocytes and other cells in immune
defense.
The activity of IL-1 in arthritis can be usefully
divided into effects on innate immunity (antigenindependent) and adaptive immunity (antigen-specific)
(46–49) (Figure 1). IL-1 up-regulates adhesion molecules on endothelial cells, facilitating transmigration of
neutrophils and other leukocytes. IL-1 activates these
immune effectors upon arrival, while engaging local
fibroblasts, chondrocytes, and macrophages to amplify
the immune response. Along with IL-6 and other cytokines, IL-1 can promote the differentiation of uncommitted T cells to the Th17 phenotype (50). IL-1 triggers
T cell expansion, activation, and IL-17 production, while
rendering Teff cells less susceptible to suppression by
Treg cells. IL-1 can even drive Treg cells to redifferentiate into Th17-like cells. Less is known about the effect
of IL-1 on B cells. Thus, in addition to mobilizing innate
immunity, IL-1 tends to disadvantage adaptive regulatory mechanisms while favoring proinflammatory T cell
differentiation, particularly in the direction of Th17.
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NOMID develop fever, rash, and striking cartilaginous
bony overgrowth. Studies of anakinra demonstrated a
remarkable response to the treatment in the first two
features, but no change in the third, suggesting the
possibility that cryopyrin might play an IL-1–
independent role in cartilage (33,34). However, patients
with genetic deletion encompassing IL-1Ra may exhibit
similar features, strongly suggesting that cartilage overgrowth refractory to anakinra treatment in NOMID
reflects incomplete IL-1 blockade (35).
Caution is therefore needed when extrapolating
from clinical observations of IL-1 antagonists because it
is difficult to know when IL-1 is adequately inhibited.
This concern is not limited to anakinra. Canakinumab
binds IL-1␤ but not IL-1␣. Rilonacept binds both cytokines, but also the endogenous IL-1 antagonist IL-1Ra.
(IL-1 biology is discussed in more detail below.) Pharmacokinetic studies of anakinra suggest that smaller
children require higher doses per kilogram of body
weight to achieve equivalent drug levels, potentially
explaining why remission was less often attained in
young patients at conventional doses of 1–2 mg/kg/day
(12,36,37).
These considerations notwithstanding, the outcomes in patients treated with anakinra are striking early
in the disease course, with persistently active disease in
10–30% rather than the expected ⬎50% of patients and
avoidance of steroid exposure entirely in most children.
First-line anakinra therapy has therefore been adopted
as one therapeutic alternative in recent consensus treatment plans developed by the Childhood Arthritis and
Rheumatology Research Alliance (CARRA) (38) and in
new ACR recommendations for treatment of systemic
JIA (39).
Efficacy of IL-6 blockade in systemic JIA
IL-1␤ is only one of multiple cytokines implicated
in the pathogenesis of systemic JIA (40). Particularly
compelling data support a role for IL-6. Levels of this
canonical proinflammatory cytokine correlate with clinical parameters, and elevated expression of IL-6 is noted
in circulating leukocytes from patients with active systemic JIA (41,42). Importantly, recent studies of the
IL-6 receptor antagonist tocilizumab found impressive
efficacy in systemic JIA, both for treatment of systemic
symptoms (fever and rash) and for treatment of chronic
arthritis (43,44). No data are available concerning the
efficacy of tocilizumab as first-line therapy in systemic
JIA, although case reports of patients with AOSD
suggest that this approach might also be effective (45).
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Figure 1. The biphasic model of systemic juvenile idiopathic arthritis (sJIA). In this model, interleukin-1 (IL-1) plays a role in innate and adaptive
immunity that defines biologic evolution of arthritis in systemic JIA. IL-1 promotes inflammation in an antigen-independent manner through
activation of endothelium, leukocytes, and resident tissue lineages, and also modulates antigen-driven T cell immunity by activating T cells, inhibiting
the efficacy of Treg cells, and directly promoting Th17 differentiation. New-onset systemic JIA, characterized by excess IL-1 production, could
thereby give rise to an autoimmune T cell–driven arthritis. If this biphasic model is correct, effective blockade of IL-1 (or IL-6) in early systemic JIA
could forestall development of T cell autoimmunity and alter the long-term course of the disease. TGF␤ ⫽ transforming growth factor ␤; IFN␥ ⫽
interferon-␥.
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IL-1 in arthritis: lessons from animal models
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Both innate and adaptive roles of IL-1 have
evident implications for inflammatory arthritis in general, and for systemic JIA in particular. Given the
complexity of IL-1 biology, we need to examine living
systems in order to understand the in vivo contribution
of IL-1. This is the role of murine studies, and fortunately they are very informative (48,51).
Models of inflammatory arthritis in the mouse
come in two basic types: those that test only effector
mechanisms, and those that test both development of
autoimmunity and effector mechanisms. Collagen
antibody–induced arthritis (CAIA) and K/BxN serum–
transfer arthritis are models of the first type. In these
systems, administration of IgG autoantibodies leads to
arthritis in recipient mice. Arthritis proceeds normally in
mice lacking T cells and B cells, but is attenuated or
blocked by deficiency of molecules and cells engaged by
IgG to cause joint inflammation, such as Fc receptors,
complement, and neutrophils (52). In contrast, collageninduced arthritis (CIA), arthritis in K/BxN-transgenic
mice, SKG arthritis resulting from a point mutation in
the T cell receptor signaling protein ZAP-70, and arthritis in mice lacking IL-1Ra require the presence of
adaptive immunity (T cells and/or B cells) as well as
downstream innate effector pathways (52–54).
Interestingly, the role of IL-1—determined using
blocking antibodies and targeted genetic deletions of
IL-1␣, IL-1␤, or both—varies strikingly across these
systems. In the CAIA and K/BxN serum–transfer models, which are mediated by IgG autoantibodies, IL-1 is
essential for initiation and perpetuation of joint inflammation, as shown by the dense disease resistance that is
evident in IL-1␣/␤–/– animals and the transience of
disease restoration by exogenous IL-1␤ (whereas IL-6 is
largely dispensable) (55–57). IL-1 is also extremely
important in mouse models that feature an autoimmune
and effector phase, such as the CIA model of arthritis,
which is mediated principally by IgG autoantibodies to
collagen generated through T cell and B cell autoimmunity (58). In this system, anti–IL-1␣/␤ antibody prevents
arthritis and treats established joint inflammation; ge-
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would be most overt in the synovium; these possibilities
have not been tested. Second, the model suggests a role
for T cells—presumably an antigen-selected, i.e., autoimmune, role—in chronic persistent systemic JIA. The
hallmark of T cell involvement is genetic linkage to the
major histocompatibility complex (MHC), and some
data do indeed suggest such an association between
systemic JIA and the MHC locus (70–72). If the biphasic
model is correct, an association of chronic arthritic
systemic JIA with antigen-presenting molecules might
be expected. Absence of such linkage in monophasic
systemic JIA could explain why the MHC association in
systemic JIA as a whole appears weaker than in oligoarticular JIA and polyarticular JIA. A role of T cells in
chronic systemic JIA is consistent with anecdotal reports
of the efficacy of abatacept (a CTLA4-Ig fusion protein
that blocks T cell costimulation) in some patients (73).
Further, if T cells are pathogenically important, then
reestablishment of tolerance could help explain how
systemic JIA resolves over time in many patients, a
phenomenon not typical of the autoinflammatory diseases.
The biphasic model is also consistent with the
evident importance of IL-6 in systemic JIA (44). Teasing
apart the relative roles of the canonical proinflammatory
cytokines IL-1 and IL-6 is a challenge, not least because
each strongly induces production of the other, such that
antagonizing one limits both. Whereas IL-6 is integrally
involved in Th17 differentiation, IL-6 antagonism could
be as potent as, or more potent than, IL-1 blockade in
forestalling the development of chronic synovitis.
This model of systemic JIA is evidently simplistic.
Unlike arthritis in genetically homogenous mice, systemic JIA likely represents a family of related disorders,
differing in underlying etiology and modified by variations in multiple genes (40,74). Even in IL-1Ra–/– mice,
arthritis emerges in only certain genetic backgrounds
(54). Further, IL-1 production alone is not sufficient to
cause chronic synovitis, as evidenced by the paucity of
chronic systemic JIA–like arthritis in NOMID and familial Mediterranean fever (despite IL-1 excess and
even Th17 enrichment). Studies of SKG mice suggest
that both specific autoreactivity and additional proinflammatory signals are also necessary (62,68,75). Finally,
the model does not directly account for myeloid abnormalities, including impaired monocyte apoptosis, observed in patients with systemic JIA (40,76,77). The
biphasic model therefore represents only a working
framework for further research into the pathophysiology
of systemic JIA.
The biphasic model of systemic JIA
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netic deletion of either IL-1␣ or IL-1␤ markedly attenuates disease susceptibility, while deficiency of both
renders mice completely resistant to arthritis (59,60).
In contrast, resistance of IL-1␣/␤–/– mice to T
cell–mediated SKG arthritis is only partial. Rather, IL-6
and IL-17 (but not interferon-␥ or IL-4, the canonical
Th1 and Th2 cytokines) are essential, suggesting that
Th17 cells, whose differentiation is strongly promoted by
IL-6, could be of major pathogenic importance (61,62).
A key role of Th17 cells is further supported by studies
in IL-1Ra⫺/⫺ mice. A priori, one might have expected
that deficiency of the major endogenous IL-1 antagonist
would result in arthritis mediated through hyperactive
innate immunity. Instead, joint inflammation is absent in
mice deficient in T cells and B cells and transferrable via
T cell adoptive transfer (63,64). Th17 cells expand as
arthritis progresses, and arthritis does not emerge at all
in animals lacking IL-17, the canonical Th17 cytokine
(65,66).
Taken together, in the context of the immune
roles of IL-1 (Figure 1), these murine data suggest the
following. In IgG-mediated arthritis, the essential role of
IL-1 reflects its broad set of roles in innate immunity. By
contrast, in T cell–driven arthritis, IL-1 facilitates differentiation of pathogenic Th17 cells, although IL-6 is
critical to this differentiation and can partially fulfill this
role if IL-1 is absent or blocked.
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If it is true that anakinra is more effective in
new-onset systemic JIA than in established synovitis, then
these animal studies suggest a potential explanation (Figure 1). In early systemic JIA, dysregulated IL-1 production
could directly trigger not only fever and rash, but also early
synovitis, reflecting principally the innate immune activity
of IL-1. Ongoing aberrant IL-1 production would then
favor the development of pathogenic Th17 responses while
inhibiting Treg cell activity, leading potentially to T cell–
driven synovitis that could well exhibit only partial dependency on continued availability of IL-1. Thus, systemic JIA
could evolve from a disease of predominantly autoinflammatory character into one sustained by autoimmunity.
This biphasic model generates several predictions
that are consistent with published human data. First,
Th17 cells should be more abundant (and Treg cells less
abundant) in patients with established systemic JIA as
compared to healthy controls; such changes have been
found by some but not all investigators (67–69). It might
be expected that these changes would be less prominent
in early disease and develop over time, and that they
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The hypothesis that systemic JIA evolves biologically over time suggests a particular research agenda
for basic and clinical investigation. Most generally, it will
be important to look closely at the role of T cells in
systemic JIA. Is there evidence of progressive skewing of
T cell responses toward Th17, and is there a corresponding defect in Treg cell number and function? Identification of clonal T cell responses in blood and joints would
lend strong support to a role for antigen-dependent
immunity in the pathophysiology of systemic JIA. Such
an observation would both motivate a renewed search
for autoantigens and provide rationale for new therapeutic approaches, for example, antagonism of IL-17 or
IL-23 in chronic refractory systemic JIA.
If systemic JIA initially begins as a “storm” of
cytokines, such as IL-1 and IL-6, it will be important to
understand how this happens. Genetic defects affecting
cell-to-cell killing in patients with systemic JIA with
MAS suggest that systemic JIA might ignite when a host
encounters an environmental trigger (e.g., an infection)
and is unable to shut down the resulting immune response (78–82). Extensive research will be needed to
develop and support this hypothesis, including studies of
systemic JIA patients without overt MAS. Such research
should include more comprehensive immunophenotyping to determine if there are subgroups of patients with
systemic JIA in whom specific cytokines or cellular
activation are predominant (74).
Of more immediate importance to patients, the
biphasic model recommends new clinical trials investigating IL-1 or IL-6 blockade in patients with systemic
JIA at disease onset, rather than in patients with established disease. Such trials should be paired with biological studies to determine whether therapy leads to
normalization of Th17 and Treg responses.
put this bluntly: it may be that further research will find
no window of opportunity during which cytokine blockade fundamentally alters the course of systemic JIA.
Even if this is the case, there remains the distinct
clinical question of whether conventional therapy (beginning with NSAIDs and corticosteroids) or early cytokine blockade represents the best first-line therapy for
our patients. Many children did well before the era of
biologic agents. Therapy with a biologic agent is expensive, uncomfortable, inconvenient, and has short- and
long-term risks that are incompletely understood (83).
Nevertheless, a “conservative” approach is not without
risk. Corticosteroids at the doses typically required for
control of systemic JIA have important long-term effects
on bone density, skin integrity, and growth, and are
accompanied by an elevated risk of serious infection
(84). Only a minority of patients with systemic JIA will
have a monophasic disease course, and such a course
may last a year or more. A “wait and see” strategy,
temporizing with NSAIDs and corticosteroids in the
hope that the disease will pass, will fail more often than
not, at a cost of incomplete disease control and lengthy
steroid exposure in more than half of patients (13).
While the risk of infection associated with anakinra use
among children with systemic JIA is not well defined, it
is reassuring that a large, placebo-controlled trial of
several hundred adults with overt sepsis treated with
anakinra at the extraordinary dose of 100 mg then 1–2
mg/kg/hour intravenously for 3 days showed a small
reduction in overall mortality (85). Further, while anakinra is expensive, its cost is similar to that of tumor
necrosis factor inhibitors, and the cost of childhoodonset disability related to growth failure, joint injury,
steroid-induced avascular necrosis, and vertebral compression fractures is incomparably higher.
Based on these considerations, many pediatric
rheumatologists (including the author) choose anakinra
(1–4 mg/kg/day or higher with a usual maximum of 100
mg twice a day) as first-line therapy in nearly all patients
with systemic JIA. Other experienced pediatric rheumatologists do not, a variation in practice that was recently
captured in the CARRA consensus treatment plans for
systemic JIA (38). Ongoing comparative effectiveness
research using these protocols will help to identify which
strategy is associated with the best outcome.
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Research implications of the biphasic model of
systemic JIA
Clinical implications—beyond the “window of
opportunity”
It is worth emphasizing that neither clinical nor
laboratory data provide unambiguous support for a
categorical difference between early and late systemic
JIA. It may well be that early, febrile systemic JIA and
established, chronic arthritic systemic JIA share more
pathophysiologic similarities than differences, and that
patients with established disease who respond poorly to
IL-1 or IL-6 blockade would have responded equally
poorly had they received treatment at disease onset. To
Conclusions
Systemic JIA begins with a highly inflammatory
febrile phase that, in more than half of patients, converts
over time to an afebrile phase characterized by chronic
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AUTHOR CONTRIBUTIONS
Dr. Nigrovic drafted the article, revised it critically for important intellectual content, and approved the final version to be published.
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The author is grateful to Drs. Scott Canna, Fabrizio De
Benedetti, and Elizabeth Mellins for insightful comments on
the manuscript.
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ACKNOWLEDGMENTS
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